Methods of regulation of the motility of the gastrointestinal tract


(57) Abstract:

The invention relates to medicine, in particular to a gastroenterologist, and for reducing the motility of the gastrointestinal tract or deceleration of gastric emptying. For this suggest the use of Amylin or Amylin agonist. The method can effectively treat diseases and conditions that must suppression of motor activity of the stomach and other digestive tract. 5 S. and 11 C.p. f-crystals, 2 tab., 17 ill.

This application is a partial continuation of patent application U.S. N 08/118 381, filed September 7, 1993, which is incorporated herein by reference.

The scope of the invention

The present invention relates to a method of regulating the motility of the gastrointestinal tract. In particular, the invention relates to the use of Amylin and Amylin agonists for the treatment of disorders that can be beneficial agents that can slow down or/and delay gastric emptying. The invention relates also to the use of Amylin antagonists to accelerate gastric emptying, for example, in the treatment of hypokinesia of the stomach and associated disorders.


Amyl is as the main component of amyloid deposits in the islets of Langerhans of the pancreas of people suffering from type 2 diabetes (Cooper and others, Proc. Natl. Acad. Sci., USA 84:8626-8632 (1987)). The Amylin molecule has two important post-translational modification: C-end amitirova and cysteine in positions 2 and 7 are cross stitched, forming H-terminal loop. The sequence of the open reading frame of the gene of human Amylin detects the presence of signal proteolytic cleavage of duotronic amino acids Lys-Arg before H-terminal codon for Lys and Gli before Liz-Arg proteolytic signal in CLAIMS-terminal position, a typical sequence for amidation enzyme amidation proteins (FAB) (Cooper and others, Biochem, Biophys. Acta, 1014:247-258 (1989)). Amylin is the essence of a patent application in the United Kingdom serial N 8709871 filed April 27, 1987, and applications of analog and USA, filed April 27, 1988, on 23 November 1988 and may 2, 1989.

It is shown that in type 1 diabetes there is a deficiency of Amylin, and as the preferred treatment was proposed combined replacement therapy instead of therapy, only one insulin, for example, to reduce the number of hypoglycemic episodes. The use of Amylin for the treatment of diabetes is the essence of a patent application in the United Kingdom serial N 8720115, podennih States. Pharmaceutical compositions containing Amylin and Amylin plus insulin as described in U.S. patent No. 5 124 314, issued June 23, 1992.

The effect of excess Amylin simulates the main features of type 2 diabetes, and blockade of Amylin was proposed as a new treatment strategy. At the same time considered public (Commonly-owned patent application U.S. serial N 275 475, filed November 23, 1988 Cooper, G. J. S., and others, are incorporated herein by reference, disclosed that Amylin causes a decrease in both basal and insulin-stimulated incorporation of labeled glucose into glycogen selectnow muscles. Reveals that the latter effect is associated with PRGK (see also Leighton, B. and Cooper, G. J. S., Nature 335:632-635 (1988)). Amylin and PRGK had approximately equal force, demonstrating a pronounced activity at concentrations from 1 to 10 nm. It was also reported that Amylin reduces insulin-stimulated glucose uptake in skeletal muscles and reduces the content of glycogen (Joung and others, Amer. J. Physiol., 259:457-461 (1990)). Disclosed the treatment of type 2 diabetes and insulin resistance with the help of Amylin antagonists.

As the chemical structure and gene sequence emilina testify uses in the building almost 50% identical to the peptides, related gene calcitonin (PLC), also consisting of 37 amino acid protein that is widely distributed as a neurotransmitter with many types of biological activities, including vasodilation. And Amylin, and PRGK have a disulfide bridge2CIS-7CIS-and C-terminal amidon, which are necessary for the manifestation of full biological activity (Cooper and others, Proc. Natl. Acag. Sci, 85:7763-7766 (1988)).

Amylin may be a member of a family of related peptides, which includes PLC, insulin, insulin-like growth factors and relaxin that share a common inherited genetic characteristics (Cooper, G. J. S., and others , Prog. Growth Factor Research 1:99-105 (1989)). These two peptide, calcitonin and PGK-1, have a common origin of calcitonin gene but different processing of a primary transcription of mRNA leads to the formation of two different peptides, with only limited gomologichnosti sequence (about 30%) (Amara, S. G., and others, Science, 229:1094-1097 (1985)). The genetic sequence of Amylin typical for secreted protein mediation, in which mRNA encodes preprepared with lots of processing for production of secreted protein in the Golgi complex or secretory granules. Amylin, basically, is amaut proinsulin to insulin.

Amylin originally synthesized in pancreatic beta-cells and is secreted in response to food stimuli, such as glucose and arginine. Studies with cloned lines of a tumor of the beta cells (Moore and others, Biochem. Biophys. Res. Commun., 179(1), (1991)), isolated islets of Langerhans (Kanatsuka, etc. FEBS Lett., 259 (1): 199-201 (1989)) and perfezione rat pancreatic glands (Ogawa and others J. Clin. Invest., 85: 973-976 (1990)) have shown that a short exposure, from 10 to 20 minutes, nutrients, stimulating the secretion, such as glucose and arginine stimulate the release of Amylin and insulin. The molar ratio of Amylin : insulin secreted proteins in different drugs varies approximately from 0.01 to 0.4, however, does not change significantly when exposed to different stimuli to the same drug. However, prolonged stimulation of the high concentration of glucose ratio of Amylin : insulin may progressively increase (Gedulin and other Biochem. Biophys. Res. Commun. 180(1)1782-789 (1991)). Thus, it is possible, due to the fact that the expression of the gene and the speed broadcast Amylin and insulin are controlled independently from each other, they are not always are secreted in a constant ratio.

Amidinopropane immunological call using rabbit antimelanoma serum and in which most of them were in the process of extraction and concentration to increase the sensitivity analysis. Reported levels of Amylin on an empty stomach 1 to 10 PM and levels after feeding or administration of glucose from 5 to 20 PM in healthy people (for example, Hartter and others, Diabetologia, 34:52-54 (1991)), Sanke. and other Diabetologia 35:129-132 (1991)), Koda and others, The Lancet 339:1179-1180 (1992)). In insulin-resistant obese Amylin levels after a meal can go even higher, reaching approximately 50 PM. For comparison, in healthy people, insulin levels fasting and after meals are 20-50 PM and 100-300 PM, respectively, which is 3-4 times higher than in insulin resistant people. In people with type 1 diabetes when beta cells are destroyed, insulin levels are at or below the detectable level and does not increase in response to glucose (Koda, etc. The Lancet. 339:1179-1180 (1992)). It is reported that in healthy mice and rats, the basal Amylin levels range from 30 to 100 PM, while in some insulin-resistant diabetic lines rodents these values are up to 600 gr (for example, Huang and others, Hypertension, 19: 1-101-1-109 (1992); Gill and others, Life Science, 48:703-710 (1991)).

It was found that some of the effects emileetamavani while exploring this first isolated protein, most likely reflect its main biological role. At least some of these metabolic effects are simulated PLC, although at doses that are expressed vasodilating (see, for example, Leighton and others, Nature, 335:632-635 (1988); Molina and others, Diabetes, 39:260-265 (1990)).

First established by the effect of Amylin was reduced insulinstimulated incorporation of glucose into glycogen in skeletal muscle of rats (Leighton and others, Nature, 335:632-635 (1988)); the muscles become "insulin resistant". Subsequent work with the soleus muscle of the rat ex vivo and in vitro have shown that Amylin reduces the activity of glycogen synthase, accelerates the transition glycogen-phosphorylase from the inactive to the active form in the a-form, accelerates net loss of glycogen (in the presence or absence of insulin), increases the levels of glucose-6-phosphate and can increase the yield of lactate (see, for example, Deems and others, Biochem. Biophys. Res. Commun., 181(1):116-120 (1991)); Joung and others, FEBS Letts, 281(1,2):149-151 (1991). Does Amylin to the transport of glucose remains unclear (see, for example, Joung and others, Am. J. Physiol., 259-E457-E461 (1990), Zierath and others, Diabetologia, 35:26-31 (1992)). Study of dose-dependent relationship between Amelina and insulin showed that Amylin acts as noncompetitive or functional antagonist of insulin in the NEC is of insulin to its receptors and subsequent activation of insulin receptor tyrosine kinase (Follett and others, Clinical Research 39(1): 39A (1991); Koopmans and others, Diabetologa, 34, 218-224 (1991)). The effect of Amylin on skeletal muscle resembles the action of adrenaline (epinephrine). However, while assume that the effect of epinephrine is mediated by camp, some researchers have come to the conclusion that the action of aniline is not mediated by camp (see Deems etc. Biochem. Biophys. Res. Commun., 181(1):116-120 (1990)), and others that Amylin still activates adenylate cyclase and increases the content of camp in skeletal muscle (Moore u Rink, Diabetes 42:5, 821 June (1993)), which is consistent with its effects on glucose metabolism through the camp-dependent phosphorylation synthase and phosphorylase protein kinase.

I believe that Amylin acts through receptors present on the plasma membranes. It is reported that Amylin works in skeletal muscle through receptorpositive mechanism which stimulates glycogenolysis by activation of the enzyme, limiting the rate of breakdown of glycogen phosphorylase (Young and others, FEBS Letts., 281:149-151 (1991)). The study of Amylin and PLC, as well as the effect of the antagonist 8-37PLC suggests that Amylin acts through its receptor (Wang and others, FEBS Letts., 219: 195:198 (1991)), in contrast to the findings of other researchers, h the tides, 12: 585-591 (1991); Znu and others, Biochem. Biophys. Res. Commun., 177 (2)-771-776 (1991)). Recently in the international PCT application N/US 92/02125, published October 1, 1992 and entitled "Methods of screening for agonists and antagonists of Amylin with receptors were described Amylin receptors and their use in the various methods of screening and study of agonists and antagonists of Amylin.

At the same time as Amylin pronounced effect on the energy metabolism of the liver in vivo, among researchers there is no agreement in the question of what the effects of Amylin are observed on isolated hepatocytes or perfoirmance liver. Available data do not support the idea that Amylin accelerates glycogenolysis in the liver, i.e., it does not act like glucagon (e.g., Stephens and other Diabetes, 40:395-400 (1991)); Gomez-Foix, etc. Biochem. J., 276:607-610 (1991)). Suggest that Amylin may act on the liver, speeding up the conversion of lactate into glycogen and increasing the amount of glucose that can be liberated under the action of glucagon (see Roden and others , Diabetologia 35:116-120 (1992)). Thus, Amylin may act as an anabolic partner of insulin in the liver, in contrast to its catabolic action in the muscles.

Recently it was reported about the effect of Amylin on regiona rat Amylin produced a more pronounced renal vasodilatation and less pronounced masteralloy vasoconstriction, than that observed with infusion-PRGC person. They conclude that stimulating renal hyperemia to a greater extent than does PRGK, rat Amylin causes less pronounced stimulation Regine-angiotensin system and, therefore, less pronounced secondary angiotensin P-mediated vasoconstriction. However, it is also noted that during co-infusion-8-37 mobile systems of human and rat Amylin realta and mesenteric vasoconstriction gemaskerde, possibly due to not meeting counteract the vasoconstrictor effects of angiotensin 11, and that this circumstance is similar to that observed during both infusion AND-PRGC and8-38PLC man (ibid, page 951).

The greasy rats, in contrast to his adrenaline-like effect on skeletal muscle, Amylin had no measurable effect on insulinstimulated glucose uptake, incorporation of glucose into triglyceride, education CO2(Cooper and others, Proc. Natl. Acad. Sci., 85:7763-7766 (1988)), epinephrineidocaine lipolysis or inhibition of lipolysis by insulin (Lupien, J. R. u Young, A. A. "Diabetes nutrition and Metabolism-Clinical and Experimental, vol 6(1), PP 13 - 18 (February 1993)). Amylin, thus, causes tkanespecificskie the nternet effect on the liver, while adipocytes appear insensitive to the presence or absence of Amylin. About direct effects of Amylin on renal tissue has not been reported.

It is also reported that Amylin has a marked effect on insulin secretion. On isolated islets of Langerhans (Ohsawa and others, Biochem. Biophys. Rec. Commun. , 160(2): 962-967 (1989)), on perfuziruemah pancreatic glands (Silvestre and other Reg. Pept., 31-23-31 (1990)) and in intact rats (Young and others, Mol.Cell. Endocrinol., 84:P1-P5 (1992)) some experiments have shown that amidin regulates insulin secretion in the decrease direction. Experiments on perfoirmance pancreas indicate that selective inhibition of the secretory response to glucose with a reduced response to arginine. Other researchers, however, failed to capture the effects of Amylin on isolated cells, isolated on Islands or on the live animal (see Broderick and others, Biochem. Biophys. Rec. Comm., volume 177: 932-938 (1991) and references in this work).

The most striking effect of Amylin in vivo is to stimulate a rapid rise in lactate in plasma, followed by the observed rise in plasma glucose (Young and others, FEBS Letts., 281 (1,2):149-151 (1991)). The facts indicate that increased amounts of lactate provides the substrate for the educated. In experiments on commit "glucose" Amylin infusion called "insulin resistance" as by reducing peripheral placement of glucose, and by limiting the insulin-mediated suppression of glucose release by the liver (for example, Frontoni and other Diabets, 40:568-573 (1991); Koopmans and others, Diabetologia, 34, 218-224 (1991)).

The shot slightly rats, starving for 18 hours to depletion of hepatic glycogen injection of Amylin stimulated increase in plasma lactate from about 0.5 to 1.5 mm, after which there were long the increased levels of plasma glucose from approximately 6 to 11 mm. These effects were observed at intravenous and subcutaneous injections (Young and others, FEBS Letts. 281(1,2):149-151 (1991)). The effects of Amylin in well-fed animals quantitatively different from its effects in hungry animals. In fed rats, which had, presumably, normal reserves of liver glycogen, Amylin causes a more pronounced and prolonged rise in plasma lactate; however, there is only a moderate increase in plasma glucose. Suggest that Amylin accelerates "return the branch cycle Measles, i.e. muscle glycogen through decay to lactate provides the substrate for gluconeogenesis glucose of mice and synthesis of muscle glycogen. Insulin and Amylin, thus, are represented by partners in the regulation of "indirect" ways of accumulation of liver glycogen after a meal. "Insulin resistance in the muscles and liver can be controlled by normal physiological regulacja amilina.

Nametables effects of Amylin include vasodilator effects that can oposredovanie interaction with receptors PLC vessels. Reported in vivo tests, which suggest that Amylin at least approximately 100 to 1000 times less powerful vasodilator than PRGK (Brain and other Eur. J. Pharmacol., 183:2221 (1990); Wang and others, FEBS Letts. 291: 195: 198 (1991)). It is reported that Amylin entered in the brain, suppresses food intake (e.g., Chance, etc., Brain Res., 539, 352-354 (1991)), together with PLC and calcitonin. Effective concentration in the cells that mediate this effect are not known. It is also reported that Amylin has an impact on isolated osteoclasts, which he calls a state of rest, as well as in vivo, where it lowers the concentration of calcium in plasma by 20% in rats, rabbits and people with Paget's disease (see, for example, Gilbey, etc. j Bone Mineral Res., 293 (1991)). Based on available data, Amylin 10-30 times weaker than human calcitonin in these effects. Is SUP>, while calcitonin does both (Alam and others, Biochem. Biophs. Res. Commun, 179 (1):134-139 (1991). Was proposed, but not confirmed, the hypothesis that calcitonin may act through receptors of two types and that Amylin may interact with one of them.

Infusion of Amylin receptor antagonists can be used to change the regulation of glucose metabolism. It is shown that8-37-PLC is a blocker of Amylin in vitro and in vivo (Wang and others Biochem Biophs. Res. Commun., 181(3): 1288-1293 (1991)), and also alters glucose metabolism after infusion of arginine fed rat (Young and others, Mol. Cell. Endocrinol., 84:P1-P5 (1992)). The initial increase in glucose concentration were attributed to argumentirovannoe secretion of glucagon by the alpha cells of the islets of Langerhans; subsequent recovery of the original glucose levels were attributed to the actions of insulin in conjunction with changes in other hormones involved in the regulation of glucose metabolism. When the effect of Amylin is blocked prior infusion 8-37PLC, the initial increase in glucose significantly different, however, then there is a decline in the glucose concentration is significantly below the original level is restored so much after approximately 80 minutes. Thus, camping by infusion of Amylin receptor antagonist. In addition, we measured the concentration of insulin at half hour intervals and found that the concentration of insulin 30 minutes after infusion of arginine was almost two times higher in animals that were administered the Amylin receptor antagonist than in normal control animals.8-37PLC is also an effective antagonist PLC. However, very similar results were observed with another Amylin antagonist, AC66, which is selective in respect of Amylin receptors compared with receptors PLC (Young and others, Mol.Cell. Endocrinol, 84: P1-P5 (1992)). These results support the conclusion that the blockade of the actions of Amylin can have an important beneficial effect in the treatment of type 2 diabetes.

It is reported that patients with type 1 diabetes, in addition to lack of insulin, have also expressed deficiency of Amylin. As noted above, the evidence suggests that diabetes type 1 expression and secretion of Amylin pancreatic beta-cells absent or significantly below normal. In animals with simulated type 1 diabetes Amylin secretion and expression of its gene suppression (Cooper and others, Diabets 497-500 (1991); Ogawa and others, J. Clin. Invest., 85: 973-976 (1990)). The definition of Amylin in plasma in patients with type 1 diabetes pack any elevated levels of Amylin (Koda and others, The Lancet 339:1179-1180 (1992)).

It was also found that surprising from the point of view described earlier renal vasodilating and other effects that Amylin significantly increases the activity of plasma renin in rats after subcutaneous administration in a way that avoids any changes in blood pressure. This is important because reduced blood pressure is a strong stimulus for renin release. Amylin antagonists, such as Amylin receptor antagonists, including selective for milinovich receptors compared with receptors PLC and/or calcitonin may be used for blocking caused by Amelina increasing the activity of plasma renin. These unexpected findings speak in favor of the assumption that Amylin antagonists will reduce the activity of plasma renin and subsequent therapeutically favorable effect on hypertension and heart failure, and other disorders associated with excessive, inadequate or undesirable activity of renin. Moreover, the additional ability of Amylin antagonists favorably modulate insulin resistance and other common metabolic disorders is about treatment.

Hypokinesia stomach

Hypokinesia gastric delayed emptying it from the liquid and/or solid content is a part of many gastrointestinal disorders. See General discussion Goodman u Gilman's b The Pharmacological Basis of Therapeutics, Chapter 38 (Pergamon Press, eighth edition, 1990). The symptoms of such disorders may include nausea, vomiting, heartburn, discomfort after eating and indigestion. Often gastro-esophageal reflux, which can cause ulceration of the esophagus; may also experience respiratory symptoms or intensive zagrodny pain that can be mistaken for asthma or myocardial infarction, respectively. Although most patients etiological cause is known, the stasis of stomach contents or hypokinesia are often the consequence of diabetic neuropathy; this condition is also often observed in patients with neurogenic anorexia, or achlorhydria, or after surgery on the stomach. Ibid, at page 928.

Medical care for patients with hypokinesia stomach usually includes assigning prokinetics agent. Although antiemetic phenothiazines or betangel can bring some relief, these medicines are not uskorea currently available prokinetics agents include metoclopramide and cisapride, while others (e.g., domperidone) are studied. Ibid.

Metoclopramide lowers the receptive relaxation of the upper part of the stomach and increases antral contraction. Pyloric Department and duodenum relax, while the tone of the lower esophageal sphincter increases. These effects combine to accelerate the evacuation of gastric contents and reduce reflux from the duodenum and stomach into the esophagus. In addition, the time of passage of material from the duodenum to the ileocecal valve is reduced due to increased peristalsis jejunum. Metoclopramide almost no effect on gastric secretion and motility of the large intestine. Ibid at page 928.

In General, dopaminergic agonists to produce the opposite effect, which mediate D2-receptors located at least partially in the gastrointestinal tract. Ibid.

The mechanism of action of metoclopramide is not entirely clear, although it is pronounced dopaminergic antagonist and can block gastrointestinally effects caused by local or systemic introduction dopaminergic agonistically atropine go other muscarinic antagonists. Moreover, not all dopaminergic antagonists accelerate gastric emptying. I believe that this drug stimulates the release of acetylcholine from neurons of the muscular layer of the intestine, however, direct evidence of this action are absent. Because betangel may exacerbate the effects of metoclopramide, increased sensitivity to acetylcholine may also play a role. Ibid, at pp. 928-929.

Domperidone is a derivative of benzimidazole and has procainamidesee and antiemetic properties. He is a dopaminergic antagonist and is expressed hyperprolactinemia; its effect on the motility of the gastrointestinal tract is also very similar to the action of metoclopramide. However, in contrast to metoclopramide, these effects are not eliminated by atropine; the explanation for this difference yet. Domperidone passes through the blood-brain barrier in very limited quantities and very rarely cause extrapyramidal side effects. As a result, it does not preclude the treatment of Parkinson's disease and may be useful to combat gastrointestinal disorders caused by levodopa and bromocriptine. Therefore, it lekarstvennoe less antiemetic activity. There on page 929. Domperidone is rapidly absorbed after oral administration, but its bioavailability is only about 15%, much of this drug and its metabolites is excreted in the feces. The elimination half-life from plasma is approximately 7 to 8 hours. There. same. Domperidone is not publicly available in the United States; it is available in other countries as motilium (MOTILIUM). The optimal dosage is not established, however, for the treatment of hypokinesia of the stomach is used daily oral doses of 40 to 120 mg ibid, page 929.

The cisapride is benzamido and its effects on the motility of the stomach and small intestine is very reminiscent of the effects of metoclopramide and domperidone; however, unlike these drugs, it also increases the motility of the colon and can cause diarrhea. The mechanism of its action on the gastrointestinal tract are poorly understood. Like metoclopramide these effects are blocked by atropine and may involve the release of acetylcholine muscle membrane of the intestine. The cisapride appears to be devoid of blocking dofaminergicheskoi activity and does not affect the concentration of prolactin in the plasma and does not cause extrapyramidal symptoms. This drug svyazyvaete to its effects on the human body is not installed. Ibid. Thus, the effectiveness of this drug in the treatment of disorders observed in hypokinesia of the stomach, it is equal to the effectiveness of metoclopramide and domperidone without the side effects of dopaminergic blockade. In addition, cisapride may be useful in the treatment of patients with chronic idiopathic constipation or hypokinesia of the large intestine caused by damage to the spinal cord. Ibid at page 929.

In contrast to the above, in medicine have also found the use of agents that serve to delay emptying of the stomach, in particular, as an aid in diagnostic radiological examinations of the gastrointestinal tract. For example, the glucagon is a polypeptide hormone secreted by the alpha cells of pancreatic islets of Langerhans. He is a hyperglycemic agent, which mobilizes glucose through activation of glycogenolysis in the liver. To a lesser extent it is able to stimulate the secretion of pancreatic insulin. Glucagon is administered in the form of glucagon hydrochloride; dosage is usually referred to as glucagon.

Glucagon is used in the treatment insulininduced intravenous injection at a dose of 0.5-1 mg (units), repeat, if necessary, after 20 minutes, however, because glucagon reduces the motility of the gastrointestinal tract, it is used for diagnostic purposes during radiological examinations of the gastrointestinal tract. The route of administration depends on diagnostic procedures. Dose 1-2 mg (units) by intramuscular begins to act through 4-14 minutes, and the duration of effect is 10 to 40 minutes; 0.2 to 2 mg (units) intravenously have an effect within one minute, which lasts 9 to 25 minutes.

Glucagon was used in some studies for the treatment of various painful gastrointestinal disorders associated with spasm. Daniel and other Br. Med. J., 1974, 3, 720, reported a more rapid symptomatic relief of acute diverticulitis in patients treated with glucagon, compared with patients treated with analgesics or antispasmodics. The review made Glauser and others, (J. Am. Coll. Emergency Physns. 1979, 8, 228), describes the relief of acute esophageal food obstruction after treatment with glucagon. In another study, glucagon significantly eased the pain and tenderness to palpation in 21 patients with biliary tract disease compared with 22 patientest glucagon vs. placebo in hydrostatic reduction ileo-colonic intussusception in studies of 30 children, A Webb and others (Med. J. Aust., 1986, 144, 124) conclude that glucagon was ineffective in the treatment of ureteric colic in the emergency room.

Suddenly, from the point of view of the previously described hyperglycemic properties Amylin, we found that Amylin and Amylin agonists, including those described herein, for example, a similar Amylin agonist,25,28,29,Pro-h-Amylin (also referred to as "AC-0137"), can reduce the motility of the stomach and slow down gastric emptying, which follows from the ability of these compounds to reduce the levels of plasma glucose after a meal.

The present invention is directed to new ways of reducing the motility of the stomach and slowing of gastric emptying, which include the introduction of Amylin or Amylin agonist, such as agonistic analog of Amylin AC-0137. These methods will be useful for treatment of, for example, food hyperglycemia, complications associated with diabetes mellitus type 2 (insulin-independent).

The term "Amylin" includes compounds defined by Young and Cooper in U.S. patent No. 5 234 906, issued August 10, 1993, hyperglycemic composition, the content of which is incorporated herein by reference. For example, it includes the peptide gormo elez. "Amylin agonist" is also known by the term and refers to compounds that mimic the effects of Amylin. Thus, he Amylin and agonistic analogues of Amylin may also be referred to as Amylin agonists. The term "agonist analogue of Amylin" refers to a derivative of Amylin, which act as agonists by Amylin is believed at the present time, the rate of binding or other direct or indirect interaction with Amylin receptors or other receptors, which itself Amylin can interact, causing biological effects described above. In addition to those described herein other useful agonistic analogues of Amylin identified in the international patent application WPI Acc. N 93-182488/22, entitled "New peptide Amylin agonists used for the treatment and prevention of hypoglycemia and diabetes", the contents of which are also incorporated herein by reference.

In one aspect, the present invention describes a method enabling regulation of the motility of the gastrointestinal tract of the patient by introducing a named patient a therapeutically effective amount of Amylin or agonist Emili is retene aimed at reducing the motility of the stomach. In another embodiment, the present invention is directed to methods of delayed gastric emptying.

These methods can be used in a patient undergoing a diagnostic study of the gastrointestinal tract, such as radiological examination or magnetic resonance imaging. Otherwise, these methods can be used to reduce the motility of the stomach in a patient suffering from dysfunction of the gastrointestinal tract, such as spasm (which may be associated with acute diverticulitis, pathology of the bile ducts or sphincter of Oddi).

In another aspect, the present invention is directed to a method for the treatment of dumping syndrome after ingestion of the patient by introducing a named patient a therapeutically effective amount of an Amylin agonist.

In another aspect, the present invention is directed to a method of treating hyperglycemia, associated with food intake, by introducing the patient a therapeutically effective amount of an Amylin agonist. In a preferred embodiment, hyperglycemia is associated with food intake, is a consequence of diabetes mellitus type 2.

Preferred Amylin agonists include25,28,29the">

In another aspect, the present invention is directed to a method of treating hypokinesia of the stomach of the patient by entering the patient a therapeutically effective amount of an Amylin antagonist. In the preferred embodiment, these methods can be applied when hypokinesia is a consequence of diabetic neuropathy and neurotic anorexia. Hypokinesia is also observed as a consequence of achlorhydria or as a result of surgery on the stomach.

In another aspect, the present invention is directed to a technique for accelerating the emptying of the stomach of the patient by entering the patient a therapeutically effective amount of an Amylin antagonist. Under the Amylin antagonist refers to a compound that inhibits the effects of Amylin, such as a connection, which in itself does not possess significant pharmacological activity, but causes effects by inhibiting the action of specific agonist, for example, competing for the binding of the agonist. Preferably, the Amylin antagonist used in these methods is the Amylin receptor antagonist. The preferred antagonist is acetyl-11,18VDR,30ASN,32 is a way to treat poisoning by introducing a number of Amylin or Amylin agonist, effective to prevent or reduce the passage of gastric contents into the intestine, and aspiration of gastric contents.

Fig. 1 shows the effect of Amylin on the levels of plasma glucose in dogs after oral glucose load compared to control.

Fig. 2 shows the glucose levels after meals in people-volunteers, who were given a placebo or 30 mg of AC-0137 intravenous bolus.

Fig. 3 shows the glucose levels after meals in people-volunteers, who were given a placebo or 100 μg AC-0137 intravenous bolus.

Fig. 4 shows the glucose levels after meals in people-volunteers, who were given a placebo or 300 μg AC-0137 intravenous bolus.

Fig. 5 shows the glucose levels after meals in people-volunteers, who were given a placebo or produced a 2-hour intravenous infusion of AC-0137 with a speed of 15 micrograms per hour.

Fig. 6 shows the glucose levels after meals in people-volunteers, who were given a placebo or produced a 2-hour intravenous infusion of AC-0137 with a speed of 50 micrograms per hour.

Fig. 7 shows the glucose levels after meals in people-volunteers, who were given a placebo or PI glucose after ingestion of food Sustacalin the initial (day 1), day 7 and day 14 of the test for tolerance to food Sustacalpeople-volunteers, which was administered 30 μg tripro-Amylin (AC - 0137) three times a day before meals for 14 days.

Figures 9a-9b show the levels of plasma glucose (mg/DL), plasma tripro-Amylin (PM) and plasma free insulin (mked/ml), starting time 60 minutes prior to the start of intravenous infusion of 25 mcg/hour tripro-Amylin. Food Sustacalgave after 60 minutes after the start of infusions tripro-Amylin.

Fig. 10a-10c show the levels of plasma glucose (mg/DL), plasma tripro-Amylin (PM) and plasma free insulin (IU/ml), starting time 60 minutes prior to the start of intravenous infusion of 50 g/h tripro-Amylin. Food Sustacalgave after 60 minutes after the start of infusions tripro-Amylin.

Fig. 11a-11c show the levels of plasma glucose (mg/DL), plasma tripro-Amylin (PM) and plasma free insulin (mked/ml), starting time 60 minutes prior to the start of intravenous infusion of 50 mcg/hour tripro-Amylin. Intravenous load of glucose (300 mg/kg) produced after 60 minutes after the start of infusions tripro-Amylin.

Fig. 12a-12b show urovni tolerance to food Sustacalpeople-volunteers who were injected with 100 µg of tripro-Amylin (AC-0137) three times a day before meals for 14 days.

Fig. 13a-13b show the levels of glucose and tripro-Amylin after taking power Sustacalin the initial (day 1), day 7 and on day 14 of the test for tolerance to food Sustacalpeople-volunteers who were injected with 300 μg tripro-Amylin (AC-0137) three times a day before meals for 14 days.

Fig. 14 shows dose-dependent effects of pre subcutaneous injection of rat Amylin on the delay of gastric contents after 20 minutes after feeding through a tube of normal and diabetic BB rats (n=3-9 animals on each item). Numbers denote average values COC, curves and determine the most appropriate logistics functions. Zero denotes the fraction of gastric contents, which were delayed in normal and diabetic rats untreated with Amelina (difference at P < 0,001).

Fig. 15 shows the concentration of plasma Amylin measured after subcutaneous injection of 1 μg or 10 μg of synthetic rat Amylin (n = 3 animals per group). Numbers denote average values COC.

Fig. 16 reflects the tritium glucose p is stockeu indicated statistical significance. Most small labels (the dotted line shows the background) caught 4 shot rats with the probe after laparotomy and ligation of the pyloric. This fact indicates that directly through the stomach wall absorbed a small amount of tritium, and that the absorption of tritium reflects the passage of glucose into the bloodstream through the small intestine.

Fig. 17 reflects the level of plasma glucose (mg/DL) after insertion through the probe saline or AC-0187.

The nomenclature of the various compounds - agonistic analogues of Amylin used in the present invention may be used to designate a peptide whose sequence is the main, and modifications made on the basis of any principal Amylin peptide sequence, such as Amylin person. Amino acid, to which the above given number, means that the named amino acid replaces an amino acid normally present in the amino acid position indicated by the top number in the primary amino acid sequence. For example, "18Arg25,28Pro-h-Amylin" refers to a peptide based on the sequence "h-Amylin" or "human Amylin is Ser at residue 28. The designation "OTC1Liz-h-Amylin" refers to a peptide based on the sequence of human Amylin, in which the first, or N-terminal amino acid is missing.

Agonistic Amylin analogues of the present invention is useful from the point of view of their pharmacological properties. The activity of Amylin agonists may be determined by activity in the study of the binding of receptors and the study on the soleus muscle, which is described below. The activity of compounds as Amylin agonists may also judged on their ability to induce hypercalcemia and/or hyperglycemia in a mammal or to reduce the levels of plasma glucose after a meal, as described in this document.

Preferred agonistic analogues of Amylin OTC1Liz-h-Amylin,28Pro-h-Amylin,25,28,29Pro-h-Amylin, 18Arg25,28Pro-h-Amylin, and the OTC1Liz18Arg25,28Pro-h-Amylin demonstrated amelineau activity in vivo in experimental animals, causing expressed hyperlactemia, followed by hyperglycemia. In addition to amelineau activity of some preferred compounds are also preferred solubility and the25About26Val28,29Pro-h-Amylin, 25,28,29Pro-h-Amylin (also referred to herein as "AC-0137") and18Arg25,28Pro-h-Amylin.

The method of the present invention can be applied Amylin agonist, including Amylin or an agonist analogue of Amylin, for example agonisticheskoe analogues acting on the Amylin receptors, such as18Arg25,28Pro-h-Amylin, OTC1Liz18Arg25,28Pro-h-Amylin, 18Arg25-28,29Pro-h-Amelie, OTC1Liz18Arg25,28,29Pro-h-Amylin, 25,28,29Pro-h-Amylin, OTC1Liz25,28,29Pro-h-Amylin, and25About26Val25,28Pro-h-Amylin. Examples of other suitable agonistic analogues of Amylin include:



OTC1Liz23Lei25About26Val28The Pro - h-Amylin;

18Arg23Lei25About26Val28The Pro - h-Amylin;





OTCR>17Ile18Arg23Lei26Val29The Pro - h-Amylin;

17Ile18Arg23Lei25About26- Val28,29Pro-h-Amylin;

13Tre21GIS23Lei26Ala28- S29About31ASP-h-Amylin;

13Tre21GIS23Lei26Ala29- Pro31ASP-h-Amylin;



13Tre18Arg21GIS23Lei28,29- Pro31ASP-h-Amylin, and

13Tre18Arg21GIS23Lei25- Pro26Ala28,29About31ASP-h-Amylin.

Some other Amylin agonists, including agonistic Amylin analogues are disclosed in WPI Acc. N 93-182488/22, "New peptide Amylin agonists used for the treatment and prevention of hypoglycemia and diabetes", the disclosure of which is incorporated herein by reference.

The activity of Amylin agonists can be estimated using certain biological studies described in this document. Research associate receptors evaluation of binding while research on the soleus muscle contributes to the discernment of agonists and antagonists of Amylin. Effects of amelino and Amylin agonists on the motility of the stomach can be identified, evaluated or selected for use of the methods described below in the examples, or other known or equivalent methods for determining the motility of the stomach.

One such method for use in identifying or evaluating the compound's ability to slow down the motility of the stomach includes:

(a) combining the test sample and the test system, called the test sample includes one or more test compounds, and named test system includes a system for assessing the motility of the stomach, which is characterized by the fact that demonstrates, for example, the increase in plasma glucose in response to the introduction of this system of glucose or food;

(b) determining the presence or the amount of rise of plasma glucose in the system. You can also use positive and/or negative controls. If desired, the test system you can add a pre-defined number of Amylin antagonist (e.g.,8-23salmon calcitonin).

Preferably, the Eney than approximately 1 - 5 nm, preferably less than 1 nm and more preferably less than about 50 PM. In the study on the soleus muscle, these compounds preferably exhibit the values of EC50the order of less than approximately 1 to 10 micromolar.

Study of the binding of the receptors described in the patent application U.S. serial N 670 231, filed March 15, 1991 and published October 1, 1992 as the international application N PCT/US 92/02125, the description of which is incorporated herein by reference. Study of the binding of receptors is a competitive examination, which measures the ability of compounds to specifically contact attached to the membranes of Amylin receptors. The preferred source of membrane preparations used in this study is the basal forebrain, which includes the membrane of the nucleus accumbens and surrounding areas. Compounds under study, compete for binding to these receptor preparations with1251 mouse-Amelina Bolton Hunter. Curves of competition, which are related to the amounts of (C) as a function of the logarithms of the concentrations of the ligand, are analyzed by computer using nonlinear regression the ALLFIT Delean and other (ALLFIT version 2.7 (NIH, Bethesda MD MD 20892 work)).

Munson, P. u Rodbard, D., Anal. Biochem., 107:220-239 (1980).

Study of the biological activity of Amylin agonists, including agonistic analogues of Amylin on the soleus muscle performed using previously described methods (Leighton, B. u Cooper, G. J. S., Nature, 355:632-635 (1988); Cooper, G. J. S. , and others, Proc. Natl. Acad. Sci USA 85:7763-7766 (1988)). The activity of Amylin agonists was assessed by measuring the inhibition insulinstimulated glycogen synthesis in cambaroides muscle. The activity of Amylin antagonists was assessed by measuring resume insulinstimulated glycogen synthesis in the presence of 100 nm rat Amylin and Amylin antagonist. The concentration of the peptide dissolved in the buffer solution not containing media was determined by quantitative amino acid analysis, as described herein. The ability of compounds to act as agonists in this study was determined by measuring EC50. Standard errors were determined by processing the sigmoidal response curves to dose using a 4-parametric logical equations (De Lean, A., Munson, P. J. Guarda basso, V. u Radbard, D., (1988), ALLFIT version 2.7, national Institute of health de is a number of Amylin agonists. It was found that compounds18Arg25,28Pro-h-Amylin, OTC1Liz18Arg25,28Pro-h-Amylin, 18Arg25,28,29Pro-h-Amylin, OTC1Liz18Arg25,28,29Pro-h-Emili, 25,28,29Pro-h-Amylin, OTC1Liz25,28,29Pro-h-Amylin, and25About26Val25,28Pro-h-Amylin compete with amilina in the study of the binding of the receptors. These compounds had little antagonistic activity according to the results of research on the soleus muscle and acted as Amylin agonists. Similar results were obtained with other agonistic compounds listed above.

Connection with the activity of Amylin antagonists used in the methods of treatment of hypokinesia of the stomach include the compounds described in patent application U.S. serial N 07/794 288, registered on November 19, 1991, the description of which in full is incorporated herein by reference.

Compounds such as described above, are prepared using standard techniques of solid-phase peptide synthesis preferably an automated or semiautomated peptide synthesis. In a typical case, the amino-protected-N-carbs is inert solvent, such as dimethylformamide, N-methylpyrrolidinone or methylene chloride, in

in the presence of interfacing agents, such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, in the presence of a base, such as diisopropylethylamine. Protecting group is N-carbarnoyl is removed from the compounds of the peptide and the resin using reagent such as triperoxonane acid or piperidine, and the reaction pair is repeated with the next N-protected acid that must be added to the peptide chain. Suitable N-protecting groups are well known in the art; the present invention are preferred t-butyloxycarbonyl (tboc) and fertilitycare (Fmoc).

Solvents, derivatives of amino acids and 4-methylbenzhydrylamine resin used in peptide synthesizer, was purchased from the company Applied Biosystems Inc. (Foster city, California), if you don't specify a different source. Amino acids with protected side chains purchased from the company Applied Biosystems Inc. included the following: BOC-Arg (MtS)*Fmoc-Arg(Pmc), Side - Tpe(BZl), Fmoc Tre (t-Bu), BOC-Ser (BZl), Fmoc-Ser (t-Bu), BOC-Tyr(BrZ), Fmoc-Tyr(t-Bu), BOC-Lys (Cl-Z), Fmoc-Lys (Boc), BOC-Glu(BZl), Fmoc-Glu(t-Bu), Fmoc-GIS(Trt), Fmoc-ASN(Trt) and Fmoc-GLn(Trt). Side-GIS(BOM) was acquired by the company Aldrich Chemical Company (Milwaukee, Wisconsin). Air Products and Chemicals (Allentown, PA) set HF. Ethyl ester, acetic acid and methanol were purchased from Fisher Scientific company (Pittsburgh, Pennsylvania).

Solid-phase peptide synthesis was performed on an automatic peptide synthesizer (model 430A, Applied Biosystems Inc., Foster city, California) using system NMP/HOBt (Option 1) and reagents tboc or Fmoc (see Applied Biosystems User's Manual for the AB1 430A Peptide Synthesizer, version 1.3 B, July 1, 1988, section 6, pages 49-70), Applied Biosystems Inc., Foster city, California) with capping.

Connection Side-peptide-resin was digested using HF (-5oC - 0oC for 1 hour). The peptide was extracted from the resin alternately with water and acetic acid, and the filtrate liofilizirovanny. Connection Fmoc-peptide-resin was digested using standard techniques (Introduction to Cleavage Techniquer, Applied Biosystems, Inc., 1990, page 6-12). Some peptides were also obtained using the synthesizer Advanced Chem. Tech. (model MPS 350, Louisville, Kentucky). The peptides were purified using GHUR with reversed phase (preparative and analytical) using a system Waters Delta Prep 3000. For isolation of peptides used C4, C8 or C18 preparative column (10 , 2,2 x 25 cm; Vydac, Hesperia, California), and purity was determined using a C4, C8 or C18 analytical koleosho 1.0 ml/min and preparative column - with a speed of 15 ml/min Amino acid analysis was performed on the system Waters Pico Tag and processed using Maxima. Peptides hydrolyzed using acid hydrolysis vapor phase (115oC, 20-24 hours). The hydrolysates were derivateservlet and were analyzed by standard methods (Cohen, S. A. Meys, M. u Tarrin, T. L. (1989), The Pico Tag Method: A Manual of Advanced Techniquer for Amino Acid Analisis, page 11-52, Millpore Corporation, Milford, Minnesota). Analysis of fast atom bombardment was performed by M-Scan, Incorporated (West Chester, PA). Exact mass measurements were performed using cesium iodide or cesium iodide/glycerol. Analysis of plasma desorption ionization using the detection time of the flight was performed on a mass spectrometer Bio-Ion 20, Applied Biosystems.

Peptide compounds suitable for the present invention can also be prepared using techniques of recombinant DNA, known to specialists. See, for example, Sambrook and other Molecular Cloning: A Laboratory Manual, 2nd edition Cold Spring Harbor (1989).

The compounds mentioned above, form salts with various inorganic and organic acids and bases. Such salts include salts prepared with organic and inorganic acids, for example HCl, HBr, H2SO4H3PO4that is th, maleic acid, fumaric acid and camphorsulfonic. Salt, cooked with bases include ammonium salts, alkali metal salts, for example sodium and potassium salts, and salts of alkaline earth metals, for example calcium and magnesium salts. Preferred acetates, hydrochloride and triptoreline. These salts can be prepared using standard techniques, for example by reaction of the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is then removed in vacuo or by freezing, or by ion exchange of an existing salt for other ions in a suitable ion-exchange resin.

The compounds described above are useful from the point of view of their pharmacological properties. In particular, the compounds of the present invention possess activity as agents to slow gastric emptying, as evidenced by their ability to lower glucose levels after food intake in mammals.

As described in example 1, was estimated effects of Amylin on tests glucose tolerance, administered orally, on dogs. Suddenly, Nilovna glucose), reduced glucose levels after meals in these experimental animals. Amylin all tested doses reduced the rate of rise of plasma glucose and peak plasma glucose test glucose tolerance, administered orally.

Example 2 describes the effects of Amylin agonist, AC-0137, on the levels of plasma glucose after a meal in clinical trials on humans. As with bolus injection, or by continuous intravenous infusion of AC-0137, in patients with juvenile diabetes mellitus was observed in a dose-dependent reduction of hyperglycemia after a meal. Example 3 describes the effect of continuous infusion of AC-0137 (triprolidine) on the levels of plasma glucose after ingestion of food Sustacaland after intravenous glucose load. When intravenous load glucose levels plasma glucose patients treated with 50 µg/h AC-0137, had no significant difference with those of patients receiving placebo. However, patients who were given the power Sustacaltreated with 25 µg/hour or 50 mcg/hour intravenous infusion of AC-0137, the levels of plasma glucose in patients treated with AC-0137, were lower compared with placebo. AC-0137 reduced concentrations of plasma glucose after a meal is on the concentration of plasma glucose after the appointment of an intravenous glucose load.

As described in example 4, a 14-day double-blind clinical trial with placebo control patients with juvenile diabetes, continued conventional insulin therapy and self-entered tripro-Amelina (AC - 0137) three times a day had lower average levels of glucose in the blood after an experimental meal than patients treated with insulin and placebo. After 14 days, a statistically significant (P=0.02) glucosegalactose effect (measured as area under the curve of glucose) was observed at 30 micrograms, peaks plasma concentrations tripro-Amylin was in the range of those found in the blood of adiabatical. Induced tripro-Amelina reduction in CPD was accompanied by an average reduction of 45-60 mg/DL peak concentrations of glucose in the blood of patients.

As described in example 5, gastric emptying was measured in normal and patients with insulin spontaneously diabetic rats CENTURIES, using the delay colored gel methylcellulose containing Phenol red and administered via a stomach tube. Painted the contents of the stomachs removed after sacrifice of the animals 20 minutes later, was determined by the spectroscopic method and compared with the contents of the stomachs of rats, womersley Aravali significantly more gastric emptying (90,3 1.7 percent passing) compared with normal rats (Harlan Sprague Dawley 49,1 4.7 percent passing, P < 0.001) and compared with neadiabaticheskie rats CENTURIES (61,1 9.2 percent passing; P < 0,001). Pancreatic-cell peptide, Amylin, which is scarce in IDDM, a dose-dependent manner inhibited gastric emptying in normal and diabetic rats. ED50reactions as normal and diabetic rats was approximately 1 μg dose, which caused the peak concentration of Amylin 76 PM 20 minutes after injection. These concentrations are within the range observed in vivo. These results support the assumption that Amylin is involved in the physiological regulation of the passage of food into the duodenum.

As described in example 6, the absorption of oral load of labeled glucose was measured on an empty stomach in rats LA/N with obesity. Pre-injection of the antagonist milinovich receptors, as-0187, accelerated the appearance in the plasma tritium from glucose. In addition, the preliminary injection of Amylin antagonist caused a higher rise of plasma glucose 15 minutes of vPost after insertion through the probe and earlier the fall of the levels of plasma glucose. These data are consistent with the fact that the Amylin antagonist AC-0187 will neutralize the effect of endogenous secreted ariannah rats was shown to that Amylin does not affect the absorption of glucose into the blood from the small intestine. In these experiments, shot to rats produced a long-term infusion of rat Amylin (0.35 nm/kg/min) or saline in the case of control animals within 3 hours. After one hour infusion of Amylin, through a tube inserted through the esophagus, animals bolus was injected glucose (1 g/kg) in the stomach or in the duodenum. Since the study was carried on shot rats, but not rats, which is in the normal state, they are not used to study the motility of the stomach, such as the speed of emptying of gastric contents into the duodenum. However, these studies have shown that glucose absorption from the duodenum into the blood did not stop amilina. For a more precise definition, does Amylin on the transit of glucose from the lumen of the small intestine into the blood, used a variety of drugs. The shot rats segment of the small intestine that connects to the body of the animal through the circulatory system were taken out and placed in the cannula so that the small intestine can be perfusionist solutions of known glucose is Lina, insulin and glucose). The lumen was perfesional glucose solution, labeled with tritium. The passage of glucose from the intestinal lumen into the blood was measured by the appearance of tritium label in the plasma. The assumption, what is the appearance of tritium in plasma really reflects the absorption of glucose from the intestine, was tested by the introduction of the blocker transport of glucose, phloridzin. Phlorizin to a large extent prevented the transit label from the intestinal lumen into the plasma. To ensure that the gradient of glucose between the intestinal lumen and plasma will remain constant during the Amylin infusion, plasma glucose "fixed" by glucose infusion, which was changed in response to changes in plasma glucose. This drug intravenous infusion of Amylin did not affect the rate at which labeled glucose was present in the small intestine, penetrate into the plasma. These results show that the low content of glucose in the blood, observed in patients treated with amilina, in the studies described above, it is likely not caused by the decrease in absorption from the small intestine, but rather was caused by the lowered rate of passage of gastric contents into the duodenum, i.e., delayed emptying of the stomach.

Compounds used in the present invention, can be prepared in the form of parenteral compositions for injection or infusion. They may, for example, suspenderbelt in inert oil, especially in the plant, such as sesame, peanut, olive, or the Ohm buffer solution with a pH of about 5.6 to 7.4. These compositions can be sterilized using standard sterilization methods or by filtration. These compositions may contain pharmaceutically acceptable auxiliary substances required to best suit the physiological conditions such as pH buffering agents. Suitable buffers include, for example, buffers, sodium acetate/acetic acid. Form of repository or depot-drug slow release can be used so that a therapeutically effective amount of drug delivered into the bloodstream over many hours or days after percutaneous injection or delivery.

The desired isotonicity can be achieved by using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, polyhydric alcohols (such as mannitol or sorbitol) or other inorganic or organic solute. Sodium chloride is particularly preferred for buffers containing sodium ions.

If desired, the solutions of the above compositions can be thickened with a thickener such as methyl cellulose. They can be manufactured in the form of an emulsion type vo agents, including, for example, acacia powder, non-ionic surfactants (such as tween) or ionic surfactants (such as alkaline polyether sulfates of alcohols or sulfonates, such as Triton).

The composition used in the present invention are prepared by mixing the ingredients according to standard techniques. For example, the selected components can simply be mixed in the mixer, or other standard device for preparing a concentrated mixture, which can then be diluted to the desired concentration and viscosity by the addition of water or thickening agent and may buffer to control pH or an extension of the solute to control osmotic pressure.

For use by a physician of the songs will be created in the form of dosage units containing a certain amount of Amylin or Amylin agonist, such as agonistic analog of Amylin with another delaying gastric emptying agent, or without it, which will be effective in one or multiple doses to control blood sugar at the selected level. A therapeutically effective amount of Amylin or Amylin agonist, such as agonistic and favorable way slowing down or regulated, amount to such amounts that reduce the levels of glucose in the blood after a meal, preferably not more than 8 to 9 mm, or such amounts that reduce the levels of glucose in the blood to the desired. Diabetics or others with intolerance glucose levels plasma glucose higher than in healthy people. Such patients can be obtained favorable reduction or "smoothing" of the levels of glucose in the blood after a meal. Specialists in this field it is known that an effective amount of therapeutic agent will vary depending on many factors, including the age and weight of the patient's physical condition, the blood sugar level or reduction steps Amylin, which is to be obtained, and other factors.

Such pharmaceutical compositions useful for application to cause the hypokinesia of the stomach of a patient and can also be used in other pathologies, when it is necessary to reduce the motility of the stomach.

Effective daily inhibiting gastric emptying dose of compounds, including18Arg25,28Pro-h-Amylin, OTC1Liz18Arg25,28Pro-h-Amylin, 18Arg25,28,29Pro-h-Amylin, OTC1Liz18Arg25,28,29Pro-h-Amylin, 25 the typical case will be in the range of 0.01 or 0.03 to about 5 mg/day, preferably from about 0.01 or 0.5 to 2 mg/day and more preferably approximately from 0.01 or 0.1 to 1 mg/day, for a patient weighing 70 kg, with the introduction of single or divided doses. The exact dose, which must be entered, determined by the attending physician; it depends on whether a particular connection in the quoted list, and the age, weight and condition of the patient. The introduction should begin at the first manifestation of symptoms or shortly after diagnosis of diabetes. The administration can be by injection, preferably subcutaneous or intramuscular. Active in oral administration the compounds can be taken inside, but the dose should be increased by 5-10 times.

In General, in the treatment or prevention of elevated, inappropriate or undesirable levels of glucose in the blood after ingestion of the compounds of the present invention can be administered to patients in need of such treatment, at doses similar to those given above, however, the compounds are administered more frequently, for example once, twice or three times a day.

Amylin antagonists used for the treatment of hypokinesia of the stomach, can be administered in doses from 0.1 to 30 mg/day, predpochtitelnye. Active in oral administration the compounds can be taken inside, but the dose should be increased by 5-10 times.

To help better understanding of the present invention, the description included the following examples, which describe the results of a series of experiments. The experiments relating to this invention should not, of course, be construed as limiting the invention; such options, currently known or later developed, which are in the competence of the expert, fall within the scope of the present invention, as described herein and claimed below.

Example 1

Previous studies have demonstrated that intravenous injection of Amylin hungry and fed to rats in the test conditions on glucose tolerance can reduce the fall in plasma glucose and increased plasma lactate dose-dependent manner. Responses to insulin also significantly decreased by Amylin infusion from hungry animals.

However, the following studies and experiments have shown that the infusion of Amylin reduces the levels of plasma glucose in dogs that have arisen in response to oral glucose load. The objectives of these studies were:

(1) assess the>(2) evaluate the effects of intravenous administration of Amylin on these indicators;

(3) to evaluate the effectiveness of Amylin antagonist AC-0253 (acetyl-11,18Arg,30Arg,32Tyr-9-32calcitonin (salmon) in the reversal onelinedrawing changes in plasma glucose of blood.

For this study used the half-dogs (9 males weighing 12-17 kg). Animals were not fed before each study during the night. Each animal served as its own control in all experiments. Animals were balanced within 30-60 minutes before beginning each experience.

Began to enter the media or Amylin AC-0253 at t = -30. The speed of doses of Amylin was 50, 100 and 300 pmol/kg/min Rate of administration AC-0253 was 500 and 1500 pmol/kg/min 25% glucose (1 g/kg) was administered through the mouth at t = 0 minutes. Introduction Amylin AC-0253 stopped at t = 120 minutes. Samples for the determination of insulin, glucose and lactate were obtained in 15-minute intervals from t = -45 to t = 180 minutes. Samples for the determination of rat Amylin and AC-0253 took at t = 60 and 120 minutes.

In healthy dogs, peak plasma glucose was observed between 30 and 45 minutes after oral glucose load. Although there was considerable variabie all tested speeds the introduction of a reduced rate of rise of plasma glucose, and her peak. During infusion of Amylin plasma glucose reached a plateau at lower values than in the control experiments, for 30-45 minutes, and began to grow again after stopping the infusion of Amylin. Between speeds doses of Amylin 50, 100 and 300 pmol/kg/min, there were no differences in the changes in plasma glucose. Fig. 5 demonstrates the effect of Amylin (50 pmol/kg/min) at the level of plasma glucose after oral administration of glucose.

The speed of doses of Amylin 50 pmol/kg/min beat selected for experiments evaluating the effectiveness of AC-0253 against reversal onelinedrawing changes in plasma glucose. AC-0253 up to 1500 pmol/min not reversional fully the effects of Amylin (50 pmol/kg/min). AC-0253 separately had no effect on changes in plasma glucose. The effect of Amylin and AC-0253 plasma lactate was negligible.

Example 2

In clinical trials of Amylin agonist AC-0137 participated 24 male patient with diabetes mellitus. Each patient is blind method was assigned to one of four groups receiving placebo, 30, 100 or 300 μg AC-0137. Patients in each group underwent two periods popelement consisted of a three-day stay in the unit of observation. In each case, the initial day of the study was dedicated to acclimatization to the experimental conditions. The second and third day was dedicated to cross-research placebo and active treatment. For example, patients selected to receive an intravenous bolus, then received an intravenous bolus AC-0137 one day and intravenous bolus placebo - another day (or in reverse order - first bolus placebo, and then bolus AC-0137). Two weeks later, patients received the same dose of AC-0137 through other way of introduction, i.e. intravenous infusion. Cross route of administration of drugs and placebo at 2 and 3 days was performed in the same way as in the first case. Six patients assigned to the placebo group received placebo during all days of the study.

In the days of the study patients were placed intravenous catheters at least 30 minutes before the start of the study. 15 minutes prior to dose patients received their usual dose of insulin by subcutaneous injection. At time 0, the patients received an intravenous bolus prescribed dose AC-0137 or placebo for two minutes or continuous infusion of AC-0137 or placebo, which lasted two hours. The infusion rate was adjusted so that westrac. Blood samples were taken between -30 and 300 minutes for measurement levels AC-0137 in plasma and glucose levels in plasma.

As follows from Fig. 2-4, the levels of drug in plasma showed the expected peak shortly after the bolus, and then disappeared from the plasma fraction with the apparent kinetics of the first order. In contrast, continuous infusion resulted in approximately stable levels within 30 minutes, and then to maintain these levels during the entire period of infusion. After the infusions, plasma levels were similar disappeared with intravenous bolus dosing.

Profiles of plasma glucose was found some unexpected and interesting results. Assessment in patients receiving placebo in each case, the levels of plasma glucose rose above the source for 60-90 minutes, and remained elevated for at least 240 minutes. Intravenous bolus AC-0137 in a dose of 30 mcg did not cause obvious changes in the glucose levels. When the bolus dose of 100 µg rise of glucose after a meal clearly was delayed and was less pronounced. At the dose of 300 µg bolus rise in glucose levels after food intake was significantly reduced.

Prolonged intravenous intuitively dubious effect, and after increasing the rate of infusion up to 50-150 g/hour was observed a striking reduction of the rise of glucose levels caused by eating. Similar trends were evident in the studies that used a bolus of medication.

Example 3

Single-blind placebo control two-stage cross-sectional study with a minimum 15-hour period for washout between treatments was undertaken to further demonstrate the effect tripro-Amylin (AC-0137) to reduce hyperglycemia-induced food intake, and to confirm the fact that reduction of hyperglycemia-induced food intake is primarily gastrointestinal effect. 27 patients with diabetes mellitus were divided into two groups with different levels of doses that were used two types of tests tolerance. Patients received treatment with long microinfusion discharge A-0137 and placebo according to a cross-way experiment. The patients were divided into three groups of 9 people each as follows: group a received power Sustacaland AC-0137 dose of 25 mcg/hour. Group b received power Sustacaland AC-0137 dose of 50 µg/cha is the clinic for three days. On the first day of the experiment, patients were acclimatized in the clinic. On 2 and 3 day patients underwent two-stage cross-sectional study using AC-0137 and placebo. In addition, patients received nutrition Sustacalor intravenous test glucose tolerance depending on the group type.

During the first day spent stabilizing the usual dose of insulin and the calories in each patient, which is then adhered to these doses of insulin and diet during the whole time of stay in hospital.

At approximately 0700 hours (T=0) began continuous infusion of the test drug. At T=30 minutes, the patients received their usual morning dose of insulin. At T=60 minutes patients received standardized meals Sustacalcontaining 355 calories, or intravenous glucose load of 300 mg/kg as an intravenous infusion D50W for five minutes using an infusion pump. Type of test tolerance was determined in accordance with the scheme of randomization. Blood samples were taken at regular time intervals to measure the levels of glucose, lactate and insulin, as well as to determine plasma concentrations of AC-0137. Introduction test what we as in day 2. Patients received their usual dose of insulin before Breakfast, as in 2 day. Patients received placebo or the drug cross using the same intravenous route of administration and schema as in the previous day (i.e., patients who received an infusion of AC-0137 second day, the third day received a placebo infusion). Again used as the second day, identical to the standardized food Sustacalor intravenous glucose load. At the end of the period of sampling blood intravenously system was removed.

As shown in Fig. 10, when the intravenous glucose load levels of plasma glucose in patients treated with 50 µg/h AC-0137, did not differ significantly from those in patients receiving placebo. These differences in injection concentrations of glucose were statistically significant when comparing the area under curve of glucose, adjusted for baseline values (P= 0,0015). Thus, the observed reduced hyperglycemia-induced food intake, during the administration of AC-0137 was confirmed using a standardized power in the presence of significantly lower plasma concentrations of AC-0137 than those that were applied p is kg/hour or 50 µg/h AC-0137 intravenous infusion, the levels of plasma glucose were reduced in treated AC-0137 patients compared with placebo.

AC-0137 portable pharmacological doses reduced the concentration of plasma glucose after oral nutrients in patients with insulin-dependent diabetes, but had no measurable effect on the concentration of plasma glucose after administration of intravenous glucose load. These results are consistent with the idea that AC-0137 modulates the absorption taken per os nutrients from the intestines, and show that the change in the speed of emptying of the stomach is responsible at least partly for this effect.

Example 4

Conducting a randomized, double-blind parallel group placebo control was created to determine the effect tripro-Amylin (AC-0137) on the levels of plasma glucose after oral administration of a standardized power Sustacal(Mead - Johnson). In 14-day clinical study involved 72 patients with insulin-dependent diabetes mellitus. Each patient random method was selected in one of four experimental groups receiving placebo, 30, 100 or 300 µg tripro-Amylin by subcutaneous injection three times a day for 14 days. In the performed tests the tolerance to the standardized food.

To test the tolerance to the standardized nutrition patients were given a liquid diet Sustacal(360 ml, contains 360 calories) at 0800 hours. Patients refrained from eating or drinking (except water) from the 2200PM the previous day. Patients did not enter his usual morning insulin dose up to 30 minutes before taking food Sustacal. For the initial test, 1 day, triprolidine (or placebo) was not introduced until the completion of the test. At 7 and 14 days tripro-Amylin (or placebo) was administered as a separate injection at the same time as the usual morning dose of insulin. Blood samples for determination of serum levels of glucose were selected on- 30, 0, 30, 60, 120 and 180 minutes relative to the start of testing. Time 0 is the time at which the patient started to take nutrition Sustacal.

As shown in table 1 below and in Fig. 8, 12 and 13, after 14 days, there was a statistically significant (P=0.02) smoothing glucose levels effect (measured as area under the curve) at dose levels of 30 µg and 100 µg. Tripro-Amylin (AC-0137)-induced reduction in the area under the curve (CPD) was accompanied by average reduction of up to 45 mg/DL 60 mg/DL peak concentrations of glucose in the blood of patients.

(a) the CPD of prala experimental meal and 3 hours after. Change ACC represents an amount equal to the value before the introduction of dose minus the value on day 14, for each patient tested both days.

(b) the values of P obtained from the nonparametric Wilcoxon test.

Example 5

Howled made following a study of the effects of Amylin agonists on gastric emptying in rodents with spontaneous autoimmune diabetes treated with insulin rats CENTURIES.

In the experiments used male rats Harlan Sprague Dawley (HSD) (161-244 g) and Biobreeding (BB) (181-405 g), obtained from the kennel Mllegard, Denmark, in 1989. The diagnosis of diabetes in BB rats was confirmed by the results of glycosuria during at least 2 days, then every day they were treated with subcutaneous injections of recombinant human insulin long-acting (Humulin - U, Eli Lilly, Indianapolis). Insulin therapy was aimed to maintain glucose, but to minimize ketone bodies in the urine, in order to avoid death from hypoglycemia. In fact, glucosuria was detected in 88% of the measurements, and ketonuria in 52%. The average duration of diabetes was 53 5 days, and daily insulin requirement was 4.7 0.3 units. Animals were kept under 22,7 0,8oC and 12:12 ibitum (diet LM-485, Tehlad, Madison, Wisconsin).

Determination of gastric emptying in the manner described below, is typically conducted after approximately 20 hours of fasting animals, to ensure the absence in the stomach chyme, which could put spectrophotometric measurements of absorption. However, rats with diabetes treated with long acting insulin (Ultralente), it was impossible to starve to 20 hours. Periods of fasting more than 6 hours resulted in hypoglycemia. These animals therefore refrained from food only 6 hours before measurement of gastric emptying. Normal rats were deprived of food for periods of 6 or 20 hours before the experiment. We noticed that even normal BB rats had higher concentrations of glycated hemoglobin, which is possible testified subclinical deficiency of insulin. Thus, for comparison with diabetic rats used healthy rats Harlan Sprague Dawley and BB. So, there were 5 experimental groups:

(1) Healthy (without diabetes) rats Harlan Sprague Dawley, starving 6 hours, n = 8.

(2) Healthy (without diabetes) BB rats, starving 6 hours, n = 6.

(3) BB Rats with diabetes, starving 6 hours = 10.

(4) Healthy (without diabetes) rats Harlan Sprague Dawley, starving 20 alocale via a stomach tube 1.5 ml contained no calories gel with 1.5% methylcellulose (M-0262, Co., St. Louis, mo) and 0.05% phenol red as an indicator. Twenty minutes after intubation, rats were anestesiologi 5% halothane gas, exposed stomach and perikli pyloric and lower esophageal sphincter using arterial clamps were removed and aparently in an alkaline solution of fixed volume. About the contents of the stomach were judged by the intensity of phenol red in alkaline solution, which was measured by absorption at the wavelength of 560 nm. In most experiments, the stomach was free. In other experiments containing particles of stomach contents were centrifuged to enlightened solution to measure absorption. Where the diluted gastric contents remained turbid, spectroscopic absorption of phenol red was calculated as the difference between those present in the alkaline solvent and acidified diluent. In separate experiments on 7 rats dissected and the stomach and small intestines and drained them in an alkaline solution. The amount of phenol red, which could be isolated from the upper part of the gastrointestinal tract within 20 minutes of probing, was 89 4%. To calculate the maximum highlight ink, comprising less than 100%, the content, Eys, murdered immediately after sensing in the same experiment.

In the original studies (where Amylin was not introduced) gastric emptying after 20 minutes was determined in five experimental groups as described above. In studies of the dependence of the response on the dose of rat Amylin (Bachem, TORRANCE, Calif.) dissolved in 0.15 M saline solution, was administered as 0.1 ml subcutaneous bolus at doses of 0, 0,01, 0,1, 1, 10 or 100 μg for 5 minutes before feeding through a tube 46 rats Harlan Sprague Dawley (without diabetes), starving 20 hours (n= 17, 2, 8, 8, 6, 5, respectively) and 29 BB rats(diabetes), starving 6 hours (n= 10, -, 3, 3, 3, 10 respectively.

In a separate experiment to assess changes in concentrations of plasma Amylin, which caused the effective dose of Amylin under the skin, took blood samples from the tailings 6 shot with halothane gas rats after subcutaneous injection of 1 μg (n = 3) or 10 μg (n = 3) rat Amylin. In another experiment the concentration of plasma Amylin compared have not starving rats Harlan Sprague Dawley (n = 8) and not starving diabetic BB rats (n = 5). Plasma from 250 µl of the samples taken in 10-minute intervals, separated and frozen at -20oC for dvuhsostavnogo immunoenzymometric analysis, developed the Yety (Dynatech, Chantilly, Virginia) were coated with antibodies F024-4.4 (Phelps, J. L., Blase, E., Koda, J. E., unpublished) by incubating overnight at 4oC with a solution containing 20 EDr antibody per ml in 50 mm carbonate, pH of 9.6. The tablets were washed with 0.05 M Tris/0.15 NaCl /0.02% of sodium azide/ 0.1% tween-20 (TBS/tween) and blocked with 1% powder nonfat dry milk in the same carbonate buffer for one hour at room temperature. The samples were thawed in ice and diluted with 4% BSA under layer 200 mg/DL bovine serum cholesterol (Miler Pentex reagents, Miles Laboratoties, Kankakee, Illinois) as needed. Samples or standards were placed on the coated and blocked plates and incubated for one hour at room temperature. After laundering was added F025-27 detects antibodies conjugated with alkaline phosphatase. Conjugation of antibodies with the enzyme was performed using a kit for conjugation of alkaline phosphatase-maleic acid imide firm Pierce Immunochemical Co. (Rockford, Illinois). The conjugate was incubated for three hours at room temperature, after which the tablets are thoroughly washed with a physiological solution with Tris buffer. Bound enzyme was detected by incubation of the tablets with the fluorescent substrate 4-methylumbelliferone signal was measured using a tablet reader Dynatech Mircofluor, and the results were analyzed using Multicalc Software (Wallac, Gaithersburg, Maryland). The Amylin concentration in plasma samples was determined by comparison to a standard curve obtained in the same study. With this method the analysis had at least caught a concentration of 2 PM.

Curves of the response of the dose for gastric emptying were reduced to a 4-parameter logistic model was used to derive the ED50repeating the method of least squares (ALL FlT, 2.7, NlH, Maryland). Because the ED50distributed logarithmically, it expresses the standard error of the logarithm. Comparison pairs was performed using one-way analysis of variants and test of multiple comparisons by the student-Newman-Celsa (Instat 2.0, Graph Pad Software, San Diego), using a significance level of P < 0,05.

8 negativly rats Harlan Sprague Dawley concentration of circulating Amylin was 11.7 1,4 PM (95% Cl 8.4-14,9 PM). For comparison, concentrations of Amylin 5 not starving BB rats with spontaneous diabetes were not found.

Faction colors, the remaining 20 minutes after insertion through the gastric tube phenol red, together with the corresponding statistical comparisons are shown in table Simo from starved animals 6 hours or 20 hours. This means that the duration of starvation (within 6-20 hours) had no significant effect on gastric emptying, defined in this way.

Stomach content expressed as a fraction of that which could be allocated immediately after feeding through a tube 2-3 rats individually, participating in the same study.

a = not different from rats, starving 20 hours

b = different from HSD rats, starving 6 hours (P < 0,001)

c = different from BB rats (without diabetes), starving 6 hours (P < 0,001)

Deserves attention is the fact that gastric emptying in rats BB with diabetes was significantly faster (P < 0,01-0,001) than in any of the 4 other experimental groups (i.e., animals without diabetes). The observation that BB rats with diabetes had a higher rate of gastric emptying than BB rats without diabetes, suggesting that this circumstance is connected with presence of diabetes, and not just due to line BB.

Given the methodological difficulties mentioned above, the effects of Amylin was studied on rats Harlan Sprague Dawley without diabetes, starving 20 hours, and BB rats with diabetes, starving 6 hours. In case culdve indicator, observed dose-dependent suppression of gastric emptying. Suppression of gastric emptying was such that the separation of the paint from the normal HSD rats, which were injected with 1 mg of Amylin, and in rats with diabetes, which was administered 1 g, was the same as what was observed immediately after feeding through a stomach tube (P=0,22, 0,14). Dose, which was observed in 50% of the maximum changes of gastric emptying (ED50), normal rats was 0,43 g (0,60 nmol Amylin per kg body weight) at 0.19 log units. In rats with diabetes ED50for suppression of gastric emptying was 2.2 µg (2.3 nmol/kg) of 0.18 log units. Processed by the curve shown in Fig. 14, it can be seen that the dose of Amylin approximately 2 µg entered the rat with diabetes, reduced gastric emptying up to speed observed in normal rats not treated with Amylin.

As shown in Fig. 15, when 3 rats were subcutaneously injected with 1 µg of rat Amylin, its concentration in plasma, measured 10 minutes later, was 66 10 PM, and the peak concentration after 20 minutes was 74 26 PM. In 3 rats, which were subcutaneously injected with 10 μg bolus corresponding to the 10 - and 20-minute concentration was 347 43 PM and 301 57 PM, respectively. 1 µg subcutaneous is and start to work soon after the injection, the inducing effect after 20 minutes. The effect, which was started about 20 minutes after the injection, for example, cannot be detected using this system. From this it follows that the concentration in the plasma, effective for 50% inhibition of gastric emptying ((ED50), was observed well before reaching peak plasma concentrations in PM 74 and, therefore, were significantly less than 74 PM.

The results of these experiments show that Amylin strongly and dose-dependent way, inhibits gastric emptying.

Example 6

The experiments described in this example were performed to study the effects of Amylin receptor antagonist on glucose tolerance, adopted per os, and absorption of tritium in labeled glucose adopted per os as a load.

Absorption adopted through the mouth glucose load were determined in 11 in consciousness starving 24 hours fat (500 - 600 g) rats LA/N in two versions, for 14 days each. In one embodiment, the rats were subcutaneously injected with 3 μg selective Amylin antagonist AC-0187 (AC-10N32Y8-32salmon calcitonin) for three minutes before feeding through a stomach tube. In another embodiment, the rats were injected with only the physiological media is taken after anaesthesia their tails through 0, 15, 30, 60, 90 and 120 minutes after feeding through a tube, investigated for the presence of tritium from glucose and glucose.

As shown in Fig. 16, the preliminary injection of Amylin antagonist AC-0187, accelerated the emergence of tritium (from glucose) in plasma by 48% after 15 minutes after feeding through a stomach tube (P < 0.02) and 45% (P < 0,001) after 30 minutes after feeding through a stomach tube (paired t-test). As shown in Fig. 17, the preliminary injection of AC-0187 has also led to a more pronounced rise of plasma levels of glucose 15 minutes after insertion through 0.5 g of glucose (of 5.89 0.17 to 8,33 0.28 mm compared to 6,83 0.28 mm, P < 0,001, paired t-test). In addition, in animals, which were injected as-0187, plasma glucose decreased before (6,89 0.28 mm compared with 8,15 to 0.39 mm after 60 minutes after administration of glucose via a stomach tube, P < 0,001, paired t-test).

Thus, in obese rats LA/N selective Amylin antagonist increased the rate of appearance in plasma labeled glucose after oral glucose load, and increased the speed of the rise and fall of plasma concentrations of unlabeled glucose. These data confirm that the Amylin antagonist, counteracting the effect of endogenous secreted Amylin, accelerates, this is of emptying of the stomach of the patient, including the introduction of the indicated patient a therapeutically effective amount of Amylin or Amylin agonist, the Amylin agonist is not PLC or calcitonin.

2. The method according to p. 1, characterized in that the method comprises the reduced motility of the stomach.

3. The method according to p. 1, characterized in that the method comprises the delayed emptying of the stomach.

4. The method according to p. 1, 2 or 3, characterized in that the patient is exposed to gastrointestinal diagnostic procedure.

5. The method according to p. 4, characterized in that the specified gastrointestinal diagnostic procedure is a radiological study.

6. The method according to p. 4, characterized in that the specified gastrointestinal diagnostic procedure is magnetic resonance imaging.

7. The method according to p. 1, 2 or 3, characterized in that the motility of the stomach is associated with lesions of the gastrointestinal tract.

8. The method according to p. 7, characterized in that the gastro-intestinal tract is a spasm.

9. The method according to p. 8, characterized in that the spasm is associated with a lesion selected from the group consisting of astroglia occur after eating, dumping syndrome in a patient, including the introduction of the indicated patient a therapeutically effective amount of an Amylin agonist, the Amylin agonist is not PLC or calcitonin.

11. The method of treatment may occur after meal hyperglycemia, including the introduction of a therapeutically effective amount of an Amylin agonist, the Amylin agonist is not PLC or calcitonin.

12. The method according to p. 11, characterized in that the said Amylin agonist is amilina.

13. The method according to p. 12, characterized in that the said Amylin is a mouse-Amelina.

14. The method of treatment may occur after meal hyperglycemia, which is a consequence of diabetes mellitus type 2, which includes the introduction of a therapeutically effective amount of an Amylin agonist, the Amylin agonist is not PLC or calcitonin.

15. The method according to any of the p. 1-3, 10, 11 or 14, characterized in that the specified agonist analogue of Amylin is25,28,29Pro-h-Amelina.

16. The method of treatment for the ingestion of the toxin, including the introduction of the Amylin or Amylin agonist in an amount effective to prevent or reduce the passage of stomach contents into the intestine, and ASPI is


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FIELD: medicine, otorhinolaryngology.

SUBSTANCE: one should treat deformation in laryngeal and tracheal lumen due to excessive growth of granulation tissue in the sites of their lesions. One should introduce hormonal preparations, moreover, one should apply Diprosan as a hormonal preparation injected once intramucosally at 0.1 ml/sq. cm of granulation tissue, but not more than 0.3 ml.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl