DE3120929A1 - Somatostatin-containing pharmaceutical composition and its use - Google Patents

Abstract

The invention relates to a pharmaceutical composition for the treatment of disorders whose pathogenesis is distinguished by destruction of blood vessels and cell membranes of the affected organs. The composition is characterised in that, besides customary excipients and/or diluents, it contains somatostatin. The invention furthermore relates to the use of somatostatin for the control of disorders whose pathogenesis is distinguished by destruction of the blood vessels and cell membranes of the affected organs.

Description

description

The invention relates to a medicament containing somatostatin as well as the use of somatostatin to combat diseases, their pathogenesis by destroying the blood vessels and cell membranes of the affected organs excels.

For some years, substances have been known that can be used in animal experiments cancel the toxic effects of phalloidin (cf. T. Wieland and H. Faulstich (1979) "The Phalloidine Story" in: Ovchinnikow Y, Kolosov M.N. (eds) Frontures in Biogenics Chemistry and molecular biology; Elsevier North Holland, pages 97 to 112). These "Phalloidon antagonists probably inhibit the transport system of hepatocytes, which is responsible for the rapid uptake of the phalloid in the cells. Other Substances (e.g.

Carbon tetrachloride) destroy this system and also prevent it the inclusion of phalloidin. The purpose of these experiments is to develop models with the help of which the pathomechanism of life-threatening conditions is clarified and appropriate therapies can be derived (e.g.

Development of shock organs); The previously known substances with the properties mentioned above are due to the known side effects for clinical application can only be used to a limited extent. The use of toxins, such as carbon tetrachloride, is ruled out from the start because of the high toxicity of these compounds.

Experiments with phalloidin-intoxicated rats (J.M.

Wdowinski et al. Research in Experimental Medicine 178, p. 155 to 163 (1981)) have shown that somatostatin also reduces the toxic effect of Phalloidin cancels. Because somatostatin is the uptake of phalloidin in the rat liver not inhibited, its effect must be explained by another mechanism than that of the substances already mentioned.

Somatostatin has already been shown to reduce the survival rate of rats treated with cysteamine increases (see U.

Schwedes, K.H. Usadel, S. Szabo (1977) "European Journal of Pharmacology" 44, pages 195-196; U.Schwedes, S.Szabo, K.

H. Usadel (1978) "Metabolism" 27 (Suppl. 1), pp. 1377-1380), in particular for peptic gastric ulcers, hemorrhages of the lungs and kidneys. A cheaper one Effect of somatostatin was also shown in the bile-induced acute pancreatitis observed on beagle dogs (cf.

U.Schwedes et al. (1979) "Hormone and Metabolic Research" 11, pp 655 to 661). The survival rate of rats intoxicated with α-amanitine was also significantly increased (cf. Wdowinski et al. (1980) "VI. International Congres of Endocrinology ", Melbourne).

The influence of somatostatin on duodenal and gastric ulcer as well as organ lesions, however, has not yet been investigated.

The invention is based on the object of providing a medicament that acts on duodenal and gastric ulcers as well as organ lesions and protected with the blood vessels (vasculo-protection) and membranes of the affected Cells are stabilized. In particular, a drug containing somatostatin is intended are made available that can be used in diseases, their Pathogenesis struck by the destruction of blood vessels and cell membranes Organs is marked.

The invention thus relates to a medicament for the treatment of diseases whose pathogenesis is through the destruction of blood vessels and cell membranes affected organs. and that is characterized by the fact that it is next to contains conventional carriers and / or diluents somatostatin. The invention also relates to the use of somatostatin to combat the above Diseases.

The synthetically produced somatostatin is a tetradecapeptide, that in its primary structure and biological effect with the naturally occurring Hormone is the same. It has the following amino acid sequence: H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp HO -Cys-Ser-Thr-Phe-Thr-Lys The synthetic somatostatin has in the 10 000-fold clinical dose administered, no toxic side effects in animal experiments shown.

It has now surprisingly been found that somatostatin on experimentally produced duodenal and gastric ulcers and other organ lesions works.

Applicant has the pathagonesis of somatostatin interactions in animal models of duodenal and gastric ulcers as well as other organ lesions (Liver, pancreas, kidneys) examined. In particular, the effects of somatostatin in (1) duodenal ulcer and adrenocortical necrosis, (2) gastric ulcer erosions, and (3) hepatic and pancreatic lesions examined. In these examinations the earlier results were confirmed that when pretreated with somatostatin (250 µg s.c. two times a day before the day of cysteamine administration) the development of duodenal ulcers and adrenocortical necrosis in rats, which were 3 times daily 28 mg / 100g cysteamine p.o. administered was prevented.

Surprisingly, it has now been found that this pretreatment with somatostatin is not required, and that somatostatin is antiduodenal ulcerogenic Shows effect in the cysteamine model. Used somatostatin at the same time as cysteamine administered, no duodenal ulcers caused by cysteamine occur become, and when they occur, their formation is significantly reduced than without Administration of somatostatin.

The acute and subacute duodenal induced by propionitrile Ulcer (6, 8 and 10 mg / 100 g s.c. 3 times a day on the first, second and third day, respectively) also take with parallel treatment with somatostatin (250 μg s.c. 2 times a day) away.

Secretory examinations were also carried out in conscious rats performed with chronic gastritis fistula, being gastric and duodenal / pancreatic Secretions were collected in separate tubes under mild vacuum. The secretions were collected at hourly intervals for 8 hours. A single dose of Somatostatin (30 min. Before propionitrile) completely eliminates the increased gastric acid release disappear and does not affect the pepsionic and duodenal / pancreatic Submission of the base. The pancreatic release of amylase and trypsin are controlled by somatostatin also significantly reduced. The inhibitions lasted 4 hours. It was surprising and did not suggest that somatostatin would release certain pancreatic Enzymes are so strongly affected and therefore somatostatin can be used as a drug for pancreatic Diseases such as acute pancreatitis serve.

It has also been found that somatostatin has a cyto-protective effect compared to the hemorrhagic gastric erosions induced by ethanol. If somatostatin (10 µg s.c. or i.p. once) is administered for 15 min. Before 1 ml 100% ethanol is administered, the intensity of the gastric erosion becomes significant decreased. The parallel administration of the sulfhydryl blocker N-ethyl maleimide works counteract the beneficial effects of somatostatin.

In the table below is the surprising effect of somatostatin on the propionitrile-induced gastric and pancreatic secretions in the Rats depicted.

Table 1 Influence of somatostatin on propionitrile-induced gastric and pancreatic secretions in the rat treatment time / hour. Acid trypsin Amylase after sample release release release pionitrile (µEg / h) (g / ul) (mg / ml) none 1 58 + 14 277 + 39 1157 + 225 2 2 105 + 19 420 + 54 1773 + 359 3 3 64 + 11 353 + 46 1600 + 257 4 53+ 7 337 + 47 1502 + 224 5 5 61+ 8 287 + 34 1118 + 127 propionitrile 1 178 + 37 ** 381 + 60 1352 + 257 2 2 194 + 18 * 429 + 45 1577 + 204 3 3 159 + 18 *** 434 + 53 1632 + 200 4 4 162 + 24 *** 480 + 47 1527 + 178 5 5 125 + 24 * 403 + 39 935 + 107 somatostatin 1 38 + 20 (**) 285 + 74 911 + 214 + propionitrile 2 33+ 9 (***) 410 + 89 1417 + 214 3 43 + 11 (***) 233 + 53 (*) 757 + 257 (*) 4 4 55 + 16 (***) 176 + 33 ( ***) * 683 + 185 (*) * 5 5 154 + 55 * 350 + 59 1816 + 296 (*) * * = p <0.050 ** = p <0. 0l = = p < 0.001 Comparison with the control (none) treatment group () = comparison with the Propionitrile group In rats, the hemorrhagic gastric erosions, those produced by ethanol, and the deadly hemorrhagic hepatic ones Necrosis induced by phalloidin, greatly reduced by somatostatin. This effect occurred with linear somatostatin derivatives whose SH groups were blocked were not on. Somatostatin shows protection for the organs.

Sprague-Dawley rats with an initial body weight of 200 g Free access to food and tap water. Each control group and each experimental group contains 3 to 5 animals. Each attempt is carried out at least 2 times and the Results are summarized. At the first examination, after the Animals have fasted overnight, the animals somatostatin (10 dough / 100 g than 0.2 ml of protamine sulfate and ZnCl2 suspension for 30 min. before 1 ml of 100% ethanol is given p.o. is administered. The sulfhydryl blocker N-ethyl maleimide (Sigma) is used s.c. in a Dose administered 10 min. After the somatostatin (or 20 min. Before the ethanol). A somatostatin derivative (bis-S-Acm somatostatin, L361,728, Merck; or di-S-tBu-somatostatin, Serono), in which the SH groups (cysteine) are replaced, is also used in 10 mg / 100 g s.c. Administered 30 minutes before the ethanol. The animals are 1 hour after the ethanol administration killed and the lesions in the stomach are scored on a scale of 0-3 (0 = normal; 1 = 1-4 small petechial hemorrhages with a diameter of about 1 mm; 2 = 5 or more petechial and hemorrhagic strips of 1-4 mm; 3 = erosions 5 mm or greater and / or continuous bleeding). Seven standardized sections the stomachs are fixed with 10% of the buffered aqueous formaldehyde and for the microscopic examination prepared.

In a second examination, 250 ßg somatostatin in 1 ml Protamine sulfate and ZnCl2 suspension 30 min. S.c.

before and 30 min. after administration of phalloidin, 0.12 mg / 100 g i.p. administered. In addition, 10 min.

before the toxin another dose of 250 μg of somatostatin in 1 ml of distilled Water i.p. administered. Other groups of rats are also given the sulfhydryl blocker N-ethyl maleimide alone or together with somatostatin 2 mg / 100 g s.c. 20 min. Before and 40 min after the phalloidin. The SH-free derivative of somatostatin is also used used instead of the normal somatostatin in the same dose and time. groups of the rats are either who killed 1 hour after intoxication or they are tested for their mortality, which inevitably takes from 2 to 4 hours. occurs. The surviving animals are after 24 hours.

killed. The hemorrhagic liver lesions are on a scale from 0-3, whereupon 0 = normal, 1 = multifocal (1-5 mm) hemorrhages, 2 = large hemorrhagic Areas and 3 = enlargement and uniform bleeding throughout the liver.

In the following Tables II and III are the results obtained summarized.

T a b e 1 1 e II Influence of somatostatin and N-ethylmaleimide on the gastric lesions produced by ethanol group pretreatment gastric Erosion (before the ethanol) (scale 0 to 3) 1 none 2.7 + 0.2 2 somatostatin 1.5 + 0.2 * 3 N -sthylmaleimide 3.0 + 0.1 4 somatostatin + N-ethyl- 2.9 + 0.2 maleimide 5 bis-S-Acm-somatostatin 2.6 + 0.1 6 di-S-tBu-somatostatin 2.5 + 0.2 * = p <0.05 T a b e 1 1 e III Influence of somatostatin on N-ethyl maleimide on the toxicity of phalloidin Pre-treatment group Mortal hepatic (before phalloidin) lesions (scale speed (%) 0 to 3) 1 none 2.0 + 0.1 100 2 somatostatin 0.7 + 0.2 * 20 * 3 N-Ä.thylmaleimid 2.3 + 0.2 90 4 somatostatin + N-ethyl maleimide 2.1 + 0.3 86 5 di-S-tBu-somåtostatin 2.7 + 0.2 92 * = p <005 The results in Table I show that normal somatostatin the intensity of gastric mucosal lesions is greatly reduced. Will on the other hand a somatostatin derivative with blocked SH groups is used or the sulfhydryl blocker is used N-ethyl maleimide administered alone with normal somatostatin is observed no cytoprotective effect in the ethanol model.

From Table II it follows that the phalloidin-induced hemorrhagic Enlargement and necrosis of the liver with the administration of somatostatin severe be reduced. N-ethyl maleimide counteracts the protective effect of somatostatin and the derivative of somatostatin with blocked SH groups has no influence.

From the above investigations it follows that somatostatin in diseases can be used whose pathogenesis is due to the destruction of blood vessels and Cell membranes of the affected organs is marked.

Somatostatin can therefore be used to combat many diseases, such as acute pancreatitis, severe acute ulcer bleeding, severe acute bleeding with erosive resp.

hemorrhagic gastritis, small intestinal fistulas, esophageal variceal bleeding, Pancreatic fistulas, development of shock organs, prophylaxis of postoperative pancreatitis, Pancreatic transplants and hepatic encephalopathy can be used.

Somatostatin can be administered intravenously, intramuscularly, subcutaneously, intraperitoneally and administered orally. It is preferably administered intravenously. The dose amount with a body weight of 70 kg is in the order of 50 to 500 μg / kg, preferably from 200 to 300 Ag / kg, most preferably from 250 g / kg.

The following example illustrates the invention.

Exemplary embodiment 3 mg of somatostatin (Serono) are physiological in 36 ml Dissolved sodium chloride solution and drawn up into a 50 ml perfusor syringe. Of the Perfusor is set to 3 ml / hour. = 250 µg somatostatin (Serono) / hour set. the Administration is intravenous. Duration of therapy: Depending on the success (longest so far known duration of treatment 14 days) (cf.

P. Hild et al. (1980) "Chirurg" 51, pages 155-157).

End of description

Claims (4)

Medicament containing somatostatin and its use Patent claims 1. Medicinal products for the treatment of diseases whose pathogenesis is affected by the Destruction of the blood vessels and cell membranes of the affected organs, by the fact that it is used in addition to the usual carrier materials and / or Contains thinners somatostatin. 2. Medicament according to claim 1, characterized in that g e k e n n -z e i c h n e t that it is in a parenterally administrable form. 3. Use of somatostatin to combat diseases, their Pathogenesis is due to the destruction of the blood vessels and cell membranes of the affected Organs. 4. Use of somatostatin to combat acute pancreatitis, severe acute ulcer bleeding, severe acute bleeding in the case of erosive or haemorrhagic Gastritis, small intestinal fistulas, esophageal variceal bleeding, Pancreatic fistulas, Development of shock organs, prophylaxis of postoperative pancreatitis, pancreatic transplants and hepatic encephalopathy.