Abstracts of papers and posters Meeting on Pharmaceutical Sciences

THE FUTURE OF HEALTH CARE IN THE NETHERLANDS: A 'FIFTH SCENARIO' AND IMPACT ON PHARMACEUTICAL RESEARCH

Russell C. Coi!e. Jr.

A 'Fifth Scenario' is proposed in response to the development of four alternative scenarios by the Study Group for Future Scenarios in Health Care (STG) on the future of medicines in the provision of health care in The Netherlands. All views of the future of health care must recognize the global spread of trends such as aging of the popuhtion, economic recession, limits on government spending, inefficient organization of health resources, and rising public expectations for technology and health spending. The four STG scenarios would have a differential impact on pharmaceutical research and development: (1) 'Risk in Avoidance' raises 'Green'-like concerns about health hazards from technology. This scenario would discourage much pharmacological research which explores new technology, e.g., genetic enginee- ring: (2) 'Sobriety in Salliciency' reflects a culture of restraint - Pharmaceutical R&D would focus on incremental improvements in existing approaches: (3) 'Free Market at Work' suggests that under the umbrella of the EC, technological innovations would cross European boundaries - An enterprise model of pharmaceutical development would encourage R&D: (4) 'Technology on Demand" represents strong social support for progress in treatment of disease - This eXtreme scenario exaggerates the role of technology in medicine, but would be very supportive of pharmaceutical research. A suggested 'Fifth Scenario' recognizes that the future will include limits on government spending ('Sobriety in Sufficiency" scenario) and mounting public concerns about technology ('Risk in Avoidance' scenario). This proposed future attempts to incorporate incentives suggested in the 'Free Market Unfettered' but realizes The Netherlands cannot afford to give in to the public's unconstrained desire for 'Technology on Demand'. The STG scenarios are dramatic illustrations of trends and counter-trends. But none of these scenarios are a realistic picture of the future of Dutch health care. What is needed is a balanced set of government private industry strategies for organizing and financing health care which include: aggressive clinical management of hospital use, reduction in length of stay and costs of care, improvement in consumer access to surgery and technology, incentives for providers and drug manufacturers for innovation, standards for quality and clinical outcomes, use of private alternatives and 'outsourcing' of high-demand services to other EC nations, reglonalization of hospitals and expensive technology, expanded ambulatory care, and multi-national partnerships in pharmaceutical and health technology development across EC members. Further, it should be noted as the US initiates 'health reform; and regulates American drugmakers, the result may be to strengthen the international pharmaceutical firms based in Europe.

Health Forecasting Group, 25044 Peachland Ave., Suite 203, Santa Clarita, California, USA

DRUG INNOVATION CHALLENGED

K. WiedhauD

Traditionally, driving forces behind

pharmaceutical innovation are the desire to cure

or alleviate illnesses and the rapid progress in

science and technology offering new drug

opportunities. While these forces will continue to

dominate in the years to come, social and economic

trends will have an unprecedented impact on new

drug development. In order to secure its task of

producing new and valuable medicines, the

innovative drug industry will have to adapt itself

to the changing environment. In preparing for this

change, the challenging scenarios of the future,

as described in the recent Dutch STG-report "The

Future of the Drug in Health Care", offer a useful

and stimulating instrument.

DEVELOPMENT OF ESTRADIOI../DYDROG ESTERONE COMBINATION TABLETS FOR HORMONE REPLACEMENT THERAPY

llva van Bommelar Miriam Mol b and Michiel de Vries b

Estrogens in Hormone Replacement Therapy (HRT) are given to control the symptoms of the post-menopause brought about by the decline in estradiol levels as the ovaries cease to function. In women with an intact uterus, a progestogen should be taken for 12-14 days per treatment cycle to prevent the increased risk for estrogen dependent endometrial hyperplasia, which in turn could lead to the development of endometrial carcinoma. An efficacious drug therapy consists of continuous supplementation with estradiol tablets (Zumenon rt) -day 1 upto 28 of the treatment cycle of 28 days- in combination with cyclic treatment of dydrogestrone tablets (Duphaston R) -day 15 upto 28 of the treatment cycle of 28 days-. To improve compliance, important for treatment efficacy and safety, a program was started to develop fLxed combination tablets of estradiol and dydrogesterone in various ratios. First, the optimal effective cyclic dosage of dydrogesterone to oppose 2 mg Estradiol, given continuously, was determined. For this purpose dydrogesterone dose ranging studies were conducted. These studies were carried out with the former separate Zumenon and Duphaston tablets. Hence, it was obligatory that the new combination tablets should be bioequivalent to the separate tablets. To accomplish this, a joint clinical-pharmaceutical development program was started. It was known that the bioavailability of dydrogesterone might be affected by formulation factors, Using deconvolution techniques a correlation between the in vitro dissolutio, profLles and the in vivo absorption characteristics for former dydrogesterone tablet formulations could be established. The in vitro dissolution profdes of the new developed combination tablets were found to be similar to the profiles of the separate tablets, used in the dose ranging studies. Finally, an in vivo bioequivalence study was carried out in post- menopausal women to demonstrate bioequivalence of the former separate dydrogestemne and estradiol tablets and the combination tablets. The results of this development indicate that two effective drugs in HRT have been successfully combined in one dosage form with an optimal ratio of both compounds.

�9 Pharmaceutical Development and bClinical Research and Development Dept., Solvay Duphar B.V., P.O. Box 900, 1380 DA Weesp, the Netherlands

ORGARAN R USE TO PREVENT EXTENSION OF ACUTE NON- HAEMORRIKAGIC STROKE

E.W. Massey, J~Biller, J.N. Davis, H.P.Adams~ J.R. Mailer, H.N. Maqnani et al.

Treatment of acute cerebral ischemia with heparin can be complicated by bleeding problems. Employment of low molecular weight heparin-like compounds with a reduced risk of bleeding could be an alternative therapy. To evaluate this hypothesis, we studied the safety of intravenous infusions of heparinoid Orgaran in 83 patients with acute ischemic stroke in an open dose-escalation study followed by a safety study. Five infusion rates were initially evaluated in 26 patients and in I.V. dose regimen consisting of an initial bolus of 2500 U, a stepped-down 24 h infusion rate of 600 U/h for 4 h then 400 U/h for 12 h then 300 U/h for 8 h followed by continuous 6 day maintenance infusion of 300 u/h. Drug response was monitored using an amidolytic assay of factor Xa inhibition with target steady-state levels of 0,2; 0,4; 0,6; 0,8 and 1,0 U/ml. When levels exceeded 1,0 U/ml the maintenance infusion rate was decreased by 50%. The drug was well tolerated and no thrombocytopenia was noted. In 79% of the patients' neurological status improved at 3 months. Six of the 83 patients died two due to hemorrhagic transformation of cerebral infarctions during treatment. The remainder were not considered drug related. One other major and 7 minor (not requiring drug withdrawal), transient bleeding episodes occured. The results indicated that Orgaran at doses to maintain plasma anti-Xa at 0,8 U/ml, can be used safely in the treatment of acute cerebral infarction. Further studies are being undertaken to confirm the safety and efficacy of Orgaran.

Medical Research and Development Unit, Organon International BV, P.O. Box 20, 5340 BH Oss, The Netherlands,

I'h,Jr,,~,JO' 114,dd EF S , , v . . ' K3 Volum~ 15 N~ ~ 1993

RECEPTOR OCCUPANCY PROFILE OF RISPERIDONE, MEASURED EX VIVO BY QUANTITATIVE AUTORADIOGRAPHY: BASIS FOR

BENEFICIAL CLINICAL ACTION

A. Schotte, P.F.M. Janssen and J.E. Leysen.

Risperidone (Risperdal~) is a novel antipsychotic drug, with a low incidence of extrapyramidal side-effects and with beneficial effects on the negative symptoms of schizophrenia. The compound was studied in comparison with reference drugs and new antipsychotics for the occupancy of neurotransmitter receptors in the rat brain, 2 h after s.c. administration. Autoradiography allowed a detailed regional investigation of various receptors in the same brain. Rispeddone displayed a predominant 5-HTz receptor occupancy, potent D2, H 1 and % antagonism and weaker o~ affinity (ED~o = 0.067, 0.66, 0.45, 0.80, 3.7 mg/kg, respectively). D e receptors were more gradually occupied, for increasing dosages of risperidone (mean slope in the striatum, nucleus accumbens and olfactory tubercle: 0.85), than with other compounds like haloperidol (slope: 1.51) or clozapine (slope: 1.44). The d6se ratio for 75 to 25 % D 2 receptor occupancy is 37 for risperidone in contrast to 8 for haloperidol and clozapine.

For clinical applications, it is suggested that partial D 2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D z receptor occupancy induces EPS. Potent 5-HT 2 antagonism was reported to modulate disturbed dopaminergic neurotransmission, i.e. restoration of phasic rather than tonic activity ~. This effect may underly the anti-dysthymic activity of 5-HT 2 antagonists as well as their ability to reduce EPS. In order to benefit from this action, a sufficient number of free dopamine receptors should then indeed be available.

It is hypothesized that the potent, predominant 5-HT 2 antagonism combined with gradual D 2 receptor occupancy underlie the low incidence of EPS and the beneficial effects on the negative symptoms of schizophrenia, observed in clinical studies with risperidone. Since its therapeutic properties result from both 5-HT 2 (>) and D~ antagonism, risperidone can be considered as a "balanced Serotonin-Dopamine Antagonist".

~Ugedo et al. Psychopharmacology 1989;98:45-50.

Janssen REsearch Foundation, Dept. of Biochemical Pharmacology, B-2340 Beerse, Belgium.

MEASUREMENT OF WATERACTIVITY (Aw) OF FREEZE-DRIED PRODUCTS VALIDATION OF TH~ CX-II AQUALAB

A-T-P SKRABANJA, L FLENDRIG

Many pharmaceutical preparations are freeze-dried to improve their stability. The activity of these compounds is lost rapidly in a solution. The water content of a freeze-dried product will give therefore an important indication for its stability. The total water content is composed of the so called bound (crystalline) and the free water. The activity of the free water is given by the term Wateractlvlty (Aw). According to Scott (1952) this wateractivlty - and not the water content - determines the stability of a product.

In contrast with the pharmaceuticai industry, in the food industry extensive research has been done on this topic and special wateractivity meters have been developed. The CX-II Aqualab is a miniaturized version of these. The Department of Pharmaceutice at Organon has a CX-II since a few months. During this period experiments have made clear that at least six factors may influence the measurement of A w with the CX-II. With this knowledge we have tried to develop a method to determine the A w of a freeze-drled cake in a vlal. Further research must demonstrate the accuracy of this method. The use of the CX-II will be discussed in detail.

Department of Pharmaceutics Organon International PO Box 20 5340 BH Ose The Netherlands

CRYOPRESERVATION OF pLANT CELLS; TOWARD3 A WIDE RANGE PROCEDURE

F. van Iren, E.W.M. Schrijnemakers, P.J. Reinhoud, J.W. Kijne.

Cells of many plant species are presently being cultured for fundamental studies of growth and metabolism, but also for the production of secondary metabolites, including pharmaca. For stable and long term storage of such cultures (also for patenting purposes) cryopreservation seems to be the only feasible option. On the basis of the classical equilibrium freezing principle (medium water crystallizes, cells vitrify) we developed a widely applicable procedure for plant cell suspensions. Using this method, we could recover about 35 cell lines out of about 50 tried. They belonged to 8 out of 12 species. This indicates a general success rate of roughly 70%. The tolerant lines included tropical as well as temperate species; both monocots (rice, barley) and dicots (a.o., tobacco, carrot, periwinkle, petunia). Some produced secondary metabolites, or had regenerative capacity; several were genetically modified. These traits appeared to be retained after storage (up to 5 years) in liquid nitrogen. In addition, we developed a procedure based on the principle of vitrification (both medium and cell water vitrifies). The few cell lines tested survive better than after equilibrium freezing, but recalcitrant ones remained so. Both procedures comprise a preculture step. Some characteristics of this step, that render cells cryo- tolerant, will be discussed.

Institute of Molecular Plant Sciences, Leiden University, Nonnensteeg 3, NL 2311 VJ Leiden, The Netherlands.

FORMULERING EN VRIESDROGEN VAN EEN 80~C HITTE- BEHANDELD STOLLINGS FACTOR VIII CONCENTRAAT

A, Knevelman. H.J.C. de Wit

In een aantal Nederlandse bloedbanken wordt een stollingsfactor concentraat geproduceerd ten behoeve van de substitutietherapie bij factor VIII defici~ntie (Hemofilie A) en yon Willebrand factor defici~ntie (ziekte van yon Wille- brand). AIs lyoprotectant en stabitisator tijdens de virucide hittebehandeling wordt het disaccharide sucrose gebruikt. Voor sucrose wordt in de literatuur een glas- rubber overgang (Tg') gemeld van -32~ De ingevroren oplossing bestaande uit de factor VIII fijke eiwitfractie, sucrose, tris, Na-citraat es calcium- chloride karl echter bij reel hogere temperatures worden gevriesdruogd. Bij een plaattemperatuur van -20~ tijdens de hoofddroogfase heeft het product een goede structuur, en is bet rendement (gemeten als stolactiviteit van her factor VIII) over vriesdrogen (VD) en de 80"C hittebehandeling godurende 72 uur (HB) ca. 90%. Bij een plaattemperatuur van 0~ treedt tijdens vriesdrogen collaps op, maar het rendement over VD en HB blijft zelfs in combinatie met de hittebehandeling hoot (ca. 85%). Tijdens verhitten van de vriesdroogbuffer ontstaat door parti~le hydrolyse van sucrose een kleine hoeveelheid glucose en fructose. Aanwezigheid van deze monosacchariden in het product tijdens de virucide hittebehandelingver- oorzaken een slechte oplosbaarheid, bruinkleufing en een hoog verlies van factor VIII activiteit. De mate van verslechtering van produeteigenschappen na hittebehandeling bij gebruik van een geautoclaveerde vriesdroogbuffer met 2% (w/v) sucrose wordt beinvloed door de plaattemperatuur tijdens de hoofddroogfase. Bij een pIaattemperatuur van 0~ is het rendement over VD en HB slechts 30%, bij een plaattemperatuur van -20~ ca. 70%. Tijdens her huidige productieproces is de coneentratie sucrose in de buffer teruggebracht tot I%, wordt de buffer na uitvullen onderworpen san een kiemreducerende nabehandeling van 100~ gedurende ! uur. Tijdens het vriesdrugen van het product is de plaattemperatuur tijdens de hoofddroogfase ingesteld op -20~ Als uitgangspunt bij de ontwikkeling van het vriesdroogproces dicnden 3 publicaties over de productie van 80"C hittebehandelde factor VIII concentra- ten met vergelijkhare vriesdroogbuffers. Desondanks heeft de ontwikkeling van een goede combinatie van product formulering en vriesdroogproces reel tijd gekost. Hierbij hebben niet theoretische achtergronden van her vriesdroogproces en de toepassing van de gebruikte hulpstoffen een doorslag- gevende rol gespeeld, maar systematisch experimenteren met her product zelf.

Rode K r . i s Bloedbauk Friesland, Poslbus 1529, 891)1 BV Lee .warde . .

K4 Ph,m.,l(y llb,/d 4; ,';,irmr

PHARMACEUTICAL DEVELOPMENT OF A LYOPHILIZED FORMULATION OF THE NOVEL INDOLOQUINONE ANTITUMOUR AGENT EO9

.I.D. de Viles t, A. BuR: and J.H. Beiinen ].

EO9 (3-hydroxymethyl-5-aziridinyl- 1 -methyl-2-( 1 H-indole- 4,7-dione)-propenol) is the lead eomponnd in a series of novel and fully synthetic bioreductive alkylating indoloquinones (1). A previous study from our laboratory showed that EO9 exhibits poor aqueous solubility and stability characteristics. The degradation rate of EO9 is strongly pH-depandent and is affected by phosphate buffer components. EO9 is most stable in the pH region 8-9 (2). The aim of this study was to design a stable parenteral dosage form of EO9. Because of the chemical instability of EO9 in aqueous solution, freeze-drying was selected as the manufacturing process. Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters. A stable, lyophilized formulation of EO9 w a s

developed. The prototype, containing 8.0 mg EO9 and 200 mg lactose per vial, was found to be the optimal formulation in terms of solubility, length of the freeze- drying cycle, stability and dosage requirements in Phase I clinical trials. Quality control of the freeze-dried formulation showed that the pharmaceutical preparation of EO9 is not negatively influenced by the manufacturing process. Shelf life studies demonstrated that the formulation is stable for at least I year, when stored at +4~ in the dark.

l. W.N. Speckamp and E.A. Oostveen, US Patent No. 5,079,257, 1992.

2. de Vries et al. Int. J. Pharm., in press.

Department of Pharmacy, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands

z Department of Pharmaceutical Analysis, Faculty of Pharmacy, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands

STABILITY OF FREEZE-DRIED HORSERADISH PEROXIDASE:

TESTING WILLIAMS-LANDEL-FERRY THEORY.

F. v. Dinther, T. Hultermans, T Beumer

To minimize loss of activity during freeze-drying and storage, bio-molecules should be [yophilized

in an amorphous medium (ref. 1). It was postulated (ref. 2) that in such a medium diffusion- controlled inactivation rates follow Williams-LandelI-Ferry (WLF)-kinetics at storage temperatures

between the gMss-transition temperature (Tg) and Tg § 50~ For T < Tg, this theory predicts constant diffusion and therefore constant inactivation.

This hypothesis was investigated using horseradish peroxidase (HRP) as a model, an enzyme

which is frequently used as a label in enzyme immunoassays. HRP samples were lyophilized at similar conditions during different drying times yielding samples with different residual moisture

contents (r.m.c.). The glass-transition temperature (Tg) of the lyophilized samples, being a

function of water content (ref. 3), was determined. Samples were stored at temperatures below

and above the Tg and stability was monitored in an enzyme assay.

The obtained data show that stability of lyophilized HRP is a function of r.m.c, and storage temperature, but not of (T - Tg), Inactivation for T < Tg was not constant. Inactivation of the

enzyme activity of HRP does not fotlow WLF-kinetics. These findings suggest that other mechanisms than diffusion-controlled inactivation are relevant for this enzyme / matrix combination. Highest enzyme recovery was obtained at r.m.c, in the order of I to 2 % w / w (90%,

4 weeks storage at 45~

References: 1) F. Franks; Materials science and the production of shelf-stable biologicals, Pharmaceutical

Technology International, October, 1991.

2) M.L. Williams et aL, J.of Am. Chem. Soc., vo[ 77, pp 3701 3706, 1955.

3) F.M. Clydesdale (ed), Beyond Water Activity: Recent advances based on an alternative

approach to the assessment of food quality and safety, CRC Press Ins, Boston, 1991.

Organon Teknika BV, Boxtel, The Netherlands.

Basic Methodology Research Unit

PHYSICAL STABILITY OF LIPOSOMES DURING THE FREEZE- DRYING PROCESS.

E.C.A. van Winden. H. Talsma and D,J.A. Crommelin.

The storage stability of l iposomal formulations may be improved by freeze-drying. In this s tudy the carboxyf luorescein (CF) retention after the pr imary freeze-drying step (at -40~ and after freeze- thawing was investigated.

The liposomes were frozen in boiling liquid nitrogen. Liposome size was varied by extrusion. Sucrose (4.4g/g phospholipid) was used as a cryoprotectant. The residual water content of the freeze-dried cakes ranged from 3 . 5 - 4 . 5 % for all lipid compositions. Liposomes with an mean s ize o f I 0 0 nm and a l ip id c o m p o s i t i o n o f d i p a l m i t o y t p h o s p h a t i d y l c b o l i n e ( D P P C ) : d i p a l m i t o y l - phosphatidylglycerol (DPPG) : cholesterol (CHOL) = 10:1:4 or 10:1:8 showed a higher retention after f reeze-drying (75+6 and 79+-6%, respectively, mean + s.d., n=3) than egg phosphati-dylcholine : egg phosphatidylglycerol : C H O L = 10:1:4 or 10:1:8 liposomes (48_+9 and 47+-7% respectively) of the same size. Omiss ion o f C H O L as in DPPC:DPPG=10 : I l iposomes resul ted in a lower CF retent ion (46+-17%), In addition, for all lipid compositions included in this study liposomes of ca. 100 nm retained consistently more CF than vesicles of ca. 200 nm. The differences in CF retention for l iposomes of varying size or lipid composit ion after freeze-drying were not or only partly observed after freeze-thawing.

.It was concluded that leakage out of l iposomes after primary freeze- drying and rehydrat ion is dependent on the lipid composi t ion and vesicle size. The actual leakage out of liposomes (mainly) occurs after the freezing step in the freeze-drying process.

Department o f Pharmaceutics, Utrecht University, PO Box 80.082, 3508 TB Utrecht, The Netherlands.

OPTIMIZATION OF THE SPEED OF FREEZE DRYING BY EVALUATION OF RATE LIMITING PARAMETERS

A.N. Fransz and H. Vromans ..........................

Freeze drying involves the removal of water from a frozen solution by sublimation and mass transfer under vacuum condition and suitable temperature. Fundamentally, the process combines heat and mass transport phenomena, either one of these being the rate limiting factor. Considering pharmaceutical freeze drying, it is known from literature that heat transport is most often the rate determining factor. Since the air-gap between shelf and container forms the largest resistance against heat transport, the chamber pressure is a useful parameter to optimize the speed of lyophilization. Eventually, this may lead to limitations caused by mass transport. To predict this, the flow regime (i.e. molecular or viscous) must be known in order to apply the appropriate mass transfer equations. By combining heat and mass equations with the phase diagram of water, a simple model was achieved which enables to predict optimum process conditions. Lyophization experiments with variations in chamber pressure and container design were carried out to check the applicability of the model. It was found that a fairly good estimation of the process is achieved.

Technology Department, Organon Int., P.O.Box 20, 5340 BH 0ss, The Netherlands.

I~h,*rm,l~ y [ l ~,rhl ,'.~ >;~i,'mr Votume 15 Nc 6 ~993 K5

URINARY EXCRETION OF MESNA AFTER ORAL DOSING IN HEALTHY VOLUNTEERS

D.A.Btoemhof =, F.J.W.van MansveR 1. J.R.BJ.Brouwers 2. J.Raemaekers ~. R.J.Boskn~. =

Introduction Mesna is used as a mucolytic agent in C.O,P.D.* and C.F.-patients and to prevent chemical cystitis in cancer patients after nigh dose cyclophosphamide of ifosfamide. In urological patients with an "Indianapouch" or "Brickerbladder" mucus formadon is sometimes a serious problem. The use of Mesnz, is a new option in the treatment of these patients. From pilot experiments = it was shown that mesna is an effective mucolytic agent after instillation in the bladder, nevertheless oral dosing will be more convenient Aim of the study Because only few pharmacological and toxicological data are known from literature we investigated the urinary excretion pattern after oral- and i.v.-Mesna. Method We studied the urinary excretion of Mesna and its metabolites after oral application of 1.5g mesna (6 tablets of 250rag) in 7 healthy volunteers and after intravenous applicatinn of 7g Mesna in 5 patients on ifosfamide (2 courses). Results In patients on ifosfamide we found a peak-concentration of 2.5 mg/mi (+/- 1.6 mg/mi), 3.5 hours (+/- 25) minutes after application. The recovery was 80% (+/- 16%) of which 26% (+/- 12%) was azalysed as mesna. In healthy volunteers we found a peak-concentration of 1.[I mg/ml (+/- 0.4 mg/ml), 35 hours (+/- 95) minutes after ingestion. The recovery was 70% (+/- 70"/0) of which 32% (+/- 4 5%) was analysed ~ mesna. As expected, the relative recovery of mesna in the oral group was found to be slightly higher but not significant. Conclusions The overall bladder exposure to mesna was significant lower in the oral group. Inter- individual differences were smaller in the oral group. Use of oral mesna in a follow-up study seems to be justified

1Dept of Clinical Pharmacy, Medical Centre Leeuwarden, The Netherlands. adept of Pharmaceutical Pharmacology and Clinical Pharmacy, University of Gronin gen, The Netherlands.

IMMUNOTARGETING AND PHARMACOKINETIC~ USING mlN-DTPA-MOC- 31 IN PATIENTS WITH SMALL CELL LUNG CARCINOMA (SCLC),

J,._ G.W. Kosterink (11 M.W.A. de Jonqe qz31, E.F. Smit 14b, R.A.M. Kenqen 16b t L de Leij Ira, D.A. Piers ts~ r D. Shochat q61 and T.H. The 121

Departments of Pharmacy m, Clinical Immunology i~l Pulmonary Diseases t4~ and Nuclear Medicine i,o), Universi ty Hospital Groningen, The Netherlands, MCA development B.V. In~, Groningen, The Netherlands, and Cyanamid Co; Pearl River, New York. U.S.A. i,i

The murine monoelonal ant ibody MOC-31, reactive with a 40 kDa membrane antigen on human Small Cell Lung Carcinoma (SCLC) was radiolabeled with Indium- 111. The aim of the study was to answer the fol lowing questions. First can mIn-DTPA-MOC-31 be administered safely to (SCLC)patients? Next, what is the pharmacokinetic profile of mln-DTPA-MOC-31? Furthermore, can mln-DTPA-MOC-31 eff iciently target to carcinoma cells in SCLC patients in v iva and is there a difference between accessibi l i ty/exposure of the antigens reactive with MOC-31 on (SCLC) tumor cells and those on normal cells for MOC-31? So far, 11 patients with histologically identified SCLC underwent scintigraphy after i.v. administration of 110 - 150 MBq H~In-DTPA-MOC-3t (0,7 - 6.3 rag) at 2, 24, 48, 72 hrs after injection. In selected patients (n = 6) blood samples were taken at regular t ime-points and 24 hrs urine was collected throughout the whole study. Chest X-ray and CT studies were used for localization of the primary tumor and metastases. Tumor biopsy specimens f rom all patients were MOC-31 positive. Up till now no adverse reactions were observed in any of the patients. Blood clearance is represented by a single compartment model wi th a half life of 17 hrs. The 24 hrs urine excretion varied from 1.5 - 6 % of the injected dose and was constant during 3 days after injection. In 8 out of 11 patients tumor or metastases Iocalizations were detected by scintigraphy. Furthermore, normal epithelia were not accessible to MOC-31. This is true at least for thyroid gland, the respiratory and probably also the gastrointestinal tract. So, m ln -DTPA-MOC-3 I can be safely administered to (SCLC)patlents and localize in SCLC tumors after i,v. injection. Metastat ic lesions appear more accessible to MOC-31 than the primary tumor and normal epithelia are not or less accessible to MOC-31. More experiments are needed to obtain fur ther proof of the usefulness of MOC-31 as an immunotarget ing device.

VINCRISTINE DISPOSITION IN CHILDREN WITH LEUKEMIA

H. Bloemhofl, S.S.N. de Graaf z. D.R.A. Uzes ~

The reason why adults are more sensitive for the neuroto• of vincristine than children is still not known. This difference could be due to a higher drug clearance in children, resulting in a relative lower systemic exposure to vincristine. To compare the kinetic parameters of vincristine in children with leukemia with earlier data from adults we developed a specific and highly sensitive HPLC assay tbr the measurement of vincristine in plasma. A solid phase extraction was used. The extract was eluted on a reversed phase column. An electrochemical detector for the quantative analysis (detection level 500 pg/ml) and an UV detector in series for the detection of any interference was used. The pharmacokinetic parameters of vincristine were estimated in eight adults (median age of 54, range 41-70 y ) and 17 children (median age of 4, range 1-12 y). An open two-compartment model was used with inverse variance of the assay weighting. The total plasma clearance of adfilts was 11.3 _+ 4.0 L,h't.m "~ and for the children 25.8 • 14.3 L.h" ~.m-'. The volume of distribution 420 • 234 L.m"- of adults and 360 • 176 L.m-' for children are not significant different. As the mean vincris- line total body clearance in children was twice as large as in adults, the systemic exposure to vincristine in adults may well be responsible t'or the clinical experience of more severe neurotoxicity in adults than in children.

K Depamnent of Pharmacy, -~ Department of Pediatrics University Hospital Groningen, The Netherlands.

Supported by the Stichting Kinderoncologie Groningen.

T H E A P P L I C A T I O N O F LC-MS T O E S T A B L I S H T H E SPE- C I F I C A C T I V I T Y AND C H E M I C A L P U R I T Y O F [=SF]-FDG

Gert Luur tsema t, Eric Franssen t, Geb Visser t, Margot Jeronimus- Stratingh 2, Andries Bruins 2 and Wire Vaalburg t

i PET-Center, University Hospital, Groningen, the Netherlands 2 University Center of Pharmacy, Department of Mass spectrometry, Groningen, the Netherlands

Positron emission tomography (PET) enables the imaging and quantification of biochemical and physiological processes non- invasively in humans. For this purpose PET-radiopharmaceuticals are routinely produced. Generally, these pharmaceuticals are used immedia te ly after production due to the short half-lives of the applied radionuelides (tSF, tV2= 110 rain). Consequently, validation of (HPLC)-purif icat ion procedures is essential to ensure the required specific activi ty and chemical purity of these pharmaceuticals. 2-[ taF]fluoro-2-deoxy-D-glucose (tSF-FDG) is a PET-radiopharma- ceutical for the evaluat ion of cardiac viabi l i ty and tumor growth. The final step of the tSF-FDG production is a purification by HPLC. This procedure was validated by Liquid chromatography combined with Mass-spectrometry (LC-MS) using the same separa- tion conditions. D-glucose, mannose and FDG were separated, identified and quantified. The specific activity of the purified t~F- FDG was larger than 1 Ci /mmol . The concentration of D-glucose was 0.5-1.0 mg/ml and the concentration of mannose was less than 10 /zg /ml (n=81) . In addition, mass-spectometry did not reveal any other potential reaction products, like furfural or polymerized sugar derivatives in the final product. Accordingly, the HPLC-purif ied FDG meets the USP-XXII requirements. In conclusion, LC-MS is a valuable tool for the identification of side-reaction-products and the validation of HPLC purification procedures in the preparation of PET-radiopharmaceuticals.

K6 I'ha..a,y Hi.ld ,b S, ic..,

AN IMPROVED, REMOTE CONTROLLED SYNTHESIS OF NON-CARRIER ADDED L-[1-11C]-TYROSINE VIA MICRO- WAVE IRRADIATION.

G. Luurtsema, J. Medema, P.H. Elsinga, E.J.F. Franssen, G.M. Visser, and W. Vaalburg.

PET-center, University Hospital, Groningen, The Netherlands.

The rate of incorparation of L-amino acids into proteins is correlated with the protein synthesis rate (PSR) in tissue. In principle, local PSR in tissue can be quantified in vivo by the use of PET with t~C-labeled amino acids. L-[l-"C]-tyrosine is synthesized via HC-carboxylation of an c~- lithiated isocyanide. This synthesis is controlled by robot and is used for routine patient studies. To increase the production capacity a remote controlled synthesis of non-carrier added L-[1-~C]-tyrosi - ne via microwave radiation was developed. The synthesis is carried out via the B6cherer-strecker reaction, from non-carrier added nC- cyanide. The [nC]-cyanide is trapped in 0.6 ml water (0-5~ When trapping is complete (8 min), the [nC]-cyanide is transfered by helium flow to a high pressure reaction vessel containing 25 mg p-hydroxy-phenylacetaldehyde bisuIphite adduct and 18 mg ammonium carbonate. The vessel is closed by pneumatic high pressure valves. The microwave irradiates the reaction mixture for 30 secondes at 400 Watt. After 1 rain the vent is opened and 100 #1 10 M NaOH and I00 /xl water are added. The vessel is closed and reirradiated for 30 seconds at 400 Watt. The vessel is opened and the reaction mixture is transfered with helium flow to a cooled trapping vessel. After 1 rain of cooling 0.7 ml 2M HC1 is added and the reaction mixture is transfered through an ion retardation column (AG11-AS). The D,L-[1-HC]-tyrosine eluate is transfered to the purification unit by an Anatech robot, D,L-[1-"C]-tyrosine is switched onto a chiral column to separate the two enantiomers. After passing through a sterile filter and QC, L-[1-HC]-tyrosine is suitable for injection. The total synthesis time is 30 minutes (EOB), in~:luding HPLC-purification, with a radiochemical yield of 40- 60%. Specific Activity is > 1000 Ci/mmoh

IN VITRO POTASSIUM BINDING CAPACITY OF THREE POLYSTYRENE SULPHONATE RESINS

Huqo van der Paauw, Max Maas r Henk de Vos r Jenny nettelaar

In the intestines polystyrene sulphonate resins can exchange the calcium or the sodium ion for the potassium ion that is present in elevated concentrations. The sodium load associated with sodium polystyrene sulphonate resins can be an undesired side-effect in patients with hypertension, heart decompensation and oliguric renal failure. In such individuals calcium polystyrene sulphonate resin is the product of choice.

We compared the potassium binding capacity in vitro of sodium polystyrene sulphonate (Resonium A m' and calcium polystyrene sulphonate (Sorbisterit ml and Calcium Resonium Im) pure powders and enemas. Suspension enemas were made with aluminium magnesium silicate (Veegum ml) as a thickening agent and methyloxybenzoate as a preservative.

Sodium polystyrene sulphonate pure powder and its suspension enema had a four times greater potassium binding capacity in vitro (mean (• 133.9 (• mg potassium per gram resin, calculated on the dried substance) than the calcium polystyrene sulphonate pure powders and its suspension enemas (mean (• 32.8 (• mg). No significant differences were found in the potassium binding capacities between the enema and the pure sodium polystyrene sulphonate powder and between the enemas and the pure calcium polystyrene powders, even after an six month storage period of the enema at room temperature.

Department of Pharmacy Slingeland Hospital P.O.nox 169 7000 AD Doetinchem The Netherlands

A STATISTIC DATA CONTROL PROGRAM FOR THE INTERNAL QUALITY CONTROL FOR TDM AND CLINICAL AND FORENSIC

TOXICOLOGY.

Jan IJmker and Donald R.A. Uges

G.L.P. requires a reliable and clear overview of all data produced in the laboratory. We have developed a quality control program "CONTROLE" for the administration and statistic processing of data from all kinds of sources e.g. drug standards, calibration of appar- atus and pipettes. The program is very flexible, so several statistical calculations can be carried out for all kinds of sources, each section with a maximum of 400 different data files. A learning set is calculated for each data file of the sections FPIA control sera (TDx, FLx and ADx), lyophilized control sera for chromatography , the controls of the Assocation for Quality Assurance in T.D.M. & Clin. Toxicology (KKGT) and calibration of pipettes used in our laboratory. Every input of data is automatically tested for deviation of the mean plus or minus three times the standard deviation. The analist is visually and by sound warned for unacceptable results. Also a Shewart and EMA sheet with day-to-day variations can be visual- ized. Today in several dutch clinical laboratories the program "CONTROLE" is used in daily practise.

Laboratory for Drug Analysis and Clinical Pharmacy, Department of Pharmacy, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.

NEONATAL ANALYSIS OF MECONIUM FOR BENZOYLECGONINE. L M L Stolk (1), W van den Brand (1), B J Smit (2), R M E Franssen (1)

Departments of Pharmacy (I) and Neonatology (2) of the Academic Medical Centre, Amsterdam.

Intrauterine exposure to cocaine is associated with low birth weight for gestati- onal age, microcephaly, congenital malformation and abnormal motor development Collection of urine of neonates is difficult and benzoylecgonine is sometimes undetectable because of rapid elimination. Meconium has been reported to be a better suitable specimen than urine for detecting benzoylecgonine. In our laboratory we developed a technique for screening of meconium for benzoyleegonine wit fluorescence polarization immunoassay (FPIA) and confirmation with HPLC and diode array detection. We used an Abbot TDxFLx analyzer and reagents for immunoassay of benzoylecgonine. HPLC was done with a reversed phase C18 stationary phase and a mobile phase (flow rate 1 ml/min) consisting of potassium dihydrogen phosphate 0.077 mol/I in water + methanol + aeetonitrit + tetrahydrofuran + triethylamine (600 + 100 + 25 + 7 + 1,5). Benzoylecgonine concentrations were measured at 232 rim. UV-speetra of eluting peaks were compared with UV spectra in the library of the system. 500 mg meconium was extracted with 2.0 ml methanol and evaporated to dryness. After redissolving the residue in t .0 ml buffer pH=6 , 0.1 ml was used for FPIA screening. The other 0.9 ml underwent a solid phase extraction procedure on a Bond Elut Certify column before HPLC analyses. Meconium was colleted frum infants of drug dependent mothers (n=3) and also from infants born to non-drug abusing mothers (n=3). The stools, obtained directly from the diaper, were pooled for each infant each day. No benzoylecgonine was found in the stools of the control infants. Benzoylecgoni- ne could still be detected with FPIA and HPLC in the meconium of two of the three possible drug-exposed infants until the second and third postnatal day respectively. Much larger amounts of benzoylecgonine were t'ound with FPIA (range 0.5-6.6 tLg/g) than with HPLC assay (range 0.3-1.3 txg/g). This discrepancy can be explained by the presence of benzoylecgonine related compounds, which are possibly reactive with the immunoassay.

Pharmat), J ~ r l d & S.~ ' . . '

volume 15 ~r. 6 1~93 K 7

PHARMACOKINETICS OF CEFTAZIDIME IN A D U L T CYSTIC FIBROSIS (CF) PATIENTS DURING CONTINUOUS INFUSION AND AMBULATO- RY T R E A T M E N T AT HOME.

A . A . T . M . M . Vinks ~, D.J. Touw ~, H .G,M. Heijerman 2, M. DanhoP, W. Bakker z. ~The Hague Hospitals Central Pharmacy and ;Adult Cystic Fibrosis Centre, Leyenburg Hospital, The Hague 3Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.

Acute exacerbations o f Pseudomonas aeruginosa lung infections were treated with ceftazidime (CTZ) bij continuous infusion (CI) in 8 CF patients. CTZ pharmacokinetics were studied after single dose and during CI. 4 Woman and 4 men (mean age 26.8 years, range 22-30; mean bodyweight 56.4 kg, range 50.0-67.7) were included in the study. CTZ was delivered with an ambulatory CADD-PLUS R (Pharmacia Deltec) infusion pump at home for three weeks. Individual pharmacokinetic parameters were calculated after a CTZ loading dose o f 2000 mg. At t=Sh a CI of 100 mg/kg/24h was started. Consecutive concentration measurements in serum, urine and sputum were made during 21 days. Samples were stored at -70"C and assayed for CTZ bij HPLC. The CTZ half-life (t,++) was (mean + SD) 1 +90 4- 0.85h, the volume of distribution (V,) was 0.28 _+ 0.08 L/kg and the total body clearance (CL) was 0.152 + 0.014 Llkg/h. CL during CI was 0.147 4- 0.019 Lllhlkg, and was equal to the CL after single dose. CTZ clearance at the start and at the end of the treatment did not differ. The CTZ serum concentration during CI was 28.7 _+ 5+0 mg/L. The steady-state concentration remained remarkably constant in each individual patient (intra-individual SD range 2.7-8.3 mglL). Furthermore no substantial difference in mean steady-state concentration between the patients was observed (range 26.7-30.6 mg/L). With the pharmacokinetic population data from the single dose study, the CTZ steady-state concentrations during CI could be predicted (precision (rsem) 3.1 mglL; bias (me) 0.4 mg/L). This method may serve a model in the development o f CTZ continuous infusion dosage regimens in CF home treatment.

USE OF DIURETICS BY THE ELDERLY IN THE INTERNAL MEDICINE OUTPATIENT DEPARTMENT

.Oriessen GJ t'3, Wo_hers R ~,~-, Go IH ~. Fennis j2 and Gribnau FWJ I

A study was carried out in the Internal Medicine OPDs of two major hospitals to determine the numbers of patientS over 65 using diuretics, the types of diuretics used, the initial indications, the prescribing physicians, the duration of the use and the relation of the use with sex, age and medical history�9 Other question-s investigated were whether continued use was still indicated and whether users of diuretics experienced more subjective and biochemical side effects than non-users. M~thods: Data were collected from medical records of all patients over 65 seen at the two OPDs from April to July 1992. The patients were invited to take part in a standard interview and physical examination, and also underwent a blood test. Data of users and non-users of diuretics were compared. On the basis of literature research on discontinuation of diuretics, criteria were formulated to determine which patients might discontinue diuretics. Users and non-users were further compared as to side effectS, laboratory findings and case histories. Re.suits: Of the 708 patients over 65, 344 used diuretics (48.7%). Use of diuretics increased with advancing age (p=0.0016), Males and females used diuretics equally often. Most diuretics were prescribed for congestive heart failure (CI-IF) (41.3%) and hypertension (43.6%). The internist prescribed over half the diuretics (52.8%), followed by the GP (21.9%) and the cardiologist (9.3%). Loop diuretics were the most popular diuretics prescribed (47.7%) followed by thiazides as monotherapy (21�9 or in combination with a potessium-sparing agent (16.7%). Loop diuretics were prescribed mostly for CHF, but also for hypertension (17.3%). Mean duration of use was 75 months, median duration 60 months (std 70 months). 162 Users of diuretics underwent interview, physical examination and laboratory testS; of these, 83 received diuretics for hypertension, 64 for CHF, five for swollen ankles and ten for other indications. In 19.1%, continued use was not indicated (23 with CHF, three with hypertension and five with swollen ankles). No significant differences were found in the diuretic and the non-diuretic group with regard to side effects such as dizziness, thirst, urine incontinence and retention, gout, muscle cramps and orthostatie hypotansion (measured). Several biochemical parameters changed during diuretic treatment (sodiuml., potassium/,, creatininet', ureat, uric acidt), hut no extreme changes were found. Conclusion: Diuretics are ofien prescribed for long-term use. In elderly patients this treatment is not always evaluated properly, especially in patientS with CHF as the initial indication; our findings are in agreement with data in the literature. Strict criteria tbr evaluation of diuretic therapy are not yet available, however�9

~Clin Pharmacol Unit, AZN Sint Radboud Hospital and Medical Faculty University Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

"- Dept.lnt.Med. Acad.Hospital Sint Radboud Nijmegen Dept Int Med. Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands

OPTIMIZATION OF THE INITIAL TOBRAMYCIN DOSE IN ADOLES- CENT AND A D U L T PATIENTS W I T H CYSTIC FIBROSIS.

D.J. Tou wL, A+A.T.M,M. Vinkr H .G .M. Heijerman;, J. Hermanr W. BakkerZ, tThe Hague Hospitals Central Pharmacy and 2Adult Cystic Fibrosis Centre The Hague, The Netherlands, ~Dpt+ of Medical Statistics, Leiden University, The Netherlands.

CF patients display different pharmacokinetics for tobramycin when compared with normal individuals. The volume o f distribution (V(d)) per kg bodyweight (BW) is increased and the elimination half-life is decreased. Some authors calculate the initial dose of tobramycin by means o f the body surface area (BSA) or BW. In our hospital tobramycin is started based on the actual BW and the dose is adjusted by drug monitoring. In order to obtain an optimal parameter to calculate the initial dose of tobramycin, we correlated the phara- cokinetic parameters and the adjusted daily dose with the patient parameters height, BW, age, BSA, and calculated lean body mass (LBM). LBM (male) = (1.1 x weigh0 - (128 x weightVheight~), LBM (female) = (1.07 x weigh0 - (148 x weight2/heightr). 34 Adolescent and adult CF patients (23 male, 11 female; mean age 23.8 years, range 16-32; mean BW 53 kg, range 31-63.5) were treated with i.v. tobramycin in an initial dose of three times daily 3.3 mg/kg BW. At the third dose, tobramycin peak and trough were drawn for analysis. Tobramycin one compartment pharmacokinetic parameters were calculated. The dose was adjusted to a 30 minutes post-dose peak of 10 mg/l and a pre-dose trough of 1 rag/1. Mean half-life was 1.9 hours, mean V(d) 14.6 I (0.28 I/kg) and mean clearance 5.44- 1/h. Mean adjusted daile dose was 554 mg (range 360-750 rag). We found a correlation o f V(d) with weight ( p < 0 . 0 2 ) , height ( p<0 .05 ) , LBM ( p < 0 . 0 0 2 ) , and BSA (p<0 .01 ) . The adjusted daile dose correlated with LBM ( p < 0 . 0 2 ) and BSA ( p < 0 . 0 5 ) but not with the actual BW. These data show that the initial dose o f tobramycin in CF should be calculated bij LBM rather than actual BW of BSA. From our data we derived an equation to calculate the initial tobramycin dose: tobramycin (mg/day/ = 270 + 6.4 x LBM.

TIME SEQUENCES IN CONCOMITANT DRUG USE IN ELDERLY PATIENTS ON DIURETIC THERAPY

Eibert R Heerdink. Hubert G Leufkens. Albert Bak~r.

Introduction: Diuretics ate among the most frequently prescribed drugs in the elderly and are often used on long term basis. Recognized interactions with diuretics include the reduction of diuretic and antihypertensive effects by concomitant use of nonsteroidal anti-inflammatory drags (NSA[Ds) possibly resulting in a (worsening of an existing) congestive heart failure. This study investigates the use of NSAIDs and cardiac drugs in time by patients on diuretics, to assess the risks of concomitant diuretic and NSAID use. Methods: Complete medication histories of an open population of users of diuretics (n=5,212) were retrospectively examined over a 6-year period. Starts of concomitant use of NSAIDs, cardiac glycosides, ACE-inhibitors, and nitrates were recorded�9 Use of comedication before and after first use of diuretics was investigated. Patients over 55 years old concomitantly using diuretics and NSAIDs were compared to a control group consisting of patients using only diuretics. Results: Over 27% of patients over 55 years old use diuretics, half of them being chronic users. Concomitant use NSAIDs is high (47.9%) and 39.5% of patients with a chronic use of diuretics and concomitant use of NSAIDs show a previous use of cardiac drugs. Chronic users of diuretics with no previous use of one of the three cardiac drugs show a slightly higher risk of starting cardiac therapy following use of NSAIDs compared to the controlgroup (RR=I.14 95%CI: 1.01-l.29 controlled for age and gender). Survival analysis of subsequent drug use shows a significant difference in subsequent use of cardiac drugs (p=0.005). Conclusions: This study indicates an increased risk on cardiac problems following concomitant use of diuretics and NSAIDs, A considerable part of the patients on diuretics and NSAIDs has a history of use of other cardiac drugs indicating previous cardiac morbidity. In these patientS use of NSAIDs may lead to serious worsening of an existing congestive heart failure.

Dept. of Pharmacoepidemiology & Pbormacotherapy, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands

Drug use in the elderly: comparison between interview data and pharmacy records

H.-q. Lau. K.S. Bcunim~. E. Postma-L[m. A. de Boer. A.J. Porsius

Data lu different sources such as pharmacy records, medical records, health insurance databases and patient questionnaires can be used in drug usage research. Discrepancies in study outcome can emerge due to differences in nature and quality of these data. We looked at possible discrepancies between data obtained from interviews and pharmacy records. Methods: 157 subjects aged 70 or older and residing in a district of a large city (66% women, 68% living alone, mean age 79.4 • 6.4) participated after informed consent was obtained. Four pharmacies and 13 general practitioners collaborated in the study. Home visits were performed by district nurses to conduct face-to-face interviews and to record all prescription and OTC drugs present. Information collected included drug name, dispense date, prescriber, directions on the container label and use of the drug. Pharmacy records of an one year's period were obtained from the pharmacies. Prescription drugs found at the home visit were compared with the pharmacy records and classified according to their presence in the pharmacy records and if present, whether there were discrepancies in dispense date. The data were entered in and analyzed with a computerized database Results: In the home inventory 654 prescription drugs (mean number of drugs per patient: 4.2 (range: 0-21)) and 91 selfmedication drugs (mean number of drugs per patient: 4.2 (range: 0-21)) were found. Of the prescription drugs, 64% (n=419) was dispensed during the six months immediately prior to the home visits ('recent drugs'), 14.4% (n=91) was dispensed in the period of 6 month-6 year prior to the home visits ('old drugs') and in 21.6% (n=141) the dispense date couldn't be retrieved. Percentages of drugs that were actually used (regardless of whether or not according to lhe directions on the container label) in these 3 categories were 91%, 53% and 86%, respectively. Considering the 'recent drugs', 77.6% was registered in the pharmacy records with and 129% without a corresponding dispense date; 2.1% could not be found in the pharmacy records. Regarding drugs with art unretrievable dispense date 82.2% was registered in the pharmacy records. Conclusions: drugs found at home and dispensed during the six months immediately prior to the home survey can largely be retrieved in pharmacy records. The dispense date of a drug found in a home survey often differs from that of the same drug in the pharmacy records. This is possibly caused by patients putting drugs in old containers or obtaining the drug from a different pharmacy.

Faculty of Pharmacy, Dept. of Pharmacoepidemiology & Pharmacotherapy, University ofUtrechL PO Box 80082, 3508 TB Utrecht, The Netherlands

THE ELDERLY AND THEIR MEDICATION. A STUDY IN THE OUTPATIENT DEPARTMENT OF INTERNAL MEDICINE

Wolters R 1":. Drlessen GJI.3.Fennis J~'. Go IH ~, and (~ribnau FW,V

Prescription of medication for the elderly is complicated by several factors (coexistent diseases, changed physiology, multiple physicians, decreased compliance). Several studies have shown that polypharmaey increases the risk of interactions and adverse reactions. We reviewed the use of medication by elderly outpatients. Methods: From April to July 1992 we included all patients aged 65 and over visiting the outpatient clinics of two major hospitals (AZN and CWZ in Nijmegen) and copied age, sex, medical history and drugs used from the patient records. Re~nit~: 798 OI.6%) of the visits were accounted for by 708 patients aged 65 and over (272 men, 436 women, mean age 73.5 years). The patients studied used an average of 3.8 different drugs. There were no significant differences between the sexes (p =0.18), nor was there a relationship with advancing age (p =0.11). 96.5% Of all patients used some kind of medication (22.9% used more than five different drugs, 4.4% more than eight). Among patients using nine or more drugs, a higher consumption of medication against cardiovaseular, pulmonary and gastric disorders was observed. Of all patients, 70.2% used cardiovascular medication. 345 (48.7%) used diuretics. In addition, B-blocking agents (22.7%), calcium antagonists (19.9%), ACE inhlbitors (16.1%), glycosides (13.8%), nitrates (12.6%) and eoumarins <12.0%) were often used. 18.8% Of the elderly used psychotropic medication. Benzodiazepines were prescribed for 14.8% of the patients (twice as much for women as for men); most bertz0diazepines were prescribed as sleeping medication. Other psychotropic drugs were only prescribed infrequently (2.3% tricyclic antidepressants, 1.4% narcotics, 1.3% anticonvulsants). Salicylates (16.0% of all patients) were the most widely prescribed NSAIDs, especially in doses used to inhibit platdet aggregation. Other analgetics included several NSAIDs (9.5%) and paracetamol (combinations) (7.5%). One-quarter of all patients used antidiabetic agents [insulin (13.1%), oral antidiabetics (12.t%)]. Other endocrine drugs used were eortieosteroids (oral 9.8%, inhalation sprays/powders 6.6%) and thyroid medication (thyromimetics 7.5%, thyrostatics 7.9%, both used mostly by women). Pulmonary drugs were used mostly by men in about equal proportions (xanthine derivatives 5.5%, sympathicomimetics 6.5%, pulmonary glucocorticolds 6.6%, pulmonary parasympathicolytics 4.9%). Combinations of gincocorticoids with sympathicomimeties or with xanthine derivatives were used most often. Conclu~k~: The average number of drags (3.8) used in the internal outpatient clinic is smaller than that used by inpatients. There was no significant relationship of number of drugs used with age or sex. Over one-fifth of all patients used five or more different drugs. Cardiovascular medication was used most (70.2%), with diuretics (4.8.7%) as its principal representative. Polypharmacy is still a difficult problem among the elderly, who should preferably be treated only with a minimum of absolutely necessary drugs.

~CIin Pbarmacol Unit, AZN Sint Radboud Hospital and Medical Faculty University Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

-" Dept.lnt.Med. Acad.Hospital Sint Radbuud Nijmegen Dept let Med. Canislus-Withelmina Hospital. Niimegen, The Netherlantls

DO ELDERLY GET THE BENZODIAZEPINE THERAPY THEY NEED?

E.R. Heerdink. H.S. Lau. A. Bakker. A.J. Porsins

Use of benzodiazepines among elderly is high. It is recommended to adapt benzodiazepine therapy to the requirements of the elderly patients, who are more prone to adverse reactions due to pharmacokinetic and pharmacodynamic changes. Benzodiazepines with a short or middle-long half-life and no active metabolites (e.g., temazepam, lorazepam and oxazepam) are preferable, and dosage should also be lower compared to younger users of these drags. In this study first-time prescriptions of benzodiazepines in elderly and younger patients are compared to examine whether the guidelines about drugs of first choice and dosage are implemented by the physicians. Data were collected from automated pharmacy records in one middle sized Dutch city (population: 60,000) and covered a period of 7 years (1985-1991). In this period 17,725 users of benzodiazepines could be identified. The first-ever prescription of a benzodiazepine of these users was analyzed, taking into account a 'wash-in period" of 6 months after first encounter with the pharmacy to exclude new-residents of the city and patients using benzodiazepines at the start of the data collection. Type of benzodiazepine prescribed and dosage were analyzed for different age groups. Oxazepam, diazepam and temazepam were the most frequently prescribed first-time benzodiazepines with tittle to no differences between the age groups. Lorazepam was among the least prescribed drugs and showed a higher use in the older age groups. Dosage of first-time benzodiazepines was on average lower in the elderly, especially in women. In men the difference between older and younger patients was much smaller. This study shows that in a considerable number of elderly first-time users of benzodiazepines the prescribed drug does not meet the guidelines concerning drug of first-choice and dosage adaption. These findings are alarming considering the frequent use of benzodiazepines in the elderly and the impact these drugs have on daily life.

Dept. of Pharmacoepidemiology & Pharmacotherapy, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands

COMMUNICATING A DRUG ALERT

MCJM. 8turkanboom ~, LTW de Jong-van d~a Berg ~, MC Cornel 2, BHCh Strickec ~ and H. W ~ l i n g ' .

Introduction: In October 1990 a recall procedure was issued l~garding the drug acitrefin. Due to the demonstration of eU'efinate in plasma of acitrefia recipients, the teratogenicity of both compounds and the long elimination half fife of ea-etinate, the posttherapy contraception period (PTCP) after aciU-etin therapy had to be extended from 2 months to 2 years. The purpose of this study was to measure the effiCiency of communication procedures in the Netherlands regarding a drug alert from health authorities through health professionals to the population at risk. Method: A three level model with intcrlevel communication lines was used to measure efficiency. Data were derived from level l (health authorities, professional associations and industry) through interviews. From/evel 2 (health professionals) data were derived through mailed questionnaires among random samples of 200 gyneacoiogists (respon,~ (P.:37%), 200 nudwives (R:43 %), 200 general practitioners (R:53 %) and 200 non-aciCetia drug dispensers (R:57%). Mailed questionnaires were sent to all 386 dermatologists (R:44%) and all 1153 drug dispensing GP's and pharmacists who had dispensed aeitretin(R:66%). From level 3 Women aged 15-4-5 yrs who had been exposed to acitretia (R:81%), data were obtained via mailed questionnaires. Results: Direct mail and mass media accounted for commnnication from level 1~2. Coverage of direct mail from the Iaspectorate on Drugs and the "Oranje Hand Enveloppu" ranged from 88-98% and 38-95% respectively among the different professionals of level 2. 40% Of the health professionals were notified fast by massmedia, 40% Of the aci~etin-drug dispensers informed a physician, mostly the GP. GP's and dermatologists did hardly contact the pharmacist or each other. 60% Of the women (level 3) were notified fast via massmedia, 30% via personal communication with one of the health professionals and 4% was never informed about the extended PTCP. 94%, 31% and 39% of the women expected to be informed by dermatologist. GP and pharmacist respectively. 19% Of the women was indeed informed by the dermatologist, 30% by the GP and 39% by the pharmacist. According to data from the patient questionnaire 35% of the women in childbearing age had never been intbrmed by any health professional about the extended PTCP. Conclusion: The Dutch health care system is sufficiently equipped for efficient communication between health authorities, industry and health professionals, The Inspectorate of Drugs is contributing the most to tiffs efficiency. However communication between health professionals and the population at risk is incomplete and needs to be improved as logistics are available. The role of drug dislpensers to inform patients should be extended in order to optimize coramuincation in case of a drug alert,

Department of Pharmeutical Pharmacology and Clinical P "harmacy, University of Groningen, : Department of Medical Genetics 3 Netherlands Center for Monitoring of Adverse Reactions to Drugs and ' Department of Clinical Pharmacology, Groningen.

I'harm,~,y II 'odd ~ S,h'me

Disturbance of micturition as a side-effect of drugs

P.M.L.A, van den Bemt 1. P.J.M. Kil 2, R.H.B. Meyboom I. G.H,P. de K0ning 1

Drugs can interfere with the normal process of micturition through a direct effect on the bladder, through interference with the autono- mous nervous system, or through an influence on the urineproduction. In this paper a survey is given of the mechanisms of drug-actions that may cause disturbances of micturition. The basis for this survey is formed by the suspected adverse drug reactions relating to micturition, as have been reported to the ADR reporting system of the Nether- lands Pharmacovigilance Foundation LAREB. Micturition disturbance as a side-effect of drug therapy can be caused as a result of: 1. an influence via the parasympathic nervous system

-cholinergic action: urinary frequency/incontinence -anticholinergie action: urinary retention

2. an influence via the sympathic nervous system -alfa-blockade: urinary frequency/incontinence -beta-blockade: (some) urinary frequency/incontinence -alfa-stimulation: urinary retention -beta-stimulation: (some) urinary retention

3. a direct effect on the bladder -urinary retention caused by calciumantagonists and opioids -urinary incontinence caused by dopaminergic drugs

4. an effect on the diuresis - diuretics - lithium - combination of diuretics and NSAIDs

Of the total of 83 cases of micturition disturbances, reported to the LAREB foundation, 50 cases can be explained by one of the above mentioned mechanisms. In the remaining cases no pharmalogicul explanation can be given and other causes may have been more likely. In some reports, however, a new reaction may have been involved, as for example in the case of 3 reports of micturition frequency on cisapride. This effect may be explained by the indirect cholinergic action of this drug.

t Netherlands Pharmacovigilanee Foundation LAREB, Tilburg (correspondence: Ringbaan West 273, 5037 PD Tilburg)

z Department of urology St. Elisabeth Hospital, Tilburg

Vaginal caodidinsis associated with acitretin?

Alma Middelbeek, Miriam CIM Sturkenboom, Lolkje TW de Jong-van den Berg

Dep. Pharmaceutical Pharmacology and Clinical Pharmacy University Center for Pharmacy, University of Gmningen

Introduction: The association of acitretin with mucocmanomis side effects like cheilitis, dry eyes etc. is very web known and the prevalence is high. However the association of acitretin with vaginal candidiasis has neve~ been described. The purpose of this study was to explore the association of acitrctin exposure with vaginal candidinsis

Method: A cohort of 160 women (median age: 38.0 3as) exposed to aciU'ctin in 1990 was recruited via prescribers and Drug Dispensing Outlets (DDO's). Medication histories of prescription drugs from computerized DDO's were collected every year. The study period sta~ed January 1, 1990 and ended December 31 1991, Persons entered the study upon fnst prescription of acitretin during the study period. A prescription for an antifimgal drug was used as a marker for vaginal candidiasis. Exposure and non-exposure time were calculated per person and aggregated. Exposure to acitrefin was defined as prescription duration + 20 days if no consecutive prescriptions were issued within 20 days.

Results: Among the cohort of 160 women, 17 "starts" of an antifimgal drug were recorded in the expusm'e time and 9 "starts" in non-exposure time. The exposure time accumulated to 37000 days and the non-expusure time to 41093 days. The incidence of antifungal "starts" during use of acitre~a was 4,59 per 10.000 persondays and the incidence of antifungal "starts" during non-exposure dine of acitretin was 2.19 per t0.000 persondays. The relative risk was 2.10 (95% CI: 0.94-4.71)

C o n c l u s i o n : Although the lower bound of the confidence interval is slightly below 1, it seems that the risk for vaginal candithasis during exposure to acitredn is higher than during non-exposure. In order to make a definitive conclusion about the conclusion further research is nec~sary.

H I'ANTIHISTAMINES: CARDIAC SNIPERS ?

Ron MC Herings I, Bruno HCh Stricker2,Hubert GM Lcufkuns l, Albert Bakker I, John Urquhart3

Objective: Scvcral Hi-antihistamines, such as, promethazine, astemizole and terfcnadine, have bccn associated with cardiotoxicity. We performed a cohort study to assess the occurrence of several cardiovascular events (CVS) in users of HI- antihistamines. Methods: From data, obtained from the PHARMO record linkage system (N=300,000), 45,396 patients could be identified that filled over 100,000 prescriptions of H l- antihistamines in an average observation period of 2.6 years. These patients were followed for CVS-related hospital admissions. The relative risk was estimated as an incidence density rate, assessed as the number of occurrences of CVS during the H l- antihistamine exposed and unexposed period within the cohort of Hi-antihistamine users.

Results: Results of this explorative study showed a significantly increased relative risk of Hi-amihistaminns for CVS (RR 1.71 CI95 % 1.32-2.22). Stratified analyses showed a significantly increased relative risks for cardiac arrhythrfiin for the class of

phenothiazines (RR 2.6 C195 % 1.82-3.76), especially for promethazine RR 2.9 (C195 % 1,28-6.55). For several other H|-antihistamincs, increased risks for CVS wcm also observed. Also, an increased relative risk was observed for congestive heart failure and acute myocardial infarction while exposed to H l-antihistamines, Discusslcm: From this study we tentatively conclude that cardiac arrhythmia and other

CVS are not only related to astemizole and terfcnadine but also to other HI- antihistamines. Further research is required as cases were not yet validated.

I. Department of Pharmacocpidemiology, University of Utrecht, Utrecht 2. Department of Internal Medicine IL Erasmus University, Rotterdam

3. Department of Epidcmiology, University of Limborg. Maastricht

ADDED VALUE OF QUANTIFYING SIDE-EFFECTS OF ANTIEPILEPTIC DRUGS.

M.W. Lammers, Y.A. Hekster, A. Keyser, H. Meinardi, W.O. Renie.r, H. Van Her.

In this prospective stndy the prevalence of side effects (SE) of antiepileptie drugs (AED) in epileptic patients, as well as the severity of these SE have been assessed. For the quantification of SE of the AED clinlmetric rating scales were used. i.e. a Neurotoxieity rating scale (NTX) and a Systemic toxicity rating scale (STX). The scoring ranges are graded according to the severity of the SE. In the whole group 38% of the patients were treated with monopharmacy, and 62% with polypharmacy. Neurological SE only were seen in 51% of the patients, 5% of the patients had systemic SE only, 23% of the patients had both neurological and systemic SE and no SE were observed in 21% of the patients. Patients on monopharmacy were more frequently without SE than patients on polypharmacy, 30% and 16% respectively. No distinct difference was seen between the two group with regard to the prevalence of neurological SE only, systemic SE only, or both neurological and systemic SE. When comparing the mean scores of the SE no distinct difference was seen between the patients on poly- and on monopharmaey (Table).

Distribution of SE in mono- and polypharmacy.

Diplopla Ny~mgmus Dysarth~a Amxla Dysdiadochokincsis T r e m o r Sedatlou Affect and mood disturbanc~ Cognitive impairments Dizzine~ Headache

Ga.stlointestinal problems ttaematopoietie problems Dermatologic problems Impotence Kidney disease Liver disease Weight gain Changes in hair/hair loss

J Monop~ey ~o mean score

5 15.0 6 6.5 7 5.0 12 8.2 1 15.0

18 12.6 37 5.9 6 6.0

27 8.5 7 5.4 9 7.1

5 5.3

2 15.0

II 8.9 12 9.8

nstitute ot Neurology. Dept. ot Ctinical Pharmacy, UniversJ

Polypharmacy % m e a n score

13 16.2 11 S.5 8 5.8 19 9.6 2 9.0

26 13.4 55 7.0 13 8.1 42 8.2 12 6.1 II 6,8

9 5.3

4 1S.5 0.4 20,0 1 50.0 2 25,0

11 �9 10.5 15 11.0

r ot Nijmegen, P.O. Box 9101, 6500 1113 N j n e g c n . T e Nether ands This study was supported by the Commissie Landclijk Epilcpsie Omlcrzoek Grant No. A-g1.

K1 0 Ph,lmracy I Vodd ~.:" S, icmc

INCIDENCE OF ADVERSE DRUG EFFECTS IN T H E GP REGISTRATION NETWORK GRONINGEN

L Veehof, R Stewart. B Meyboom-de Jon~. FM Haaiier-guskamo

The Netherlands knows two systems for monitoring adverse drug reactions, both based on voluntary reporting. Information about the incidence of side effects is however often lacking, since these systems do not yield data about the incidence. Population based data bases are needed for that purpose and these often only include prescription data. Information about the incidence of 'diagnosed' adverse effects is scarce. General problems concern differences in the definition of adverse effects and differences in method of registration. In the national study of morbidity in General Practice (NIVEL) the incidence/prevalence found was resp 10.4 and 16.4 per 1000/year. In the 'Transitionproject ' the incidence of "adverse effect of medical agent with proper dose' was 18/1000/year and the prevalence 19/1000/year. In the Regional Network of Groningen episode-linked prescription data are collected. Incidence and prevalence are also coded and used for the study of 'polypharmacy and the elderly ' , coded with the ICPC code A85. In this project a pilot was done in one RNG practice (5000 patients) looking at the following questions: 1. What is the incidence of A85 in one GP practice? 2. What drug caused the adverse effect noted? 3. What is the kind of adverse effect concerned? 4. What solution of the problem has been used?

Northern Centre of Health Care Research, University of Groningen GUIDE, University of Groningen Ant Deusinglaan 4 9713 AW Groningen

TOM OF HOLLAND

J.W.F. van Mil. Th.F.J. Tromp

The principles of therapeutic Outcome Monitoring, a form of Pharmaceutical Care developed by Hepler in

the USA, will be applied to astma-patients in

community-pharmacies. 300 patients with astma in 15

pharmacies will be selected in the agegroup 20-45 and given a special coaching by trained pharmacists. A

group of patients of other reference-pharmacies will

serve as blanks, One of the items in the coaching will be the self-

management of asthma based on PEV-values, but also

general principles of handling medicines and disease

will be discussed. Before the actual coaching starts,

pharmacist will receive a training on all aspects of asthma and communication. The emphasis of the project

will be on analyzing the impact of this form of

pharmaceutical care on the Health Related Quality of

Life of the patient, his disease and drug-use, cost-

effectiveness and the professional satisfaction of

the pharmacist. Changes over time will be measured in

the intervention-patients and in comparison with the

reference-group. TOM of Holland is part of an international study. TOM of Holland is part of a PhD project on Pharmaceutical

Care.

Werkgroep Farmacie en Samenleving, University Centre

for Pharmacy, Groningen, Ant. Deusinglaan 2, 9713 AW

Groningen. The Netherlands

ACE-INHIBITOR-INDUCED COUGH: ESTIMATING THE FREQUENCY IN GENERAL PRACTICE.

LE Visser(1) t BHCh Strlcker (2,&), J van der Velden(3) t AHP Paes (I), A 8akker t~; .

Background: All ACE-inhibitors have been documented to induce cough with an estimated frequency varying from less than 1% to greater than 14% of treated patients. In the literature it has been suggested that women are more susceptible, but conclusive evidence fails. Objective: (1) To quantify cough as an adverse reaction to ACE- inhibieors. ( 2 ) TO study whether women are more at risk of reporting cough as a side effect of ACE-inhibitors than men. Settino: Practices of 161 Dutch general practitioners (GP), in which all consultations, morbidity and medical interventions were registered during four 3-month periods (approximately 40 GP's each) in 1987/88. Desiqn: A retrospective cohort study. Patients & methods: Two mutually exclusive cohorts were formed of 1503 patients receiving ACE inhibitors (index-group) and 1431 patients receiving calcium-channel blockers (control-group) respectively. Both cohorts were reviewed regarding the occurrence of cough. Crude relative risks were calculated with 95% confidence intervals (CI). The following variables were considered as potential confounders: age; gender; history of or current asthma, chronic bronchitis, emphysema Or congestive heart failure; use of NSAID's; smoking; number of consultations and general praceicioner. Analyses simultaneously controlling for the potential confounders were performed by unconditional logistic regression. Results: Cough occurred in 144 patients receiving ACE-inhibitors and in 96 users of calcium-antagonists (3-months cumulative incidence: 0.096 and 0.067 respectively; risk difference: 0.029), giving a crude relative risk IRR) of 1.43 (95%CI: i.ii-1.83). For males the crude RR was 1.08 (95%cr: 0.75-1.54) and for female patients 1.88 (95%CI: 1.31- 2.69), giving a female to male RR of 1.22 (95%CI: 0.88-1.68) in the index cohort and 0.7 (95%ci: 0.47-1.03) in the control cohort. After controlling for potential confounders, the overall RR was 1.55 (95%CI: 1.17-2.08), for males 1.23 (95%CI: 0.81-1.87) and for females 2.13 (95%ci: 1.40-3.25). After excluding those patients of whom we were not sure that the prescription preceded the cough, the Overall RR became 1.52 (95%ei: 1.07-2.15), for male patients 1.31 (95%CI: 0.79-2.17) and for females 1.69 (95%CI: 1.03-2.76). Female to male RR in the index cohort: 1.08 (95%CI: 0.70-1.68) and in the control cohort 0.86 (95%CI: 0.50-1.50). Conclusions: Firstly, our results confirm that the use of ACE- inhibitors increase the risk for coughing almost twofold when compared to calcium-antagonists. Also the cumulative incidence is comparable to figures from the literature. Nevertheless, the incidence is probably underestimated as not all patients with cough will consult their GP. As this will occur similarly in the control cohort, however, the relative risk is not necessarily underestimated. Secondly, although a direct comparison failed to demonstrate a higher risk for coughing in women, only in this gender ACE-inhibitors increased the risk for coughing in comparison to calcium-antagonists. Finally, automated databases in general practice may be an important resource for postmarketlng surveillance.

(I) Department of Pharmacoepidemiology & Pharmacotherapy, University of Utrecht, PO Box 80082, Utrecht, The Netherlands. (2) Netherlands Centre for Monitoring of Adv-rse Reactions to Drugs, PO Box 5406, 2280 HK Rijswijk. (3) Netherlands Institute of Primary Health Care, PO BOX 1568, 3500 BN Utrecht. t4) Department of Internal Medicine II, Pharmacoepldemiology Unit, University Hospital Dijkzigt, Rotterdam.

The quality o f medication o f 94 patients with as thma/COPD and ischemic hear t disease: the use of organic ni t rates and respira tory drugs .

J.E. Nagto~aal and A.J. Porsius

We investigated the quality of pharmacotherapy of patients using both organic nitrates (mostly for ischemic heart disease) and medication lbr asthmaJCOPD. This particular population seemed of interest since under these circumstances therapeutic problems arise with respect to the choice of drugs. In 30 community pharmacies all patients with these caracteristics were collected and eventually 94 individuals were randomly selected for further analysis. Of all selected patients 36 were women (mean age 75,9 years) and 58 were men (mean age 69,7 years). In order tot establish the quality of medication, drug use was analysed for appropriateness for a period of 1 year using pharmacy medication records of these patients. Explicit criteria llke drug choice, dosage schedules, double medication, overprescription, drug-drug interactions and drug-disease interactions were considered to be important elements of appropriate medication and were used for evaluation. About half (52%) of the patients used organic nitrates both by oral and sublingual route; 42% used only nitrate preparations by oral route and 6% took only sublingual tablets. The dosage of isosorbidedinitrate (slow-release) was appropriate (2 times daily I tablet) in 31% of the patients, whereas dosage schedules of 3 times I tablet and even 4 times I tablet per day were seen in 58% and 8% of the cases, respectively. The drug pattern of astbmaJCOPD medication was assessed. Of all patients studied 68% used short-acting and 10% Iongacting sympathicomlmetic drugs for inhalation; 6% took sympathicomimetics orally. It should be emphazised that only 46% of all patients used inhaled corticosteroids chronically and that 25% did not get these preparations at alL As many as 24% (!) used tbeopbylline regularly. Eighty five percent of these patients took sympathomimetic drugs in combination with theopbyHine. The use of antibiotics tbr respiratory infections was evaluated as well. The combination of amoxlci[line and clavulanatr (Augmentin) seemed to be a favourate preparation and was prescribed both by general practitioners (20% of all antibiotic prescriptions) and specialists (26% of all antibiotic prescriptions). In one case the liver enzyme inhibitor ciprofloxacine (daily 2 times 500 rag) was combined with chronic theophylline tberapy, a condition that might induce unexpected high plasma levels of tbeophylline. It is conluded that the quality of the medication of these particular patients can be improved. Physicians and pharmacists should be more aware of tile fact that the choice of drugs for COPD and asthma is complicated when patients simultaneously suffer from angina pectoris, vice versa. For instance, tracheal administration of corticosterolds reduces the use of sympathieomimetic agents and possibly also or theopbylline, drugs wbich enbance oxygen consumption of cardiac tissue and. Iberelbre, inight worsen the condition of these patients. Theretbre, the medication of such patients should be ntonitored and evaluated carelhlly hi twder to prevent inappropriate drug use.

[:acuhy of Phannacv Dept. of Pharmacoepldcmiology & Pbarnlaculherap3, I1 ~ versity of I'trecht, PO Box 80082. 3508 ."B Utrecht. [be Nclherhtnds

Phar,n.zQ, H~,rhl L :~ S,w.,e K I ] Volume 15 Nr 6 1993

T h e qual i ty of medicat ion of 94 pat ients wi th a s t h m a / C O P D and ischemic hear t disease: the appropr ia teness of co-medicat ion.

N. Stecher and A.J. Porsius

We investigated the quality of pharmacothempy of patients using both organic nitrates (mostly for ischereic heart disease) and medication for asthma/COPD. This particular population seemed of interest since under these circumstances therapeutic problems arise with respect to the choice of drugs. In 30 community pharmacies all patients with these caracteristics were collected and r 94 individuals were randomly selected for further analysis. Of all selected patients 36 were women (mean age 75,9 years) and 58 were men (mean age 69,7 years). In order tot establish the quality of medication, drug use was analysed for appropriateness for a period of I year using pharmacy medication records of these patients. Explicit criteria like drug choice, dosage schedules, double medication, overprescription, drug-drug interactions and drug-disease interactions were considered to be important elements of appropriate medication and were used for evaluation. As expected, in addition to asthrea/COPD medication and organic nitrates, these patients used a substantial number of other drugs, like benzodiazepines (44%), loop-diuretics (43%!), calciumantagonists (37%), digoxine (22%), NSAIDs (22%), low doses of aspirin (21%), and ACE-inbibitors (15%). Some of these drugs (aspirin, NSAIDs) might induce asthma attacks, in spite of the respiratory disorder, 15 patients used betablockors: I1 patients took selective (reetoprolol, atenolol) and 4 individuals took non-selective (propranolol, sotalol, pindolol) betabtockers, in 8 patients the (non-) selective betablockers were combined with sympathicoreireetic drugs, in 4 cases patients used both a betablocker and theophylline. These patients might be severly at risk. In 31% of all patients overprescription of drugs was noted: cardiovascular drugs (5%), benzodiazepines (5%) and CARA medication (21%). Of all patients in this study 24% took reucolytic drugs, it was striking to note that of 14 patients who took medication for peptic disorders (H:antagonists) as many as 13 patients used a reucolytic agent. On the other hand, 16 individuals who used a mucolytic drug were not given inhibitors of gastric acid. Both groups used NSAIDs to the same extent. The results might indicate that the (chronic) use of reucolytic agents induces peptic disorders. Further (pharrnaco-epidemiological) studies are necessary to support such a statement. it is conluded that the quality of the medication of these particular patients can be improved. Physicians and pharmacists should be more aware of the fact that the choice of drugs for ischemic heart dissase is complicated by the presence of asthrea/COPD. Therefore. the medication of such patients should be monitored and evaluated carefully in order to prevent inappropriate drug use.

Faculty of Pharmacy, Dept. of Pharmacoepidemiology & Pharmacodlerapy, University of Utrecht, PO Box 80082, 3508 TB Utrecht, The Netherlands

USE OF ANTI -ASTHMATIC DRUGS IN A UNIVERSITY HOSPITAL

M.K~Casoarie. A.Kuiioers, P.M.J.Stuvt and Y.A.Hekster

This study is part of a hosp!tal-based quality assessment program on rational prescribing.

The use of anti-asthmatic drugs (AAD) in the University Hospital of Nijmegen based upon pharmacy data was studied over a one-year period. The overall prescription rate of AAD in 1992 was 38.8 DDD/IO0 beddays. The highest use was seen on the intensive care units (153.3 DDD/IO0 beddays) followed by the internal medicine and surgical wards (64.9 and 31.1 DDD/100 beddays, respectively); division of pulmonary, a part of the department of internal medicine, showed a use of 366.0 DDD/100 beddays. Because inhalation therapy is delivered by the hospital pharmacy in quantities higher then the amount used by one patient during hospitalization these figures are overestimations. A better estimation could be made by using mean duration of hospitalization per ward for number of DDD's for inhalation devices. Then AAD use on the intensive care units, the internal medicine and pulmonary wards was 91.2, 48.1 and 299.7 DDD/100 beddays, respectively.

The use of AAD as a predictive value for asthma and chronic obstructive pulmonary disease (COPD) was assessed in hospitalized patients on the pulmonary ward during an 8-month period using medication records. 78 of 149 (52%) admitted patients reeieved one or more AAD; in 76% of AAD users the diagnosis asthma or COPD could be made by discharge diagnosis data or medical record data. The cases without this diagnosis suffered from malignancy {10), cystic fibrosis (5) and other diseases like pneumonia (4). Although patients without asthma or COPD used less different AAD than those with these diseases, a clear distinction could not be made by medication record.

Drug use was analysed in the 59 cases with asthma or COPD. 75% used maximal AAD therapy (adrenergics, glucocorticoids, antichollnergic inhalants and xanthines). Theofylline was prescribed to 50 patients in which in 82% plasma concentration measurements were performed during the period between one month before and one month after hospitalization. 75% showed therapeutic levels in this period (for some patients more than one measurement was needed). Concomitant antibiotic drug use was high in patients with asthma and COPD, 73% with amoxicillin/clavulanio acid as drug of first choice (in 43% of cases with antibiotics).

in conclusion, drug utilization studies in AAD, as based upon pharmacy medication data lead to an overestimation of their use, Medication records can be used to identify patients with asthma and COPD although use of AAD not always indicates these diseases.

Oepts. of Internal Medicine and Clinical Pharmacy, University Hospital of Nijmegen, PO Box 9101, 6500 HB Niimegen, The Netherlands.

THE QUALITY OF REPEAT PRESCRIPTIONS WITHOUT DIRECT CONTACT BETWEEN PATIENT AND DOCTOR.

F.W. Dijkers

About 30% of the prescriptions of the general practitioners are repeat prescriptions without direct contact between patient and doctor. It

11 2) seems that this number is growing . The writing of these precriptions is the most occuring activity of the practice-assistant . Several recommendations are mentioned in the (English) literature in order to improve the quality of these prescriptions. We can not simply take over these recommendations, because we do not know how the request for a repeat prescription results in a new one.

In a community with about 20.000 inhabitants (8 general practitioners and 2 chemists) research is done into the way a request for a repeat prescription is settled and into the quality of these repeat prescriptions. Observations were made in the surgeries by an experienced practice-assistant on this matter. Attention was payed to:

The organisation of the medical adminstration. The extent of task delegation to the practice~assistant. The way in which one applies for the repeat prescription. The settlement and the check by the practice-assistant. The check, approvement and signature of the doctor. The information to the patient.

During 100 days all the prescriptions of the general practitioners are being checked in both pharmacies on the following quality criteria:

The name and/or adress of the patient are incomplete, indistinct or incorrect. The name of" the medicine is incomplete, indistinct or incorrect. The strength, the quantity or the directions for use are not given, indistinct or incorrect. The prescription does not fulfil the volume criteria of the G.V.$. (the Dutch medicine compensation system). Additional payment is necessary because of the G.V.S. The maximum c.q. most current dosage has been exceeded. There is a contra-indication or an interaction, by which the prescription had to be changed. The prescription does not fulfil the terms of the Opium Law.

Before delivery the repeat prescriptions without direct contact between patient and doctor wore marked by the practice-assistant. By that it is possible to examine in the pharmacy how these prescriptions will score on the quality criteria with respect to the other ones,

I) DiJkers FW. Management van hot herhaalrecept, Een literatuurstu- die. Muisarts Wet 1992; 35: 420-4.

2) Nij land A. De Prakti jkassistente [Dissertatie]. Groningen: Rijksunivorsiteit Groningen, 1991.

F.W. Dijkers, general practitioner, Raadhuisstraat Ii, 3299 AP Maasdam, the Netherlands.

The proport ion of general p rac t i t i oners ' prescript ions or ig inat ing from specialists' prescribing Nicolien M. van Diepen, Corinne S. de Vries, Lolkje T.W. de Jong-van den Berg and Dick F.J. Tromp Department of Pharmaceutical Pharmacology and Clinical Pharmacy; section of Pharmacy and Society Introduction: During pharmacotherapeutic consultation between general practitioners (GP's) and pharmacists prescription data are presented more and more often. When presenting these data, one of the problems encountered is that a proportion of GPs' prescriptions originate from specialists' prescribing. In the study described, the magnitude of this problem is being investigated. Methods: During a four week period GPs' prescriptions for a limited group of drugs are identified by pharmacists who cooperate in the AFTO-study. Next, questionnaires are sent to the prescribing GP's. In this way information is obtained on whether the prescriptions were In fact repeat prescriptions. I f this was the case, further inquiries are made as to whether or not they had been prescribed by a specialist, originally. Patients receive a similar questionnaire. At a later stage specialists will be interviewed. Results: Several pharmacists and their GP's, who cooperate in the AFTO- study, participate. At this instant pharmacy data and patient- and GP- questionnaires are being collected and compared. The f i rs t results will be presented. Conclusion: The aim of the study is to indicate the proportion of GP's prescriptions originating from specialists' prescribing. In this way prescription data, or prescribing behaviour, can more distinctively be allocated to either specialists or GP's.

K1 ~ 1 V,a.na, i, I I b,ld & .% w. . '

IS THE GP CAPABLE OF PRESCRIBING RATIONAL AND CREATING AN ADEQUATE SYSTEM OF RECORDING AND MONITORING OF PRESCRIBING? CM vd Ree, BA Ruben, HGA Mokkink, D Post and JW Gubbels.

In I0 general practices and 1 pharmacist during 13 weeks all prescriptions written by GP's (86%), specialists 02%) and others (2%) were encoded as such, reviewed and analyzed. Medicines used for chronic diseases were much more freqnently (46-87% versus 9-30% prescribed by GP's during indirect consultation than during direct consultation. For elderly patients 50% of all the prescriptions were given during indirect consultation. Medicines with known dangerous side-effects for elderly people (psychotropic medication and diuretics) were frequently (63 and 47%) prescribed during indirect consultation. To improve rational prescription and medication survey it is necessary to reduce the amount of indirect repeat prescription and to connect the computersystems of GP's and computersystems of GP's and pharmacist.

CM van der Ree, GP, Melkweg 10, 8151 AA Dronten

AFTO: a computer instrument to present prescription data Corinne S. de Vries, Paul B. van den Berg, Lolkje T.W. de Jong-van den Berg and Dick F.J. Tromp Department of Pharmaceutical Pharmacology and Clinical Pharmacy; section of Pharmacy and Society Introduction: During pharmacotherapeutic consultation between GP's and pharmacists (FTO) there is a need for the presentation of prescription data. In order to improve prescribing behaviour, GP's must be aware of their own prescribing habits. To this end AFTO has been developed. AFTO stands for "Analyse voor Farmacotherapie Overleg" (analysis for pharmacotherapeutic consultation). I t is an instrument, used during FTO, to present computerized feedback on prescription data to GP's. Methods: All FTO-groups who cooperate in the study have the disposal of AFTO. Prescription data, available from pharmacies, are read in into the AFTO-computer. The data can now be presented to the GP's through tables and graphs. When the data are made anonymous, pharmacists supply us with these data so they also become available for analysis in our department. Results: At this instant several ways of presenting prescription data are possible with AFTO. Examples will be given. In order to obtain these data the AFTO-user is prompted for the ATC-code of the drug(group) of interest. As a result of comments from the FTO-groups who use the program, the possibilities of AFTO are to be expanded. Conclusion: At present, the instrument is effective in presenting prescription data. Standardization for several variables (e.g. the average age of the population, the size of a practice) is necessary. Also, the influence of repeat prescriptions and specialists must be examined. The effectiveness of presenting prescription data during FTO on prescribing habits of GP's is being investigated.

DRUG UTILIZATION REVIEW IN DUTCH GENERAL PRACTICE

L:J. Stokx, M Foets

introduction: Preecriplion of drugs is the most common form of therapy in General Praclice (besides of communicative interventions). In about half of the contacts a prescription in dutch General Practice. Existing dutch databases do not give a representative insight in the use of drugs in general practice because they contain incomplete data about the different insurance types in the population and/or abodt the drug prescriber. Furhthermore detailed information is needed about the costs, the indications, the duration of therapy, the prescribed doses and the relationship between recommended therapeutic practice and actual clinical practice.

methods: Data are used from the Dutch National Survey of General Practice. This data offers the opportunity for representative information about both privately and sick fund insured population linked to morbidity data. It concerns a study of a random non-proportionally stratified sample of dutch general practitioners (161 GPs in 103 practices who service 2.5 % of the dutch population).

results and conclusions: privately insured patients get less drugs prescribed than sick-fund insured patients. 40 chemical substances comprise 50 % of all prescriptions in dutch general practice. The costs of drugs prescribed in General Practice are about half of the total expenditure on farmaceutical care in the Netherlands. Hypertension with t7 % of total expenditure for drugs in General Practice and anficonception (5%) are the largest costmakers in General Practice. After the Dutch GP has made the decision to prescribe drugs the way he makes the prescription is to be iudged merely positive. The indication, the dose and the length of lhe prescription globally match the dutch farmacotherapeutic recommendations. It is however important to mention that this conclusion rests on means and that considerable individual differences are existent. The qlost important deviations from dutch farmacotherapeutic Standards concern the prescription of cough preparations, vitamines and benzodiazepines, respectively because of the indication and the length of prescription.

Netherlands Institute of Primary health care (N)VEL), Postbox 1568, 3500 BN Utrecht, The Netherlands.

Drug Therapy Of Patients In Clinics (D-TOPIC): report of the pilot study

#H.S. Lau. PC. Florax, #,4. de Boer, ",4. van DOk. #A.J. Porsius

Drug-related hospital admissions arc caused by several factors such as intoxications, undertreatment (drug non-compliance and inappropiate drug choice) and side effects of drugs which are in part unavoidable, in part avoidable e.g. because of drug interactions and use of contraindicated drugs. Lack of comprehensive information among the physicians about all the drugs used by a patient is also a contributing factor which merits further investigation. In the D-TOP[C (Drug Therapy Of Patients In Clinics) study some of these problems are investigated by studying the quality of drug therapy in patients before, during and after hospitalization. Main questions are the occurrence and extent of drug related hospital admissions and the relation of the quality of drug therapy with these hospital admissions. Furthermore. in a randomized trial standard medical care is compared with an intervention based on a discussion of quality of pharmacotherapy by a pharmacist with the attending phycisian in addition to medical care. Here we report on the pilot study.

Thirty-lbur patients (59% women, mean age 67 (range: 34-86)) admitted to the general ward of an acute care hospital were included in the'study after obtaining informed consent. An interview emphasizing the drugs used before hospitalization was conducted. Relevant medical data were extracted from the medical notes. Pharmacy records and additional medical data were collected from the community pharmacists and the general practitioners, respectively. Data were entered in and analysed with a computerized database. Quality of medication was assessed using a method proposed by our group. Suboptimal drug use was allocated to one of the following categories: choice of drugs. dosage, overprescription. (pseudo)double-medication, drug interactions or contra- indications. Severity of suboptimal drug use is indicated by two grades: grade I is given when medication is considered inappropriate or unnecessary dangerous; grade It is given when the medication is suboptimal, but risks are probably low.

Most common reasons Ibr hospital admission were gastro-lntestinal problems (30%) and poor control of diabetes mellitus (15%). Suboptimal drug therapy of grade I and grade II was scored 12 and 29 times, respectively. One hospital admission was probably drug related. Although 172 drugs should have been used according to the pharmacy records data. only I27 drugs were reported by the patients. Non-compliance of drug use was seldom reported (6%). The effectiveness of a drug was reported to be good in 63%,The response of genera[ phycisians to requests for information was low (50%). in contrast, the response of the community pharrnacists was 100%.

There is a considerable discrepancy between the number of drugs used as reported by patients admitted to a general ward compared to pharmacy records. As a restdt oflhc pilot study several modifications to the study protocol were made.

# Dept. of Pharmacoepidcmiulogy & Pharmacothcrapy, University of Lltrr * I lospital Pharmacy, l lospital Oudcnrijn, Utrecht

l)h,mn,wy II bdd t: S, wine vo,~, ,5 N , 6 , 9 9 ~ KI 3

BUILDING AN INDICATION-RELATED MEDICATION DATA-BASE IN THE USE OF DRUG IN'FORMATION SOURCES BY" PHYSICIANS: PRIMARY HEALTH CARE BY RECORD LINKAGE DEVELOPMENT OF A DATA GENERATING METHODOLOGY

E.T.J. Peters. G.T. van der Weft and F.M. H~aijet3Ruskamp

The object of the project is to study the feasibility of different record linkage methods to construct a indication-related medication data base in the primary health care. This will be done with data from prescription forms based on pharmacy records which are routinely collected by Sickfunds and diagnoses and prescription data collected by the Registration Network Groningen. This network has been developed by the department of General Practice in 1990, The inclusion of prescription data is only recent and is still in a developing stage. In total I5 GPs of 4 practices are participating covering a population of more than 30,000 patients.

Record linkage can be performed when the records contain similar variables wich can form a linkage key. The deterministic or 'all or none' approach generates links if the records agree uniquely on all or almost all variables. With the use of a unique patient identifier e.g. sickfuod number this can 'easily' be done. Such a identification number, however, gives raise to problems with the confidentiality of the patients data. Therefore another approach of record linkage will also be examined. The probabilistic method is based on estimating the probability that 2 records belong to one patient given a combination of non-unique characteristics like date of birth, gender and GP,

This project will result in a technical report about the different possibilities also regarding privacy aspects.

Northern Centre for Health Care Research/Groningen-Utrecht Institute for Drug Exploration, University of Groningen. A. Deusinglaan 1. 9713 AV Groningen, The Netherlands.

Ellis J.C Boerkamo t , Flora M Haaijer-Ruskamp ~, Jan C Reuvl ~ . Albert Versluis J

Introduction. In this study we show a methodology to collect complex patient cases in which physicians make use of drug information sources during different stages of their decision making process (that is the diagnosis, therapy choice and implementa- tion). As such, the study is pa,'X of a larger project, in which the aim is to gain insight into how drug information suppliers are selected and used by physicians in hospitals.

Methodology. In order to elicit valid and reliable patient cases from physcians, in which it will be almost certain that they will make use of drug information sources we formulated several conditions. We present a step-wise approach in which patient cases are evaluated by a sample of internists according to criteria such as need for consultation, degree of difficulty, time pressure, rareness, personal experience, risk of decision and relevancy. We formulated acceptable ranges for these criteria. Mean scores and standard deviations were used. Cases which were rated within these ranges were selected and will be used to measure the use of information sources in ease of complex patient problems.

Results. In the first step cases were developed: 5 internists formulated 35 complex patient problems out of their practice in which they consulted personal drug information sources. After evaluation by the researchers 20 cases seemed useful. These cases in combination with a questionnaire were sent for evaluation to a sample of 59 internists (response rote. was 68%). ARer analyzing these results 6 cases could meet the formulated criteria. The cases will be used to measure the use of information sources in case of complex patient problems.

Faculty of Economics, Department of Busines Administration, P.O. Box 800, 9700 AV Groningen, The Netherlands. "- Deparment of Health Sciences, University of Groningen. 3 University Hospital Pharmacy, Groningen.

PRESCRIBING DECISIONS OF GENERAL PRACTITIONERS FOR CYSTITIS AND STOMACH COMPLAINTS

P. Denis. F.M. Haaijer-Ruskamp, H. Wesseling

Many initiatives taken to improve the quality of prescribing focus mainly on the exchange of information and knowledge about drug treatments. How much this can improve prescribing behaviour is not eertainL Among hospital physicians it has been found that choosing less desirable drugs is not always related to having incorrect expectations of the drugs 2. To get insight in the role of knowledge with regard to the prescribing quality in general practice a study is conducted in the north of The Netherlands. It is tested to what extent the variation in treatment choices can be explained by the differences in:

1) knowledge regarding the relevant aspects of the drugs, 2) selection criteria used, and their relative weight, 3) decision strategies used.

Five detailed descriptions of patients with either cystitis or stomach complaints were presented to 61 general practitioners (GPs). The GPs were asked how they would manage these patients. Their considerations and decision strategies were elicited with a structured questionnaire and the thinking-aloud method. The reported management choices will be compared to actual prescribing behaviour.

Preliminary results show that prescribing short courses for cystitis is best explained by thinking more highly of the efficacy of these short courses. Also, attaching more weight to the criterium of 'user-friendliness' can be of influence. Prescribing 'heavier' drugs for stomach complaints is best explained by attaching more weight to the efficacy, and less weight to the cost of the treatment. Furthermore, expecting less side effects, attaching more weight to "user-friendliness', and responding to subjective patient demand are in some cases of influence.

It is too early to reach final conclusions, but it is clear that having the correct factual knowledge does not guarantee optimal prescribing. This knowledge must be applied in practice as well. It seems that the weight attached to certain selection criteria can be an important factor explaining different treatment choices in practice. Continuing medical education should address this issue.

1. P. Denig, F,M. Haaijer-Ruskamp. Pharm Weekbl [Sci], 14 (1992) 9. 2. P. Denig, F.M. Haaijer-Ruskamp, H. Wesseling, A. Versluis. J Intern

Med, 234 (1993) 155.

Dept. of Health Sciences, Dept. of Clinical Pharmacology, University of Groningen, Ant.Deusinglaan 1, 9713 AV Groningen, The Netherlands

Setting the agenda: Does tlm scientific medical literature set the agenda for medicines discussed in newspapers7

Anke M van Tri~,t ~. l~Ikie T.W de Jon~- vd Ber~ ~. Janp Willerns ~. Flora M Haniier-

As a part of our study "Mass media and medicines" wc looked into the relation between the kind of drugs discussed in the scientific medical literature and those discussed in Dutch newspapers.

A content analysis of ten scientific and medical journals over a nine-months poriod (jan- sept 1991) was compared to a content analysis of five Dutch ncwspape~ over a four- months period (jane-sept 1991). The drugs discussed were classified according to the ATC system to make comparison possible. Results. A total of 1574 publications about medicines was found in the scientific and medical fiterantse over the 9 months period. In the medical and scientific literature the categories "general anti-infectives" (in particular, the subclasses virustafics and vaccins) and "central nervous system" were most often discussed. Approximately a quarter of all publications, concerning drugs, focussed on the negative consequences of drug use, e.g. side effects. In the daily newspapers a total of 178 publications was found over a four-months period. The most important categories of medicines discussed were the general anti-infectives, followed by medicines for the central nervous system and drugs in the category "genito urinary system and sex hormones'. The negative consequences or problems with medicinas were discussed in 14% of all publications in the newspapers. Approximately three quarter of all publications were classified as "good news" stories. There was no significant difference found in attention for good or bad news for the different types of newspapers. Six of the ten most frequently discussed ATC subclasses were found on both the agenda of the scientific and medical literature and the agenda of the newspapers: vaccins (J07), ,sex hormones and stimulants of the genital system (G03), analgesics (N02), Hypotcusives (C02), virustatics 005), anticoagulants (B01L The negative consequences of drug-use received proportionally more attention in the scientific and medical literature than in the newspapers. Conclusion. The scientific medical litarature sets to some extent the agenda on medicines of the newspapers.

tDepartment of Pharmacology and Pharmacotherapeutics, section Social Pharmacy. University of Groningen A. Deasinglann 2, 9713 AW Groningen, The Netherlands. :Faculty of Sciences. University of Nymegen)Dcpt. Health Sciencas. University of Gmningen.

volume 15 Nf. 6 1991

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Direct-to-the-public advertisements of health- and medicinal products in 11 countries

Hans Kaldeway, Nicolien Wieringa, Andrew Herxheimm', Rein Vos Wetensobapswinkel your Geneesmiddelen Universitair Centrum your Farmacie, RUG

Introduction In the field of health- and medicinal products advertisements are often an important information source for consumers, in quantity an availability. The International Organiza- tion of Consumers Unions (IOCU) is concerned that advertisements for these products often contain incorrect and insufficient information, according to international rules and regulations.

Aim Toe aim of the present project is to analyze the contents of direct to the public advertisements of health- and medicinal products, and to assess the contents of these advertisements against two international standards: 1) the EC Directive on Adverdsing of Medicinal Products 2) the WHO Ethical Criteria for the Promotion of Medicinal Products.

Material From 11 countries (4 EC, 7 non-EC) 321 advertisements of health- and medicinal products have been collected. 276 advertisements were suitable for the analysis.

Methods From the rules of the WHO Criteria and the EC Directive a number of items have been exWacted, upon which the content of the advenisoments are checked. These items are divided into two groups: items that are sot allowed to appear in the advecUsemants, and obliged items that all advertisements should contain. A contest analysis of the advertisements is made, to be sure all the elements of the advertisements are catched. In this way a detailed and clearly structured source of information is made, which is used to check the advertisements on the various items.

Results Of all the analyzed advertisements, only 3 adverdsements completely confirm to the EC and WHO standards. E s p e c i a l l y the obliged items are often missing: about 75',% of the advertisements do not mention contra-indications, side-effects and warnings. About 40% do not mention the sub.race(s) of the product.

Conclusion The majority of the advertisements in the present study, does not adhere to one or more rules of the EC and WHO standards. The results will be published hi a Wet~hapswinkel/IOCU report and in the magazines of the participating member consumers organizations.

Changing relations Changes in the relations between Doses, Effects, Adverse Drug Reactions "and Indication in the scientific field of the Angiotensin-Converting Enzyme Inhibitor,s over the period 1979-1986

Jennifer Hei_iman. Floor Rikken_ Rein Vos

Introduction: Captopril, the fh'st ACE-Inhibitor was introduced on the market in 1979. The maximum daily dose for the treatment of hypertension was 450 nag. In 1985 the registered doses were lowered to a maximum of 150 mg daily and for congestive heart failure even lower. In this study we wanted to reconstruct the changing of the doses with emphasis on whei-e the trigger came from for decreasing the doses. How did the main aspects of a drug (Doses, Effects, Adverse Drug Reactions and Indication) relate to each other and influence this decrease. Material & Methods: The material used is a database derived from Medline, Online over the period 1979-1986 (search profile with emphasis on clinical, doses and ADR related aspects of ACE-Inhibitors). The database was divided into four subdatabases and two periods, 1979-1983 and 1984-1986. Three of these included all articles on one indication (Essential- and Renovascular hypertension, Congestive Heart Failure) and one with all dose-related articles. The abstracts of these articles were used in a co-word-analysis, a quantitative texts analysis which gives co- occurrences of every two words. The Jaccard Index was used to correct for the frequencies of the words. The last step was a multidimensional scaling and clustering analysis. Results: The analysis resulted in relations between words that stand for the different mentioned aspects, Doses, Effects, Adverse Drug Reactions and Indication. Differences between the subdatabases were the number of relations found. In the subdatabases of Essential Hypertension and Renovascular Hypertension more often a relation between doses and ADR was found. In the two periods different kinds of relations were found. In the first period a relation between doses and ADR was more prominent than in the second period; in the second period there was more emphasis on effects and its relations with other words. Discussion & Conclusions: The used method seems to be appropriate in order to detect changes in this scientific field. The results of this part of the study in combination with other methods used, suggest that after the introduction of a drug, setting the dose must be established first betbre expansion of effect related objectives occurs.

Social Pharmacy. Dept. Pharmacology & Pharmacotherapeutics: University of Groningen, A. Deusinglaan 2, 9712 AW Groningen, the Netherlands

A RAPID METHOD TO ESTIMATE THE INCIDENCE RATE AND PREVALENCE

OF INSULIN DEPENDENT DIABETES MELLITUS

IN CHILDREN 0-19 YEARS OF AGE

Run MC Herings 1, Anthonius de Boer I. Bruno HCh Stricker 2,

Albert Bakker 1 , Ferd Sturmans 3

O b j e c t i v e - To trace new cases of insulin dependent diabetes mellitus (IDDM) on an

ongoing basis and to estimate the incidence rate and prevalence in children 0-19 years

of age.

M e t h o d s - Estimation method of the prevalence and the incidence rate of IDDM derived

from the rate of prevalent users and new starters of insulin as obtained from pharmacy,

patient-based drug dispensing histories in a well-definod population encompassing

257,113 individuals in The Netherlands,

R e s u l t s - The IDDM incidence rate was estimated as ll.5 [CI95 % 6.6-I7.8] per

I00,000 person years in 1989-1990 in children 0-19 years of age. The prevalence was

estimated as 11.0 [CI95% 8.6-13.4] per 10,000 children 0-19 years of age.

D i s c u s s i o n - The incidence rate is comparable to that found in a large, national survey

among all pediatricians and internists involved in diabetes care in The Netherlands. Our

method proved to be rapid and inexpensive in order to estimate the IDDM incidence

rate and to estimate the prevalence of IDDM in children 0-19 years of age. Furthermore.

the method is suitable as a rapid, eontinous and cost-efficient recrutement of cohorts of

incident IDDM patients which fosters research to identify and quantify etiological

factors and co- morbidity by follow-up studies.

1. Department of Pharmacoepidemiology, University of Utrecht, Utrecht 2. Department of Internal Medicine II. Erasmus University, Rotterdam 3. Department of Epidemiology, University of Limburg, Maastvicht

Managing industrial pharmaceutical innovation: a com- parative study

Omta SWF 1,2. Bouter LM 2 and van Enqelen JML 1

Drug regulation and pricing have put strong pressure on the cost-benefit ratio of innovative pharmaceutical industry. Therefore a study has been performed in four- teen large and medium sized companies to determine some

important organizational and managerial factors influ- encing success in pharmaceutical innovation. The study consists of structured interviews with Research Direc- tors and questionnaires, submitted to the heads of the different research departments. Tentatively the following conclusions are drawn. Firstly, the data suggest that a threshold investment of around $ 150-200 million is needed to keep up the innovative potential. Above around $ 750 million 'economies of scale' seem to appear in pharmaceutical innovation. Secondly, an incremental strategy, directed to reduce the duration of the development process, for instance by parallel development, seems to be more successful than a radical strategy, which lays more emphasis on discovery. Third- ly, pure play pharmaceuticals seem to be more successful than pharmaceutical divisions of conglomerates. Concerning management control, especially the way and manner in which reorganizations are performed is assessed more positively in pure play pharmaceuticals. Fourthly, the greater emphasis on human resources management in Anglo-American in comparison to conti- nental European companies seems to be an important explanatory factor for their greater success on the pharmaceutical market.

1 Fac. of Management and Organization, University of Groningen

2 Institute for Research in Extramural Medicine, VU Amsterdam

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vol . . . . 5 Nr 6 1993 K'~ 5

REFILL COMPLIANCE OF ETIDRONATE (DIDROKIT)

A.H.P. Paes and H.G.M. Leufkens

Non-compliance with drugs i~ a widespread and important public health problem, in which prescribers, dispensers, patients and producers are involved. Nearly 50% of the patients do not use drugs as pr~scribed. The problem becomes worse whefl medication has to be taken on a long eerm bases or when the paeiene has to take more medicines a~ differene times a day. Stopping She medication after a while is one of the most common errors made by patients with a chronic medication, This often OCCURS when the disease is asympeomatic and when the patiene does not percelve their illness as serious or important. Illnesses without complaints have only a weak effect on the health perception of the pallets and contribute to noncDmplianee, patients with primary oseeoporoois have in general not serious complaints and would nee perceive directly an improvement in eheir health situation.

In 1991 nidrokit, a fixed conlbi~ation of etidronate and calcium has been ineroduced on the Dutch market for the treatment of posemenopausal osteoporosis. The kit provides a eherapy regimen for 90 days and must be used for 3 years, Data on refill compliance of recipients of Didrokit (from Nowrich E~ton), show that approximately 40% of patients does not visit the pharmacy to refill their prescriptions afte~ the first prescription.

Our department started an intervention study to improve refill compliance within the possibilities of community pharmacy.

Two differene strategies to improve compliance are compared with 'normal practice' as present today. First recipients of Didrokit are divided into three groups: strategy I, strategy If, reference group. Group ~ (n=86): patient receives a patient booklet and a written reminder 14 days before the next kit is due. G~oup II (n=97): patlent receives a patient booklet plus a newsletter sent every 3 months to the patient at home, six week after they get their medication. The newsletter provides additional information on osteoporosis, importance of patient compliance and lifestyle (exercise, diet, etc.) GVoup ~ (n=108): control group, only receives a patient booklet.

Every patient received standard information about how no take the medication and the importance of taking all the medication as instructed. Pharmacies participating in this project (n~62) are divided in these three groups: they send the reminder and newsletter. Patients selected are women, 55 yea~s and older, receiving Didrokit for the first timm (almost 80% of the Didrokit users are women). During one year the patients receive a reminder (Group ~) or a newsletter (Group I~}.

The non-compliance in all the groups was lower than the data provided by Norwich Eaeon (40%). This must be the result of the boo,let which was given to every patiene and is not normal in every pharmacy. In the control group almost 1/4 of the patients failed to refill their kits and 1/5 of the patients in the two other groups. Patients receiving a newsletter with information aboue ereatment and lifestyle showed the highest kit-to-kit compliance asd

In Group I we try to measure she influence of social control, AS expected sendin~ a reminder improves the short term kit eo kie compliance. More ehan 80% returned at time to refill their prescriptions, but in this group are more patients delayed than in group It. In Group II we try eo measure the influence of an improvement of She 9.~owledge of therapy and illness. This strategy also shows the highest improvement in kit-to kit compliance.

Dept. of Pharmacoepidemlology and Pharmacotherapy Faculty of p~armacy, University Utrecht POnox 8008~, 3508 TB Utrecht, The Netherlands

SELECTIVE DECONTAMINATION OF THE DIGESTIVE TRACT (SDD): RETRO- AND PROSPECTIVE FOLLOW-UP AT AN ICU

_H.A. Tissot van Paint. J.A. Leusink, B.M. de Jonah, H.S. Lau, A. de Boer

SDD with non-absorbable antibiotics was extensively used at intensive care units (ICU) in Europe to prevent nosocomial infections in patients receiving mechanical ventilation (MV). After three recent nets-analyses in which it was demonstrated that SDD did not influence hospital stay and mortality in these patients several hospitals decided to stop the regular use of SDD at the ICU. The aim of this study was to examine the effects of the cessation of SDD on nosocomial infections, mortality and hospital stay at an tCU. A retro- and prospective follow-up of all post-operative patients with MV for > 5 days at an ICU was performed. Exclusion criteria were infection at the start of MV and pre-operative antibiotic treatment. The retrospective group (SDD group) comprised of 138 patients (mean age 66, range 10-91; 80% male) and was admitted during the period 1986 and 1991. The SDD regime included eolistin. tobramyein and amfotericin B and was administered four times daily to the oropharynx and digestive tract by a nasogastral tube. The prospective group (non- SDD group) comprised of 35 patients (mean age 67, range 46-85; 57% male) and was admitted in 1992 and 1993. Medical, laboratory and microbiological data were daily collected up to 21 days ICU-stay. Standard criteria were used to score infections (positive culture required). Duration of ICU stay and death were noted. Survival analysis was performed by Cox's proportional hazard regression model. Both groups were comparable regarding duratibn of MV and ICU stay (p>0.05). Of the 173 patients 65 died on the ICU. The risk of death was lower in the non- SDD group (relative risk 0,5; 95% CI 0.3-1.0), Adjustment for 13 base-line variables that were either unbalanced between the two groups or individually predictive of death did not substantially influence these results (RR 0.6; 95% CI 0.2-1.3. During the 21 days follow-up 91 patients developed a respiratory tract infection (RTI). The incidence of RTI (per 1000 persondays) was 80 (95% CI 48- 113) in the non-SDD group versus 19 (95% CI 8-22) in the SDD group. The risk of RTI was higher in the non-SDD group (RR 3.8; 95% CI 2.2-6.5). After adjustment for potential confounders the RR was 4.3 (95% CI 2.3 to 8.3). In summary,, although there appeared to be an increase in infection rate after cessation of SDD there was no increase in duration of ICU stay and mortality. The results might be biased by the fact that a positive culture was required for infection diagnosis. Therefore, infection rate might be underdiagnosed in the SDD group by sterilisation of sputum by the antibiotics of the SDD regime.

Faculty of Pharmacy, Dept. of Pharmaeoepidereiology and Pharmacotherapy, University of Utrecht. PO Box 80082. 3508 TB Utrecht: St. Antonius Hospital. PO Box 2500. 3430 EM Nieuwegein, The Netherlands.

DRUG AND DIET SUPPLEMENT USE AMONG BODYBUILDERS.

B. Steffcns. A.J. Pnrsius, J.J.H. Thiissen, D. de Boer. A. de Boer

Few data are available on the use of drug and diet supplements among bodybuilders in the Netherlands. In the present study we evaluated an anonymous questionnaire focussed on the use of these supplements among bodybuildcrs. Although the main object of this pilot study was to evaluate study procedures and the questionnaire, only demographic data of participants and answers on questions will be presented. Three gyms participated in the study. Owners of these schools distributed by face-to-face contact 127 questionnaires, including pre-stampcd envelopes, among bodybuilders. Two month alter distribution 32 questionnaires (25%) were returned to the investigators. The mean age of the participants was 29 years (SD 9) and on average they practiced bodybuilding for 6 years (SD 4). Twenty two percent was involved in competitive bodybuilding. Vitamin and amino-acid preparations were used by 78 and 53% of the responders, respectively. Seventeen of the 32 participants (53%) had ever used anabolic steroids, Stanazolol was reported most often (t3 users) and 59% sometimes used more than one anabolic steroid concomittantly ("stacking"). On average two cycles (duration approximately 8 weeks) per year were used and daily doses ranged from 5 to 285 mg. Twelve users (71%) administered the anabolic steroids (71%) by the oral and parenteral route. Adverse events during the use Cf anabolic steroids were reported by 88%. Especially. acne (30%), increased aggressiveness (25%) and sexual desire (53%), holding water (30%) and increased sweating (30%) were frequently reported. Ninety percent of all responders found anabolic steroids to be harmful, although. 60% of them thought this to be the case only at high dose levels. Other drugs then anaholic steroids were used by 31% of the responders. Choriongonadotrofin (Pregnyl R) was reported by 25% and ctenbuterol (13_,-agonistl was used by two participants. Furthermore, the use of clomifen, tamoxil'en. ionareine, triacana and thiomucase was reported. In conclusion, anabolie steroids, other compounds and diet preparations are extensively used among bodybuiiders. Due to the low response, the representa- tiveness of the results is unknown.

Dept of Pharmacoepidemiology and Pharmacotherupy, Dept. of Analysis and Toxicology. University of Utrecht, PO Box 80082, 3508 TB Utrecht. The Netherlands.

ANTI-EPILEPTIC COMEDICATION IN PATIENTS USING ANTIDEPRESSANTS

Eibert R Heerdink. Hubert G Leufkens. Albert Bakker

Introduction: Convulsions are a known side-effect of some antidepressants and epilepsy is contra-indicated with most antidepresslve drugs. Fluoxetine is a relatively new drug with no convulsive action reported, and not contraindicated in epileptic patients. The objective of this study was to assess the risks of convulsions during the use of the various antidepressants, by comparing the incidence densities of starts of anti-epileptic therapy during antidepressant use. Methods." Dispensing data of a population of 65,000 people were gathered from automated pharmacy records. Medication histories of users of antidepressants over a period of 5 years were investigated. Incidence density rates of starts of anti-epileptic treatment during the use of an antidepressant were calculated using amitryptiline as a reference since this was the most widely used antidepressant. Person-days of antidepressant use were used as the denominator. By using amitryptiline use as a reference risk-profiles of individual antidepressants could be assessed. Resides: In a five year period 3.175 patients using antidepressants could be identified. Of these, 188 patients (5.9%) also used an anti-epileptic drug during this period. Drugs with known strong convulsive side-effects showed low incidence density rates compared to amitryptiline [mianserine 0.61 (95% CI: 0,36-1,00), clomipramine 0.69 (0.45-1.07), maprotiline 0.94 (0.71-1.24)1. while fluoxetine showed a high incidence density rate of 1.60 [0.87-2.94]. The incidence density rates were corrected for age and gender by pooling with Mantel-Haenzsel estimators, Discussion: The high incidence density rate found for fluoxetine may be explained by 'channeling', i.e. the phenomenon that new drugs that are often marketed as being safer, are predominantly prescribed to patients with a complicated medical history. There is an overall, relatively high incidence of anti-epileptic drug use by patients on antidepressants, despite the serious side-effects, showing the need for an appropriate therapy. Assessment of risk-profiles of individual drugs can facilitate a deliberate chalice.

Dcpl. of Pharmacoepidenliology & Pharmacothcrapy, Utrecht University, PO Box 80082, 35(/8 TB Utrecht. The Netherlands

K] 6 l~lmtma~y I t~,rl,I ,~: S, icme

P h a r m a c i s t a n d i n f l u e n z a v a c c i n a t i o n : c o o p e r a t i o n w i t h t h e g e n e r a l p r a c t i t i o n e r s u c c e s s f u l

Lolk je T . W . de J o n g - v a n den Berg , l nge H . Reuve r s , T r e a A. van

de r G a l i r n and Dick F .J . T r o m p D e p a r t m e n t o f P h a r m a c e u t i c a l P h a r m a c o l o g y and Clinical P h a r m a - cy; Sect ion o f P h a r m a c y and Socie ty

I n t r o d u c t i o n : In this s tudy a m o n g a r a n d o m sample o f 213 c o m - mun i ty p h a r m a c i e s ( respons 6 0 , 8 % ) the con t r ibu t ion o f the c o m m u - nity p h a r m a c i s t to the in f luenza vacc ina t ion c a m p a i g n is eva lua ted .

M e t h o d : T h e da ta w e r e co l lec ted t h r o u g h a ques t ionna i re distr ibu-

ted b y mai l . R e s u l t s : 92 ( 7 2 , 4 % ) P ha rmac i s t s had t r aced pat ients at r isk th rough the i r c o m p u t e r i z e d med ica t ion sy s t em. Pat ients at r isk are def ined as peop le for w h o m the c o n s e q u e n c e s o f in f luenza are m o r e ser ious

than the a v e r a g e popula t ion . F o r 6 5 , 2 % this was the f irs t t i m e to ident i fy pat ients at r isk in this w a y . T h e o ther pha rmac i s t s had a l r eady done this p rev ious ly . 35 ( 2 7 , 6 % ) pha rmac i s t s d id not t race pat ients at r isk because o f the fac t that the genera l pract i t ioners w e r e not interes ted. T h e inc rease in the n u m b e r o f d ispensed vacc ins in 1992 c o m p a r e d to 1991 was 3 7 , 4 % in the p h a r m a c i e s w h e r e p h a r m a c i s t had t r aced pat ients at r isk and 19 ,8% in the p h a r m a c i e s w h e r e no pat ients at r i sk w e r e t raced. N e a r l y all phar-

macis t s s t ressed the fact tha t t r ac ing pat ients at r isk is a mutual task o f bo th genera l p rac t i t ioner and pha rmac i s t . C o n c l u s i o n : W e conc lude that the con t r ibu t ion o f the pha rmac i s t to the inf luenza vacc ina t ion c a m p a i g n resul ts in an increase o f vacc ina - t ion o f pat ients at r isk.

Beyond the adverse drug reaction A Multivariate approach for analyzing scientific literature in order to detect Adverse Drug Reactions as starting point for innovative developments in pharmaceutical research

_Floor Rikken. Rein Vos

In this study we use techniques, mathematical and linguistic, which can be used in order to follow changes in a scientific field, observe used standards more closely, and starting points of developments can be located petter in time. This can have relevant applications in drug utilization' studies, or pharmacoepidemiological studies. In this study these techniques are used in order to analyse the role ef the Adverse Drug Reaction in medical research in the field of the ACE-Inhibitors. A D R s are often specifically found in one context, without connection to another context. We use a model of disconnected logic in which new information is generated by linking disconnected databases together. In this model the ADR can be the trigger to make a connective shift resulting in new information. A database on ACE-lnhibitors, containing 6500 records of medical articles, is used for the quantitative textanalysis. We have first focused on the place of ADRs in medical research, and therefore performed an analysis of the structure of the field and where and how ADRs are seen. Results of the first analyses are pictures of the structure of a scientific field, using the 50 most used words in a certain period in this field. The technique, co-word- analysis, reveals all relatkms between words in the database, giving a square, symmeU'ical matrix, with co--occurrences. This was corrected with a Jaccard index and then a Multidimensional scaling and a hierarchical clustering analysis were performed. These structure pictures can be made of different time periods, and changes in time can be observed. There are two important aspects that influence the analysis. The first is the time period used, and whether or not overlapping periods are made. The second is the way in which the list of words is generated that is used to do the analysis. The results show that overlapping periods are more precise. For the lists of words it is shown that events occurring in a short period can best be found with a list of words for that period and looking at events that are important over a longer time a general list of words for the complete database should be made.

Social Pharmacy and Pharmaco-epidemiology, Dept. of Pharmaceutical Pharmacology and Clinical Pharmacy, University Center of Pharmacy, A. Deusinglaan 2, 9713 AW Groningen, The Netherlands.

PRIVACY ASPECTS CONCERNING COMPUTER LINKING FOR RESEARCH

N.E.H.W. Hendrikx. E.M. Haaijer-Ruskamp, G.Th. van der Werf

Privacy is one of the issues of epidemiological studies today. Public authorities therefore provided rules to protect the privacy of the individuals.

The Northern Center for Health Care (NCH) GUIDE are working on a feasability study to a indication related medication database of general practitioners (GP's). For this purpose data from GP's (patient background information, diagnosis and medication) and the health insurance fund (patient background information and medication) in Groningen will be linked and reliability and validity of the linked database will be assessed. In this study we investigated the juridical privacy aspects concerning this linking.

Data from the GP's and the health insurance fund are registrated in databases of respectively the Registration Network Groningen (RNG) and the Drug information Project (GIP). Data can be linked either by using the health insurance number (determinative) or by probability (comparing for example age, sex, zipcode).

The privacy act in the Netherlands is the "Wet Persoonsregistraties" (WPR). This act is only applicable for registrations containing to a person reducible data. For providing reducible data to a third party, informed consent of the person registered is required. However, the main problem of the WPR is the vague distinction between reducible and non-reducible data. In this case, the guideline for interpretati- on of this act is the intention of the legislator: data are considered non-reducible if disproportionate time, money and manpower is neccesary to reduce data to a natural person.' It is not allowed to register and provide data which are not neccesary for the purpose of the registration.

It can be concluded that both databases (RNG and GIP) do not contain direct reducible data (e.g. name, street). The health insurance number in the GIP-database can be considered as an indirectly reducible number. However, within the professional group the reducibility of the health insurance number is very large. Although linking with use of this number is allowed it should not be registered in the linked database. To minimalize the chance to create a reducible linked database, it is not allowed, to provide (and link) indirect identifying data not neccesary for the purpose of the linking. When these conditions are fulfilled, the linked database will not be reducible and int'ormed consent is not required.

1 Explanatory Memorandum, Second Charnbre 1984-1985;19 095, I-3:35.

Northern Center for Health Care (NCH) GUIDE, University of Groningen. Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

A KNOWLEDGE SYSTEM AS A COMPUTER TOOL IN PATIENT COUNSELING AND DRUG INFORMATION

THE CONCEPT OF INTERACTIVE INDIVIDUALIZATION

R. VOS'. J.A.A. Swart" . and Th.F.J. TrQm_~

Informing patients on the use of drugs may contribute to the improvement of health care, e.g. by reducing misuse and avoiding possible side effects. The information provided is directed to different categories of patients: children, adults, pregnant women, and elderly people. Patients may need information tailored to their own situation. In quite a number of Dutch pharmacies a computer assisted form of individualized information, based on the medication records of patients, has been introduced. Providing individualized information to the patient should be considered as an knowledge intensive task because it is based on continuously changing pharmaceutical and medical knowledge, and varying wishes of the patient. Because knowledge systems are computer programs containing consultable knowledge for a particular task in a particular field, they may be used to support the task of providing drug information.

To be acceptable in the case of drug counseling, the underlying model of the computer software program should be in agreement with both the patient's and professional's view and demands on drug information and education. For the realization o7 a knowledge system a more detailed analysis and modeling of pharmaceutical knowledge and the counseling proces is needed. Especially, the construction of declarative knowledge structures on medicines, patients, information items, and texts, and, a further decomposition of the task of providing drug information is required. Several methods to do this are available.

We have recently realized a prototype of a knowledge system using these modeling tools. The prototype contains knowledge on a few medicines and patients; the computer program will be demonstrated. In the near future we want to upscale this prototype to evaluate its effectiveness and value in supporting the important task of drug information by the pharmacist.

"Social Pharmacy and Pharmaco-epidemiology, Dept. of Pharmaceutical Pharmacology and Clinical Pharmacy, University Center of Pharmacy, University of Groningen, A. Deusinglaan 2, 97f13 AW Groningen, The Netherlands.

Volum~ 15 Nr. 6 199~

PHARMACEUTICAL ASPECTS OF ENZYMOSOMES CONTROLLED RELEASE OF PROTEINS FROM DEXTRAN HYDROGELS .

MH Vineerheeds 1. RHP Smit 1 . HJ Haisma 2. DJA Crommelin I and G Storm 1

Enzymosomes are liposomes bearing enzymes on their surface. These enzymes

are capable of converting non-toxic prodrugs to active cytostatic agents. In earlier in

vitro studies it was found that "immuno-enzymosomes" bearing the enzyme 13-

glucuronidase and the anti-ovarian cancer monoclonal antibody OV-TL3 were able to

bind specifically to ovarian cancer cells and to activate the prodrug epirubicin-

glucuronide, which resulted in a significant antitumor effect. However, the antitumor

effect was less than the effect of the parent compound epirubicin.

To increase the antitamor activity, attempts were made to couple more enzyme

molecules to the liposomal surface, However, above a coupling ratio of about 10 ~g

enzyme/p.mol lipid, aggregation of the liposomes was observed. The aim of this

study was to increase the enzyme density on liposome,~ while avoiding aggregation.

An increased electrostatic repulsion of the enzymosomes created by inclusion of

additional negatively charged lipids and/or by decreasing the ionic strength of the

hydration buffer resulted in coupling ratios of at least 20 p.g enzyme/I.tmol lipid

without the occurrence of aggregation. These results clearly point to the requirement

of low ionic strength of the hydration medium.

Before coupling of the enzyme to the liposomes extra thiol groups were

introduced in the protein using iminothiolane. When the thiolating agent SATA (N-

succinimidyl S-acetylthioacetate) was used in stead of iminothiolane, coupling ratios

over 30 l.tg enzyme/p.mol lipid could be achieved without aggregation. This high

coupling efficiency was obtained even when the ionic strength of the buffer was not

lowered.

In conclusion, [3-glucuronidase can be coupled to liposomes at a high

enzyme/lipid ratio without the occurrence of aggregation if SATA is used to introduce

sulfhydryl groups in the protein.

lDepartment of Pharmaceutics, Utrecht University, PO Bax 80.082, 3508 TB Utrecht,

The Netherlands

2Department of Medical Oncology, Free University Hospital, Amsterdam, NL.

I , IPOSOMAL DRUG DELIVERY TO THE LYMPHATIC SYSTEM

C. Oussoren, G. Storm. D.J.A. Crommelin, and J. Zuidema

The lymphatic system is an important pathway for the spread of malignancies. The most effect ive treatment of lymphatic metastases -usttally part of the treatment of the pr imary tumor- invo lves sys t emic adjuvant therapy. Nevertheless. recurrence is frequent. To improve the therapy of lymphatic metastases attempts have been made to deliver antineoplastic agents selectively to the lymphatic system. Since colloidal particles are taken up from the interstitial space more readily by the lymphatics than by blood vessels, an interesting route for targeting to the lymphatic system is local administration of drugs incorporated in particulate carriers, such as liposomes. Recently, we have performed several exper iments to study l iposome related factors iunuenc ing the biodistrlbution le.g. lymphatic uptake and lymph node retention) of fiposomes after s.c. administration to rats.

Liposomes of various sizes, lipid composition and surface characteristics were labelled with [3H I-cholesteryloleoylether and injected s.c. in the right foot of rats. The main factor controlling lymphatic uptake of liposomes after s.c. injection appears to be liposome size. Small l iposomes (mean size up to 100 nm) are taken up from the injection site to a much larger 'extent than larger liposomes Imean size 250 nm). At 96 hours after injection only 20 % of the injected dose of the small l iposomes was recovered from the injection site, whereas in the case of the larger l iposomes about 60 % of the injected dose remained present at the injection site. Another important factor controlling lymphatic uptake of t iposomes after s.c. administration is bilayer rigidity. Liposomes with rigid bilayers showed higher lymph node retention than liposomes with fluid bilayers.

In conclusion, s.c. administration of small t iposomes is a promising approach for achieving selective drug delivery to the lymphatic system. Basic research is presently nnderway at our laboratory to investigate and exploit the potential of this approach for the therapy of lymph node metastases.

l)eparlment of Pharmaceutics. Utrecht University, PO Box 80.082. 3508 TB Utrecht. The Netherlands

JCH Borchert. MW Versantvoort. MJ van Steenber~en and WE Hennink

Most current vaccines need a multiple administration to obtain a sufficient

protective immune response. The development of single-dose delivery systems for

antigens would eliminate this need'for booster immunisatioes. Dextran hydrogels may

possess favourable properties for the controlled release of antigens. In this study the

release of model proteins from dextran hydrogels, which vary in crosslink density and

water content, was investigated.

Dextran hydrogels were synthesised by potymerisation of methacrylated

dextrans, which were obtained by coupling of glycidyimethacrylate to dextran. The

polymerisation was initiated by a system consisting of amonium persulfate (APS) and

N,N,N',N'-tetramethylethylenediamine. By using methacrylated dextrans with

different degrees of derivatisation, the crosslink density of the hydrogels was varied.

Three model proteins (lysozyme (Mw 14.400), bovine serum albumin (Mw 67.000)

and IgG (Mw 150.000)) were incorporated in the hydrogels and their release in an

aqueous buffer was monitored.

It was shown that the release rate of the proteins increased with a decreasing

molecular weight and was highly dependent on the water content of the gels. The

release rate for a given protein from a hydrogel with a high water content (> 85 %) was

hardly affected by the erosslink density of the gels. However, at lower water contents

(70 % and less) the release rate of the proteins was substantially affected by the

cresslink density of the gels. Interestingly, it was found that besides the gel parameters

(crosslink density and water content! the release rate was also affected by the initiator

concentration used to synthesise the gel: higher the APS concentrations resulted in

lower release rates of an incorporated protein.

In conclusion, the release rate of proteins from dextran hydrogels depends on

the molecular weight of the protein and can be tailored by the water content and

crosslink density of the hydrogel and by the polymerisation conditions. The gels are

presendy under investigation as delivery systems for antigens.

Dept. of Pharmaeeutics, Faculty of Pharmacy, Utrecht University, PO Box 80.082,

3508 TB Utrecht, The Netherlands.

THE METHACRYLATION OF DEXTRAN AND NEI'WORK FORMATION AS STUDIED BY FTIR

H Talsma. MJ van Steenbereen and WE Hennink

Within our department microspheres based on methacrylated dextrans are

presently under investigation as protein releasing matrices. In vitro results (see abstract

Borchert et al.) show that the release of proteins is affected by the hydrogel charac-

teristics (crosslink density and equilibrium water content) and the polymerisation con-

ditions applied.

An analytical method to determine the degree of methacrylation of dextrans by

Fourier-Transform-Infrared (FTIR) spectroscopy was developed. This method uses the

absorbance ratio at 813 vs. 764 cm "l to determine the amount of methacrylic double

bonds present in the derivatiscd dextrans. Comparison with NMR data shows a good

correlation between both methods. The effect of polymerisation conditions on network

formation was also investigated with this method. As initiator for the pelymerisation

reaction ammonium persulfate (APS) was used and as catalyst N,N,N',N'-tetra-

methylethylenediamine (TEMED) was added. Using FTIR analysis the amount of

residual methacrylic groups in crosslinked dextrans could be established as a function

of the polymerisation time, the concentration of the initiator and catalyst, and the con-

centration of the methacrylated dextran.

It appeared that in the absence of TEMED the polymerisation rate was low and

dependent on the APS concentration. Using high APS concentrations the ultimate con-

version which was reached after 6 hours amounted 70 %. In.the presence of TEMED

the polymerisafion rate was high and difficult to control. Up to 80% of the methacrylic

groups was potymerised within 60 minutes, independent of the APS concentration.

Further, it was shown that in the polymerisation rate was dependent on the concen-

tration of methacrylated dextran. Higher initial concentrations of methacrylated dextran

resulted in slightly slower polymerisation rates. However, after 1 hour polymcrisation

time the same ultimate conversion (upto 80 %) was reached.

In conclusion, FTIR is a suitable technique to collect information on the

polymcrsiation of methacrylated dextrans ms well as on the kinetics of this process.

Dept. of Pharmaceutics, Faculty of Pharmacy. Utrecht University. PO Box 80.()82,


K'~ ~ Pha..a, ;, [ I b,ld ~ S,h'me

SYNTHESIS AND CHARACTERISATION OF

ETHYLENE GLYCOL-L-LACTIDE COPOLYMERS

W.N.E. Wohhnis. fiLM. van Hooff and W.E. Hennink

Hydrogel materials possess many attractive features for drug delivery purposes,

especially for proteins and pcptides. However. many hydrogels based on synthetic

polymers studied are not biodegradable. Conseqaendy, there is a need for biocompatibte

and biodegradable hydrogels, which combine predictable swelling characteristics with

predictable degradation rates. Such hydrogels can probably be prepared from block

copolymers composed of a degradable and hydrophobic polymer such as polylactide and

a non toxic and hydrophilic polymer such as polyethylene glycol.

Triblock copolymers (ABA) were synthesised by bulk polymerisation starting

from L-lactide (A) and polyethylene glycol (PEG; B) using stannous octoate as catalyst.

The block copolymers were obtained in high yields (> 80%) and were characterised by

NMR, IR, DSC and GPC analysis. It was shown that the molecular weight of the

triblock copolymers, which were synthesised at a fixed ratio of PEG/catalyst, depended

on the ratio of lactide/PEG in the feed: the higher this ratio, the higher the molecular weight. Further, it appeared that at a fixed PEG/lactide/catalyst ratio the molecular weight

was only marginally affected by the polymerisation temperature in the range studied (130-

180oc).

In conclusion, the results show that block copolymers of PEG and polylactide

with different molecular weights and different ratios of PEG/PLA can be obtained.

Presently the effect of catalyst concentration and polymerisation time on yield and

molecular weight of the block copolymers is studied. In addition, the range of block

copolymers is extended starting from polyethylene glycols with different molecular

weights. Next these materials will be evaluated as delivery systems for proteins in

particular.

Dept. of Pharmaceutics, Faculty of Pharmacy, University of Utrecht, P.O. Box 80082.


AMYLODEXTRIN AS COMPLEXING OR DISPERSING AGENT WITH DRUGS BY FREEZE-DRYING AND KNEADING

G,H.P. "re Wierik. A.C. Eissens. C.F. Lerk

Amylodextrin is a linear ollgnsaccharide containing about 35 glucose units per molecule. Blends of amylodextdn with various model compounds were freeze- dried and kneaded at elevated temperature, respectively, in analogy with the preparation of complexes of drugs with cyclodextrins (containing 6, 7 or 8 glucose units per molecule). The products were analyzed by DSC, X-ray diffraction and FTIR spectroscopy. Complex formation of amylodextrln by freeze-drying was found not to occur with diazepam but did with prednisolone at an equimolar ratio. The freeze-dried product of diazepam with amylodextrin proved to be a solid dispersion, Solid dispersions were formed by both wet (with ethanol) and dry kneading at elevated temperature of low melting point drugs such as lidocaine, diazepam and methyl-PABA with amylodextrin. No solid dispersions were obtained for high melting point drugs such as prednisolone and salicylic acid. The results point to the formation of solid dispersions by a melting mechanism during the process of kneading at elevated temperature of low melting point drugs with amylodextrin.

G.H.P. "re Wierik, Preparation, characterization and pharmaceutical application of linear dextrins. Thesis, University of Groningen, NL-Groningen, t993, pp. 49-64.

Dept. of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

DEVELOPMENT OF A MICRODIALYSIS BASED GLUCOSE SENSOR

K./.C. Wienties. F.J. Schmidt. A.J.M. Schoonen

Since the early sixties scientists are trying to develop a glucose sensor for use in diabetic patients. This glucose sensor should measure the glucose concentration on-line, 24 hours a day, seven days a week. Such a glucose sensor would be a great relief for diabetic patients. When coupled to an insulin delivering device, it could keep the blood glucose concentration near normal values. All kinds of side effects of diabetes can in this way be diminished. Despite many efforts a reliable glucose sensor is yet still not available.

We developed a wearable glucose sensor based on mierodialysis. In this closed loop system, a probe made of cellulose fiber, is placed subcutaneous in the abdominal tissue. A saline solution is pumped through the fiber and takes up the glucose. An enzyme, glucose oxidase, is used as selector. This enzyme reacts specifically with glucose, and consuming oxygen to complete the reaction. The concentration of oxygen in the system is measured on-line with a Clark oxygen electrode. A coal filter is used to guarantee that the perfusion fluid is free of enzyme before it's pumped through the 15robe fiber. Before in vivo use, the glucose sensor is calibrated in vitro. All measurements of the glucose sensor are stored in a compouter. With this sensor it's possible to measure continuously for at least six days, which is tested on eight healthy volunteers and two diabetic patients. There is a good correlation between the sensor values and the blood glucose values.

Dept. of Pharmaceutical Technology and Biopharmacy, University of Gronin- gen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Comparable l idocaine metabol ism in s l ices,hepatocytes and microsomes from human l iver Olinga, P.,Merema, MT., Slooff', MHJ., Meijer, DKF and Groothuis, GMM. Dept. Pharmacology and Therapeutics, University Center of Pharmacy and "Dept. Surgery, University of Groningen, The Netherlands (In cooperation with the Human Liver Group Groningen) Due to considerable interspecies differences in metabolic path- ways, extrapolation of data on drug metabolism from animal to man is often inadequate. Therefore, studies on drug metabolism in human liver tissue in vitro could be of great value to predict the in vivo metabolic pattern in man.The experiments described give the onset to a study in which the metabolic capacity of various human in vitro liver preparations are compared to the in vivo situation in man. Metabolism of lidocaine by a cytochrome P450-mediated N-deethylation to monoethyl-glycinexylidide (MEGX) is used to compare the metabolic capacity of hepatocytes, slices and microsomes; each prepared from the same human livers. Liver slices were made with the Krumdieck slicer, which resulted in reproducible liver slices of 200 - 300 ~m thick. Isolated hepatocytes were prepared by standard collagenase perfusion. Microsomes were prepared from homogenated liver tissue. Liver slices were incubated at 37 "C on an iron mesh in stirred medium with 3as supplemented. The 5 human livers showed considerable interindividual differences in MEGX formation rate.However, the rate of lidocaine metabolism was similar in the three liver preparations. The quantitatively similar metabolic activity of slices and cells suggest that all hepatocytes in the liver slice are involved in metabolism of lidocaine. The results also indicate that interindividual differences in lidocaine metabolism are equally reflected in microsomes, isolated hepatocytes and tissue slices. Liver slices and hepatocytes seem equally valuable to study drug metabolism in man.

V o l u ~ ;5 Nr. 6 1993

RENAL TARGETING OF A RUBIDIUM-COMPLEXING AGENT

M Haas W.I. lwema Bakker DN. geinhoudt, D.K.F Mijer, D. de Zeeuw.

The renal blood flow (RBF) is an important parameter in the (patho) physiology of the kidney Compared to conventional RBF measurements, the gb/Kr ratio method has certain advantages. It is non-invasive, has a high time-resolution and measures both kidneys separately. The technique is based on the t~.ct that once the radioactive 81rubidium (81Rb) reaches the kidney after intravenous injection, it starts generating the radioactive 81mkrvpton (81mKr). This inert gaz will be washed out by the bloodflow. Thus, the gl'Rb/81mKr ratio represents the organ bloodflow. A serious drav, back however is the fact that only part of the rubidium reaches the kidney and rather quickly diffuses over the rest of the body pool. Theretbre. we looked tbr a way to increase the accumulation of Rb in the kidney and to limit the diffusion of Rb out of the kidney. We approached this item by coupling the gb via a complexing agent to a protein carrier. Gamma-camera studies in the intact rat showed that 80 % of intravenously injected iodinated low-molecular-weight proteins (LMWP) accumulate in the kidneys. Large differences were tbund in the renal rate of degradation of the three LMWPs studied (halflife eytocbrome-c. 11; lysozyme, 252 and aprotinin, 443 rain). These results indicate that LMWPs, and in particulary slowly degrading LMWPs like aprotinin, are suitable to carry the Rb-ion to the kidney I To couple the Rb-ion to the carrier and to reduce diffusion in the body, a Rb- complexing agent had to be developed The calixspherand (CSP) is a strong cationic complexing agent, due to the present of a cavity in which the cation is enclosed. To obtain a suitable calixspherand tbr our purpose, the cavity was manipulated by introducing different groups surrounding the cavity The stability of 22Na and 86Rb, eomplexed in the three newly synthesized calixspherands (pentamethoxy, monoethoxy and diethoxy-calixspherand) was tested in sodiumpicrate enriched (10 mM) dimethylsulfoxide The results show that the pentamethoxy-CSP favours sodium above rubidium (halflil~ 22Na, 2524; 86Rb, 9 min) while the diethoxy-CSP has the opposite preference (halflife 22Na, 64; 86Rb, 378 rain). Yet, the monoethoxy-CSP appeared to be the most suitable complexing agent tbr our goal. Although it favours sodium above rubidium, compared to the other two compounds it has the best stability for rubidium (halflife 22Na, 9322, 86Rb, 922 min) By introducing a carboxylic group on the calixspherand molecule, a peptide bond between the calixspherand and the LMWP. lyso~'me, could be obtained. This was verified by massa-spectrometry and hydrolysis studies.

t M. Haas et al. Kidney lm 43 (1993) 949-954.

Nephrology, Dept. Int. Medicine, University Hospital Oostersingel 59 NL-9713 EZ Groningen, The Netherlands. Pharmacology, Centre of Pharmacy, University Groningen. The Netherlands. Org Chemistry. University Twente, The Netherlands.

Optimization of the reaction conditions for the synthesis of neo-glycopmtein- aztmp conjugates

M. Kui0ers 1,P.J Swart 1. MM.W.B. Henddks 2, and DK.F. Meijer 1

1 UnitaRy Cenue for Pha~acy, Departme~ of Pha~aCOklnetlcs and Pha~cotherapeu~cs, Gronmgen The Netherlands 2UnlVe~r~ Centre for Pharmacy, Reiearch g r i p of Cherflomehlcs, Gmnlngeft, ~ e Ne~edancls

The coupling of the monophosphate derivative of 3-azido,2,3-dideoxythymidine (AZT) to neo-glycopmteins by watersoluble carbocliimide (ECDI) according to a previously adapted method still resulted in the production of relative high degree of polymerized material, but also in a low degree of AZTMP-coupled conjugates, in proportion to the amount of AZTMP added. This low degree of AZTMP-coupling iS partly due to hydrolysis of the activated intermediates to the native compounds. The hydrolysis can be delayed considerably when the activated phosphate group is converted into an active ester by addition of N- hydroxysulfosucoinimide (NHS). In the present study we showed that the conjugation reaction could be greatly improved by using this second activator. In order to minimize the use of compounds needed for this reaction, the present study was undertaken to find out if the reaction conditions could be optimized towards a degree of loading of one or two AZTMP-molecules per tool neo-glycoprotein. In addition a high proportion of monomeric conjugates was desired. Optimization was achieved studying the shape of the response surface area, in which the degree of AZTMP-coupling and the percentage of monomeric conjugates are regarded as the relevant responses. The variables were reaction time, NHS concentration and AZTMP concentration. Techniques used for the optimization were Response Surface Methodology in combination with a Factorial Design. Statistic polynomial models were used to describe the effects of the variables on the responses within the factor space covered by the design. It appeared that the amount of AZTMP covalently coupled to the neo- glycopretein decreased by increasing the NHS concentration. A longer incubation time always resulted in conjugates with more AZTMP coupled, and a similar effect was seen with increasing AZTMP amounts. This model could not be used for the prediction of the percentage of monomeric conjugates, because of an uncontrolable and unknown variable in the coupling method. However, it appeared that an increase in NHS amounts resulted in a higher percentage of monomeric conjugates. In conclusion: the optimal conditions for coupling I to 2 moles of AZTMP to one mole of neo-.glycopretein, taking into account the influence of NHS on the relative proportion of monomers, were an incubation time of 30 hrs, an AZTMP amount of 4 rag, a NHS amount between 8 and 15 mg and a neo-glycoprotein amount of 50 rag.

Correlat ion between physlco-chcmical properties and pharmaeokinetic and dynamic parameters of muscle relaxants

J.H. Proost. J.M.K.H. Wicrda. D.K.F. Meijcr

Department t)f Pharmacology and Therapeutics, University Centre for Pharmacy, and Research Group for Exlx:rimentul Anesthesiology and Clinical Pharmacology. University Hospital, Groningen. The Netherlands

In ordcr to obtain more insight in the relationship between physlco-chemical properties of muscle rcbtxants and their pharmacoklnctie and pharmacodynamic characteristics, a series of lS steroidal neuromuscular blocking agents (NMB) was investigated in a screening program. METHODS: Lipophilicity was determined as the partition c(xffficient (P) between octanol and Krebs solution (pH 7.4). Plasma concentrations and dynamics were measured in anesthetized cats after a dose of 2 x EDg0 of the NMB. Twitch height response of the left dblalls muscle was measured after supramaximal stimulation at 0.1 Hz. The data were used for pharmacoklnedc/ pharmacodynamic (PK/PD) modelling according to the method of Sheiner [Shciner ct al 1979]. The model is characterized by th~re.~ parameters: the transfer rate constant between plasma and the site of action (k,0), the concentration at 50% effect (ECs0) and the steepness of the concentration - response curve (gamma). After fitting of an appropriate pharmacokinetic model to the plasma concentration data, the dynamic mode[ was fitted to the dynamic data using the program PkPdFit (developed by J.H Proost). RESULTS AND DISCUSSION: We found significant correlations between the lipophilicity (P) and, a.o., protein binding, unbound clearance, k~, onset and duration of action, and recovery index. The strong correlation between k,o and litx)philiclty suggests membrane passage between plasma and biophase. The onset time was found be llneady related to the reciprocal of the k ~ with a minimum value of about one minute (circulation dine?). A similar pattern was found for the correlation between the initial unbound clearanc~ (total of dlstribudon and elimination clearance) and the dme to maximum effect. CONCLUSION: Studies of physlco-chemical properties, pharmacokinetics and dynamics, and PK/PD modelling are useful tools in understanding the factors which govern the time course of action and potency of NMB's. REFERENCES: Sheiner et ul. Clin.PharmacoLThur. 25:358-371.1979.

C o n j u g a t e s o f i i p o s o m e s a n d c o v a l e n t l y a t t a c h e d p r o t e i n s as c a r r i e r s f o r a n t i v i r a l a n d a n t i t u m o r d r u g s . J . A . A . M . Kamps , P . J . Swart , B. S t ruska , C. Thomas , A . M . Nijenhuis, D . K . F . Mei jer and G . L . Scherphof . Depar tment o f Phys io logica l Chemis t ry and Depar tment of Pha rma- cokinet ics and Pharmaco the rapeu t i c s .

In o rder to c o m b i n e the ca r r i e r qual i ty o f l iposomes wi th the target ing po tency o f homing devices such as monoc lona l ant ibodies (moab) and (modif ied) h u m a n se rum a lbumins (HSA) , the cova len t coupl ing o f these prote ins to small type l iposomes, using the

heterobifunct ional r eagen t N-succin imidyl -S-ace ty l th ioaceta te (SA- TA), was charac te r ized . Coupl ing o f H S A to l iposomes s igni f icant ly increases the l iposome diameter . Depend ing on the degree o f der ivat izat ion with aconi t ic anhydr ide (ACO) o f the H S A eNH2 g roups , which are also used for coupl ing o f the pro te in to the l iposomes, 17 to 75 ~g o f (ACO) H S A / # m o l total l ipid (TL) could be coupled . The in vivo disposi- t ion o f l iposome-(modif ied) H S A conjuga tes can be modula ted by modif ica t ion o f the H S A coup led to the l iposomes. Cur ren t ly antiviral effects o f l i p o s o m e - A C O - H S A conjugates are investigated. Cova len t coup l ing to l iposomes o f C C 5 2 moab , d i rected agains t a surface ant igen o f C C 5 3 1 tumor cells, a lso increases l iposome diameter . Besides convent ional immuno l iposomes , a poly ethylene glycol coated l i posome-CC52 conjuga te was synthesized to avoid uptake by the m o n o n u c l e a r phagocy te sys tem. In vi t ro studies wi th f luorescent ly label led immunol iposomes have indicated that both

l iposome-moab con juga tes specif ical ly bind to CC531 tumor cells and to t umor foci in l iver c ryos ta t sect ions o f t umor bear ing rats. In conclus ion the coup l ing procedure , us ing the reagent S A T A , is reproducib le and con juga tes are stable in vi t ro as well as in vivo. Therefore this p rocedure provides the possibil i ty to design and cons t ruc t a potent d r u g carr ier sys tem.

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PROPERTIES AND APPLICATION OF AMYLODEXTRIN IN FATTY SUPPOSITORIES

O,H.P. "re Wierik. A.C. Eissens. C.F. Lerk

Amylodextrin is a linear dextrin and can be prepared by enzymatic hydrolysis of the it-l,6 glycosidic bonds of amylopectin. It shows partial dissolution of 18% in water at room temperature, the soluble fraction containing molecules witb a lower DP (degree of polymerization). Amylodextrin exhibits eomplexing or dispersing properties with drugs. Drug release from suppositories containing a solid dispersion of amylodextrin with diazepam or a complex with prednisolone can be described by a sedimentation and dissolution mechanism. Being present in sdppositories as a suspension in the fatty base, particles of complex or solid dispersion are transported to the lipid-water interface by sedimentation. After entering the aqueous phase they partially dissolve. The suppositories show increased drug release as compared to the corresponding suppositories containing drug only. Application o[ the water-soluble fraction of amylodextrin for both the solid dispersion and the complex demonstrates further improved release profiles.

G.H.P. Te Wierik, Preparation, characterization and pharmaceutical application of linear dextrins. Thesis, University of Groningen, NL-Groningen, 1993.

Dept. of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

OPTIMIZATION OF A GRANULATION -DRYING PROCESS WITH A VACTRON ~

MICROWAVE VACUUM MIXING/DRYING EQUIPMENT.

J. van Dij~H.RM. Gorissen, Y.M. Groot-Padberd.

Convectional drying processes for granular material, like fluidized bed drying or drying in

an oven, have several disadvantages. The material has to be transported from the mixing

equipment to the dryer, creating a potential dust problem, there is a risk of dust explosion

(flu~iaed bed drying) and drying times may be very long.

A new technique is the use of a vacuum dryer in combination with a microwave generator

in a mixing bowl. [n this case, the material can be handled in a completely closed system.

In this investigation, a Vactrorf ~ machine (Collette Gral 75) was tested in a

granulation/drying process. Critical parameters were investigated by the use of an

experimental design.

Variables studied for the granulation process were mixing time, mixing speed and the

amount of granulation fluid used. For the drying pat1, the following parameters were varied:

microwave power, vacuum, temperature of the bowl and mixing rate.

The granulates were compressed on a Courtoy RO e rotary press.

Responses were: total drying time, produCt temperature after drying, water content, particle

size distribution, bulk and tapped density, hardness and friability of the tablets,

disintegration time, dissolution profile, and content uniformity.

Results of the granulation process show comparable responses as found in a conventional

mixing/granulation process. The Vactroff ~ drying process proved to be more efficient

compared to a fluidized bed drying process. Tablet properties were within the speeilicetions

set. The outcome of the experimental design was used to define optimal process

conditions.

In conclusion, the microwave vacuum mixing/drying equipment is a safe and valuable

extension of tile currently available pharmaceutical techniques.

Pharmaceutical Development Dept., Solvay Duphar BV, P.O. Box 900. 1380 DA Weesp.

RATIONAL DRUG DESIGN: PRODRUG TARGETING TO THE INTESTINAL

PEPTIDE CARRIER

Peter W gwaan, ,Marco C Stehouwer, Eric IC BInk :lnd [~set ] "l'~,Jkkr

The dipeplide carrier in tile gastrointestinal-tract is the most flexible carrier known. It is used widely by di-and tripeptidc(like) drugs like cephalosporins, pcnicillins, and ACl~-inhibitors. The minimal requirements for transport of a small pcptide is a free earboxyHc acid moiety and an amide bond. Lntil now the peptidc carrier has only becn used for transport of peptide-like drugs, or produgs of those drugs, and for transport of non-peptide drugs. We used a model compound (phosphonoformic acid, PFA) that has a good sc&d.~ility in water (= 80 .g/l) but is fully charged (=-3) at physiological pl I. As a result, PFA shows poor membrane transport -pardy through the phosphate cartier- and h)w oral I)ioavailabili W (=17%). We coupled PFA to an amino acid (glycine), resulting in a pcptidc mimicking prodrug (DEPF-Gly). Bioconversion of PFA-Gly was tested in intestinal juices, and small intestinal and liver homogenate. Conversion into free PFA occurred in liver homogenate. Transport ir~ vilro of the prodrug was tested in rat intestine, using Ussing chambers (~ 1.0 cm 2). Since cephalexin and GlyPro both inhibited the transport of DEPF-GIy, whereas amino acids and phosphate did nor. it was con(h)ded that the pro(lrug is -at least partly- transported by the peptide carrier. Oral admJnistration of PFA and DEPF-GIy to 4 male Wistar rats showed a bioavailability of 12-25% and 68-75% for PFA and DI..'PF-G{y, respectively. "rhese results show that, under certain conditions, a non-peptide compound can be transported by the peptide carrier, and thus l)e transported to a much higher extent.

l)cpartnlcnt of ]qlarmaceutics, Utrecht Institute of Pharmaceutical Sciences, t.;niversity of t'trecht, PO Box 80082, 3508 TF,, The Netherlands.

BIOAVAILABIUTY OF MONOLITHIC ENTERIC-COATED (EC)

DICLOFENAC PRODUCTS IN HEALTHY VOLUNTEERS.

INFLUENCE OF GASTRIC pH.

Oltinq M, van Gelderen CEM, Satemons P, 8arends DM,

Meulenbelt J, Rauws AG

Three generic EC diclofenac products have been compared with Voltaren a in

16 healthy volunteers in a 4x4 Latins square design as regards AUC, Cma x,

tlag and dissolution in vitro under different pH-values with, and without

mechanical stress.

Only one generic product was fully bioequivalent with Voltaren a. The others

showed significantly different flag values, although equivalent as regards AUC

and Cma x. The in vitro test of enteric coating according to Pharm. Eur. did not detect

differences between the products. In vivo data were best predicted by testing

the products on dissolution at different pH-values applying mechanical stress.

in a second experiment the two products differing most were compared in

healthy volunteers under conditions of normal and increased gastric pH,

obtained by administration of ranitidine. In this experiment Cma x values were

not equivalent, The t~a e vafues were not significantly shortened alter ranitidine

treatment. The large variabilities of ttag at normal pH and the small variabilities at

increased gastric pH suggest that at normal gastric pH the flag is determined

by the very variaNe gastdc passage time, whereas at high gastric pH it is

determined-by the rather reproducible dissolution rate of the enteric coating.

So the use of H2-inhibitors with enteric coated NSA(D's may expose the

gastric mucosa directly to these substances.

National Institute of Public Health and Environmental Protection, PO Box 1,

3720 BA Bilthoven and National Institute Ior Quality Controt of Medicinal Pro-

ducts, W,Barentzstraat 7, 2315 TZ Leiden, The Netherlands.

p/ .......... r n'o~/a ~ x,~,.,,,,, K21 Volume 15 Nr 6 1993

THERMO-ELECTRICAL ANALYSIS OF THE SKIN BARRIER

W. H. M. Craane-van Hinsberg, J. C. Verhoef, H..funginger and H. E. Boddt,

LACDR Centre for Drug Research. Division of pharmaceutical Technology. University of Leiden, p.o. Box 9502, 2300 RA Leiden, The Netherlandz.

ABSTRACT

In the present study the influence of temperature on the resistance and capacitance components of hurram stratum corneutu in ~frro was studied to determine where within substructures of s~a'atum corneum, the electrical resistance and capacitance componenLs reside.

The heating-cooling cycles were based on thermal analysis and X-ra~ diffraction of stratum comeum, which have shown two lipid phase transitions at 45 and 70 "C, a lipid-protein phase transition at 80 "C and a protein denaturation temperature at 120 *C ~.

Two dift'erent protocols were used: (A) Heat treatment and electrical analysis took place at the same time in phosphate buffered saline of pH 7.4-, starong off with prehydrased stratum corneum (70 % w/w) of pH 7.4. (B) Heat ~eatment was performed belbre electrical analysis, using dried stratum coraeutu ( < I0 % w/w). followed by prehydration and measurement t~f the electrical properties in phosphate buffered saline at 20 C.

The conductances and capacitances were measured using altnrae.ting square-wave current pulses, which were applied for I second every 60 seconds. The pulse duration was 5 ms. I~ amplitude was successively l0 ~tA pesidve, zero, 10 tLA negative, zero, id. Analysis of the resulting voltage wavetorm across su-atum eorneurn yielded an eqinvalem electyical model of stratum coraeum composed of a series connection of two RC-circuits (R, II C~ and R= II C,).

When temperatures rose from 20 ~ to 60 "C, a gradua[ increase of the conductances was measured, while the capacitances remained constant. The activation ettergy of inn transfx)rt was 5.9 +_ 0.7 kCal.moP. Between 60 and 75 ~ the conductance and capacitances started to increase rapidly. Beyond 75 ~ no further thcrea.se of the conductances was observed, allthough the capacitances continued to increase, The temperature range of the transition in the electrical properties corresponded with the gel- liquid phase transition of the intercellular lipids. The conductance and capacitance change was irreversible after cooling down fi'nm 75 ~ C. Heating desiccated s~aturn corneum to 120 ~ resulted in an irreversible decrease of C~ and an increase of C~.

The major conclusions from this study are that the abrupt and ([) irreversible increase of stratum cornearrt canductances and capacitances between 60 " and 75 *C is caused by a gel-liquid phase transition of the intercellular lipids, which indicates that the conductance and capacitance compenents reside within the intercellular lipid bilayers. The canductances are determined by the free intercellular lipids, while the cal~acitances are determined by the flee as well as the protein-bound lipids.

Bouwst~a. J.A., Goods, G.S., SaJomons-dc Vries, M.A., van der Spek, J.A. and Bras. W. SmJcmre of human stratum comcum as a function of tamperamre and hydrathm: A wide-angle X-ray diffi'action s~udy. Int. L Pharm., 84 (1992) 205- 215,

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Abstracts of papers and posters Meeting on Pharmaceutical Sciences

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