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PubMed2001

Metabolism of ipecac alkaloids cephaeline and emetine by human hepatic microsomal cytochrome P450s, and their inhibitory effects on P450 enzyme activities.

In this study, we identified the metabolites and the CYP forms that are specifically involved in emetine O-demethylation in human liver microsomes, and cleared the inhibitory potential of cephaeline and emetine on the activity of the major drug-metabolizing CYP enzymes. Incubation of emetine with human liver microsomes yielded three metabolites identified by using HPLC by comparison of the retention time with the authentic sample of cephaeline, 9-O-demethylemetine and 10-O-demethylemetine. CYP3A4 and CYP2D6 were able to metabolize emetine to cephaeline and 9-O-demethylemetine, and CYP3A4 also participated in metabolizing emetine to 10-O-demethylemetine. Cephaeline and emetine inhibited probe substrates metabolism. IC50 for cephaeline against CYP2D6 and CYP3A4 were 121 and 1000 microM, respectively. For the emetine, CYP2D6 and CYP3A4 were 80 and 480 microM, respectively. Inhibition constants (Ki) for both compounds on the CYP2D6 and CYP3A4 activities were determined by graphic analysis of Dixon plots at various concentrations. The obtained Ki values of cephaeline for CYP2D6 and CYP3A4 were 54 and 355 microM, respectively, and the values of emetine were 43 and 232 microM, respectively. We concluded that these in vitro inhibitions of cephaeline and emetine would hardly increase plasma concentrations of co-administered drugs in clinical therapy.

Chromatography, High Pressure Liquid↗
PubMed1978

[Azotized emetine analogues: synthesis and evaluation of the anti-amebic and anti-tumoral action of aza-3 emetine and attempted synthesis of aza-2 emetine].

The synthesis of the N,N-bis-(acetylhomoveratrylamido)-1-hydroxymethyl and 1-carboxypropylamines (III a) and (III b) is described. Until now, these molecules could not been cyclized to the corresponding isoquinoline compounds. An attempted synthesis of 3-azaemetine by condensing homoveratrylamine with acetonedicarboxylic acid or its esters did not yield the expected diamide (XIV). However, by subjecting 1,3-bis-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)acetone (XV) to a reducing aminoalkylation, one obtained the corresponding ethylamino derivative (XVI) which could be cyclized through Mannich reaction to give 3-azaemetine. The pharmacological screening showed 3-azaemetine to be less toxic than emetine in the mouse and without antiamebic and antitumor activity against P 388 Leukaemia in the mouse (25).

Amebicides↗
PubMedDate not supplied

[Reliability of the PEHPS culture medium for the in vitro evaluation of antiamebic drugs].

Monophasic liquid media for axenical cultivation of Entamoeba histolytica, have permitted to define diverse aspects of this parasite's biology, without associated organisms interference. In addition, these media have allowed the in vitro evaluation of new drugs with potential antiamebic properties. PEHPS, a new medium recently developed in our laboratory, was used in order to determine its usefulness in the searching for new antiamebic compounds. The antiamebic potency of currently employed drugs in clinical therapy: emetine, metronidazole and diiodohydroxyquinoline on E. histolytica, strain HM-1, trophozoites grown in PEHPS was tested. The IC50 for each drug was 0.082 microgram/ml, 0.10 micrograms/ml and 5.84 micrograms/ml respectively. Results obtained with each drug are statistically reliable and reproducible, and agree with the species sensibility reported by several other authors. Accordingly, we propose PEHPS as a useful medium for new antiamebic drug research.

Animals↗
PubMed1980

Evaluation of ten potential organic spermicides.

The following compounds, selected as possible vaginal or cervical spermicides, were tested in vitro for their ability to decrease the motility of human spermatozoa: cytochalasins A and B, N-cetylpyridinium chloride (CPC), N-cetyl-N,N,N-trimethylammonium bromide (CTAB), sodium deoxycholate (SDC), quinine and emetine hydrochlorides, 4-nitrophenyl-4-guanidinobenzoate hydrochloride, n-hexanal, and 6-amidino-2-(4-amidinophenyl) dilactate. The most effective spermicide was the antibacterial cytochalasin A which instantaneously abolished motility at a concentration of 0.01%. The two cationic detergents CPC and CTAB were also very potent and instantly immobilised spermatozoa at a concentration of 0.1%. Quinine, emetine and 4-nitrophenyl-4-guanidinobenzoate hydrochlorides at a concentration of 0.1% abolished motility in 30-60 minutes. n-Hexanal, SDC, and the antihaemostatic compound 6-amidino-2-(4-amidinophenyl) dilactate at 0.1% depressed motility but never rendered the sperm completely immotile. Cytochalasin B had little or no effect on sperm motility even at 0.1%.

Cetrimonium Compounds↗
PubMed1987

Sensitivity of protein and RNA synthesis to emetine in axenic Entamoeba histolytica.

The action of emetine on the incorporation of (14C)1-DL-valine and (14C)-8-adenine in TCA insoluble fraction of axenic Entamoeba histolytica was investigated. These compounds were almost exclusively incorporated in the 'protein' and 'RNA' fractions, respectively. Incorporation of the purine showed a significantly higher sensitivity to emetine. While the percentage inhibition of valine incorporation by emetine decreased with increasing pH, the susceptibility of adenine incorporation was greater in the alkaline range.

Adenine↗
PubMed1987

Coadministration of methylxanthines and inhibitor compounds potentiates teratogenicity in Xenopus embryos.

Inhibitors of DNA synthesis (hydroxyurea and cytosine arabinoside), protein synthesis (cycloheximide and emetine), and nucleic acid synthesis (5-fluorouracil) were administered with each of three methylxanthines (caffeine, theophylline, and theobromine) to determine if teratogenic effects could be potentiated in Xenopus laevis embryos. The animals were exposed for 96 hours to methylxanthine and inhibitor concentrations that, alone, produced low percentages of malformations. Coadministration of caffeine or theophylline with each inhibitor greatly increased the incidence of malformed embryos. Similar potentiation was induced when theobromine and the protein synthesis inhibitors were tested. A lesser potentiative response was produced when theobromine and the nucleic acid synthesis inhibitor were administered together. Teratogenic potentiation did not occur when theobromine was administered in conjunction with the DNA synthesis inhibitors. Growth reduction in the treatments proved to be the most sensitive indicator of the potentiative effects. This study had two significant findings: the teratogenicity of the protein synthesis inhibitors was greatly increased upon coadministration with each methylxanthine, even though they are typically not very teratogenic by themselves, and coadministration of the DNA synthesis inhibitors with theobromine did not result in teratogenic potentiation. Additionally, this study serves as one method of validating the frog embryo teratogenesis assay-Xenopus (FETAX), since the results obtained concur with results from similar mammalian studies.

Abnormalities, Drug-Induced↗
PubMed1979

[Comparative study, in the Allium test, of the cytotoxicity of tubulosine and of 6 synthetized pseudo-tubulosines].

Comparing cytotoxicity of tubulosine and of six newly synthesized pseudo-tubulosines in the Allium test, we have characterized all the current features of protein inhibition. Nevertheless cytotoxicity of the six pseudotubulosines is much weaker. Furthermore, "floating poles anaphasis", a disturbance characteristic of the action of tubulosine, has been found with a lesser intensity with the other compounds.

Emetine↗
PubMed1984

An in vitro screen for new fasciolicidal agents.

In vitro screens employing newly excysted, 6- and 12-week-old flukes, in a medium permitting the linear growth of the parasites, were assessed. When exposed to certain known fasciolicides, newly excysted flukes were susceptible only to diamphenethide, the free amine of diamphenethide, emetine hydrochloride and albendazole. Older flukes were affected by a much wider range of compounds including the chlorinated hydrocarbons, the substituted phenols and the salicylanilides. However their susceptibility to diamphenethide and its active metabolite was decreased significantly. The activity of fasciolicides in these in vitro assays therefore closely parallels their activity in vivo. When several broad spectrum anti-nematode agents were evaluated against newly excysted flukes in these screens the benzimidazole, isothiocyanate, pyrimidine and imidazothiazole anthelmintics showed activity but 12 potent antiprotozoal agents were all inactive. It is concluded that these in vitro assays were useful for detecting any intrinsic activity that a compound might possess against flukes. Such activity could often be missed in conventional in vivo screens because of problems associated with host pharmacokinetics. Negative results from such in vivo screens could preclude the development of more bioavailable derivatives or pro-drugs as novel and useful fasciolicidal agents.

Animals↗
PubMed1986

Effect of Salmonella typhimurium porins on the cardiovascular and renal apparatus.

The cardiovascular effects of porins were evaluated using porins isolated from Salmonella typhimurium SH5014. In dogs porins depress arterial systemic pressure, vasomotor reactivity of norepinephrine and peripheral vagal stimulation. They are capable of modifying the sinocarotidal baroreceptor reactivity. In mice porins increase the cardiotoxic effects of isoprenaline, thyroxine, emetine and of p-nitrophenol. In rats porins increase the arrhythmogenic and lethal effects of BaCl2 and also give rise to renal lesions, probably at the tubular level.

Animals↗
PubMed2002

Inhibitory effect of isoquinoline alkaloids on movement of second-stage larvae of Toxocara canis.

To find new anthelmintics against parasites living in host tissues, we used an in vitro assay to screen isoquinoline alkaloids for nematocidal activity on the larva of dog roundworm, Toxocara canis. To evaluate the efficacy of anthelmintics in vitro, Tsuda et al. previously introduced the concept of Relative Mobility (RM) of Toxocara larvae. After improvement of the assay system using image data processing, we generated a new index, RM(50), the concentration at which RM=50%. However, except for pyrantel, the RM(50) of most existing anthelmintics could not be calculated because of low activity. Of the isoquinoline alkaloids tested, emetine, sanguinarine, 6-methoxydihydrosanguinarine (6-MS), chelerythrine and berberine showed strong nematocidal activities. However, these compounds were highly cytotoxic; thus, the prospect of their direct application is low. We then tested the cytotoxicity (IC(50)) of other isoquinoline alkaloids in HL60 tissue-culture cells. We continued our search for new anthelmintics by examining in detail the relationship between RM(50) and IC(50). We determined that an ideal target compound would exhibit a low RM(50)/IC(50) ratio. Allocryptopine, dehydrocorydaline and papaverine were identified as potentially effective anthelmintics.

Alkaloids↗
PubMed1998

Molecular modeling study of tubulosine and other related ipecac alkaloids.

A molecular modeling study of two alkaloids, tubulosine and psychotrine, isolated from the sap of Pogonopus speciosus, and other related ipecac alkaloids, showed that these flexible alkaloids favor a nonplanar structure. The biologically active compounds had conformations with a similar angle between aromatic ring A, the nitrogen in ring B, and ring D. This angle was related to the biological activity reported for these compounds. Our results support the hypothesis of two different types of receptor interactions, one for the nonplanar compounds and another for the planar compounds.

Alkaloids↗
PubMed1984

A model system for measuring comparative toxicities of cardiotoxic drugs with cultured rat heart myocytes, endothelial cells and fibroblasts. I. Emetine, chloroquine and metronidazole.

Neonatal rat hearts were separated into separate cultures of beating myocytes (M cells), endothelial cells (E cells) and fibroblasts (F cells). Their susceptibilities to the toxic effects of emetine, chloroquine and metronidazole were then compared using a quantitative metabolic inhibition test (QMIT) and morphologic and beating changes as indices of injury. Measurements on the same cultures were made at 6 h and 12 h daily for 7 days with E and F cells; with M cells for 3 days. Metronidazole was non-toxic for all cell types at 810 micrograms/ml, whether as the parent compound or after attempted rat liver microsomal activation. QMIT data, integrated as time-concentration effects, showed all cell responses to either emetine or chloroquine to be parallel (P less than 0.05), and their order of susceptibility to be: E greater than M greater than F cells. Although morphologic signs of injury and changes in beating are not readily evaluated statistically, there was a general parallelism between these indices of injury and those of QMIT. As judged by QMIT emetine was more toxic than chloroquine. However, at equivalent QMIT grades chloroquine produced greater effects on morphology and beating. Toxic concentration-50 values for chloroquine with the QMIT were similar to reported human toxic and lethal blood concentrations.

Animals↗