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At least 19 recordsLinked to original sources
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↗
PubMed1980

Biochemical and genetic evidence for a new class of emetine-resistant Chinese hamster cells with alterations in the protein biosynthetic machinery.

We have isolated a number of emetine-resistant mutants from several different clones of CHO and CHL cells. Protein synthesis in extracts derived from each of the mutants is much more resistant to emetine than in the parental, emetine-sensitive cell lines, indicating the lesions affect the protein synthetic machinery directly. However, hybrid cell lines, derived from fusing either of two different emetine-resistant CHO mutants with either one of two different emetine-resistant CHL cells, are much more sensitive to growth inhibition by emetine than either parent. In addition, the incorporation of [3H] amino acids into protein in vivo and protein synthesis in vitro in extracts derived from these hybrids is much more sensitive to emetine inhibition than in either emetine-resistant parent. In contrast, no complementation was observed in hybrids derived from fusing two emetine-resistant CHO mutants or in hybrids derived from fusing two emetine-resistant CHL cell lines. These results indicate the CHO emetine-resistant mutants belong to one complementation group and the CHL emetine-resistant mutants belong to another. The genetic loci represented by these two complementation groups must both encode for gene products involved in protein synthesis.

Alleles↗
PubMed2003

Emetine inhibits glycolysis in isolated, perfused rat hearts.

This work was designed to test whether phosphofructokinase is a target for emetine action on the heart. The effects of 37 microM emetine on the activities of phosphofructokinase and hexokinase were measured in homogenates from perfused hearts. The action of increasing concentrations of emetine was determined in nonperfused heart homogenates. The effect of 37 microM emetine or control solutions on the concentration of fructose-6-phosphate and fructose- 1,6-phosphate was measured. The effect of 37 microM emetine or control perfusion on the utilization of fructose-6-phosphate by phosphofructokinase in centrifugation supernatants of homogenates and in reconstituted 27,000g pellets was measured. Double-reciprocal plots of fructose-6-phosphate concentrations vs phosphofructokinase activities were plotted. Emetine decreased phosphofructokinase activity in homogenates from both perfused and nonperfused hearts. Emetine did not inhibit cardiac hexokinase activity. In homogenates from nonperfused hearts, the maximal inhibition with high concentrations of emetine was approx 50%. Emetine perfusion caused a simultaneous increase in the phosphofructokinase substrate fructose-6-phosphate and a decrease in the phosphofructokinase product fructose-1,6-bisphosphate. Phosphofructokinase and, consequently, glycolytic flux appear to be subcellular targets for emetine in the heart. Homogenate centrifugation studies indicate that emetine acts on bound rather than unbound phosphofructokinase. The inhibition may be uncompetitive in nature.

Animals↗
PubMed1993

Effects of emetine on the specific association of T-2 toxin with mammalian cells.

The effects of emetine on the association of T-2 toxin with Chinese hamster ovary cells were examined. T-2 toxin-cell association at both 4 degrees C and 37 degrees C was reduced by up to 90% after preincubation of cells with emetine. Emetine-induced reduction in T-2 toxin-cell association was time-, temperature-, and concentration-dependent. A 4-min preincubation with emetine at physiological temperature was required to develop the maximum inhibitory effect. After brief exposures (< or = 5 min), emetine's inhibitory effects on toxin-cell association were reversible. However, after longer exposure periods to emetine (60 min), toxin-cell association was irreversibly blocked. The addition of emetine to cells prebound with toxin resulted in dissociation at a rate 2 to 3 times slower than a competitive chase with nonlabeled toxin. Emetine did not compete directly for T-2 toxin binding to its receptor on isolated, purified, run-off ribosomes. However, the binding of toxin to purified ribosomes prepared from cells preincubated with emetine was markedly reduced. Scatchard analysis indicated that emetine's inhibitory effects on T-2 toxin-cell association were mediated through mixed allosteric and competitive types of inhibition at specific, intracellular, T-2 toxin ribosomal binding sites.

Animals↗
PubMedDate not supplied

Absorption, distribution and excretion of 3H-labeled cephaeline- and emetine-spiked ipecac syrup in rats.

The maximum plasma radioactivity levels of tritium (3H)-labeled cephaeline, (24.3, 28.7 and 40.6 ng eq./mL) were reached at 2.00-3.33 hours following oral dosing of ipecac syrup. The maximum plasma radioactivity levels of 3H-emetine (2.71, 6.47 and 9.62 ng eq./mL) were reached at 1.08-2.33 hours following ipecac syrup administration. The Cmax values of 3H-cephaeline were followed by a biexponential decrease with half-lives t 1/2(lambda z) of 3.45-9.40 hours. On the other hand, the t 1/2 (lambda z)of 3H-emetine were 65.4-163 hours, which revealed a biexponential decrease. The radioactivity of both tritium-labeled compounds was distrbuted maximally in most tissues at 24 hours. For 3H-cephaeline, the maximum radioactivity levels in tissues were approximately 100-150 times greater than in plasma. For 3H-emetine, the radioactivity levels in tissues were approximately 1000-3000 times greater than in plasma. Tissue radioactivity levels decreased at a substantially slower rate than that observed in plasma. Tissue radioactivity of 3H-emetine decreased more slowly than that of 3H-cephaeline. For 3H-cephaeline, the cumulative biliary excretion of radioactivity was 57.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity in these rats was 16.5% and 29.1%, respectively, of the dose at 48 hours following dosing. For 3H-emetine, the cumulative biliary excretion of radioactivity was 12.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity was 9.4% and 34.1%, respectively, of the administered dose at 48 hours. The radioactivity level of 3H-emetine remaining in the carcasses at 48 hours was equivalent to approximately 50% of the dose. A portion of each tritium-labeled compound was subjected to entero-hepatic circulation. Thus, the absorption rate of 3H-cephaeline and 3H-emetine was estimated to be approximately 70% on the basis of the data obtained from excretion studies. There was no difference in the absorption process between these two compounds. However, the difference was admitted in the biliary clearance, which is the main excretion route of both compounds. Delayed excretion of 3H-emetine may be primarily due to its resorption as related to entero-hepatic circulation and tissue retention. This study has determined the absorption, distribution and excretion of 3H-cephaeline and 3H-emetine in rats.

Absorption↗
PubMed1989

Giant miniature end-plate potentials at the untreated and emetine-treated frog neuromuscular junction.

1. Intracellular recordings from the cutaneous pectoris muscle fibres of the frog showed that giant miniature end-plate potentials (gMEPPs) occurred in untreated preparations. Emetine (10 microM), after a 15-20 min delay, increased the frequency of gMEPPs. In both cases gMEPPs disappeared in the presence of (+)-tubocurarine. 2. There was no correlation between the frequency of gMEPPs and the frequency of normal MEPPs (nMEPPs) in untreated or emetine-treated fibres. 3. Tetraphenylborate (TPB, 50 microM) applied to muscles pre-treated with emetine caused the frequency and amplitude of both nMEPPs and gMEPPs to decrease gradually. All MEPPs disappeared in about 10 min. 4. Chloride permeability was modified by changing the pH of the Ringer solution. Changing the pH from 7.2 to 8.2 or 6.2, which in both cases caused marked increases in nMEPP frequency, had no significant effect on gMEPP frequency in untreated muscles. 5. Decreasing the pH from 7.2 to 6.2 blocked the ability of emetine to increase gMEPP frequency. Increasing the pH from 7.2 to 8.2 had no significant effect on emetine ability to increase gMEPP frequency. 6. Treatment with the Cl- channel blocker SITS (0.5 mM) had no effect on gMEPPs in untreated muscle or on the ability of emetine to increase the frequency of these potentials. 7. The Ca2+ sensitivity of gMEPPs in untreated or emetine-treated muscles was tested by treatments which are known to alter intracellular Ca2+. Raising extracellular Ca2+ (10 mM), treatment with Mn2+ (10 mM), Mg2+ (10 mM), K+ (7.5 mM), hypotonic solution, ouabain (0.2 mM) or ethanol (0.5 M), although causing profound changes in nMEPP frequency had no significant effect on gMEPP frequency in untreated fibres or on the ability of emetine to increase gMEPP frequency. 8. It is concluded that at the frog neuromuscular junction generation of the normally occurring or emetine-induced gMEPPs is independent of Ca2+ and does not seem to be influenced by changing membrane C1- permeability.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
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↗
PubMedDate not supplied

[Protective effect of glucose-insulin-potassium solutions in myocardial damage caused by emetine].

This study was carried out on 170 dogs. Cardiotoxic effects of doses of 15 mg/kg of emetine hydrochloride were studied in 20 dogs. 20 mg/kg of emetine hydrochloride were administered intravenously over 60 min. to the remaining 150 animals. These dogs were distributed in groups of 25. One group received emetine alone. Phleboclyses with saline serum, glucose-insulin-potassium, glocose-insulin, glucose-potassium and glucose serum alone, respectively, were administered to the other 5 groups during the emetine infusion and cardial contraction and several electrograms were recorded. Mean systolic blood pressure was measured continuously in the femoral artery. Observations covered a 4 hour period. During the infusion of emetine alone, ventricular myocardial contraction and systemic arterial pressure decreased abruptly. Intra-atrial, atrio-ventricular and intraventricular conduction disorders, as weel as primary ventricular repolarization changes, were also observed. At the end of this infusion, the Q-T interval increased 25% and the heart rate decreased 26% of the control values. In the group also receiving glucose-insulin-potassium solution, the fall of the ventricular contraction amplitude was significantly less than in animals given emetine alone. Primary ventricular repolarization changes were less evident. The mortality rate reached only 4 per cent. In conclusion, the doses of emetine hydrochloride employed here have depressive cardiocirculatory effects. Glucose-insulin-potassium solution, administered simultaneously with emetine, seems to have a favorable metabolic effect against the emetine cardiotoxicity. This protective action of the G-I-K solution is superior to that obtained with each component, administered separately, and with saline serum.

Animals↗
PubMed1982

Effect of emetine treatment on subcellular nucleic acid and protein metabolism.

The subcellular RNA and protein metabolism have been studied in emetine-treated rats. Emetine treatment for a period of 10 days reduced the incorporation in vivo of [14C]-leucine into proteins of nuclear fraction of liver. This was accompanied by a reduction in the nuclear protein content. The mitochondrial fraction of heart exhibited an increase in the protein content after emetine treatment. This was, however, not accompanied by an increased rate of incorporation into its protein. On the other hand, the nuclear fraction of heart of emetine-treated rats showed a diminution in the rate of incorporation into its protein without having been reduced in protein content. The mitochondrial and microsomal RNA of liver and the microsomal RNA of heart responded to emetine treatment by showing increased levels. The liver RNase activity was reduced after emetine treatment, while the heart RNase remained independent of the treatment. It has been suggested that both synthesis and breakdown of liver proteins are reduced by emetine treatment. The synthesis of liver nuclear proteins was supposedly affected more than was its breakdown by emetine. The synthesis of rapidly turningover proteins of heart nuclear fraction and the catabolism of slowly turningover proteins of its mitochondrial fraction are thought to be reduced by the emetine treatment.

Animals↗
PubMedDate not supplied

Biotransformation of the ipecac alkaloids cephaeline and emetine from ipecac syrup in rats.

The metabolism of cephaeline and emetine, which are the primary active components of ipecac syrup, were investigated in rats. Cephaeline-6'-O-glucuronide was found to be a biliary metabolite of cephaeline. Cephaeline (6'-O-demethylemetine) and 9-O-demethylemetine were observed to be enzyme-hydrolyzed biliary metabolites of emetine. Cephaeline was conjugated to glucuronide, while emetine was demethylated to cephaeline and 9-0-demethylemetine, and may be conjugated to glucuronides afterwards. Urine, feces and bile were collected from rats within 48 hours following the administration of ipecac syrup containing tritium (3H)--labeled cephaeline or emetine. Metabolites were separated and quantified by thin layer chromatography (TLC) or high-performance liquid chromatography (HPLC). Biliary and urinary excretion rates of 3H-cephaeline were 57.5% and 16.5% of the dose, respectively. Cephaeline-6'-O-glucuronide was comprised 79.5% of biliary radioactivity and 84.3% of urinary radioactivity. Unchanged cephaeline was detected in 42.4% of the dose in feces. Biliary excretion rate of 3H-emetine was 6.9% of the dose. Emetine, cephaeline and 9-0-demethylemetine comprised 5.8%, 43.2% and 13.6% in hydrolyzed bile, respectively. There were no emetine-derived metabolites in urine or feces. The occurrence of unchanged emetine was 6.8% and 19.7% of the dose in urine and feces, respectively.

Animals↗