Studies on chemotherapy of parasitic helminths (IX). Effects of praziquantel on the motility of various parasitic helminths and isolated host tissues.
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Biomedical subjects
Publications and source records attributed to M Terada.
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A rapid and sensitive method for determination of methamphetamine and amphetamine in urine was developed by using electron-capture gas chromatography. The extraction procedure, the experimental conditions for pentafluorobenzoyl derivative formation and the percentage recovery of the drugs from urine are described. The pentafluorobenzoyl derivative of methamphetamine showed a higher electron-capture sensitivity and was detected in at least 23-fold lower concentration than the heptafluorobutyryl derivative which is commonly used as a derivatizing agent for the amine. The detection limit of pentafluorobenzoyl derivatives of methamphetamine and amphetamine was ca. 10 pg. A concentration as low as 10 ng/ml of methamphetamine and amphetamine in urine was easily detected by this method.
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Effects of N-methylcytisine (N-MC) and matrine (Mat), alkaloids from Sophora flavescens on the motility of parasitic helminths and isolated frog rectus and mouse ileum were studied. 1) The motility of Angiostrongylus cantonensis was affected spastically by N-MC (1.2 X 10(-6) approximately 1.2 X 10(-4) M), but paralytically by Mat (10(-5) approximately 10(-4) M). 2) The motility of Dipylidium caninum and Fasciola hepatica was affected paralytically by N-MC (1.2 X 10(-4) approximately 1.2 X 10(-3) M), but spastically by Mat (10(-4) approximately 10(-3) M). 3) Treatment with N-MC (10(-3) M) and Mat (8 X 10(-4) M) had little effect on the motility of Schistosoma japonicum. 4) Both N-MC (1.2 X 10(-5) approximately 2.4 X 10(-5) M) and Mat (10(-4) M) stimulated the twitch response induced by guanidine (2.5 X 10(-5) M) in the frog isolated rectus preparation. 5) The motility of the mouse isolated ileum preparation was affected paralytically by N-MC (1.2 X 10(-5) approximately 1.2 X 10(-4) M), but spastically by Mat (10(-4) approximately 10(-3) M). Thus, N-MC and Mat acted antagonistically on all the preparations with the exception of the frog rectus preparation. From the results on interactions between these alkaloids and known neuropharmacological agents, it is suggested that the effects of both alkaloids are elicited through a neuropharmacological mechanism in parasitic helminths and host tissues.
Effects of tuberostemonine (TS), an alkaloid from Stemona japonica, on the motility of parasitic helminths and isolated frog rectus and mouse ileum were studied. 1) TS (6.7 X 10(-6) approximately 2 X 10(-5) M) paralyzed the motility of Angiostrongylus cantonensis. 2) TS (6.7 X 10(-5) M) showed contractive effects on the motility of Dipylidium caninum and Fasciola hepatica. 3) Treatment with TS (6.7 X 10(-5) approximately 4.8 X 10(-4) M) had little effect on the motility of Schistosoma japonicum. 4) TS (6.7 X 10(-5) M) paralyzed the motility of the mouse isolated ileum preparation. 5) TS (6.7 X 10(-7) 6.7 X 10(-6) M) stimulated the twitch response induced by guanidine (2.5 X 10(-3) M) in the frog isolated rectus preparation. 6) Eserine and TS acted antagonistically on all preparations with the the exception of S. japonicum. 7) TS and strychnine were antagonistic in isolated host tissues, whereas these compounds acted similarly on parasitic helminths. Thus, it is suggested that some of the experiential effects of the crude extracts of Stemona such as the anthelmintic effects are caused through the action of TS on parasitic helminths and host tissues.
12-)-Tetradecanoylphorbol-13-acetate (TPA), the prototype polyfunctional diterpene ester tumor promoter of two-step carcinogenesis in mouse skin, induced differentiation of human promyelocytic leukemia cells (HL-60) in culture. Differentiation of HL-60 cells was characterized by increased phagocytosis, increased lysozyme activity (EC 3.2.1.17) in the growth medium, and changes in morphology to those characteristics of more mature cells resembling macrophages. Many of the cells treated with TPA became aggregated, attaching firmly to culture flasks. The average intracellular myeloperoxidase activity (EC 1.11.1.7) per cell decreased during induction of differentiation by TPA. It was also found that TPA enhanced, rather than inhibited, differentiation of HL-60 cells induced by DMSO. In addition to TPA, several polyfunctional diterpene esters of the tigliane, ingenane, and daphnane type have been tested for their ability to induce morphological and functional changes of HL-60 cells. The activities of the compounds to induce these changes correlated well with their activities as tumor promoters in two-step carcinogenesis in mouse skin. In particular, half the concentrations required for induction of adhesion of the cells to flasks were roughly correlated to the potency of these compounds as tumor promoters. Among the compounds tested, phorbol-12,13-didecanoate (PDD), ingenol-3-hexadecanoate, Pimelea factor P1 and Pimelea factor P2 were as active as TPA, while 4-O-methyl-TPA and 4 alpha-PDD were much less active. Phorbol and ingenol were totally inactive up to a concentrations 10,000-fold higher than that of TPA.
Nitropyrenes, which are highly mutagenic in the Salmonella assay, were shown also to be potent mutagens on Chinese hamster lung cells without metabolic activation when resistance to diphtheria toxin was used as a selective marker. Among nitropyrenes tested, 1,8- and 1,6-dinitropyrenes were the most mutagenic, and 1,3-dinitro- and 1,3,6-trinitropyrenes were less active, but showed still much higher mutagenic activity than methyl methanesulfonate or N-methyl-N-nitrosourea. 1-Nitropyrene and 1,3,6,8-tetranitropyrene did not induce diphtheria toxin-resistant mutants at concentrations of up to 20 micrograms/ml.
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Effects of various neuropharmacological agents on the motility of Dipylidium caninum was studied. 5-HT stimulated the motility of D. caninum, while other drugs such as GABA, adrenaline, phenylephrine, isoproterenol, dibenamine, and propranolol showed little effect. The stimulatory action of 5-HT was antagonized by tryptophol. Stibnal caused paralysis which was blocked by the pretreatment with 5-HT. Paralytic effects were caused by eserine, dichlorovos, ACh, carbachol and DMPP, but not by pilocarpine and McN-A-343. d-Tubocurarine, hexamethonium, and atropine all showed little effect on the motility and on the paralytic action of eserine. Though guanidine showed little effect, strychnine remarkably stimulated the motility. The action of strychnine was stimulated by 5-HT but partially inhibited by tryptophol. Morphine and picrate slightly stimulated the motility, but showed little influence on the paralytic action of eserine. These two agents stimulated the paralyzed preparation by tryptophol transiently and sustainedly, respectively. These results on the cholinergic and serotonergic drugs basically showed good agreement with those reported in trematodes such as Schistosoma mansoni and Fasciola hepatica.
Effects of various cholinergic agents on the motility of Angiostrongylus cantonensis were studied to define the neuropharmacological properties of this worm. Stimulation of the motility and/or contraction were shown by eserine, ACh, carbachol, nicotine, DMPP, pyrantel, and Ba2+, but not by pilocarpine and McN-A-343. Contraction was similarly observed by these agents in the preparations paralyzed with praziquantel. Paralysis was caused remarkably by d-tubocurarine and slightly by succinylcholine, while the contraction induced by eserine and DMPP was little influenced by these drugs. Both the motility and the eserine-induced contraction were little influenced by hexamethonium, but stimulated remarkably by atropine. Though hemicholinium-3, morphine, and picrate showed little effect, guanidine stimulated remarkably the motility and also the eserine-induced contraction. The stimulatory action of guanidine was antagonized by strychnine. Strychnine paralyzed the motility, and the eserine-induced contraction was antagonized by the pre- and post-treatment with strychnine. From these results, it is suggested that the excitatory cholinergic mechanism in A. cantonensis is nicotinic, and it is basically similar to that reported in Ascaris suum.
Effects of some possible neurotransmitters such as GABA, adrenergic drugs, and 5-HT and their antagonists on the motility of Angiostrongylus cantonensis were studied. Paralysis was caused by GABA, avermectin BIa (Av-BIa), piperazine and alpha-adrenergic agonists such as adrenaline, noradrenaline, phenylephrine, clonidine and methoxamine, but not by beta-adrenergic agonists such as isoproterenol. The paralysis by GABA or Av-BIa was antagonized by GABA antagonists such as picrotoxin and/or bicuculline with cholinergic agents such as N-methylcytisine (N-MC) or eserine. The paralysis elicited by alpha-adrenergic agonists was antagonized by alpha-adrenergic antagonists such as phentolamine and dibenamine, but not by beta-adrenergic antagonists such as propranolol. 5-HT affected the motility of A. cantonensis paralytically or spastically. The paralysis induced by 5-HT was antagonized by alpha-adrenergic antagonists such as phentolamine and dibenamine, while the contraction induced by this compound was further stimulated by N-MC, but antagonized by strychnine. Other agents such as glutamine, glycine, aspartic acid, taurine, and substance P showed little effect on the motility of A. Cantonensis. From these findings on the neuropharmacological properties of A. cantonensis, it is suggested that this worm is useful as an excellent nematodal model for the investigation of anthelminthics. In addition, this worm may also useful as one of screening models of drugs affecting the central nervous system in mammals.
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Dihydroteleocidin B, which is a derivative of teleocidin from Streptomyces, showed potent tumor-promoting activity in vivo when painted on mouse skin. Although the chemical structure of dihydroteleocidin B is entirely different from those of phorbol esters, the tumor-promoting activity of dihydroteleocidin B was found to be comparable to that of 12-O-tetradecanoylphorbol 13-acetate (TPA) in vivo. Teleocidin from Streptomyces and lyngbyatoxin A and debromoaplysiatoxin from the marine blue-green alga Lyngbya majuscula induced ornithine decarboxylase activity when painted on mouse skin, their effects being similar to those of dihyroteleocidin B and TPA. 13-cis-Retinoic acid inhibited this ornithine decarboxylase induction when painted on the skin 1 hr before these natural products. These three compounds produced adhesion of human promyelocytic leukemia cells (HL-60) to the flasks and inhibited differentiation of Friend erythroleukemia cells induced by dimethyl sulfoxide. The in vitro biological potencies of teleocidin and lyngbyatoxin A were almost as great as those of dihydroteleocidin B and TPA, but that of debromoaplysiatoxin was much weaker.