Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1993-03-25
1995-09-05
Rollins, John W.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
514 25, 514456, 424451, 424464, A61K 3578, A61K 3170
Patent
active
054477190
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a .beta.-glucuronidase inhibitor which inhibits .beta.-glucuronidase and is useful in the field of medicine.
BACKGROUND ART
Camptothecin is a kind of a plant alkaloid contained in "Kiju" (Camptotheca acuminate Decne.) native to China, and the like. Although the development thereof was advanced as an antitumor agent, it was suspended due to toxicity thereof such as strong inhibition of bone marrow. Thereafter, the camptothecin was used as a starting material and subjected to various chemical modifications to synthesize a compound represented by the following formula I and having a high antitumor activity and a wide range of an antitumor spectrum (see Japanese Examined Patent Publication (Kokoku) No. 3-4077). ##STR2##
However, the compound represented by the formula I was found to cause diarrhea as an adverse effect when it was clinically applied. The substance causative of the diarrhea has been estimated to be a compound (7-ethyl-10-hydroxycamptothecin) represented by the following formula III ##STR3## which is produced when a glucuronic acid inclusion compound (7-ethylcamptothecin-10-yl .beta.-D-glucopyranosidouronic acid) which is a main metabolite of the compound represented by the formula I and represented by the formula II ##STR4## is subjected to the action of .beta.-glucuronidase in an alimentary canal.
For this reason, it is expected that the prevention of the elimination of glucuronic acid through the inhibition of the enzymatic activity of .beta.-glucuronidase in the alimentary canal enables the formation of the compound represented by the formula III to be prevented, so that the occurrence of diarrhea can be suppressed.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to develop a .beta.-glucuronidase inhibitor excellent in the effect of relieving the adverse effect, especially diarrhea, caused in the administration of the compound represented by the formula I.
The present inventors have made extensive and intensive studies with a view to solving the above-described problem and, as a result, have found a Chinese and Japanese traditional prescription, a crude drug and a compound contained in the crude drug each having a capability of inhibiting the enzymatic activity of .beta.-glucuronidase, which has led to the completion of the present invention.
Specifically, the present invention provides a .beta.-glucuronidase inhibitor comprising at least one compound selected from the group consisting of baicalin, oroxylin A-7-O-glucuronide and luteolin-3'-glucuronide (these three compounds being hereinafter collectively referred to as "active ingredient compound of the present invention"); an extract of scutellaria root (baikal skullcap; Scutellariae Radix) and/or schizonepeta spike (Japanese catnip; Schizonepelae Spica); or a Chinese and Japanese traditional prescription comprised of scutellaria root (baikal skullcap; Scutellariae Radix) and/or schizonepeta spike (Japanese catnip; Schizonepelae Spica) as a crude drug.
BEST MODE FOR CARRYING OUT THE INVENTION
Baicalin is known as an ingredient contained in scutellaria root (baikal skullcap; Scutellariae Radix) (see Chuyaku Daijiten published by Shanhai Kagaku Gijutsu Shuppansha and edited by Shogakukan Inc.). Baicalin useable in the present invention may be commercially available from Wako Pure Chemical Industries, Ltd. Further, it can be easily produced by a method described in "Yakkyoku", vol. 13, No. 8, 53-55 (1962) or Acta Phytochim., 5, 219 (1931), and baicalin thus produced may also be used in the present invention.
Oroxylin A-7-O-glucuronide and luteolin-3'-glucuronide can be produced respectively from scutellaria root (baikal skullcap; Scutellariae Radix) and schizonepeta spike (Japanese catnip; Schizonepelae Spica) as follows.
Scutellaria root (baikal skullcap; Scutellariae Radix) or schizonepeta spike (Japanese catnip; Schizonepelae Spica) is extracted with water, an alcohol, a mixed solvent comprising water and an alcohol or a mixed solvent comprising water
REFERENCES:
Yoshiyuki Kimura et al, "Effects of Baicalein on Leukotriene Biosynthesis and Degranulation in Human Polymorphonuclear Leukocytes", Biochimica et Biophysica Acta, vol. 922, No. 3, pp. 278-286 (1987).
E. Middleton et al, "The Effects of Citrus Flavonoids on Human Basophil and Neutrophil Function", Planta Medica, vol. 53, No. 4, pp. 325-328 (1987).
M. Narita et al, "Inhibition of Beta-Glucuronidase by Natural Glucuronides of Kampo Medicines Using Glucuronide of SN-38 (7-ethyl-10-hydroxycamptothecin) as Substrate", Xenobiotica, vol. 23, No. 1, pp. 5-10 (1993).
Masaru Kawasalo et al, "8-Hydroxytricetin 7-Glucuronidase Inhibitor from Scoparia Dulcis", Phytochemistry, vol. 27, No. 11, pp. 3709-3711 (1988). Abstract.
W. Suzuki et al, "Studies of the Metabolic Fate of CPT-11(2): Pharmacokinetics in Rats Following a Single Intravenous Dose (2)--Metabolites Pattern in Serum, liver, Kidney and Intestinal Tissue", Xenobiotic Metabolism and Disposition, vol. 6, No. 1, pp. 97-104 (1991).
L. M. Ball et al, "Formation of Mutagenic Urinary Metabolites from 1-Nitropyrene in Germ-Free and Conventional Rats: Role of the Gut Flora", Carcinogenesis, vol. 12, No. 1, pp. 1-5 (1991).
The Merck Index, 11th edition, published 1989, pp. 150-151, Compound No. 954.
Y. Takino et al, Chemical and Pharmaceutical Bulletin, vol. 35, No. 8, pp. 3494-3497 (1987) "Determination of Some Flavonoids in Scutellariae Radix by High-performance Liquid Chromatography".
Xian Fany Liu et al, Molecular Oncology, vol. 37, No. 6, pp. 911-915 (1990), "Inhibition of rat Liver NAD(p)H".
Rollins John W.
Tsumura & Co.
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