Efficacy of various anthelmintics against third-stage larvae of Ancylostoma caninum in the brain of mice

In an experimental larval infection of Ancylostoma caninum in mice, the efficacy of various anthelmintics against the larvae migrated and established in the brain is reported for the first time. Albendazole and flubendazole were the most effective drugs. Thiabendazole, benacil, phenacizole, oxfendazole and mebendazole showed significant larvicidal activity. Tetramisole, levamisole, fenbendazole, Sch 18099, pyrantel pamoate, morantel tartrate and oxantel pamoate did not show any significant activity even at relatively high dose levels.     

A comparison of the genetic activity of pyrvinium pamoate with that of several other anthelmintic drugs in Saccharomyces cerevisiae

Several anthelmintic drugs that are used routinely in oxyuriasis therapy were analyzed for genotoxicity in a diploid mitotic recombination and gene conversion assay (strain D5 of Saccharomyces cerevisiae), and in a haploid yeast reversion assay (strain XV185-14C). Piperazine citrate, piperazine adipate, mebendazole and thiabendazole did not appear to be genotoxic in either yeast strain. Pyrvinium pamoate induced the reversion of the missense, nonsense and frameshift alleles in strain XV185-14C, whereas pyrantel pamoate induced only the reversion of the frameshift allele. Pyrvinium pamoate was recombinogenic in strain D5, and there is an indication that pyrantel pamoate, at the lowest dose that was tested, might induce gene conversion or aneuploidy.     

Mutagenicity of antiamebic and anthelmintic drugs in the Salmonella typhimurium microsomal test system

4 amebicides (chloroquine diphosphate, diiodohydroxyquin, iodochlorohydroxyquin and dehydroemetine) and 6 anthelmintics (bephenium hydroxynaphthoate, 4-hexylresorcinol, mebendazole, niclosamide, pyrantel pamoate and pyrvinium pamoate) were tested for mutagenicity in the Salmonella typhimurium microsomal test system. Frameshift mutations were induced by dehydroemetine and niclosamide following activation by microsomal enzymes, while pyrvinium pamoate induced both frameshift and base-pair substitution mutations with or without metabolic activation. The urine of mice treated with dehydroemetine or pyrvinium pamoate showed no mutagenic activity. However, urine obtained from mice treated with niclosamide was mutagenic in strains TA98 and TA1538. The fluctuation assay showed chloroquine diphosphate to be mutagenic in TA1537, a strain which detects frameshift mutations.     

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.     

Activity of Oxantel Pamoate Monotherapy and Combination Chemotherapy against Trichuris muris and Hookworms: Revival of an Old Drug

Background

It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations.

Methodology

We studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo.

Principal Findings

We calculated an ED₅₀ of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI) = 2.53). Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED₅₀s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively). A highly synergistic effect (CI = 0.15) was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg) lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo.

Conclusion/Significance

Our study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be launched.     

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.     

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.     

Necator americanus: optimization of the golden hamster model for testing anthelmintic drugs

Laboratory golden hamsters (Mesocricetus auratus) were infected with Necator americanus under several different parasite and host conditions to optimize the model for testing anthelminthic drugs. The results confirmed that male hamsters were more susceptible to infection than females. Host age in the range of 5-15 weeks was not a factor that impacted on adult worm burden, and similar worm burdens were achieved using doses of 150, 250 or 500 N. americanus L3 (NaL3). The largest numbers of adult hookworms were recovered on days 21-28 post-infection, with a significant decrease at days 40-50 post-infection. Therefore adult worm recovery is maximal approximately 11-18 days prior to patency and host blood loss. From these studies a drug evaluation protocol was developed using 150 NaL3 as the infectious dose and then evaluating the anthelminthic effects of the drugs albendazole, tribendimidine, and pyrantel pamoate on days 21-28 post-infection. The model confirms the anthelminthic activity of albendazole, tribendimidine, and pyrantel pamoate and has the potential as a laboratory animal model to detect emerging drug resistance.     

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.     

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.     

Egg excretion indicators for the measurement of soil-transmitted helminth response to treatment

BackgroundPeriodic administration of anthelmintic drugs is a cost-effective intervention for morbidity control of soil-transmitted helminth (STH) infections. However, with programs expanding, drug pressure potentially selecting for drug-resistant parasites increases. While monitoring anthelmintic drug efficacy is crucial to inform country control program strategies, different factors must be taken into consideration that influence drug efficacy and make it difficult to standardize treatment outcome measures. We aimed to identify suitable approaches to assess and compare the efficacy of different anthelmintic treatments.MethodologyWe built an individual participant-level database from 11 randomized controlled trials and two observational studies in which subjects received single-agent or combination therapy, or placebo. Eggs per gram of stool were calculated from egg counts at baseline and post-treatment. Egg reduction rates (ERR; based on mean group egg counts) and individual-patient ERR (iERR) were utilized to express drug efficacy and analyzed after log-transformation with a linear mixed effect model. The analyses were separated by follow-up duration (14–21 and 22–45 days) after drug administration.Principal findingsThe 13 studies enrolled 5,759 STH stool-positive individuals; 5,688 received active medication or placebo contributing a total of 11,103 STH infections (65% had two or three concurrent infections), of whom 3,904 (8,503 infections) and 1,784 (2,550 infections) had efficacy assessed at 14–21 days and 22–45 days post-treatment, respectively. Neither the number of helminth co-infections nor duration of follow-up affected ERR for any helminth species. The number of participants treated with single-dose albendazole was 689 (18%), with single-dose mebendazole 658 (17%), and with albendazole-based co-administrations 775 (23%). The overall mean ERR assessed by day 14–21 for albendazole and mebendazole was 94.5% and 87.4%, respectively on Ascaris lumbricoides, 86.8% and 40.8% on hookworm, and 44.9% and 23.8% on Trichuris trichiura. The World Health Organization (WHO) recommended criteria for efficacy were met in 50%, 62%, and 33% studies of albendazole for A. lumbricoides, T. trichiura, and hookworm, respectively and 25% of mebendazole studies. iERR analyses showed similar results, with cure achieved in 92% of A. lumbricoides-infected subjects treated with albendazole and 93% with mebendazole; corresponding figures for hookworm were 70% and 17%, and for T. trichiura 22% and 20%.Conclusions/significanceCombining the traditional efficacy assessment using group averages with individual responses provides a more complete picture of how anthelmintic treatments perform. Most treatments analyzed fail to meet the WHO minimal criteria for efficacy based on group means. Drug combinations (i.e., albendazole-ivermectin and albendazole-oxantel pamoate) are promising treatments for STH infections.     

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.     

Response of pre-adult and adult stages of Trichuris muris to common anthelmintics in mice.

The common anthelmintics, oxantel, mebendazole, albendazole and pyrantel were assessed for their comparative activity against Trichuris muris in mice. Mice were infected with T. muris and the infection was maintained by a brief cortisone administration during the second week of infection. Mice carrying the infection with different life cycle stages, viz. fourth stage larvae (L4), pre-adult and adult stages were dosed with anthelminitics. The worm burdens in control infection groups varied although infection dose and other conditions were uniformly followed. With various dose regimens tested, oxantel was highly potent; it eliminated completely pre-adult and adult stages, respectively at 25 and 12.5 mg kg-1 dose levels with significant activity also against adult worms at a 1.56 mg kg-1 dose level and against pre-adults at a 6.25 mg kg-1 level. Pre-adults required twice the dose given to that of adults for complete (100%) activity. Mebendazole was the next most active; a dosage of 37.5 mg kg-1 was completely active against pre-adults whereas a dosage of 2 x 50 mg kg-1 was required for complete elimination of adult worms. In addition, about 90% of the worms were eliminated with a single dose of 150 mg kg-1. However, a significant activity was seen against adults at a 25 mg kg-1 level and pre-adults at 37.5 mg kg-1, the lowest level tested. In comparison, albendazole did not induce complete clearance of pre-adult and adult stages even when tested at dose levels as high as 150 and 2 x 75 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of propylene oxide for mutagenic activity in 3 in vivo test systems

Propylene oxide (CAS No. 75-56-9) was tested for mutagenic activity following vapor exposure using 3 in vivo test systems. Rat dominant lethal and mouse sperm-head morphology assays were conducted using males exposed to propylene oxide at 300 ppm in a dynamic exposure chamber for 7 h per day on 5 consecutive days. A sex-linked recessive lethal test in Drosophila melanogaster employed a 24-h static exposure to propylene oxide at 645 ppm. Male mice were killed 1, 3, 5, 7, and 9 weeks post-exposure for evaluation of sperm-head morphology. Propylene oxide exposure did not result in an increase in abnormal forms. Male rats were mated with 2 virgin females per week for 6 weeks following exposure. A statistically significant increase in preimplantation losses and a statistically significant reduction in the number of living implants in the first post-exposure week did not appear to be treatment related. A highly significant increase in sex-linked recessive lethal mutations was observed in two germ cell stages (mature sperm and developing spermatocytes). These results warrant continued caution in potential human exposure to propylene oxide.     

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.     

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.     

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.     

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。     

Relative efficacy of short-term tests in detecting genotoxic effects of cadmium chloride in mice in vivo

The ability of intraperitoneally administered cadmium chloride (0.42-6.75 mg/kg) to induce genotoxic damage in somatic and germ cells of mice was evaluated using chromosomal aberrations, sister-chromatid exchanges (SCE), micronuclei and sperm-head abnormalities as end-points. A significant increase in the frequency of chromosomal aberrations and SCEs was observed in almost all treated series when compared to the negative control. Micronucleus formation in polychromatic erythrocytes was not affected significantly except at the highest concentration used (6.75 mg/kg). Significant differences were observed in the frequency of sperm with abnormal head morphology at all concentrations tested except the lowest one. The clastogenic effects of cadmium chloride in both somatic and germinal cells are found to depend directly on the concentrations used.     

Influence of the Uvr repair system on the mutagenicity of antiparasitic drugs

One amebicide (chloroquine diphosphate) and 2 anthelmintic compounds (niclosamide and pyrvinium pamoate) were found to be mutagenic for Salmonella typhimurium TA1537, TA1538, TA100 and TA98 Uvr- strains respectively. Drugs tested on homologous Uvr+ strains (TA1977, TA1978, UTH8414 and UTH8413) showed decreased mutagenic activity of the compounds. This indicates that premutational damage induced by the drugs was totally or partially repaired. Furthermore, results obtained in the present study suggest that niclosamide and pyrvinium pamoate induce premutational lesions by adduct formation, and that chloroquine diphosphate, known as an intercalating agent, behaves as an adduct-forming compound as regards its effects on Uvr- and Uvr+ S. typhimurium strains.