WO2001062244A1

WO2001062244A1 - Agents ameliorating sickness behaviors

Info

Publication number: WO2001062244A1
Application number: PCT/JP2001/000791
Authority: WO
Inventors: Toshihiro Okamoto
Original assignee: Nippon Chemiphar Co., Ltd
Priority date: 2000-02-23
Filing date: 2001-02-05
Publication date: 2001-08-30
Also published as: JP2001233771A; AU2001228876A1

Abstract

Agents ameliorating body weight loss or anorexia in association with diseases such as liver diseases and agents ameliorating sickness behaviors. Preparations containing zaltoprofen as the active ingredient are used as agents ameliorating body weight loss or anorexia and agents ameliorating sickness behaviors.

Description

Improve agent for varnish behavior

Technical Field The present invention relates to an agent for improving sickness behavior. Background Art Symptoms Among patients suffering from diseases such as chronic liver disease, there are symptoms such as fatigue, fatigue, loss of appetite, weight loss, weakness, and reduced concentration. (Hepatology Book

(1995) 22: 1606-1608, | 1 (1990) 12: 98-105, [! (1998) 28: 1561-1565) These symptoms are called "Sickness behavior". However, even though patients may report symptoms of sickness beha vior such as loss of appetite, fatigue, and malaise, no treatment has been established in many cases, and no solution has been provided. It is. Therefore, it has been proposed that Sickness behavior is a target for drug development. (Trends Pharmacol Sci (1992) 13: 24-28) By the way, it is known that the induction of this sickness behavior involves the expression of cytokins such as Intel eukin-1 j3 and TNF-a in [!]. ing. (Hepatolo gy (1998) 28: 1561-1565) On the other hand, zanoretoprofen ((±) -12- (10,11-dihydro—10-oxodibenzo [b, fjthiepin-2-yl) propionic acid) is excellent. It is widely used in Japan as a nonsteroidal analgesic. No publications have been made indicating that zaltoprofen is effective as an agent for improving the above-mentioned sickness behavior. There is a need to provide an inhibitor for weight loss or appetite loss associated with various diseases. There is also a need to provide an improving agent for the above-mentioned thick varnish behavior. Disclosure of the invention

In Concanavalin A-induced liver injury model (mouse), administration of Concanavalin A to experimental animals shows a decrease in body weight and food consumption of the experimental animals. Here, it was found that administration of Zaltoprofen prevented such weight loss and food consumption reduction. On the other hand, Interleukin-1β and TNF-a are not expressed in normal mouse brain; (Brain Research 795: 77-86 1998) Interleukin-1 and TNF-α power, however, were confirmed to be expressed in the brain in the Concanavalin A-induced liver injury model described above. Based on the above findings, the present inventors have found that Zarta π-phen is effective as an improving agent for Sickness behavior and completed the present invention. BEST MODE FOR CARRYING OUT THE INVENTION That is, the present invention relates to an agent for improving Thick scabies containing zaltoprofen as an active ingredient. The present invention also relates to an agent for improving weight loss associated with a disease containing zaltoprofen as an active ingredient: The present invention also relates to a decrease in appetite associated with a disease containing zaltoprofen as an active ingredient. An improvement agent for the following. Furthermore, the present invention relates to an agent for improving sick nis behavior associated with chronic liver disease, comprising zaltoprofen as an active ingredient. Zaltoprofen, an active ingredient of the present invention, is widely used as an anti-inflammatory agent, and its safety has been confirmed. Next, the pharmacological effects of the present invention will be described: As described in Example 2 below, in a liver injury model induced by Concanavalin A (sometimes abbreviated as Con A), a decrease in body weight of an experimental animal (mouse) was observed ₌ ( Table 1) Food consumption is also decreasing (Table 2), and it is considered that the decrease in food consumption is one of the causes of weight loss. On the other hand, administration of zaltoprofen suppressed a decrease in food consumption and body weight. (Tables 1 and 2) However, with regard to I: elevation of AL-dose due to administration of Concanavalin A, administration of zaltoprofen 8 hours after administration of Concanavalin A did not suppress the elevation of ALT. (Table 3) Therefore, it is considered that zaltoprofen inhibited food consumption and weight loss regardless of liver injury. Therefore, a preparation containing zaltoprofen as an active ingredient is useful as an agent for improving weight loss associated with diseases such as various infectious diseases, terminal stages of cancer, anorexia nervosa, and liver disease, and an agent for improving anorexia. In human chronic liver disease, no treatment has been developed for patients to complain of so-called sick nis behavior such as fatigue, fatigue, loss of appetite, and weight loss. Thick varnish behavior is said to be triggered by the expression of site forces such as Interleukin-1β and TNF-α in the brain. Reference Example 1 In the Concanava lin A liver injury model, expression of Interleukin-1β and TNF-a mRNA in the brain was confirmed. Therefore, it is considered that in Concanavalin A hepatic injury, a decrease in food consumption and a decrease in body weight (Tables 1 and 2 in Example 2 described later) are induced by cytodynamic force expressed in the brain. Losing appetite, weight loss goes through a series of sick varnishes Zaltoprofen was associated with improved fatigue and reduced body weight loss (Tables 1 and 2 in Example 2 below) in a Concanavalin A liver injury model. It is useful as an agent for improving sick varnish behavior such as fatigue, loss of appetite, weight loss, weakness, and reduced concentration. The preparation containing zaltoprofen of the present invention as an active ingredient can be prepared in the same manner as in the case of using zaltoprofen as an active ingredient as an anti-inflammatory agent. That is, it can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration. For formulation, it can be manufactured into tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by usual methods in the technical field of formulation. For these preparations, ordinary excipients, disintegrants, binders, lubricants, pigments, diluents and the like are used. Here, lactose, D-mannitol, crystalline cellulose, glucose, etc. are used as excipients, starch, carboxymethylcellulose cellulose (CMC-Ca), etc. are used as disintegrants, and lubricants are used as lubricants. Are magnesium stearate, talc, etc. As binders, hydroxypropylcellulose (HPC), gelatin, polyvinyl alcohol

In general, for adults, the dosage is about 0.5 mg to 100 mg / day of zaltoprofen, which is the active ingredient in an injection, and 1 mg / day orally; I OOO mg, but it may vary depending on age, symptoms, etc. Can be. EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1 Formulation example (tablet) In one tablet (150mg), _c active ingredient containing the following ingredients (the 40mg lactose 70

30 Magnesium stearate 2 Hydroxypropyl sesolelorose 8

Example 2 Pharmacological experiment (effect on body weight and food consumption)

(Experimental method) Experiment of measurement of body weight change and food consumption change Female BALBZc mouse (5 weeks old; M. Concanavalin A (12. Smg kg) was intravenously administered, and body weight change from 8 hours to 24 hours after administration of Concanavalin A Serum was collected 24 hours after administration of Concanavalin A, and ALT was measured by the Karmen method.The test drug zaltoprofen (1 OmgZkg, po) / ^/ kg, ip) Poma was administered 8 hours after administration of Concanavalin A. Concanavalin A was administered at 10 o'clock in the morning, and the test drug was administered at 6 o'clock at night. (Experimental results) The experimental results are shown in Tables 1 to 6. Show. Table 1 Changes in body weight (Saltprof.

Table 2 Changes in food consumption (Sartarov.

Table 3 Serum ALT (Zaltoprof:

Table 4 Changes in food consumption (daricyrrhizin) Food consumption (g) Number of subjects Control 2. 78 5

Con A 0. 18 5

Con A + glycyrrhizin 0.25 Table 5 Changes in body weight (daricyrrhizin)

Table 6 Serum

In the Concanavalin A-induced liver injury model, weight loss was observed, and (Table 1) a reduction in food consumption was also observed. (Table 2) Here, it was observed that the administration of zaltoprofen suppressed weight loss and food consumption. (Tables 1 and 2) On the other hand, regarding ALT elevation by administration of Concanavalin A, administration of zaltoprofen 8 hours after administration of Concanavalin A did not suppress the elevation of ALT. (Table 3) Administration of glycyrrhizin, however, suppressed the increase in ALT caused by Concanavalin A administration by 50% (Table 6), but did not suppress the reduction in food consumption and body weight. (Tables 4, 5)

[Reference Example 1] Pharmacological experiment (Effect on expression of cytotoxicity) Intell eukin-1β and TNF-a in the brain of mice treated with Concanavalin A Detection of mRNA expression

(Experimental method) Concanavalin A (12.5 mg / kg, i.v.) was administered to mice, and the whole brain was sampled 6 hours and 24 hours after administration, and frozen on dry ice. RNA was extracted from the sample according to the method described in the literature (Biochem Biophys Res Commun 197: 878-885 1993), and cDNA was obtained from the obtained RNA using reverse transcriptase. After the PCR reaction, the obtained DNA was electrophoresed by agarose gel electrophoresis, and the presence or absence of expression of Interleukin-1β and TNF-H mRNA was confirmed by UV lamp (260 nm).

The process from the synthesis of the cDNA to the detection with a UV lamp was in accordance with the method described in the literature (Biochem Biophys Res Commun 226: 762-768 1996).

The following primers for Interleukin-13 were purchased from Continental Products Incorporation, and primers for TNF-a were described in the literature (Biochem Biophys Res Commun 226: 762-768 1996). Was used.

PCR primers:

Interl eukin— 1 β

Sense: 5'-CAGGATGAGGACATGAGCACC-3 ^!

Ant i sense: 5 '-CTCTGCAGACTCAAACTCCAC-3' TNF- a

Sense

Antisense: 5 '--3'

PCR conditions:

94 ° C45 seconds, 55 ° C45 seconds, 72 ° C1. 5 minutes _c to 30 cycles of amplification were performed under conditions of

(Experimental result)

In Concanavalin A liver injury model, the expression of mRNA of Interleukin-1; 3 and TNF-a in the brain was confirmed.

Claims

The scope of the claims

Modification to thickis behavior containing zaltoprofen as active ingredient

2. An agent for improving weight loss associated with diseases containing Zaltoprofen as an active ingredient.

_{3. An} agent for improving appetite loss associated with diseases containing zaltoprofen as an active ingredient.

4. An agent for improving sick nis behavior associated with chronic liver disease, which contains zaltoprofen as an active ingredient.