PHARMACEUTICAL COMPOSITION FOR PROPHYLAXIS OR TREATMENT OF KETOSIS IN LIVESTOCK

Abstract: A pharmaceutical composition for prophylaxis or treat­ ment of ketosis in livestock which contains a dithia derivative represented by the general formula (I), wherein R and R′ may be the same or different and are each individually a lower alkyl group, n is an integer of 0, 1 or 2; and A is a group of the formula, -CH₂-, (where M is a hydrogen atom or a salt-forming residue), -CH = CH-, -CH₂CH₂-,

Description: The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of ketosis in livestock. More particularly, the present invention relates to the use in the preparation of a medicament for the prophylaxis or treatment of ketosis in livestock of a dithia derivative represented by the general formula (I): wherein R and R' may be the same or different and are individually a lower alkyl group; n is an integer of 0, 1 or 2; and A is a group of the formula, -CH₂-, DESCRIPTION OF THE PRIOR ART Part of the dithia derivatives represented by the general formula (I) are already known as treating agents for curing hepatopathy of humans and animals, in Japanese Patent Publication Nos. 18576/1981 to 18579/ 1981, and also known as for agricultural-horticultural disinfectants in Japanese Patent Publication Nos. 44526/1969 and 34883/1976. Methods of synthesis are described in FR-A-231037, FR-A-2313038, FR-A-2313041 and JP-A-58185581. The pharmacological activity which is the part of biological activities of the dithia derivatives represented by the general formula (I) exhibits as a curing agent for hepatopathy has been thought to be as follows. That is, when the function of liver is damaged by a factor such as alcohol, malnutrition, viruses, chemicals, toxicants, bile duct obstruction, hepatic circulation dyscrasia or the like or their combination and as a consequence there appears a disease such as fatty liver, toxipathic hepatisis, alcoholic hepatitis, viral hepatitis, congested liver hepatopathy due to cholestasis, icterus, hepatocirrhosis caused by these diseases or the like or their combination, the part of the dithia derivatives represented by the general formula (I) activate protein synthesis at liver and prevents liver fibrosis, whereby the functions of liver are generated and liver cells are reactivated and finally dyshepatia is alleviated or cured. Meanwhile, ketosis in livestock , particularly in dairy cows is characterized in that dairy cows contracting this disease have poor appetite, their body weight decreases, and they produce milk of lower quality in a lesser quantity. The number of the dairy cows hitherto seized by ketosis has been numerous. Nevertheless, the cause of this disease as well as the mechanism of appearance of the disease has not been clarified and accordingly no reliable method for curing ketosis has been established. With respect to the process up to ketosis appearance, the following explanation is made in JUI-BYORIGAKU-TOKURON (A special issue on pathology of veterinary science) by YAMAGIWA. "The mechanism of ketosis appearance has not fully been clarified. Ketosis is analysed below as a phenomenon. Firstly, digestion in rumen is focused. In the rumen, carbohydrates are digested by the enzymatic activity of many microorganisms. Volatile fatty acids (i.e., acetic acid, butyric acid and propionic acid) are formed and absorbed becoming energy sources for cows. Of these fatty acids, acetic acid and butyric acid are converted into ketone bodies, while propionic acid is not converted into a ketone body but is used for production of glycogen at liver. Of the volatile fatty acids formed, the first two acids (acetic acid and butyric acid) occupy 80% and the last acid (propionic acid) 20%. Parental cows store glycogen at their fetal livers toward the end of pregnancy and, after delivery, send glycogen into milk; hence, in parental cows before and after delivery, the normal balance of glycogen is collapsed. When lactation starts, milk production takes place suddenly and more nutrients are required for enabling the production. Increased supply and digestion of carbohydrates in rumen becomes necessary. In cows in the midst of lactation, metabolism of carbohydrates becomes smooth only when nutritional demand and intake are balanced. Hence, in cows in the period from the end of pregnacy to the early stage of lactation, health can be maintained only when the above-mentioned conditions are satisfied. In cows in such a period, nutritional demand is very high, however, it is self-controlled so that the hyperemia of breast can be prevented. As delivery approaches, the blood sugar level of cows continues to decrease and, after delivery, it further decreases sharply and the low level lasts for a certain period. In this period, ketone bodies are present in bloods of cows. Ketone bodies are also present in normal animals, however, the amount is negligible to 5 to 6 mg per cent in their bloods and negligible to 15 to 16 mg per cent in their urines. With these amounts, no ketosis appears. Clinical ketosis rarely appears when dairy cows have a constant appetite and are fed with appropriate feeds. However, if ketone bodies are accumulated in blood in a concentration of 80 mg per cent and excreted in urine in a concentration of 550 mg per cent and furthermore sugar level in blood decreases down to 50% (20 to 30 mg per cent), that is, ketonemia, ketouria and hypoglycemia are present concurrently, there appears clinical ketosis." As explained above, ketosis is a diseases wherein dairy cows have lower appetite, their carbohydrate metabolism becomes non-smooth, acetic acid and butyric acid are converted into respective ketone bodies and are accumulated in their blood and excreted in their urine , in high concentrations, and their expired air and excreted urine have acetone odors. For prevention of ketosis of cows, studies have been made from the aspect of controlled breeding such as use of a special feed for the period before and after delivery. For therapy of ketosis, studies have been made from the following aspects. (1) Increase of nutritional supply and enhancement of digestive ability in rumen (a) Administration of digestive (b) Supplementation of nutrients (glucose, sodium propionate.) (2) Enhancement of carbohydrates-metabolizing ability of cows by administration of, for example, a vitamin such as B₁₂, a hepatotonic such as methionine, and a hormone. None of these therapeutic studies has brought about a noticeable effect. Based on the results of these past therapeutic studies for ketosis of cows, the present inventors made extensive research on effects of nutritional physiology, administration of drugs, on ketosis conditions of cows. As a result, it was found that the diathia derivatives represented by the general formula (I) reduce abnormal accumulation of ketone bodies during ketosis and have a noticeable prophylactic and preventive effects for ketosis. The present invention was completed by these findings. In the symbol A of the general formula (I), M as a salt-forming residue is specifically a sodium atom, a potassium atom, an ammonium group, an organic amine group. Typical examples of the dithia derivatives represented by the general formula (I) and their toxicities are as follows. Included in the invention are the compounds of formula (I) above wherein: The compounds (a) are disclosed in DE-A-3323105 and its equivalent applications SE-A-8303588, GB-A-2124213, NL-A-8302271 and FR-A-2541276. Accordingly, the Applicant has voluntarily limited the present application and submitted separate claims for the Federal Republic of Germany, Sweden, the United Kingdom, the Netherlands and France. When the active ingredient contained in the pharmaceutical composition of the present invention is administered to livestock, it is administered (a) singly, as it is, (b) in the form of a mixture with a feed, or (c) in an ordinary administration unit form such as powder, granule, tablet, sugar coated tablet, capsule, suspension, ampule, injection preparation As compositions (b) there may be mentioned in particular formalations containing the active compound in combination with propionic acid or with sodium chloride in the form of a livestock salt lick. The dose of pharmaceutical composition according to the present invention can vary depending upon the kind of domestic animal, age, body weight, stage of disease, condition of disease, etc. In general, it is advantageous that 0.1 to 250 mg, preferably 1 to 100 mg per kg of body weight per day is orally administered and 0.01 to 250 mg per kg of body weight per day is administered parenterally. PHARMACOLOGICAL TESTS Pharmacological tests for the active ingredient of pharmaceutical composition of the present invention were conducted, by making the active ingredient into granules as in Example 1 and forcibly administering the granules orally to cows seized by ketosis in a predetermined dose once daily for 6 weeks. Examinations of various check items were made for blood and urine taken from the cows before and 1, 3 and 6 weeks after the administration. In serum biochemical diagnosis, blood was taken, coagulated and then subjected to centrifugation (3,000 rpm, 15 min.) to obtain respective serums and these serums were used. Blood sugar level was determined by a method using a glucose oxidase; free fatty acids were determined by an ACS-ACO-POD method; and ketone bodies in blood were determined by a diffusion colorimetry using salicyl aldehyde (THIN-ROBERTSON method). Ketone bodies in urine were determined by the use of Labstix (Sankyo Miles). As shown in Table 1, high levels of acetoacetic acid in blood before the administration which are characteristic of ketosis were reduced by the administration of a dithia derivative of the present invention and returned to the normal values in 3 to 6 weeks after the administration. High levels of free fatty acids in blood which are generally used as an indication of ketosis returned to the normal values in 3 to 6 weeks after administration. Ketone bodies in urine were hardly detected in 3 weeks after the administration. As a common phenomenon, the cows administered with the test dithia derivative recovered appetite gradually and had normal appetite in 3 weeks. Their lactation amounts also returned to normal levels in 3 to 4 weeks after the administration. As is obvious from these results, the active ingredient of the present invention is highly effective for cows afflicted with ketosis. Among the dithia derivatives represented by the general formula (I), those having i-propyl groups as to the symbols R and R'; and A is a group of the formula -CH=CH- or -CH₂-CH₂- are effective. Particularly, diisopropyl 1,3-dithiolan-2-ylindene malonate is most effective. Example 1 50 Parts of a compound No. 6, 15.0 parts of light silicic acid anhydride, 5.0 parts of precipitated calcium carbonate, 5.0 parts of corn starch, 2.0 parts of crystalline cellulose, 5.0 parts of a polyvinyl alcohol and 30 parts of water are homogeneously mixed and kneaded. Then, the mixture is ground, pelletized, dried and sifted to prepare granules. The granules are used for curing of ketosis of cows. Example 2 30 Parts of a compound No. 4 and 70 parts of sodium chloride are homogeneously mixed. The mixture is compression-molded to prepare solids. Cows and other livestock are allowed to lick these solids for prevention or cure of ketosis. Example 3 1 Gram of a compound No. 6 is added to 1 kg of a cattle feed. The resulting feed is given to cows or other livestock for prevention or cure of ketosis. Example 4 30 Parts of a compound No. 6, 30 parts of magnesium propionate, 30 parts of calcium carbonate and 10 parts of calcium tertiary phosphate are mixed to prepare a powder. This powder is used for cure of ketosis of cattle and other livestock. It was also found that a combined use of a compound of the present invention and a nutrient such as glucose, propionic acid further enhances the therapeutic effect of the present invention compound.

Claims: A compound of the formula wherein R and R' may be the same or different and are each a lower alkyl group, M being hydrogen or a salt-forming group. A compound as claimed in claim 1 wherein R and R' are each i-C₃H₇, A is -CH₂-, -CH=CH-, A compound as defined in claim 1 or claim 2 for use as a livestock medicament. A pharmaceutical formulation for prophylaxis or treatment of ketosis in livestock which contains as the active ingredient a compound as defined in claim 1 or claim 2. A formulation as claimed in claim 4 which further comprises livestock feed, sodium chloride in the form of a livestock salt lick, or propionic acid. A pharmaceutical composition comprising a compound of the formula: wherein R and R' may be the same or different and are each a lower alkyl group, n is an integer of 0, 1 or 2 and A is a group of the formula (wherein M is a hydrogen atom or a salt-forming group), together with livestock feed,together with sodium chloride in the form of a livestock salt lick or together with propionic acid. The use of a compound as defined in claim 6 in the preparation of a medicament for the prophylaxis or treatment of ketosis in livestock. A composition as claimed in claim 6 or use as claimed in claim 7 wherein said compound is as defined in claim 1 or claim 2, or wherein R and R' each are i-C₃H₇, A is a group of the formula and n is an integer of 0 or 1. A composition or use as claimed in claim 8, wherein said compound is diisopropyl 1,3-dithiolan-2-ylidene malonate or diisopropyl 1,3-dithiol-2-ylidene malonate. Claims for the following Contracted States: BE, IT, LU, and CH/LI: A compound of the formula wherein R and R' may be the same or different and are each a lower alkyl group, and either or M being hydrogen or a salt-forming group. A compound as claimed in claim 1 wherein R and R' are each i-C₃H₇, and either or A compound as defined in claim 1 or claim 2 for use as a livestock medicament. A pharmaceutical formulation for prophylaxis or treatment of ketosis in livestock which contains as the active ingredient a compound as defined in claim 1 or claim 2. A formulation as claimed in claim 4 which further comprises livestock feed, sodium chloride in the form of a livestock salt lick, or propionic acid. A pharmaceutical composition comprising a compound of the formula: wherein R and R' may be the same or different and are each a lower alkyl group, n is an integer of 0, 1 or 2 and A is a group of the formula (wherein M is a hydrogen atom or a salt-forming group), together with livestock feed, together with sodium chloride in the form of a livestock salt lick or together with propionic acid. The use of a compound as defined in claim 6 in the preparation of a medicament for the prophylaxis or treatment of ketosis in livestock. A composition as claimed in claim 6 or use as claimed in claim 7 wherein said compound is as defined in claim 1 or claim 2, or wherein R and R' each are i-C₃H₇, A is a group of the formula and n is an integer of 0 or 1. A composition or use as claimed in claim 8, wherein said compound is diisopropyl 1,3-dithiolan-2-ylidene malonate or diisopropyl 1,3-dithiol-2-ylidene malonate. Claims for the following Contracting State: AT: The use in the preparation of a medicament for the prophylaxis or treatment of ketosis in livestock of a compound of the formula wherein R and R' may be the same or different and are each a lower alkyl group, n is an integer of 0, 1 or 2 and A is a group of the formula (wherein M is a hydrogen atom or a salt-forming group), A method of preparing a mixture comprising a compound as defined in claim 1, comprising (a) mixing together said compound with livestock feed; (b) mixing together said compound with sodium chloride and compression-moulding the mixture to form a livestock salt lick; or (c) mixing together said compound with propionic acid. A method of making a pharmaceutical formulation for prophylaxis or treatment of ketosis in livestock comprising a compound as defined in claim 1, the method comprising formulating the compound into said formulation.

Inventors: HAYASHI, MASHIRO, HOKAZONO, AKIO, SHIMADA, TAKEHIRO, SHIMOSAKO, MASAHIRO, SUGIMOTO, TATSUYOSHI
Applicants: NIHON NOHYAKU CO., LTD.
Application year: 1984
Main classification: A61K31
IPC codes: A61P3, A61K31, C07D339