Emetine Hydrochloride Research Articles

Emetine enhances the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of pancreatic cancer cells by downregulation of myeloid cell leukemia sequence-1 protein

Although the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent, it shows limited efficacy in human pancreatic cancer cells. Protein synthesis inhibition has been reported to sensitize cancer cells to apoptosis-inducing agents, but the detailed mechanism by which protein synthesis inhibition sensitize cells to TRAIL has not been determined. To investigate the mechanism underlying pancreatic cancer cell resistance to TRAIL, we performed a small scale high-throughput compound screening in AsPC-1 pancreatic cancer cells using a bioactive small molecule library. We identified 8 compounds that reproducibly sensitize AsPC-1 cells to TRAIL-induced apoptosis. One of these compounds, emetine hydrochloride, when combined with subtoxic concentrations of TRAIL, induced massive apoptosis in AsPC-1 and BxPC-3 pancreatic cancer cells. Cell death analysis revealed that the sensitizing effects of emetine were specific to TRAIL. Emetine downregulated the expression of the TRAIL-related anti-apoptotic protein Mcl-1 in a dose- and time-dependent manner. Furthermore, specific knockdown of Mcl-1 using small interfering RNA without emetine treatment sensitized pancreatic cancer cells to TRAIL. Emetine sensitization of pancreatic cancer cells to TRAIL via Mcl-1 was confirmed under hypoxic conditions. Taken together, these findings strongly suggest that Mcl-1 is involved in pancreatic cancer cell resistance to TRAIL, and emetine facilitates the apoptosis of TRAIL-tolerant pancreatic cancer cells by specifically inhibiting Mcl-1 function.

Simultaneous Determination of Cephaeline and Emetine in Ipecac and Its Preparations Using RP-HPLC

ObjectiveTo control the quality of ipecac and its preparations, and to investigate the simultaneous quantitative determination of cephaeline and emetine. MethodsAfter ultrasonic extraction with acidic methanol solution or direct diluting preparations, cephaeline hydrochloride and emetine hydrochloride in ipecac and its preparations were separated within 20 min using a mixture of acetonitrile-methanol-0.1% phosphoric acid (9:3:88) as the mobile phase on a C18 column by HPLC. UV detector was set at 205 nm. The flow rate was set at 1.0 mL/min. ResultsThe methodological study showed that a good linear correlation existed in the range of 0.014 560.2184 μg (r = 0.999 97) for cephaeline hydrochloride and 0.0321—0.321 μg (r = 0.999 97) for emetine hydrochloride, respectively. The average recovery of cephaeline hydrochloride and emetine hydrochloride was 96.93% and 99.47%, and the RSD values (n = 9) were 1.31% and 2.02%, respectively. ConclusionThe assay is sensitive, accurate, specific, and applicable to comprehensive evaluation on the quality of ipecac and its preparations.

TOXICITY AND TISSUE DISTRIBUTION STUDIES ON THE HYDROCHLORIDE, BISMUTH IODIDE COMPLEX AND A RESINATE OF EMETINE.

Abstract The hydrochloride, the bismuth iodide complex and a resinate of emetine have been compared on mice, cats and dogs for toxicity, on cats for emetic activity and on rats for distribution of emetine in the tissues. Emetine hydrochloride, injected sub-cutaneously, was as toxic as emetine hydrochloride or emetine bismuth iodide administered orally, but only one-sixth as emetic. Given orally emetine resinate was considerably less toxic and emetic than the other preparations. The patterns of emetine distribution in the tissues of rats were similar for all the preparations, but the tissue concentrations were much lower with emetine resinate. In infected rats the resinate was as amoebicidal as the hydrochloride or the bismuth iodide complex. It is suggested that emetine resinate might be better than emetine bismuth iodide for the treatment of intestinal amoebiasis.

Spectophotofluorometric determination of emetine in animal tissues.

Abstract A simple rapid spectrophotofluorometric method for assaying emetine in animal tissues is described. Tissue emetine concentrations have been determined in rats at intervals up to 14 days after single doses of emetine hydrochloride or emetine bismuth iodide: the hydrochloride was administered orally or subcutaneously and the bismuth iodide complex orally. Subcutaneously administered emetine hydrochloride produced the highest concentrations. Given orally, emetine hydrochloride produced higher tissue levels than did emetine bismuth iodide.

Letters to the Editor: The Specific Rotation of Emetine Hydrochloride

Letters to the Editor: The Specific Rotation of Emetine Hydrochloride

Determination of Chlorpheniramine Maleate and Tincture Ipecac in Dosage Form by Liquid Chromatography with Ultraviolet Detection

A procedure was developed and validated for measuring chlorpheniramine maleate and tincture ipecac (as emetine hydrochloride) by reversed-phase liquid chromatography with methanol-10 mM sodium heptanesulfonate (20 + 30) as the mobile phase; the pH was adjusted to 4 with acetic acid, and the flow rate was at 1.5 mL/min, with ultraviolet detection at 254 nm. Propyl paraben was used as the internal standard. The standard curves were linear (r = 0.998 and 0.9998) for both chlorpheniramine maleate and emetine hydrochloride over the ranges of 5-100 and 0.1-40 microg/mL, respectively. The mean recoveries +/- standard deviation were 101.37 +/- 2.77% for chlorpheniramine maleate and 98.8 +/- 1.47% for emetine hydrochloride. The proposed method was applied to the determination of chlorpheniramine maleate alone in tablet and syrup dosage forms. The method also was applied to the determination of the emetine content of ipecac liquid extract and tincture ipecac; the results were compared with those of the method of the British Pharmacopoeia. The proposed method was applied successfully to the simultaneous determination of chlorpheniramine maleate and tincture ipecac, as emetine hydrochloride, in syrup dosage form. Both drugs and the internal standard were separated from all interfering components in < 5 min. The proposed method is simple, specific, and economical, when compared with other published methods that determine each component alone.

Thin Layer Chromatographic Scanner Method for the Determination of Some Natural Products in Raw Materials and Pharmaceutical Preparations

The suggested method depends upon the determination of lobeline, khellin and emetine hydrochloride. The method is simple, accurate, precise, and depends on the quantitative TLC spectrodensitometric evaluation of lobeline I, khellin II, and emetine hydrochloride III. Excellent separation with discrete spots was quickly obtained. The proposed method determines 8.50−22.00 mg.mL−1, 0.02−0.14 mg.mL−1, and 0.8−3.6 mg.mL−1 with mean percentage accuracies of 99.34% ± 0.49%, 99.99% ± 0.62%, and 99.69% ± 0.50% for I, II, and III respectively. The proposed method was successfully applied to the analysis of I, II, and III in raw materials, and to pharmaceutical preparations. The results obtained were compared statistically with those obtained by applying the official methods, furthermore, the validity of the results was assessed by applying the standard addition technique.

A Novel Strategy for Preparation of Solid-Phase Reactors. Fluorimetric Determination of Emetine Hydrochloride.

Abstract A novel strategy for preparation of solid-phase reactors is proposed. The reagent “impregnates” the inner wall of a pump tubing. The reactor is of the open-tubular type; however, the pressure of pump cylinders establish a close contact immobilized reagent-sample solution providing a high reactivity degree. The procedure is applied to iodine immobilization for fluorimetric determination of emetine, the calibration graph is linear over the range 0.1 - 100 ug ml of emetine and is applied to determination of emetine chlorhydrate in pharmaceutical formulations.

Experimental emetine myopathy: enzyme histochemical, electron microscopic, and immunomorphological studies.

Ipecac, containing emetine hydrochloride, is used by patients with anorexia nervosa to induce vomiting. Its chronic usage may result in a myopathy and a cardiomyopathy, the former marked by cytoplasmic bodies. We studied myopathological changes after daily injections of female Wistar rats with emetine hydrochloride intraperitoneally for periods of 4, 5, 9, and 10 weeks. The extensor digitorum longus muscle and the soleus muscle showed core-like lesions, streaming of the z-discs, nemaline bodies, cytoplasmic bodies, and spheroid cytoplasmic bodies. Immunomorphological studies revealed increased amounts of desmin. During a period of repair, i.e., 2, 4, and 6 weeks after termination of emetine application, these myopathological alterations faded while proliferation of the T-tubular system, i.e., honeycomb structures, was more often prevalent. Pathological features completely disappeared between 6 and 12 weeks of recovery.

Continued development and unconditioned stimulus characterization of selectively bred lines of taste aversion prone and resistant rats.

This report updates the bidirectional selective breeding of taste aversion (TA) prone (TAP) and TA resistant (TAR) rat lines from the 8th through the 22nd generations. A palatable saccharin solution and the aversive consequences of a cyclophosphamide injection are the respective conditioned stimulus (CS) and unconditioned stimulus (US) of line development. Nonsibling matings within each of the two extremes of TA conditionability have produced TAP and TAR lines having markedly different TA propensities. As previously reported, the substitution of a rotational (i.e., motion sickness) US for cyclophosphamide during TA conditioning also produced characteristic line differences in conditioned taste aversion acquisition. The present report extends the effective line separating USs to include injections of lithium chloride, emetine hydrochloride, and EtOH. A range of EtOH dose levels produced dose-dependent TAs within TAP rats but failed to induce TAs in TAR rats. Following the conclusion of TA testing, the administration of a hypnotic EtOH dose produced equivalent loss of righting capability and equivalent hypothermia in both TAP and TAR rats. The line differences in EtOH induced TA conditionability therefore do not reflect general line differences in EtOH sensitivity. The lines may be useful within studies of biological bases of TA conditionability and animal analog studies of prevention and treatment of alcohol dependence.

Psychotrine and its O-methyl ether are selective inhibitors of human immunodeficiency virus-1 reverse transcriptase.

Psychotrine dihydrogen oxalate and O-methylpsychotrine sulfate heptahydrate (MP), the salts of isoquinoline alkaloids from ipecac, were found to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). We currently report the results of additional studies designed to characterize the mechanism of inhibition facilitated by MP. The inhibition was noncompetitive with respect to TTP and uncompetitive with respect to poly(rA) and oligo(dT)12-18 (4:1) at low template-primer concentrations but competitive at high concentrations (greater than 200 microM). Identical non-Michaelis-type kinetics were observed when activated DNA was used as the template. The biphasic nature of the double-reciprocal plots and Hill coefficients of less than 1 indicate that MP functions as an allosteric inhibitor of the enzyme which appears to possess multiple active sites that interact in a cooperative (negative) fashion in the presence of the inhibitor. MP was selective for the recombinant HIV-1 RT (p66) utilizing poly(rA) and oligo(dT)12-18 (4:1) as template-primer. Greater inhibition was observed with this template primer as compared with other natural and synthetic template-primers tested. MP had significantly less effect on avian myeloblastosis virus RT as well as mammalian or bacterial DNA and RNA polymerases. Other members of the ipecac class of alkaloids, e.g. emetine hydrochloride, were inactive against all of these enzymes, including HIV-1 RT. Conversely, MP did not inhibit in vitro protein synthesis, a property manifested by all the other ipecac alkaloids tested. Studies conducted with structural analogs revealed that the imine functionality at positions 1' and 2' of MP is the key structural requirement for HIV-1 RT inhibitory activity. Therefore, MP appears to possess unique structural properties that enable interaction with HIV-1 RT in a manner that can be differentiated from other polymerases. Use of these alkaloids for the definition of this viral enzyme-specific topology may lead to the development of therapeutically useful chemotherapeutic agents.

A Human Case of Hepatic Resection for Liver Fascioliasis in Korea

Human Fasciola hepatica infection is a rare entity involving infestation of the liver and biliary tree with adult flukes. which can result in hepatitis. cirrhos is and biliary tract inflammation. obstruction and lithiasis. The patient had the typical diagnostic tetrad of fever. eosinophilic leukocytos is. tender hepatomegaly and fluke ova in the stools. Theatment consistes of Emetine hydrochloride administration for hepatic involvement and common bile duct exploration for removal of flukes. with cholecystectomy for associated cholelithiasis. The combination of medical and surgical therapy cal be expected to produce an arrest of this infection. The removed liver revealed eggs of the fasciols species in the intrahepatic bile duct. The clinical history. pathological findings and treatment of this case were described.

Ultrastructural pathology in emetine-induced myopathy

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.

Treatment of leishmaniasis nodosa (oriental sore) with intralesionally injected emetine hydrochloride

Treatment of 31 patients with a total of 50 leishmaniasis nodosa (oriental sore) lesions with intralesional injections of emetine hydrochloride led to 100% cure. The injections were given once in 15 days except in the case of one patient, who was treated once a week. The total amounts injected were: 10 to 13 mg for lesions up to 0.5 cm in size in one injection and 160 mg for the largest lesion, which covered almost the entire surface of the patient's nose, in five weekly injections.

Development of topical treatment for cutaneous leishmaniasis caused by Leishmania major in experimental animals

Topical treatment, with drug-containing ointments, of cutaneous leishmaniasis caused by Leishmania major in BALB/c mice was studied. Twenty chemotherapeutic agents having potential or established antileishmanial activity were formulated in different ointment and cream bases. Only 15% paromomycin sulfate with 12% methylbenzethonium chloride, 12% benzethonium chloride, 12% cetalkonium chloride, or 12% dimethyl sulfoxide, all incorporated in white soft paraffin (United Kingdom patent application no. 2117237A), were completely effective. Topical treatment twice daily for 6 or more days caused total elimination of the parasites and healing of the lesion in all treated mice. All the other antileishmanial compounds, including sodium stibogluconate, pentamidine, amphotericin B, emetine hydrochloride, metronidazole, co-trimoxazole, allopurinol, and rifampin, either showed a slight effect on the parasites or were highly toxic to the animal host at the concentrations tested.

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.

Generation of human T-cell hybrids with the characteristics of human peripheral blood T-lymphocytes

Using a selection system based on the two irreversible biochemical inhibitors, actinomycin-D and emetine hydrochloride, we have constructed human T-lymphocyte hybrids between the human T-cell line, Molt-4F, and mitogen-activated human lymphocytes. The cells were identified as true hybrids by their karyotype, differences in supernatant activities, responses to mitogen and membrane characteristics. These hybrid cells are stable in culture and express functions found in mature human T-lymphocytes.

Treatment of leishmaniasis recidivens with intralesional injections of emetine hydrochloride: a case report

A patient, suffering for 42 years from the late tuberculoid-type of leishmaniasis located in his face, was successfully treated with intralesional injections of emetine hydrochloride. Previous treatments, which included intralesional injections of steroids and concomitant intramuscular injections of antimonials, flagyl, fluorocytosine, infusions of amphotericin B--with and without concomitant treatment by steroids systemically and/or intralesionally--and amphotericin B intralesionally, were altogether ineffective. In addition, the patient underwent five operations in a plastic surgery department.

Principles of Clinical Electrocardiography

This tenth edition ofPrinciples of Clinical Electrocardiographyby Goldman is little changed from the ninth edition. With few exceptions, the organization, structure, content, and illustrations are unchanged from previous editions. The book is easy to read; the language is simple, concise, and uncluttered; and the diagrams and illustrative ECGs are generally of good or excellent technical quality. The text is profusely illustrated and is complete and current, though of necessity in a book of this type, many topics are given brief and sketchy treatment. Some discrepancies and unevenness in the quality and relevancy of the material covered are noted here and there. For example, a few paragraphs are given to the effects on the ECG of such drugs as emetine hydrochloride, phenothiazines, and daunorubicin hydrochloride and such conditions as malignancy and hypothermia, yet there is no discussion of the ECG in pulmonary embolism. Brief but adequate mentions are made

Experimental (−) emetine myopathy: Ultrastructural and morphometric observations

The ultrastructural changes induced by (-) emetine hydrochloride were studied in two skeletal muscles of the rat. (-) Emetine was administered at a dose level of 2 mg/kg for periods ranging from one to four weeks. Changes were noted after the one week stage and were progressive with all muscle components appearing to be affected. Myofibrillar changes included Z line streaming, rod formation, myofilament loss and contraction clumping. Mitochondrial degeneration was detected, but the most striking feature of the induced myopathy was the extensive membrane proliferation. The membranes were considered to be involved in the isolation of sarcoplasmic constituents in the production of autophagic vacuoles. Morphometry was carried out in order to quantify some of the changes in the fibre components.