Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-07-25
1998-04-28
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514387, 514464, A61K 31415, A61K 3136
Patent
active
057444943
DESCRIPTION:
BRIEF SUMMARY
This application is a 3.71 of PCT/GB94/00193 filed Feb. 2, 1994.
The present invention relates to pharmaceutical compositions comprising benzimidazole anthelmintic agents, particularly though not exclusively for veterinary use, and potentiation thereof by means of piperonyl butoxide or other methylenedioxyphenyl insecticide synergist.
BACKGROUND OF THE INVENTION
Benzimidazoles are a well known class of anthelmintic agents which are widely used for the control of endoparasites, particularly nematodes, in domestic and agricultural animals. Albendazole is indicated for use in humans. Whilst these agents have been used successfully, a number of these anthelmintic benzimidazoles are degraded by oxidative mechanisms in vivo, which accelerates their excretion and this may limit their efficacy and may mean that periodic administrations are necessary.
Furthermore, certain parasites may be resistant to particular benzimidazoles.
Piperonyl butoxide is a well known insecticide synergist (see Merck Index 7446). This and other methylenedioxyphenyl insecticide synergists have been widely used in conjunction with pyrethroid insecticides.
It has been reported (Food Chem. Toxicol. (1992 December); 30(12), 1021-30) that the acute toxic effects of the benzimidazole thiabendazole on the kidneys of mice are enhanced by pretreatment with inhibitors of the microsomal monooxygenase system viz 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride and piperonyl butoxide. The reference is limited to a consideration of toxicity and does not disclose any effects regarding the anthelmintic efficacy of the treatments.
DESCRIPTION OF THE INVENTION
Generally speaking, the present invention relates to the discovery that the anthelmintic effects of benzimidazoles may be enhanced by co-administration with a methylenedioxyphenyl insecticide synergist such as piperonyl butoxide.
Thus, the present invention particularly provides a pharmaceutical composition which comprises an anthelmintically effective amount of a benzimidazole or pro-drug thereof together with a methylenedioxyphenyl synergist.
The benzimidazole is particularly one subject to oxidative degradation in vivo. Where the benzimidazole contains a thio group, oxidation in vivo generally proceeds via the sulphoxide metabolite (which may also have anthelmintic activity) to the inactive sulphone.
Another oxidative mechanism involves hydroxylation for example at the 5-position on the benzimidazole ring.
The invention also relates to the use of a methylenedioxyphenyl synergist to potentiate such benzimidazole or pro-drug thereof.
Furthermore, the invention includes methods of treating animals and humans for the treatment of endoparasitic infections by the administration of the benzimidazole or pro-drug thereof together with a methylenedioxyphenyl synergist.
The methylenedioxyphenyl synergist is an inhibitor of the hepatic cytochrome P450 system. Many such insecticide synergists (which have no anthelmintic or pesticidal activity themselves) are known as synergists of the pyrethroid group of insecticides and these are generally encompassed by the present invention. Specific synergists include piperonyl butoxide, piperonyl cyclonene, carboxyethyl piperonyl cyclonene, sesamine, n-propyl sulfinyl)propyl!benzene).
The pharmaceutical composition may include a pharmaceutically acceptable inert carrier or diluent appropriate to the method of administration. Thus, the composition may be administered orally or parenterally (including subcutaneous, intramuscular and intravenous injection). For oral administration, the pharmaceutical compositions may be presented as a drench, such as a solution or suspension in water. The drench may include as appropriate suspending agents, preserving agents, thickening agents or emulsifying agents according to well known formulation techniques. Oral administration may also be by way of incorporation of the composition into foodstuff or as a feedblock. The composition may also be formulated as pellets or granules. Particularly for human administration, the compos
REFERENCES:
patent: 5135953 (1992-08-01), Potter et al.
Y. Tada et al. "Acute renal toxicity of the thiabendazole . . . " Food Chem. Toxic., vol. 30, No. 12, 1992, pp. 1021-1030.
T. Mizutani et al. "Nephrotoxicity of thiabendazole in mice . . . " Food Chem. Toxic., vol. 28 No. 3, 1990, pp. 169-177.
Isshiki K. et al. "Effects of post-harvest fungicides . . . " J. Food Hyg. Soc. Jpn., vol. 24 No. 3, 1983, pp. 268-274.
Benchaoui Hafid Abdelaali
McKellar Quintin Archibald
British Technology Group Limited
Cintins Marianne M.
Moezie M.
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