Comparative study on gastric absorption of albendazole and mebendazole in rats

1. A study was carried out to determine the kinetics of the gastric absorption of two wide spectrum benzimidazole anthelmintics, albendazole and mebendazole.2. The method used was gastric recirculation of solutions containing the drugs in concentrations ranging from 0.5 to 100 mM.3. The results obtained showed that absorption corresponds to first order kinetics, with diffusion constants of 0.0087 min⁻¹ for albendazole and 0.0077 min⁻¹ for mebendazole.4. Blood levels of the drugs for the whole range of concentrations were always higher in the case of albendazole.     

An in vivo evaluation of induction of abnormal sperm morphology by some anthelmintic drugs in mice

Using the murine sperm-head abnormality test, the mutagenicity of pyrantel pamoate, levamisole, albendazole, mebendazole and niridazole was evaluated. Pyrantel pamoate and niridazole induced increases in sperm-head abnormalities statistically significant over the negative controls at all the dose levels that were considered; the induction was dose-dependent indicating that both drugs might be mutagenic. Levamisole, albendazole, mebendazole and thiabendazole, all were unable to induce statistically significant increases in sperm-head abnormalities over the negative controls at all the dose levels tested; there was no correlation between dose level of administered drugs and incidence of abnormal sperms, indicating that the drugs might not be mutagenic.     

A comparative study of different albendazole and mebendazole regimens for the treatment of intestinal infections in school children of Usigu Division, western Kenya

A clinical trial to compare the effectiveness of 4- and 6-mo repeated treatment with albendazole 600 mg (Zentel, SmithKline Beecham) or mebendazole 600 mg (Vermox, Janssen) on geohelminth infections was carried out on children in 6 primary schools; the study included 1,186 children, ages 4 to 19 yr. Kato-Katz examination was performed on stool samples before and after treatment. Overall, albendazole produced better cure rates and egg reduction rates for geohelminths. The cure rates for albendazole were 92.4% for hookworm infection, 83.5% for Ascaris lumbricoides, and 67.8% for Trichuris trichiura. Mebendazole given either 2 or 3 times in a year had cure rates of 50 and 55.0% (respectively) for hookworm, 79.6 and 97.5% for A. lumbricoides, and 60.6 and 68.3% for T. trichiura infection. The geometric mean intensity of hookworm eggs per gram (epg) of stool decreased by 96.7% after albendazole treatment compared with 66.3 and 85.1%, respectively, for 2 or 3 doses of mebendazole (P < 0.05) over the same period. Reductions in epg for A. lumbricoides and T. trichiura were comparable for both drugs. Our results indicate that treatment with albendazole at a 6-mo interval was more effective than mebendazole regimens and may be the best choice for use in the control of the 3 geohelminths.     

Systematic review of exposure to albendazole or mebendazole during pregnancy and effects on maternal and child outcomes,with particular reference to exposure in the first trimester

Soil-transmitted helminth infections cause an important burden of morbidity worldwide, primarily from blood loss and malabsorption of nutrients. Where STH endemicity ≥20%, the World Health Organization (WHO) recommends preventive chemotherapy with single dose anthelminthic drugs: albendazole or mebendazole. Although WHO recommends that women of reproductive age, including pregnant women after the first trimester, be included in large-scale deworming programs, there are concerns related to the use of anthelminthic drugs during pregnancy, especially inadvertent use in the first few weeks when the pregnancy may not yet be confirmed. We therefore conducted a systematic review using the MEDLINE database with the aim of appraising all peer-reviewed evidence, published up to July 1, 2018, on the association between exposure to albendazole or mebendazole and outcomes in pregnant women, including those in the first trimester of pregnancy, and their children. From a yield of 205 papers based on titles alone, 58 papers, reporting results from 46 originator studies conducted in pregnant populations, constituted the initial evidence base. Among the nine originator observational studies which had included women in the first trimester of pregnancy within their study population, five compared birth outcomes between women exposed in the first trimester with women who were not exposed, and none reported higher rates of adverse birth outcomes in the exposed group. Due to heterogeneity in terms of study design, sample size, deworming drug, dosage and outcomes measured, data from these studies could not be pooled. Based on this cumulative evidence, it is unlikely that inadvertent exposure to albendazole or mebendazole in the first trimester carries an additional risk of adverse birth outcomes. To optimize relevance for policy making, future research in pregnant populations should aim to provide data disaggregated by trimester and to report on maternal and child adverse events, whenever possible.     

Low efficacy of single-dose albendazole and mebendazole against hookworm and effect on concomitant helminth infection in Lao PDR

Background

Albendazole and mebendazole are increasingly deployed for preventive chemotherapy targeting soil-transmitted helminth (STH) infections. We assessed the efficacy of single oral doses of albendazole (400 mg) and mebendazole (500 mg) for the treatment of hookworm infection in school-aged children in Lao PDR. Since Opisthorchis viverrini is co-endemic in our study setting, the effect of the two drugs could also be determined against this liver fluke.

Methodology

We conducted a randomized, open-label, two-arm trial. In total, 200 children infected with hookworm (determined by quadruplicate Kato-Katz thick smears derived from two stool samples) were randomly assigned to albendazole (n = 100) and mebendazole (n = 100). Cure rate (CR; percentage of children who became egg-negative after treatment), and egg reduction rate (ERR; reduction in the geometric mean fecal egg count at treatment follow-up compared to baseline) at 21–23 days posttreatment were used as primary outcome measures. Adverse events were monitored 3 hours post treatment.

Principal Findings

Single-dose albendazole and mebendazole resulted in CRs of 36.0% and 17.6% (odds ratio: 0.4; 95% confidence interval: 0.2–0.8; P = 0.01), and ERRs of 86.7% and 76.3%, respectively. In children co-infected with O. viverrini, albendazole and mebendazole showed low CRs (33.3% and 24.2%, respectively) and moderate ERRs (82.1% and 78.2%, respectively).

Conclusions/Significance

Both albendazole and mebendazole showed disappointing CRs against hookworm, but albendazole cured infection and reduced intensity of infection with a higher efficacy than mebendazole. Single-dose administrations showed an effect against O. viverrini, and hence it will be interesting to monitor potential ancillary benefits of a preventive chemotherapy strategy that targets STHs in areas where opisthorchiasis is co-endemic.

Clinical Trial Registration

Current Controlled Trials ISRCTN29126001     

3种苯并咪唑类药物对大熊猫西氏贝蛔虫的驱虫效果初步观察

西氏贝蛔虫Baylisascaris schroederi是圈养大熊猫Ailuropoda melanoleuca最常见、危害最严重的一种体内寄生虫,采用药物驱虫是目前控制圈养大熊猫蛔虫病的主要措施。为了筛选有效的驱虫药物,本研究观察了3种苯并咪唑类药物(阿苯达唑片剂、芬苯达唑膏剂和甲苯咪唑片剂)对大熊猫蛔虫的驱虫效果,统计了驱虫前后粪检蛔虫卵转阴率及排虫情况。结果表明,除芬苯达唑按5 mg·kg^-1体质量口服,每天1次,连续服用2 d,效果较差外,3种药物按10 mg·kg^-1体质量口服,每天1次,连续服用2 d,用药安全且有较好的驱虫效果。     

Treatment of Toxocara canis infections in mice with liposome-incorporated benzimidazole carbamates and immunomodulator glucan

Benzimidazole carbamates (mebendazole, albendazole and fenbendazole) are the most commonly used anthelmintic drugs for the treatment of larval toxocariasis (Toxocara canis) in paratenic hosts. However, the bioavailability of these drugs for tissues is very low due to their extremely low solubility, resulting in the administration of relatively high doses over a long period. To overcome this problem, neutral, negatively or positively charged and stabilized liposome drug carriers were examined in the chronic phase of T. canis infections in mice each orally inoculated with 1000 eggs. Moreover, liposomized albendazole and fenbendazole were co-administered with liposomized immunomodulator glucan. The highest efficacy of both drugs, evaluated 4 weeks after treatment, was recorded after their subcutaneous administration (ten doses of 25 mg kg(-1)) in stabilized liposomes and intramuscular co-administration of liposomized glucan (two doses of 5 mg kg(-1)). Fenbendazole was more effective in muscles (91.5%) whereas albendazole was more effective in the brain (92.2%). Liposomes with incorporated benzimidazole carbamate anthelmintics provide sustained drug-release reservoirs and can considerably enhance drug efficacy. Moreover, despite suppression by T. canis antigens, stimulation of the immune system by the immunomodulator glucan potentiates the effects of these antiparasitic drugs.     

The kinetics of mebendazole binding to Haemonchus contortus tubulin.

The kinetics of the binding of mebendazole (MBZ) to tubulin from the third-stage (L3) larvae of the parasitic nematode, Haemonchus contortus, have been characterized. In partially purified preparations, the association of [3H]MBZ to nematode tubulin was rapid, k1 = (2.6 +/- 0.3) x 10(5) M-1 min-1, but dissociation was slow, k-1 = (1.58 +/- 0.02) x 10(-3) min-1. The affinity constant (K(a)) for the interaction, determined by the ratio k1/k-1, was (1.6 +/- 0.2) x 10(8) M-1. Similar results were obtained with crude cytosolic fractions. In equilibrium studies, performed with partially purified nematode tubulin under similar conditions, a K(a) of (5.3 +/- 1.6) x 10(6) M-1 was obtained. The best estimate for the K(a) of the MBZ-nematode tubulin interaction is considered to be the 'kinetic' value determined from the ratio of rate constants. The slow dissociation of MBZ from nematode tubulin, which contrasts with the rapid dissociation of MBZ from mammalian tubulin, supports the hypothesis that the selective toxicity of the benzimidazole anthelmintics results from a difference between the affinities of mammalian and nematode tubulins for these drugs.     

The activity of drug-metabolizing enzymes and the biotransformation of selected anthelmintics in the model tapeworm Hymenolepis diminuta

The drug-metabolizing enzymes of some helminths can deactivate anthelmintics and therefore partially protect helminths against these drugs' toxic effect. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (albendazole, flubendazole, mebendazole) in the rat tapeworm Hymenolepis diminuta, a species often used as a model tapeworm. In vitro and ex vivo experiments were performed. Metabolites of the anthelmintics were detected and identified by HPLC with spectrofluorometric or mass-spectrometric detection. The enzymes of H. diminuta are able to reduce the carbonyl group of flubendazole, mebendazole and several other xenobiotics. Although the activity of a number of oxidation enzymes was determined, no oxidative metabolites of albendazole were detected. Regarding conjugation enzymes, a high activity of glutathione S-transferase was observed. A methyl derivative of reduced flubendazole was the only conjugation metabolite identified in ex vivo incubations of H. diminuta with anthelmintics. The results revealed that H. diminuta metabolized flubendazole and mebendazole, but not albendazole. The biotransformation pathways found in H. diminuta differ from those described in Moniezia expanza and suggest the interspecies differences in drug metabolism not only among classes of helminths, but even among tapeworms.     

Effect of two formulations of benzimidazole carbamates on the viability of cysts of Echinococcus granulosus in vivo

Two different preparations, solution and suspension, of three benzimidazole carbamate drugs, mebendazole, albendazole and ricobendazole, were compared by analyzing their in vivo activity against Echinococcus granulosus cysts in a mouse model. Polyvinylpyrrolidone was used for the elaboration of drug solutions and these formulations manifested better results in terms of reduction of number of viable hydatid cysts in mice than the reference drug suspensions. The effect was more prominent on mebendazole-treated mice, at doses of 25-50 mg/kg. There was a correlation between ED50 and pharmacokinetical parameters of AUC0-infinity and Cmax, showing that a significant improvement on solubility affects the in vivo activity of these drugs.     

Effect of a single dose (600 mg) of albendazole on Loa loa microfilaraemia

The problem of Loa-encephalopathy, which may occur after ivermectin treatment of patients harbouring high Loa microfilarial loads, might be solved if one could find a treatment regimen bringing about a significant but progressive decrease in the Loa microfilaraemia. A trial was performed in Central Cameroon, whose aim was to follow up for 10 months, and to compare the changes in the Loa microfilarial loads in two groups of patients, one treated with a single dose (600 mg) of albendazole (Alben, SmithKline Beecham) given with fatty food, and the other treated with mebendazole (100 mg, twice a day, generic tablets) at a fasting state. The microfilarial loads remained stable in the mebendazole group, whereas a significant decrease in microfilaraemia was recorded in the albendazole group (initial median load: 230 microfilariae per 50 microliters; median load ten months after: 84 microfilariae per 50 microliters). This should encourage further trials to evaluate the effects and the safety of two- or three-day albendazole regimens in patients infected with Loa loa.     

Medical treatment of pulmonary hydatid disease: for which child?

There have been many encouraging studies on medical treatment of pulmonary hydatid disease due to Echinococcus granulosus infection. Our aims were to demonstrate the safety and efficacy of medical treatment in pulmonary hydatid disease and to describe a pediatric population who would benefit from medical treatment, especially in respect to the diameter of the hydatid cyst. All patients were treated with mebendazole or albendazole. Treatment outcome was defined as cure, improvement or failure. Among 82 patients, 34.1% were cured, 34.1% improved and 31.8% failed. When 102 cysts were individually evaluated, 36.31% were cured, 32.4% improved and 31.3% failed. The cure and the failure rates were statistically insignificant in cysts treated with mebendazole and albendazole; however statistically significantly more cysts were improved with albendazole. The results were statistically insignificant between continuous and cyclic albendazole treatment. The mean size of successfully treated cysts was 5.3+/-3.4 cm, but "failed" for cyst with a mean size of 7.3+/-4.3 cm. There was a positive, weak and statistically significant correlation between the cyst size and treatment results. The major complication was infection. We suggest that selected pediatric patients with uncomplicated pulmonary hydatid cysts sized less than 5 cm should have a trial of medical treatment with a very close follow up.     

Effects of three benzimidazoles on growth, general morphology and ultrastructure of Tritrichomonas foetus

Tritrichomonas foetus is a venereal pathogen of cattle, which causes infertility, early embryonic death or abortion. In order to evaluate the potential trichomonicidal activity of benzimidazoles, the effects of thiabendazole, mebendazole and albendazole were analyzed on the multiplication, general morphology and ultrastructure of T. foetus. It was found that mebendazole presented the highest IC(50%) (2.3 microM), when compared with albendazole (IC(50%)=9.4 microM) and thiabendazole (IC(50%)=142.6 microM), and that such effects were irreversible. Concerning microscopic analysis, thiabendazole- and mebendazole-treated cells presented increased volume, internalization of the flagella, disruption or multiplication of the nucleus, multiple organelles and cytoplasmic vacuolization. Albendazole-treated cells exhibited slight alterations, because the parasite became slightly rounded, its flagella were not internalized but the cytoplasm was vacuolated. Mebendazole was indeed highly effective as an in vitro trichomonicidal agent, and this might open up new possibilities for the use of mebendazole in the therapy of bovine trichomoniasis.     

Efficacy of mebendazole and albendazole against Trichinella spiralis in mice

Changes in the sensitivity of Trichinella spiralis to anthelmintic treatment during the first 3 days of infection in mice were studied. Oral administration of either mebendazole or albendazole at 6.25 mh/kg 2 hr after exposure to infection eliminated 95-100% of the worms as determined at necropsy on day 7 postinoculation. Beyond the first day of infection the sensitivity of the parasite to benzimidazole therapy was much reduced and an oral dose of 50 mg/kg was only partially but significantly active against the adult worms. Despite decline in drug sensitivity during the enteral phase, gavage administration of either mebendazole or albendazole at 50 mg/kg for 5 consecutive days during the invasive phase of infection significantly reduced (96 and 67%, respectively) the number of larvae subsequently recovered from host musculature on day 45 postinoculation.     

Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells

Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 micromol/L using two chemoresistant melanoma cell lines (M-14 and SK-Mel-19) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC(50) of 0.32 micromol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent.     

Giardia lamblia: ultrastructural study of the in vitro effect of benzimidazoles.

Axenically grown Giardia lamblia trophozoites treated with low concentrations of the benzimidazole carbamates albendazole and mebendazole detach from glass culture tubes and lose viability. Scanning electron microscopic observations revealed that these drugs produce grotesque modifications of the cell shape of the parasite and disassembly of the adhesive disc. Transmission electron microscopy showed several stages of the fragmentation of adhesive discs with dispersion of microtubules and microribbons in the cytoplasm. Flagella appeared undamaged. In drug-treated trophozoites electron-dense precipitates were selectively deposited on microtubules and microribbons. The results indicate that the antigiardial effect of benzimidazoles is the result of binding to microtubules and subsequent alterations of the cytoskeleton. The electron microscopic observations also suggest that the drugs may bind to microribbon components of the adhesive disc, possibly giardin proteins.     

Interaction of benzimidazole anthelmintics with Haemonchus contortus tubulin: binding affinity and anthelmintic efficacy

The ability of various benzimidazoles (BZs) to bind tubulin under different conditions was assessed by determining their IC50 values (the concentration of unlabeled drug required to inhibit 50% of the labeled drug binding), Ka (the apparent equilibrium association constant) and Bmax (the maximum binding at infinite [BZ] = [drug-receptor]). The ability of unlabeled benzimidazoles--fenbendazole, mebendazole (MBZ), oxibendazole (OBZ), albendazole (ABZ), rycobendazole (albendazole sulfoxide, ABZSO), albendazole sulfone, oxfendazole (OFZ), and thiabendazole--to bind tubulin was determined from their ability to inhibit the binding of [3H]MBZ or [3H]OBZ to tubulin in supernatants derived from unembryonated eggs or adult worms of Haemonchus contortus. The binding constants (IC50, Ka, and Bmax) correlated with the known anthelmintic potency (recommended therapeutic doses) of the BZ compounds except for OFZ and ABZSO whose Ka values were lower than could be expected from anthelmintic potency. The binding of [3H]ABZ or [3H]OFZ to tubulin in supernatants derived from BZ-susceptible and BZ-resistant H. contortus was compared. [3H]ABZ demonstrated saturable high-affinity binding but [3H]OFZ bound with low affinity. The high-affinity binding of [3H]ABZ was reduced for the R strain. Tubulin bound BZ drugs at 4 degrees C with lower apparent Ka than at 37 degrees C.     

Ancylostoma ceylanicum: immunological consequences after anthelmintics therapy in hamsters (Mesocricetus auratus).

Alterations in immunological response before and after chemotherapy were investigated in hamsters infected with A. ceylanicum. Four reference anthelmintics mebendazole, albendazole, levamisole and pyrantel pamoate and one newly synthesized anthelmintic compound 81-470 were used. Drugs in curative doses were administered on day 30 post infection and the humoral response was assessed by counter immunoelectrophoresis and ELISA and cell mediated immunity by delayed type of hypersensitivity reaction. In infected untreated animals the precipitins appeared on day 30 and remained prominent till day 250 post infection. However with ELISA the antibodies could be demonstrated as early as day 3 post infection and peaked on day 40. Delayed type of hypersensitivity could not be demonstrated during the course of infection. All the drugs including Comp. 81-470 were effective in removing the parasites. Precipitin antibodies were only demonstrable till day 60 post treatment. ELISA depicted gradual depletion of antibody titre following treatment with mebendazole, albendazole and pyrantel pamoate. In levamisole treated hamsters the initial fall in serum antibody was restored by day 20 post treatment. With Compound 81-470, immediately after the treatment there was sharp rise in antibodies concentration followed by gradual fall and on day 60 post treatment the titre was still higher than the pretreated titre. Thus the study denotes that effective therapy will bring down immune responses of the host if the drug possess no immunopotentiating action. Therefore the immune parameters may be used as supportive indicator to successful therapy particularly in systemic parasites where parasitic forms are nondemonstrable in excreta or blood.     

Giardia lamblia: Ultrastructural Study of the In Vitro Effect of Benzimidazoles

ABSTRACT Axenically grown Giardia lamblia trophozoites treated with low concentrations of the benzimidazole carbamates albendazole and mebendazole detach from glass culture tubes and lose viability. Scanning electron microscopic observations revealed that these drugs produce grotesque modifications of the cell shape of the parasite and disassembly of the adhesive disc. Transmission electron microscopy showed several stages of the fragmentation of adhesive discs with dispersion of microtubules and microribbons in the cytoplasm. Flagella appeared undamaged. In drug-treated trophozoites electron-dense precipitates were selectively deposited on microtubules and microribbons. The results indicate that the antigiardial effect of benzimidazoles is the result of binding to microtubules and subsequent alterations of the cytoskeleton. The electron microscopic observations also suggest that the drugs may bind to microribbon components of the adhesive disc, possibly giardin proteins.     

Exogenous carbohydrate oxidation from maltose and glucose ingested during prolonged exercise

Intestinal perfusion studies have shown that glucose absorption from maltose occurs faster than from isocaloric glucose. To determine whether ingested maltose might be a superior source of carbohydrate (CHO) for endurance athletes, we compared the rates of gastric emptying, absorption and oxidation of 15 g.100 ml-1 solutions of maltose and glucose. Six endurance-trained cyclists drank 1200 ml of either U-14C maltose or U-14C glucose as a 400-ml loading bolus immediately before exercise, and as 8 x 100-ml drinks at 10-min intervals during a 90-min ride at 70% of maximal oxygen consumption. The rates of gastric emptying [maltose 690 (SD 119) ml.90 min-1; glucose 655 (SD 93) ml.90 min-1], the appearance of U-14C label in the plasma, and the peak rates of exogenous CHO oxidation [maltose 1.0 (SD 0.09) g.min-1; glucose 0.9 (SD 0.09) g.min-1] were not significantly different. Further, the 51 (SD 8) g of maltose and the 49 (SD 9) g of glucose oxidised during exercise were similar. Each accounted for approximately 20% of the total CHO oxidised during the 90 min of exercise. Since only half of the CHO delivered to the intestine was oxidised in the 90-min ride (maltose 49%; glucose 50%), we conclude that neither the rate of gastric emptying, nor digestion limited the rate of ingested CHO utilisation during the early stages of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)