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Molecules (Basel, Switzerland) Oct 2023Albendazole is the preferred deworming drug and has strong insecticidal effects on human and animal helminth parasites, showing remarkable activity against...
Albendazole is the preferred deworming drug and has strong insecticidal effects on human and animal helminth parasites, showing remarkable activity against hepatocellular carcinoma and colorectal cancer cells. However, it is classified as being in class II in the Biopharmaceutics Classification System due to its poor water solubility (0.2 mg/L) and high permeability, which make the clinical application of albendazole impractical. Through complexation with methyl--cyclodextrin, as the best result so far, albendazole's water solubility was increased by 150,000 times, and albendazole could be 90% released during the first 10 min. In an in vivo pharmacokinetic study, the and of the active metabolized sulfoxide were changed from 2.81 µg/mL at 3 h to 10.2 µg/mL at 6 h and the AUC was increased from 50.72 h⁎μg/mL to 119.95 h⁎μg/mL, indicating that the inclusion complex obtained can be used as a new oral therapeutic anti-anthelmintic and anti-tumor agent formulation.
Topics: Animals; Humans; Albendazole; Cyclodextrins; Solubility; Anthelmintics; Water
PubMed: 37959715
DOI: 10.3390/molecules28217295 -
Clinical Infectious Diseases : An... Jul 2021Infections with hookworms affect about half a billion people worldwide. Recommended therapy includes 400 mg of albendazole, which is moderately efficacious. Higher doses... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Albendazole in Hookworm-infected Preschool-aged Children, School-aged Children, and Adults in Côte d'Ivoire: A Phase 2 Randomized, Controlled Dose-finding Trial.
BACKGROUND
Infections with hookworms affect about half a billion people worldwide. Recommended therapy includes 400 mg of albendazole, which is moderately efficacious. Higher doses have been rarely assessed.
METHODS
A randomized, controlled dose-finding trial was conducted in Côte d'Ivoire with the aim of recruiting 120 preschool-aged children (PSAC), 200 school-aged children (SAC), and 200 adults. Eligible PSAC were randomized 1:1:1 to 200 mg, 400 mg, or 600 mg of albendazole; the other age groups were randomized 1:1:1:1:1 to placebo or 200 mg, 400 mg, 600 mg, or 800 mg. The primary outcome was cure rates (CRs) assessed 14-21 days post-treatment by quadruplicate Kato-Katz thick smears. Hyperbolic Emax models were used to determine dose-response.
RESULTS
38 PSAC, 133 SAC, and 196 adults were enrolled. In adults, predicted CRs increased with ascending doses of albendazole, with a CR of 74.9% (95% confidence interval [CI], 55.6%-87.7%) in the 800-mg arm. Observed CRs increased with ascending doses of albendazole reaching a maximum of 94.1% (95% CI, 80.3%-99.3%). In SAC, the predicted dose-response curve increased marginally, with CRs ranging from 64.0% in the 200-mg arm to 76.0% in the 800-mg arm. Sample size in PSAC was considered too small to derive meaningful conclusions. 10.7% and 5.1% of participants reported any adverse event at 3 hours and 24 hours post-treatment, respectively.
CONCLUSIONS
A single 800-mg albendazole dose provides higher efficacy against hookworm and is well tolerated in adults and should be considered for community-based strategies targeting adults. For PSAC and SAC, current recommendations suffice.
CLINICAL TRIALS REGISTRATION
NCT03527745.
Topics: Adult; Albendazole; Ancylostomatoidea; Animals; Anthelmintics; Child; Child, Preschool; Cote d'Ivoire; Humans; Schools
PubMed: 32668456
DOI: 10.1093/cid/ciaa989 -
Microbiology Spectrum Aug 2022Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on...
Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. In this study, a simplified compound, -(4-methoxyphenyl)pentanamide (N4MP), based on the structure of the most widely used anthelmintic (albendazole), was chemically prepared using 4-anisidine and pentanoic acid. -(4-Methoxyphenyl)pentanamide was evaluated against the nematode Toxocara canis, an ascarid roundworm of animals that can infect humans. Similar to albendazole, bioassays showed that -(4-methoxyphenyl)pentanamide affected the viability of parasites in a time- and concentration-dependent manner. Interestingly, -(4-methoxyphenyl)pentanamide showed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Pharmacokinetic, drug-likeness, and medicinal chemistry friendliness studies demonstrated an excellent drug-likeness profile for -(4-methoxyphenyl)pentanamide as well as an adherence to major pharmaceutical companies' filters. Collectively, the results of this study demonstrate that the molecular simplification of albendazole to give -(4-methoxyphenyl)pentanamide may be an important pipeline in the discovery of novel anthelmintic agents. Infections caused by parasitic helminths have enormous health, social, and economic impacts worldwide. The treatment and control of these diseases have been dependent on a limited set of drugs, many of which have become less effective, necessitating the search for novel anthelmintic agents. Considering this scenario, the present study reports the preparation of -(4-methoxyphenyl)pentanamide (N4MP), a simplified molecule based on the structure of the most widely used anthelmintic (albendazole). N4MP was evaluated against the nematode Toxocara canis, a common ascarid roundworm of domestic animals that can infect humans. Similar to albendazole, bioassays showed that N4MP affected the viability of parasites in a time- and concentration-dependent manner but displayed a profile of lower cytotoxicity to human and animal cell lines than albendazole. Therefore, this study demonstrates that the molecular simplification of albendazole to give N4MP may be an important pipeline in the discovery of novel anthelmintic agents.
Topics: Albendazole; Animals; Anthelmintics; Humans; Toxocara canis; Toxocariasis
PubMed: 35900089
DOI: 10.1128/spectrum.01807-22 -
PLoS Neglected Tropical Diseases Aug 2023Echinococcus multilocularis and E. granulosus s.l. are the causative agents of alveolar and cystic echinococcosis, respectively. Drug treatment options for these severe...
Echinococcus multilocularis and E. granulosus s.l. are the causative agents of alveolar and cystic echinococcosis, respectively. Drug treatment options for these severe and neglected diseases are limited to benzimidazoles, which are not always efficacious, and adverse side effects are reported. Thus, novel and improved treatments are needed. In this study, the previously established platform for E. multilocularis in vitro drug assessment was adapted to E. granulosus s.s. In a first step, in vitro culture protocols for E. granulosus s.s. were established. This resulted in the generation of large amounts of E. granulosus s.s. metacestode vesicles as well as germinal layer (GL) cells. In vitro culture of these cells formed metacestode vesicles displaying structural characteristics of metacestode cysts generated in vivo. Next, drug susceptibilities of E. multilocularis and E. granulosus s.s. protoscoleces, metacestode vesicles and GL cells were comparatively assessed employing established assays including (i) metacestode vesicle damage marker release assay, (ii) metacestode vesicle viability assay, (iii) GL cell viability assay, and (iv) protoscolex motility assay. The standard drugs albendazole, buparvaquone, mefloquine, MMV665807, monepantel, niclosamide and nitazoxanide were included. MMV665807, niclosamide and nitazoxanide were active against the parasite in all four assays against both species. MMV665807 and monepantel were significantly more active against E. multilocularis metacestode vesicles, while albendazole and nitazoxanide were significantly more active against E. multilocularis GL cells. Albendazole displayed activity against E. multilocularis GL cells, but no effects were seen in albendazole-treated E. granulosus s.s. GL cells within five days. Treatment of protoscoleces with albendazole and monepantel had no impact on motility. Similar results were observed for both species with praziquantel and its enantiomers against protoscoleces. In conclusion, in vitro culture techniques and drug screening methods previously established for E. multilocularis were successfully implemented for E. granulosus s.s., allowing comparisons of drug efficacy between the two species. This study provides in vitro culture techniques for the reliable generation of E. granulosus s.s. metacestode vesicles and GL cell cultures and describes the validation of standardized in vitro drug screening methods for E. granulosus s.s.
Topics: Animals; Echinococcus granulosus; Albendazole; Niclosamide; Drug Evaluation, Preclinical; Echinococcus multilocularis
PubMed: 37540716
DOI: 10.1371/journal.pntd.0011343 -
Nature Communications Feb 2022Soil-transmitted helminth infections represent a large burden with over a quarter of the world's population at risk. Low cure rates are observed with standard of care...
Soil-transmitted helminth infections represent a large burden with over a quarter of the world's population at risk. Low cure rates are observed with standard of care (albendazole); therefore, a more effective combination therapy (albendazole and ivermectin) is being investigated but showed variable treatment efficacies without evidence of intrinsic parasite resistance. Here, we analyzed the microbiome of Trichuris trichiura and hookworm-infected patients and found an association of different enterotypes with treatment efficacy. 80 T. trichiura-infected patients with hookworm co-infections from Pak-Khan, Laos, received either albendazole (n = 41) or albendazole and ivermectin combination therapy (n = 39). Pre-/post-treatment stool samples were collected to monitor treatment efficacy and microbial communities were profiled using 16S rRNA gene sequencing, qPCR, and shotgun sequencing. We identified three bacterial enterotypes and show that pre-treatment enterotype is associated with efficacy of the combination treatment for both T. trichiura (CR = 5.8%; CR = 16.6%; CR = 68.8%) and hookworm (CR = 31.3%; CR = 16.6%; CR = 78.6%). This study shows that pre-treatment enterotype enables predicting treatment outcome of combination therapy for T. trichiura and hookworm infections.Trial registration: ClinicalTrials.gov, NCT03527732. Registered 17 May 2018, https://clinicaltrials.gov/ct2/show/NCT03527732 .
Topics: Albendazole; Anthelmintics; Feces; Helminthiasis; Humans; Ivermectin; Microbiota; Parasite Egg Count; RNA, Ribosomal, 16S; Soil; Trichuriasis
PubMed: 35217670
DOI: 10.1038/s41467-022-28658-1 -
International Maritime Health 2023Dermatological disorders are among the most common complaints of patients seeking medical assistance after returning from trips to tropical countries. Among exotic...
Dermatological disorders are among the most common complaints of patients seeking medical assistance after returning from trips to tropical countries. Among exotic dermatoses, one of the frequently encountered diagnoses is Cutaneous Larva Migrans (CLM), primarily caused by the nematodes Ancylostoma braziliense and A. caninum. Cats and dogs, which serve as the definitive hosts for these nematodes, excrete with their stool parasite eggs into the environment, where they transform into larvae. Human infection occurs through the invasive form of the larvae, which penetrate the skin, causing itching and the characteristic serpiginous, slightly raised, and enlarging lesion at the site of invasion. Diagnosis is made based on the highly characteristic clinical presentation, although in non-endemic countries, diagnostic errors and delays in initiating effective causal treatment are relatively common. Effective therapy includes oral albendazole and ivermectin. Prevention of CLM involves avoiding skin contact with potentially contaminated soil by wearing shoes and using towels and mats on the beach. Due to the high interest in travel and the risk of importing exotic diseases, it is important to promote knowledge of tropical medicine among healthcare professionals as well as the travellers.
Topics: Humans; Animals; Cats; Dogs; Larva Migrans; Ivermectin; Albendazole; Travel; Feces
PubMed: 38111246
DOI: 10.5603/imh.98098 -
PLoS Neglected Tropical Diseases Jan 2021Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics,...
BACKGROUND
Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of Albendazole, Mebendazole and Praziquantel locally collected in Burkina Faso, Côte d'Ivoire, Ghana and Tanzania were analysed.
METHODS
Samples of 88 different batches were obtained from randomly selected facilities. Sampling took place in Northwest Tanzania, Western Burkina Faso, Southeast Côte d'Ivoire and Southwest Ghana. Visual examination of both packaging and samples was performed according to the WHO 'Be Aware' tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC).
FINDINGS
Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6% of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. Evaluating TLC results, only 4 out of 83 batches narrowly missed specification limits, 18 batches slightly exceeded them. Not more than 46.3% (31 / 67) of the tablets assayed passed the respective pharmaceutical criteria for dissolution. HPLC findings confirmed TLC results despite shifted specification limits: 10 out of 83 tested batches contained less than 90%, none exceeded 110%.
CONCLUSION
In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or fall below specification limits. Galenic characteristics however, especially dissolution profiles, revealed great deficits.
Topics: Albendazole; Anthelmintics; Burkina Faso; Cote d'Ivoire; Ghana; Helminthiasis; Humans; Mebendazole; Praziquantel; Schistosomiasis; Tablets; Tanzania
PubMed: 33493211
DOI: 10.1371/journal.pntd.0009038 -
Parasites & Vectors May 2023Few anthelminthics are currently available, manifesting the urgent need for new treatment options. In vitro profiling of current anthelminthics against larval and adult...
BACKGROUND
Few anthelminthics are currently available, manifesting the urgent need for new treatment options. In vitro profiling of current anthelminthics against larval and adult stage helminths displayed varying effects on closely related worm species and between life stages of the same species. Conversely, limited research has been performed on the egg stage of human hookworms, and the effects of investigational compounds on the egg stage are not routinely assessed.
METHODS
We profiled the development and hatching of Heligmosomoides polygyrus, Ancylostoma duodenale and Necator americanus eggs isolated from rodent faeces in liquid media with various nutrient levels, osmolar concentrations, and acidities in dependence on incubation temperature and light exposure. Incubation conditions were optimised to allow the study of drug effect on immature and embryonated eggs. We analysed concentration-effect relationships of commercially available anthelminthics over 72 h.
RESULTS
Rapid embryonation and hatching were observed at room temperature with and without light exposure without nutrient supplementation in a wide range of acidities. Hookworms hatched optimally at room temperature in PBS achieving > 75% hatching over 34 h. Developmental delays were seen when eggs were stored at 4 °C with no effect on viability. Similar delays were also seen with increased osmolar concentrations resulting in decreased viability. Benzimidazole anthelminthics effectively reduced the viability and prevented hatching of hookworm eggs, with albendazole and thiabendazole eliciting particularly potent effects at EC values below 1 µM. Macrolide anthelminthics as well as emodepside, oxantel pamoate, and pyrantel pamoate were inactive while monepantel, levamisole, and tribendimidine displayed varied potencies among the hookworm species.
CONCLUSION
The presented egg-hatching assay will complement ongoing anthelminthic drug discovery and allow a full characterisation of drug activity against all life stages. In the development and application of the egg-hatching assay, good accordance was observed between the three hookworm species evaluated. Marketed anthelminthics show differences of drug action compared to larval and adult stages highlighting the importance of profiling drug activity against all life stages.
Topics: Animals; Adult; Humans; Anthelmintics; Hookworm Infections; Ancylostomatoidea; Albendazole; Necator americanus; Ancylostoma; Larva
PubMed: 37143169
DOI: 10.1186/s13071-023-05771-8 -
La Tunisie MedicaleHydatidosis is an endemic parasitosis in Tunisia that affect mostly the liver and the lung. Brain involvment is rare.
BACKGROUND
Hydatidosis is an endemic parasitosis in Tunisia that affect mostly the liver and the lung. Brain involvment is rare.
AIM
To focus on diagnostic, therapeutic and evolutive characteristics of cerebral hydatidosis.
METHODS
We report all cases of cerebral hydatidosis seen in the infectious diseases and neurosurgery departments between January 2013 and June 2020.
RESULTS
Six cases of intracranial hydatid cyst were reported. The male to female ratio was 3:3. Age ranged from 3 to 60 years with a median age of 20,5 years. All patients lived in rural areas. The clinical symptomatology was progressive in 4 cases. It was dominated by headache (all cases). Brain imaging confirmed the diagnosis in all cases. The hydatid cyst was solitary and supratentorial in 3 cases. All the patients were operated. Albendazole was prescribed immediately after surgery, for 6 months in 5 cases and for 3 years in the case of disseminated hydatidosis. The outcome was favorable without recurrence in all patients with an average follow-up of 3,5 ± 0,5 years.
CONCLUSION
Hydatid cyst of the brain is characterized by the severity of the neurological signs, the mandatory use of surgery because of life threatening and the excellent outcomes.
Topics: Adolescent; Adult; Albendazole; Brain; Brain Diseases; Child; Child, Preschool; Echinococcosis; Female; Humans; Male; Middle Aged; Tomography, X-Ray Computed; Young Adult
PubMed: 35822333
DOI: No ID Found -
PLoS Pathogens Sep 2022Giardia duodenalis causes giardiasis, a major diarrheal disease in humans worldwide whose treatment relies mainly on metronidazole (MTZ) and albendazole (ABZ). The...
Giardia duodenalis causes giardiasis, a major diarrheal disease in humans worldwide whose treatment relies mainly on metronidazole (MTZ) and albendazole (ABZ). The emergence of ABZ resistance in this parasite has prompted studies to elucidate the molecular mechanisms underlying this phenomenon. G. duodenalis trophozoites convert ABZ into its sulfoxide (ABZSO) and sulfone (ABZSOO) forms, despite lacking canonical enzymes involved in these processes, such as cytochrome P450s (CYP450s) and flavin-containing monooxygenases (FMOs). This study aims to identify the enzyme responsible for ABZ metabolism and its role in ABZ resistance in G. duodenalis. We first determined that the iron-containing cofactor heme induces higher mRNA expression levels of flavohemoglobin (gFlHb) in Giardia trophozoites. Molecular docking analyses predict favorable interactions of gFlHb with ABZ, ABZSO and ABZSOO. Spectral analyses of recombinant gFlHb in the presence of ABZ, ABZSO and ABZSOO showed high affinities for each of these compounds with Kd values of 22.7, 19.1 and 23.8 nM respectively. ABZ and ABZSO enhanced gFlHb NADH oxidase activity (turnover number 14.5 min-1), whereas LC-MS/MS analyses of the reaction products showed that gFlHb slowly oxygenates ABZ into ABZSO at a much lower rate (turnover number 0.01 min-1). Further spectroscopic analyses showed that ABZ is indirectly oxidized to ABZSO by superoxide generated from the NADH oxidase activity of gFlHb. In a similar manner, the superoxide-generating enzyme xanthine oxidase was able to produce ABZSO in the presence of xanthine and ABZ. Interestingly, we find that gFlHb mRNA expression is lower in albendazole-resistant clones compared to those that are sensitive to this drug. Furthermore, all albendazole-resistant clones transfected to overexpress gFlHb displayed higher susceptibility to the drug than the parent clones. Collectively these findings indicate a role for gFlHb in ABZ conversion to its sulfoxide and that gFlHb down-regulation acts as a passive pharmacokinetic mechanism of resistance in this parasite.
Topics: Albendazole; Animals; Anthelmintics; Biotransformation; Chromatography, Liquid; Cytochromes; Flavins; Giardia lamblia; Heme; Humans; Iron; Metronidazole; Mixed Function Oxygenases; Molecular Docking Simulation; RNA, Messenger; Sulfones; Sulfoxides; Superoxides; Tandem Mass Spectrometry; Trophozoites; Xanthine Oxidase; Xanthines
PubMed: 36166467
DOI: 10.1371/journal.ppat.1010840