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No prior studies have shown that gaping reactions are produced with the avoidance of conditioned taste caused by cisplatin and emetine. Therefore, we tried to demonstrate it using a taste reactivity test in rats and found the gaping reactions induced when saccharin is readministered after gustatory conditioning that paired saccharin with cisplatin or emetine. Since conditioned gaping reactions indicate the aversion to saccharin taste and conditioned nausea, the present study suggest that the taste aversion is induced by cisplatin and emetine. It was also found that with intraperitoneal injections of emetine alone, gaping almost never occurs.

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Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (-)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 µM), which loses its potency due to the change of configuration at C-1'. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.

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Two cases of ipecac myopathy, one with associated cardiomyopathy are reported. Both patients were young women with eating disorders who came to medical attention because of diffuse muscle weakness. Clinical and electromyographic data suggested ipecac myopathy and muscle biopsies confirmed this diagnosis. One patient had associated clinical and echocardiographic evidence of significant cardiomyopathy. The myopathy resolved and the echocardiogram returned to normal after discontinuing the use of ipecac.

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Amoeba proteus is proposed as a low-cost multi-purpose biochemical tool for screening and standardizing cytotoxic plant extracts with possible application in the laboratories of developing countries. Advantages and limitations of this test are examined and different mathematical treatments (probit analysis versus curve fitting to Von Bertalanffy and Hill functions) are investigated. Known anti-cancer (doxorubicin, daunorubicin, dacarbazine, 5-fluorouracil) and antiparasitic (emetine, dehydroemetine, metronidazole, cucurbitine, chloroquine) drugs were tested using this method and only metronidazole appeared inactive. Application of this model to Euphorbia hirta established that a 100 degrees C aqueous extraction of fresh aerial parts allows efficient extraction of active constituents and that drying the plant material before extraction considerably reduces activity.

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Emetine is still an important agent for the treatment of invasive intestinal amebiasis and amebic liver abscess. Its most relevant side effect is its well documented cardiotoxicity. The authors review the hypotheses that have been suggested concerning the mechanism of this cardiotoxic action.

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Toxic injury is one of the many ways by which the functional integrity of the heart may become compromised. Any of the subcellular elements may be the target of toxic injury, including all of the various membranes and organelles. Understanding the mechanisms underlying cardiotoxicity may lead to treatment of the toxicity or to its prevention. Doxorubicin and its analogs are very important cancer chemotherapeutic agents that can cause cardiotoxicity. Other agents which are cardiotoxic and which have profound public health implications include the alkaloid emetine in ipecac syrup, cocaine, and ethyl alcohol. The most important cardiotoxic mechanisms proposed for doxorubicin include oxidative stress with its resultant damage to myocardial elements, changes in calcium homeostasis, decreased ability to produce ATP, and systemic release of cardiotoxic humoral mediators from tissue mast cells. Each of the first 3 mechanisms can lead to each of the other 2, and the causal relationships between all of these mechanisms are not clear. New evidence suggests that doxorubicinol, one of the metabolites of doxorubicin may be the moiety responsible for cardiotoxicity. Several other potential mechanisms also have been proposed for doxorubicin. Emetine in ipecac syrup is the first aid treatment of choice for many acute toxic oral ingestions and the alkaloid, itself, is used to treat amebiasis. Cardiotoxicity occurs following chronic exposure, such as occurs therapeutically in amebiasis and with ipecac abuse by bulemics. A number of mechanisms are proposed for emetine cardiotoxicity, but the current mechanistic literature is quite scarce. Cocaine abuse recently has caught the public interest, in particular because of the drug-related sudden deaths of certain athletes. Cocaine can cause hypertension, arrhythmias, and reduced coronary blood flow, each of which can contribute to its lethality. However, it may be possible that cocaine sudden death episodes are more related to hyperthermia and convulsive seizures, rather than to cardiovascular toxicity. Chronic alcohol use leads to dilated cardiomyopathy and failure as part of the general physical degeneration that occurs with alcoholism. Several mechanisms are proposed for the cardiomyopathy, but only 2 things seem clear. The cardiotoxicity is due to an intrinsic effect of alcohol, rather than to malnutrition or co-toxicity, and abstinence is the only effective treatment for the cardiomyopathy. Recent articles indicate that very moderate use of alcohol may be beneficial and protect against cardiovascular-related morbidity. One explanation for these findings seems to be that the non-drinking groups, against whom the moderate drinking comparisons were made, were enriched in former drinkers with significant alcohol-related cardiovascular pathology.

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Progressive myopathy developed in two women who consumed ipecac syrup containing emetine hydrochloride to induce vomiting as part of their anorexia nervosa. Muscle biopsy specimens were characterized by severe disruption of the sarcomeres. The ultrastructural spectrum extended from "Z-band streaming" to the formation of cytoplasmic bodies and also comprised abnormalities of the sarcotubular system, thus suggesting that muscle weakness may be related to both sarcomeric and sarcotubular lesions in this self-inflicted myopathy. It is tempting to suggest that muscle weakness may be correlated with or based on the pathology in sarcomeres and the sarcotubular system. As the myopathy is clinically reversible upon discontinuation of ipecac consumption the morphological findings should also be potentially reversible. Experimentally induced emetine myopathy may, thus, serve as a useful model to study morphological dynamics of sarcomeric lesions, which may be observed separately or simultaneously in a variety of spontaneously occurring human neuromuscular disorders.

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We report two female patients with a history of alcohol abuse presenting with proximal painful muscle weakness following aversion therapy with emetine hydrochloride. Muscle biopsy of Case 1 showed a reversible floccular-shaped loss of myosin ATPase and dehydrogenase, an accumulation of PAS positive material, and a normal lipid content. Repeat biopsy showed core change with no focal loss of myosin ATPase. In Case 2, muscle biopsy was taken 1 month after commencement of emetine therapy and revealed similar but milder changes to Case 1. Electron microscopy revealed Z-band streaming with a decrease or loss of mitochondria. Sarcotubular systems appeared normal in shape and size. Anaerobic glycolysis on homogenate from the initial biopsy of Case 1 showed generalized reduction of lactate formation, which returned to normal in the repeat biopsy.

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A correlative electrocardiographic and ultrastructural study of myocardium in rabbits, administered 1 mg/kg of emetine hydrochloride intramuscularly for 5 successive days of a week over 2 to 4 week period, was conducted. The study revealed electrocardiographic changes and a spectrum of ultrastructural lesions involving myocardial cells and interstitial neural elements. The severity of these lesions was related to the cumulative dose of the drug. Myocardial cell lesions were characterized by fatty infiltration, increase in glycogen content, myofibrillolysis, focal cytoplasmic degeneration, contraction-band necrosis and intercalated disc disjunction, herniation and fragmentation of the close junction (nexus). Neural lesions included mesaxonal and axonal myelinoid bodies and alterations in dense-core vesicles of biogenic amine containing cells. Atrial myocardial lesions were relatively fewer and less severe than those in the ventricular myocardium. The myocardial cell and neural lesions may be inter-related and underlie the pathogenesis of emetine-induced cardiomyopathy.

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Emetine has long been recognized as a cardiotoxic drug, but its mechanism remains unknown. Since many studies reported an effect of emetine on cardiac metabolism, permanent damage to the heart could result from such treatment. To investigate this action of emetine in relation to the cardiotoxicity seen after a therapeutic regimen, New Zealand albino rabbits were given 2 mg/kg/day ip of emetine for 9 days. Heart and liver mitochondrial metabolism was assessed polarographically using pyruvate, pyruvate plus malate, or succinate as the substrate. Heart mitochondrial metabolism was reduced in emetine-treated rabbits in comparison to the normal controls. However, the metabolic activity of the pair-fed control group was equally reduced. Only the liver mitochondrial metabolism of the pair-fed control group was reduced in relation to the normal controls, while the liver mitochondrial metabolism of emetine-treated rabbits remained unchanged. These data indicated that the reduction in heart mitochondrial metabolism resulted from the inanition induced by the chronic emetine treatment and not from a primary effect of the drug.

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The therapeutic and prophylactic effect of dehydroemetine and pentostam on Leishmania donovani in experimentally infected golden hamsters (Mesocricetus auratus) have been investigated. The intracardially infected hamsters with L. donovani and treated with dehydroemetine showed significantly lower weights in liver and spleen, and less in spleen length than those treated with pentostam. Dehydroemetine and pentostam failed to provide these animals with any protection against experimental infection with L. donovani when the drugs were administered prophylactically.

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A study involving forty patients, all sixty years of age or over, compared the use of dehydroemetine in twenty and triamcinolone in twenty for the treatment of herpes zoster. Pretreatment evolution was less than ten days. Patients treated with dehydroemetine did not experience postherpetic neuralgia, and in fourteen pain completely disappeared at the end of only one series of treatment, which in four patients consisted of only three injections. Postherpetic neuralgia developed in only eight patients out of those treated with triamcinolone, and in four pain persisted for more than six months. The results of laboratory tests, including cardiovascular evaluation, remained normal with both drugs.

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A case of ventricular tachycardia in patient who was being treated with dehydroemetine and chloroquine for amoebic liver abscess is reported. The patient had 15 episodes of this arrhythmia. The hazard of using dehydroemetine and chloroquine in conventional doses, even sequentially, is emphasized.

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