Agent for preventing and treating pancreatitis

A pancreatitis and prophylactic technology, applied in the field of pharmaceuticals for the prevention or treatment of pancreatitis, can solve the problems of no prompt, no explanation of the relationship between pancreatitis and the like

Inactive Publication Date: 2008-06-11
CYTOPATHFINDER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no suggestion that this effect is based on 5-HT2A receptor antagonism
[0017] In addition, although Yoshino et al. (J.Pharmacol.Exp.Ther.283(3), 1495-1502, 1997) suggested that the activation of 5-HT2 receptors is related to the pathogenesis of acute pancreatitis, regarding 5-HT2A, 5-HT2B and 5-HT2C receptor antagonism and pancreatitis without any indication

Method used

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  • Agent for preventing and treating pancreatitis
  • Agent for preventing and treating pancreatitis
  • Agent for preventing and treating pancreatitis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Using antagonists of 5-HT2A receptors, 5-HT2B receptors, and 5-HT2C receptors, receptor subtypes involved in the onset of pancreatitis were investigated. As an animal model, acute pancreatitis was used in which mice were induced by excessive administration of cholecystokinin from frog skin. Unlike CDE pancreatitis, this model is not affected by food intake, so a stable pathological state can be obtained and more accurate data analysis can be performed.

[0083] method:

[0084] Five administrations were performed by subcutaneously injecting an aqueous solution of frog skin cholecystoin (0.05 mg / Kg) to 5-week-old mice at intervals of 1 hour. The 5-HT2 antagonist was suspended in a solvent (physiological saline containing 0.5% methylcellulose), and subcutaneously administered on the back 15 minutes before the initial administration of cholecystokinin. As 5-HT2 antagonists, katanserin (5-HT2A / C antagonist), SB204741 (5-HT2B antagonist), and SB242084 (5-HT2C antagonist) c...

Embodiment 2

[0088] To investigate the effects of various 5-HT2A antagonists on the activities of amylase and lipase in plasma of mice with frog skin cholecystoin pancreatitis. As 5-HT2A antagonists, use risperidone (Risperidone), spiperone (Spiperone), ketanserin (ketanserin), AMI-193 and MDL11939 with the dosage shown in the figure, and the frog The cholecystokinin pancreatitis model mice were administered, and the amylase and lipase activities in the plasma were measured.

[0089] The results are shown in Table 2. Calculate the inhibitory rate of each drug (3.2mg / Kg) to amylase activity, and arrange in order of strength of action as follows: risperidone (52%)>spiperone (41%)>ketanserin (37%)>AMI -193 (17%) > MDL11939 (-4%). This sequence also showed the same results in other doses and lipase activities.

[0090] Moreover, this order is consistent with the known affinity strength of each drug for the 5-HT2A receptor subtype (Table 1).

[0091] Table 1

[0092] Binding activity of va...

Embodiment 3

[0100] To investigate the effects of various 5-HT2 antagonists on the activities of amylase and lipase in plasma of mice with frog skin cholecystoin pancreatitis. As 5-HT2 antagonists, use Metergoline (Metergoline), Methysergide (Methysergide) and Litanserin (Ritanserin) with the dosage shown in figure, same as embodiment 1, to the frog skin cholecystokinin pancreatitis model The mice were administered, and the activities of amylase and lipase in plasma were measured. As shown in Table 2, the above-mentioned 5-HT2 antagonists have higher binding activity to 5-HT2A receptors than the above-mentioned ketanserin, and are tied to spiperone, but also have high binding activity to 5-HT2B and 5-HT2C receptors active.

[0101] Table 2

[0102] Binding activity of various drugs to 5-HT2 receptor subtypes

[0103] 5-HT2A

pKi±SEM

5-HT2B

pKi±SEM

5-HT2C

pKi±SEM

Methergot

8.40±0.16

9.44±0.05

8.60±0.05

Litanserin

...

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Abstract

A pharmaceutical composition for preventing and treating pancreatitis comprising as an active ingredient, a 5-HT2A receptor antagonist, characterized in that the binding activity (pKi) of the 5-HT2A receptor antagonist to 5-HT2A receptor is higher by a value of not less than 1.0 than the binding activity to 5-HT2B and 5-HT2C receptors is disclosed. The binding activity (pKi) of the 5-HT2A receptor antagonist to 5-HT2A receptor is preferably 7.0 or higher and more preferably 8.0 or higher. The invention also provides a method of identifying a candidate substance of the agent for preventing / treating pancreatitis comprising measuring whether or not a test substance has a 5-HT2A receptor antagonism.

Description

technical field [0001] The present invention relates to medicines for preventing or treating pancreatitis. Background technique [0002] Pancreatitis is an inflammation of the pancreas and can be divided into acute pancreatitis and chronic pancreatitis. Pancreatic juice contains digestive enzymes such as amylase (to break down carbohydrates), trypsin (to break down proteins), lipase (to break down fats). Pancreatitis refers to a state in which pancreatic juice cannot flow smoothly due to excessive intake of alcohol or gallstones, and the pancreas is self-digested by the above-mentioned enzymes. It can be broadly classified into a mild type in which interstitial edema and peripancreatic fat necrosis are seen, and a severe type in which extensive necrosis of peripancreatic and intrapancreatic fat, pancreatic parenchymal necrosis, or hemorrhage can be seen. [0003] When the pancreas is inflamed, the amylase or lipase contained in the pancreatic juice flows out into the blood...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/50A61K45/00A61P1/18A61P43/00G01N33/15A61K31/517C07D401/06C07D471/04C07D471/10
CPCC07D471/04G01N2500/04G01N33/6893G01N2800/067G01N33/942C07D401/06A61K31/517C07D471/10A61P1/18A61P29/00A61P43/00G01N33/15G01N33/50
Inventor 山口勇浜田健太郎樫原康成
Owner CYTOPATHFINDER INC
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