ΧΑΡΑΛΑΜΠΟΥΣ Ι. ΔΕΜΕΡΤΖΙΔΗ - IKEE

’

: . .

. 2006 - 07 . 2185

( )

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2006

1

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: . .

. 2006 - 07 . 2185

( )

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2006

3

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6

………………………………………………………………………. 8

1. …………………………………………………………………...... 111.1 ………………………………………………………………... 111.2 ……………………………………………………………………. 11

1.2.1 ………………………………………………………….. 111.2.2 ………………………………………...…………. 121.2.3 ………………………………………………... 12

1.3 ……………………………………………………... 151.4 …………………………………………………………………..... 17

1.4.1 …………………………... 171.4.2 ………….…………… 171.4.3 T ……………………………… 18

1.5 …………………….. 19

2. ……………………………………………………………. 212.1 …………………………………... 212.2 ……………………………………………….. 222.3 …………………………………….. 232.4 ………………………………………………….. 262.5 ……………………………………………….. 27

3. ………………………………………………………….. 273.1 …………………………………………………… 273.2 ………………………………………... 293.3 ……………………………………... 313.4 …………………………………... 313.5 ……………………………………………………... .. 33

4. …………………………………………………… 344.1 ……………………………………………………………………. 344.2 ……………………… 364.3 ……………………... 384.4 ……………………………………………………………… 464.5 ……………………………………………………………………. 484.6 Gave …… 514.7 ………………. 524.8 ………………………... 53

7

– …………………………………………………………... 59

1. …………………………………………... 60

2. ……………………………………………………….. 612.1 ……………………………………………………….. 612.2 …………………………………………… 622.3 - ………………………... 632.4 ………………………………………………… 632.5 …………………………………………… 672.6 ………………………………………………... 682.7 - …………………………….. 692.8 ( ) …………………………. 692.9 (image analysis) …………………………. 692.10 …………………………………………….. 70

3. ……………………………………………………………... 714.1 …………………………………………………………………. 714.2 …………………………………………………………………. 714.3 ……………………………………………………………. 734.4 …………………. 754.5 …………………………………….. 764.6 ……………………………………………….. 784.7 ……………………………………………... 93

4. ……………………………………………………………………. 100

5. ……………………………………………………………………. 105

6. SUMMARY …………………………………………………………………….. 107

7. ……………………………………………………………….. 108

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41

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52

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61

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5 D3 5000 IU 7 mg 6 E 100 mg 50 mg

9 K 25 mg 50 mg 1,2 B1 2 mg 40 mg 0,8 B2 4 mg 4 mg

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1,1 B12 20 mg 0,35 . . 16 mg + 0,65 30 mg

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70

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2.10

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± (standard deviation). ,, 25

75 .«Box - Whisker».

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25 75,

.

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71

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72

9: H (ml)

( ) ( )1 18 17 2 29 25 3 28 36 4 30 11 5 46 42 6 27 29 7 16 25 8 42 33 9 29 19 10 18 22 11 36 47 12 11 54 13 9 24 14 21 35 15 17 16 16 35 13 17 22 20 18 13 10 19 11 27 20 19 19 21 25 31 22 43 35 23 14 16 24 - 44 25 - 8

10:

n ml ml ml (23) 24,3 9 46 10,77 (25) 26,3 8 54 12,18

73

3.3

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11:

( ) (Placebo)1 13,4 17,2 2 12,5 16,3 3 11,1 12,9 4 11,5 14,5 5 12,7 16,3 6 10,6 13,0 7 12 15,2 8 9,2 11,6 9 12,5 16,0 10 12,4 15,4 11 11,5 14,7 12 9,9 11,3 13 14,3 18,2 14 13,6 17,0 15 11 14,0 16 12,5 16,2 17 9,5 12,0 18 11,3 15,0 19 10,4 13,5 20 10 13,7 21 12,4 16,0 22 12,6 15,5 23 10,3 13,0 24 14,525 12,4

74

1 2 :

1. ( – ) 2. ( - placebo)

- Shapiro-Wilk W=.97127, p=.71946

Expected Normal

8 9 10 11 12 13 14 15

mmHg

0

1

2

3

4

5

6

7

8

.

- Shapiro-Wilk W=.97805, p=.84384

Expected Normal

13 14 15 16 17 mmHg

4,0

4,5

5,0

5,5

6,0

1. ( ) 2. ( )

-

8 9 10 11 12 13 14 15

Value

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0,5

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1,5

2,0

2,5

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11 12 13 14 15 16 17 18 19

Value

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2,5

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.

75

12: .

(mmHg)

11,6 9,2 14,3 1,36 14,61 11,3 18,2 1,84

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(p<0,001). 21,5% ( 1).

Mean ±SE ±1,96*SE 10,5

11,0

11,5

12,0

12,5

13,0

13,5

14,0

14,5

15,0

15,5

16,0

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77

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78

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,.

13, 14 15 :

1 5 20538.54 4107.708 5 14396.58 2879.316 2 14 4719.26 337.09 9 61572 6841.333 3 6 22945.23 3824.205 8 29653.47 3706.684 4 6 38104.08 6350.68 6 48024.88 8004.147 5 9 70305.88 7811.764 7 55931.07 7990.153 6 3 14559.93 4853.31 4 23054.13 5763.533 7 3 12273.03 4091.01 6 38986.2 6497.7 8 4 23282.83 5820.708 7 10225.71 1460.816 9 6 70534.49 11755.75 8 57836.8 7229.6

10 4 8439.75 2109.938 12 110315.6 9192.967 11 3 14048.1 4682.7 7 46620.09 6660.013 12 4 54776.69 13694.17 16 116849.7 7303.108 13 5 20473.2 4094.64 8 49201.07 6150.134 14 5 38180.29 7636.058 7 54671.34 7810.191 15 7 19275.3 2753.614 11 43759.22 3978.111 16 3 6838.92 2279.64 6 37592.45 6265.408 17 5 53077.85 10615.57 8 41739.33 5217.416 18 4 14287.68 3571.92 9 56194.26 6243.807 19 7 33595.64 4799.377 7 29835.18 4262.169 20 6 28654.98 4775.83 7 49730.14 7104.306 21 8 31745.12 3968.14 9 21649.52 2405.502 22 7 39734.11 5676.301 6 50034.18 8339.03 23 9 32125.05 3569.45 8 33295.84 4161.98 24 8 47539.12 5942.39 25 9 57326.32 6369.591

13: ,

79

1 7 1688,12 241,16 28 4471.51 159.6968 2 16 10003,82 625,2389 17 10907.93 641.6432 3 7 6313,23 901,89 18 22043.78 1224.654 4 10 9432,92 943,292 13 10668.85 820.6808 5 12 7713,36 642,78 20 9501.53 475.0763 6 13 4934,005 379,5389 23 12291.50 534.4129 7 14 1978,48 141,32 43 5782.34 134.473 8 25 7325,917 293,0367 20 12467.83 623.3915 9 14 6056,393 432,5995 22 13492.13 613.2786

10 11 6556,22 596,02 17 9764.34 574.3729 11 13 7145,45 549,65 24 10726.29 446.9288 12 14 10828,3 773,45 19 9816.34 516.6495 13 16 6676,64 417,29 25 6387.72 255.5088 14 10 6541,7 654,17 16 18275.63 1142.227 15 8 3863,52 482,94 17 10893.44 640.7906 16 9 5925,06 658,34 21 11298.34 538.0162 17 11 5834,62 530,42 24 8462.02 352.5842 18 9 6922,17 769,13 15 13629.33 908.622 19 12 10142,04 845,17 19 8173.2 430.1684 20 13 8612,28 662,4831 27 15237.12 564.3378 21 15 10558,81 703,9207 14 8293.06 592.3614 22 9 8863,38 984,82 17 9127.39 536.9053 23 11 7176,18 652,38 20 10382.28 519.114 24 25 12893.18 515.7272 25 17 9875.24 580.8965

14: ,

80

1 11 2326,84 465,368 21 13831.4 658.6379 2 9 10326,72 737,623 16 38628.98 2414.312 3 9 3324,03 554,005 13 6311.845 485.5265 4 4 2760,072 460,012 10 13797.64 1379.764 5 7 3467,628 385,292 22 11112.16 505.098 6 18 1572,698 524,2325 25 14786.44 591.4578 7 12 2676,217 892,0723 27 28219.27 1045.158 8 3 7172,748 1793,187 20 17653.34 882.667 9 8 5924,07 987,345 19 19876.53 1046.133

10 8 3812,16 953,04 21 16987.76 808.941 11 10 1447,77 482,59 13 20638.43 1587.572 12 6 5572,647 1393,162 22 17654.87 802.4941 13 12 3196,95 639,39 28 18723.11 668.6825 14 7 4641,514 928,3029 27 25876.45 958.387 15 11 6120,002 874,286 19 13245.09 697.11 16 9 2687,73 895,91 17 27285.44 1605.026 17 7 6467,45 1293,49 15 25789.11 1719.274 18 7 3562,846 890,7114 14 16492.33 1178.024 19 11 7174,93 1024,99 21 14882.93 708.711 20 12 4336,615 722,7692 22 21678.23 985.3741 21 12 6531,92 816,49 17 28621.08 1683.593 22 9 4310,81 615,83 28 12883.93 460.1404 23 11 7849,62 872,18 12 14992.2 1249.35 24 21 25552.33 1216.778 25 19 18675.22 982.9063

15: ,

81

,Shapiro-Wilk.

.

1. 2.

Shapiro-Wilk W=.91485, p=.05172 Expected Normal

-10000 0 10000 20000 30000 40000 50000 60000 70000 80000

m2

0

1

2

3

4

5

6

7

0 10000 20000 30000 40000 50000 60000 70000 80000

Value

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

2,0

2,5

Exp

ecte

d N

orm

al V

alue

. Shapiro Wilk (p<0,05172).

..

:

(n)23 47441.37 10225.71 116849.7 24299.48

82

.

1. 2.


-2000 0 2000 4000 6000 8000 10000 12000 14000

m2

0

1

2

3

4

5

6

7

8

9

10

-2000 0 2000 4000 6000 8000 10000 12000 14000 16000

Value

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Exp

ecte

d N

orm

al V

alue

, Shapiro Wilk (p=0,013). :

:

(n) 25 75

23 4682.7 337.1 13694.17 3571.92 6350.68

.

,,

..

Shapiro-Wilk W=.86269, p=.00466Expected Normal

0 2 4 6 8 10 12 140

1

2

3

4

5

6

7

8

9

83

:

:

(n) 25 75

23 5 3 14 4 7

.

1. 2.


-20000 0 20000 40000 60000 80000 1E5 1,2E5

m2

0

2

4

6

8

10

12

14

16

0 20000 40000 60000 80000 1E5 1,2E5 1,4E5

Value

-3

-2

-1

0

1

2

3E

xpec

ted

Nor

mal

Val

ue

, Shapiro Wilk (p<0,00212)

..

:

(n) 25 75

25 47539.12 10225.71 116849.7 33295.84 55931.07

84

.

1. 2.


0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000

m2

0

1

2

3

4

5

6

7

8

No.

of o

bs.

1000 2000 3000 4000 5000 6000 7000 8000 9000 10000

Value

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

2,0

2,5

Exp

ecte

d N

orm

al V

alue

«»

Shapiro Wilk (p=0,319). :

:

(n)25 5911.176 1460.816 9192.967 1963.344

.

.

Shapiro-Wilk W=.86075, p=.00284Expected Normal

2 4 6 8 10 12 14 160

2

4

6

8

10

12

14

85

:

:

(n) 25 75

25 8 4 16 7 9

.

1. 2.

Shapiro-Wilk W=,94905, p=,27955 Expected Normal

0 2000 4000 6000 8000 10000 12000

m2

0

1

2

3

4

5

6

7

8

9

10

11

0 2000 4000 6000 8000 10000 12000

Value

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

2,0

2,5

Exp

ecte

d N

orm

al V

alue

Shapiro Wilk (p=0,273). .

:

(n)23 7004,027 1688,120 10828,30 2438,376

86

.

1. 2.


0 200 400 600 800 1000

m2

0

1

2

3

4

5

6

7

8

9

10

100 200 300 400 500 600 700 800 900 1000 1100

Value

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

2,0

2,5

Exp

ecte

d N

orm

al V

alue

« » , Shapiro Wilk (p=0,88).

:

:

(n)23 642,7800 141,3200 984,8200 432,5995

.

,,

..

Shapiro-Wilk W=,87613, p=,00841Expected Normal

5 10 15 20 25

X <= Category Boundary

0

2

4

6

8

10

12

14

No.

of o

bs.

87

:

:

(n) 25 75

23 12 7 25 9 14

.

1. 2.


0 5000 10000 15000 20000 25000

m2

0

2

4

6

8

10

12

14

16

20004000

60008000

1000012000

1400016000

1800020000

2200024000

Value

-3

-2

-1

0

1

2

3

Exp

ecte

d N

orm

al V

alue

«» (p=0,0725).

.

:

(n)25 10994,49 4471,511 22043,78 3746,560

88

.

1. 2.


0 200 400 600 800 1000 1200 1400

m2

0

2

4

6

8

10

12

14

16

Var9: =v1/v2

0 200 400 600 800 1000 1200 1400

Value

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Exp

ecte

d N

orm

al V

alue

« » Shapiro Wilk (p=0,0167) .

:

:

(n) 25 75

25 573,7007 134,4730 1224,654 475,0763 623,3915

.

.


5 10 15 20 25 30 35 40 450

2

4

6

8

10

12

14

89

:

:

(n) 25 75

25 20 13 43 17 24

EN

.

1. 2.


0 5000 10000 15000 20000 25000

m2

0

2

4

6

8

10

12

14

NewVar: =v13*v10

02000

40006000

800010000

1200014000

1600018000

2000022000

24000

Value

-3

-2

-1

0

1

2

3

4

Exp

ecte

d N

orm

al V

alue

Shapiro Wilk (p=0,00106). .

:

(n) 25 75

23 6916,763 2096,930 22290,59 3694,980 8016,403

90

.

1. 2.


200 400 600 800 1000 1200 1400 1600 1800

m2

0

1

2

3

4

5

6

7

8

9

10

200 400 600 800 1000 1200 1400 1600 1800 2000

Value

-3

-2

-1

0

1

2

3

Exp

ecte

d N

orm

al V

alue

« ) , Shapiro Wilk (p=0,0365).

:

:

(n) 25 75

23 834,8816 385,2920 1793,187 554,0050 953,0400

.

,,

..


0 2 4 6 8 10 12 14 16 180

1

2

3

4

5

6

7

8

9

91

:

:

(n) 25 75

23 9 3 18 7 11

.

1. 2.


0 5000 10000 15000 20000 25000 30000 35000 40000

m2

0

1

2

3

4

5

6

7

8

9

Normal P-Plot: Var1

5000 10000 15000 20000 25000 30000 35000 40000

Value

-3

-2

-1

0

1

2

3

Exp

ecte

d N

orm

al V

alue

« »(p=0,225). .

:

(n)25 19367,84 6311,845 38628,98 7034,084

92

.

1. 2.


0 500 1000 1500 2000 2500

m2

0

2

4

6

8

10

12

14

Normal P-Plot: Var5

Var5: =v1/v3

200400

600800

10001200

14001600

18002000

22002400

2600

Value

-3

-2

-1

0

1

2

3

Exp

ecte

d N

orm

al V

alue

« » Shapiro Wilk (p=0,04385) .

:

:

(n) 25 75

25 982,9063 460,1404 2414,312 697,1100 1249,350

.

.


5 10 15 20 25 300

1

2

3

4

5

6

7

8

9

10

11

93

:

:

(n) 25 75

25 20 10 28 16 22

3.7

«», « » « »

,Box Whisker.

Mann Whitney U test.

p 47441.37±24299.48 47539.12(33295.84,55931.07) 0,0037

4682.7(3571.92,6350.68)

5911.176±1.963.344 0,09

5(4, 7) 8(7, 9) 0,01

94

Median 25%-75% Min-Max

no propranolol0

20000

40000

60000

80000

1E5

1,2E5

1,4E5

m2


no propranolol-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

m2


no propranolol2

4

6

8

10

12

14

16

18

95

( ) ..

.

. « » student’s t test

. « » « »


p 7004,027±2438,37 10994,49±3746,56 0,0001

642,7800±432,59 573,7007(475,0763, 623,39)

0,25

12(9, 14) 20(17, 24) 0,00001

96

-


no propranolol0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

m2


no propranolol0

200

400

600

800

1000

1200

1400

m2


no propranolol5

10

15

20

25

30

35

40

45

97

(p=0,0001 p=0,00001 ). ’

(p=0.25).


p 6916.76(3694.980,

8016.4)19367,84±7034,084 0,0008

834.88 (554.05, 953.04)

982.9(697.11, 1249.35) 0,1

9(7, 11) 20(16, 22) 0,00001

98


propranolol placebo0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

m2


propranolol placebo200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

m2


no propranolol5

10

15

20

25

30

35

40

45

99

.

(p=0,0008 p=0,00001 ).

(p=0,1).

100

4.

, « », « »,

« », « ».

.

263.,

. 50% 264, Primignani

80% 265.

’

.

., ,

73,74.

(TIPS).

.

12mmHg266.,

,.

, 12mmHg.

267,,

.

-, ,

101

Isosorbine-5 – mononitrate. ,

( ) .

.

.’

,- 268.

.-

.

268.’

12 mmHg ’ 20% .

269. Angelo Luca .

(HVPG) .

. (p<0001) HVPG 19,2 ± 4,1 16,2 ± 4,3 mmHg,

563 ±204 387±136 ml/min (FBF) 237±79 176 ±58 ml/m2/min.

. - 24

25% 15%.

,, .

..

102

,

.

.

Tarnawski Sarfeh270,271

, – .

90% 272

. , CCl4 .

,

272,273,274.

, .

273. Proctor

Chatamra259,274 CCl4

CCl4.

254,257..

. CCl4

.

.258.

.

,, ,

, .

,

103

.

. ,

(p<0,001) placebo.

11,6±1,36mmHg, 14,61±1,84 mmHg. -

21,5%, .

20%

., (11,6±1,36mmHg), 12mmHg

« » .,

,

.

257., .

., ,

.,

..

,

. Duir 275

Helicobacter Pylori.

,

.

.

104

(placebo) ..

. (p<0,05)

. ,,

..

(p<0,05) placebo .

. (p=0,09).

.

. ’

. ’.

.

..

.

105

5.

.,

,.

12mmHg.

.

.,

.

. , ,

o. ,

. 12

.

21,5% .

..

.

,

. ,

106

,.

,

.

107

6. SUMMARY

Gastric mucosa alterations resulting from the effect of portal hypertension are widely known as portal hypertensive gastropathy. The distinct endoscopic, histopathologic and hemodynamic features of the affected gastric mucosa led to a new nosological entity which has been the focus of numerous clinical and experimental studies over the past two decades. Lesions in portal hypertensive gastropathy correspond to dilated vessels in the gastric mucosa and submucosa and absence of signs of inflammation while portal pressure level is over 20mmHg. Given the fact that until recently the therapeutic approach in portal gastropathy included only the treatment of its complications - mainly hemorrhage - besides treating hemorrhage we focus on prevention from a new bleeding episode.The purpose of this experimental study was to investigate whether the early administration of propranolol prior to the appearance of signs of portal hypertension prevents from the formation of gastric mucosal lesions. Study design was based on current data which support the fact that the early and continuous administration of drugs that decrease portal pressure inhibit the formation of widespread portosystemic collaterals and consequently portal gastropathy. The chosen experimental model in rats simulates the development of portal hypertension in humans. Liver cirrhosis was induced by long term administration of carbon tetrachloride in rats that had previously undergone ligation of the left adrenal vein and deskeletonization of the left renal vein. The hemodynamic characteristics of the gastric mucosa in these rats simulate the hemodynamic characteristics in a cirrhotic patient. Propranolol was administered twice daily via orogastric catheter and resulted in significant reduction of both the portal flow and the pressure of gastroesopageal varices. Portal pressure measurements showed that the continuous administration of propranolol in the study group resulted in 21.5% lower portal pressure in comparison to the control group, a difference which is statistically significant.Histologic results revealed significantly higher vascularity in both the superficial and deep layers of the mucosa in the control group in comparison to the propranolol group.Vascular morphometric study showed higher number of vessels in all mucosal layers. The total vascular surface was significantly higher in the control group as opposed to the propranolol group, but there was no statistically significant difference between the mean vascular surface of the vessels of the submucosa of the control and study groups. Our study clearly shows that the increased mucosal blood flow is manifested by a marked increase of vessel count. In conclusion, the early administration of propranolol prior to the development of portal hypertension in rats prevented from intense vascular congestion which characterizes portal gastropathy.

108

7.

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