Albendazole :: pharmacology
Fatty acids oxidation and alternative energy sources detected in Taenia crassiceps cysticerci after host treatment with antihelminthic drugs.
Carolina Miguel Fraga, Tatiane Luiza Costa, José Clecildo Barreto Bezerra, Ruy de Souza Lino Junior, Marina Clare Vinaud
Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Setor Universitário, Goiânia, Goiás CEP 74650-050, Brazil.
Human cysticercosis caused by Taenia crassiceps is rare however it is considered of zoonotic risk. The treatment of the infected patients was successful when using albendazole or praziquantel. The active forms of albendazole inhibit the glucose uptake and the active forms of praziquantel alter glycogen levels and nutrients absorption. The aim of this study was to analyze the production of organic acids that indicate the oxidation of fatty acids and the use of alternative energy sources from T. crassiceps cysticerci removed from the peritoneal cavity of mice treated with low dosages of albendazole (5.75 and 11.5mg/kg) or praziquantel (3.83 and 7.67 mg/kg). The beta-hydroxibutyrate production was higher by the larval stage cysticerci in all treated groups and the propionate production was higher in final stage cysticerci treated with 11.5mg/kg of albendazole when compared to the control group. The larval stages of cysticerci from the groups treated with 5.75 mg/kg of albendazole and 3.83 mg/kg of praziquantel produced more urea than the initial and final stages which indicate amino acids breakdown. We conclude that it was possible to detect the fatty acid oxidation and amino acids breakdown which indicate the use of alternative energy production sources as the used dosages only cause a partial blockage of the glucose uptake and leads to metabolic alterations in the cysticerci. The metabolic behavior observed after host treatment was different from former descriptions of the in vitro one which indicates great host-parasite interaction.
Most cited papers:
L A Gil-Grande, F Rodriguez-Caabeiro, J G Prieto, J J Sánchez-Ruano, C Brasa, L Aguilar, F García-Hoz, N Casado, R Bárcena, A I Alvarez
Department of Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain.
The efficacy of albendazole in hydatid disease is still unclear, because there has been no study that assessed the status of the parasite after treatment. The significance of albendazole-induced echographic changes in the cyst therefore cannot be judged. We did a prospective, controlled, randomised, open study of albendazole in patients with liver hydatid disease, and assessed parasite viability after treatment. 18 patients received no albendazole treatment (controls), 18 received albendazole (10 mg/kg daily) for 1 month (group A), and 19 received the drug for about 3 months (group B). Echography was done before and during treatment; all patients underwent surgery on completion. Parasite (protoscolex viability and development of cysts in mice) and ultrastructure studies were done for all cysts removed. 8 (50%) of cysts in the control group, 13 (72%) in group A, and 16 (94%) in group B were non-viable (p = 0.015). Protoscolex and cyst viability were significantly (p = 0.039 and p = 0.018, respectively) lower in treated patients than in controls. Treatment was also significantly associated with total cyst membrane disintegration. 68% of cysts treated for 3 months showed echographic changes, and only 1 of 20 cysts showing echographic changes during treatment was judged viable. The efficacy of albendazole at a dose of 10 mg/kg daily for 3 months suggests that it is a suitable alternative to surgery in uncomplicated hydatid liver disease, as initial treatment.
Lymphatic Filariasis Support Centre, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. firstname.lastname@example.org
Department of Microbiology and Immunology, Medical College of Pennsylvania, Philadelphia 19129.
In vitro growth of the protozoan parasite Giardia lamblia was highly sensitive to certain anthelmintic benzimidazoles. Albendazole and mebendazole were 30- to 50-fold more active than metronidazole and 4- to 40-fold more active than quinacrine. Thiabendazole, a noncarbamate benzimidazole, was less active. Since lack of intestinal absorption makes mebendazole an attractive new antigiardial agent, its in vitro activity was further characterized. At low concentrations (0.05 micrograms/ml) mebendazole had a static effect on G. lamblia growth; however, lethal activity was observed at a concentration fivefold lower (0.3 micrograms/ml) than necessary for the cidal agent metronidazole. Two observations are consistent with a microtubule target for mebendazole. First, attachment of cells to the culture tube, mediated by the ventral disk and flagella, was rapidly disrupted by mebendazole treatment. Second, the characteristic cell structure was grossly distorted by treatment. No mebendazole-resistant G. lamblia were detected in a population of 10(8) cells.
Wellcome Trust Centre for the Epidemiology of Infectious Disease (WTCEID), University of Oxford, South Parks Road, Oxford, UK OX1 3FY. email@example.com
The widespread use of mebendazole and albendazole for treating intestinal nematode infections in human populations is raising concerns that careful monitoring pro- cedures should be in place to identify any emergence of drug resistance. In this article, Andy Bennett and Helen Guyatt discuss whether benchmark parasitological drug efficacy rates can be defined for these anthelmintics, by analysing published data on cure rates and egg reduction rates in the treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm.
Department of Microbiology, Tulane Regional Primate Research Center, Covington, Louisiana 70433, USA. firstname.lastname@example.org
Presently, the two most commonly used drugs for treating microsporidiosis in persons with AIDS are albendazole and fumagillin. Albendazole is effective for treating disseminated infections due to Encephalitozoon spp. but is variably effective against Enterocytozoon bieneusi infections. Fumagillin is highly effective when used topically to treat ocular infections with Encephalitozoon hellem or Encephalitozoon intestinalis but is too toxic for systemic use. In this study, the fumagillin analog TNP-470 was assayed for antimicrosporidial activity in vitro. The MICs of TNP-470 at which 50% of isolates were killed (MIC50s) were 0.35 +/- 0.21 and 0.38 +/- 0.11 ng/ml for E. intestinalis and Vittaforma corneae, respectively, and were similar to the MIC50s of fumagillin for these organisms, which were 0.515 +/- 0.002 and 0.81 +/- 0.014 ng/ml, respectively. The MIC50 of albendazole for E. intestinalis was 8.0 +/- 4.23 ng/ml, significantly less (P < 0.01) than its MIC50 for V. corneae, which was 55.0 +/- 7.07 ng/ml. TNP-470 inhibited replication of E. intestinalis in RK-13 cells if it was given at the same time as infection or if treatment was initiated 7 days later. In addition, treatment of the infected cultures with TNP-470 at a dose of 10 ng/ml for 2 weeks, followed by discontinuation of the drug treatment, resulted in no significant increase in E. intestinalis shedding during the following 3 weeks in culture. Because TNP-470 acts against both E. intestinalis and V. corneae, and because TNP-470 was found by others to be less toxic in vivo, TNP-470 may be a promising new drug for the treatment of microsporidiosis.
Evaluation of prevalence and clinical implications of anthelmintic resistance in gastrointestinal nematodes in goats.
Lars L Mortensen, Lisa H Williamson, Thomas H Terrill, Robin A Kircher, Michael Larsen, Ray M Kaplan
Danish Center for Experimental Parasitology, Department of Veterinary Microbiology, Section for Parasitology, Royal Veterinary and Agricultural University, DK-1870 Frederiksberg C, Denmark.
OBJECTIVE To determine prevalence of resistance to all anthelmintics that are commonly used to treat gastrointestinal nematodes (GINs) in goats. DESIGN Prospective study. ANIMALS 777 goats. PROCEDURE On each farm, goats were assigned to 1 of 5 treatment groups: untreated controls, albendazole (20 mg/kg [9.0 mg/lb], p.o., once), ivermectin (0.4 mg/kg [0.18 mg/lb], p.o., once), levamisole (12 mg/kg [5.4 mg/lb], p.o., once), or moxidectin (0.4 mg/kg, p.o., once), except on 3 farms where albendazole was omitted. Fecal samples were collected 2 weeks after treatment for determination of fecal egg counts (FECs), and percentage reductions were calculated by comparing data from anthelmintic-treated and control groups. Nematode populations were categorized as susceptible, suspected resistant, or resistant by use of guidelines published by the World Association for the Advancement of Veterinary Parasitology. RESULTS Resistance to albendazole was found on 14 of 15 farms, and resistance to ivermectin, levamisole, and moxidectin was found on 17, 6, and 1 of 18 farms, respectively. Suspected resistance to levamisole and moxidectin was found on 4 and 3 farms, respectively. Resistance to multiple anthelmintics (albendazole and ivermectin) was found on 14 of 15 farms and to albendazole, ivermectin, and levamisole on 5 of 15 farms. Mean overall FEC reduction percentages for albendazole, ivermectin, levamisole, and moxidectin were 67, 54, 94, and 99%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Anthelmintic resistance in GINs of goats is highly prevalent in the southern United States. The high prevalence of resistance to multiple anthelmintics emphasizes the need for reexamination of nematode control practices.
CSIRO, Division of Animal Health, Animal Health Research Laboratory, Parkville, Victoria 3052.
Composite strains of Trichostrongylus colubriformis and Ostertagia spp consisting of 0, 1, 10, 25, 50, 75, 90, and 100% of known resistant strains were prepared and tested for benzimidazole resistance using faecal egg count reduction tests, in vitro egg hatch assays and tubulin binding assays. All tests detected resistance where the proportion of the resistant strain in the composite was 50% or more, whereas none of the tests unequivocally detected resistance below 25%. Egg count reduction tests were no less sensitive than the in vitro tests in detecting low levels of resistance but the egg hatch and tubulin binding assays provided a better quantitative estimate of moderate to high levels of resistance. Faecal egg count reduction therefore, provides a suitable means of detecting resistance in the field but tests, more sensitive to low levels of resistance are required. Results indicate that the use of post-treatment counts alone provides an adequate indication of anthelmintic efficiency.
Interaction of benzimidazole anthelmintics with Haemonchus contortus tubulin: binding affinity and anthelmintic efficacy.
Institute of Parasitology, McGill University, Macdonald College, Ste-Anne de Bellevue, Quebec, Canada.
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.
Detection of benzimidazole resistance-associated mutations in the filarial nematode Wuchereria bancrofti and evidence for selection by albendazole and ivermectin combination treatment.
Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec, Canada.
The Global Program to Eliminate Lymphatic Filariasis has been implemented to reduce human microfilaremia to levels low enough to break the transmission of the disease by using single annual doses of albendazole in combination with diethylcarbamazine or ivermectin. Many veterinary helminth parasites have developed resistance against both albendazole and ivermectin. Resistance to albendazole in veterinary nematodes is known to be caused by either of two single amino acid substitutions from phenylalanine to tyrosine in parasite beta-tubulin at position 167 or 200. We have developed assays capable of detecting these single nucleotide polymorphisms (SNPs) in Wuchereria bancrofti, and have applied them to microfilaria obtained from patients in Ghana and Burkina Faso. One of the SNPs was found in worms from untreated populations in both locations. Worms from treated patients had significantly higher frequencies of these mutations. These findings indicate that a beta-tubulin allele associated with benzimidazole resistance is being selected in these populations.
Division of Veterinary Biology, School of Veterinary Studies, Murdoch University, Western Australia.
The effects of albendazole were assessed against Giardia duodenalis in vitro and compared with those of tinidazole and metronidazole. Trophozoite morphology, adherence and viability were markedly affected by albendazole, to a far greater extent than by either metronidazole or tinidazole. The results of this study, and in particular the superior potency of albendazole in vitro, are discussed with respect to its potential value as a new approach to the chemotherapy of giardiasis.