Evaluation of the efficacy of albendazole sulfoxide (ABZ-SO)-loaded chitosan-PLGA nanoparticles in the treatment of cystic echinococcosis in laboratory mice.

Albendazole is known as the drug of choice for medical treatment of cystic echinococcosis (CE). Albendazole sulfoxide (ABZ-SO), as the main active metabolite of albendazole, has low efficacy in the disease due to low water solubility and poor absorptivity. PLGA nanoparticles (NPs) enhance the dissolution of poorly soluble drugs, and chitosan (CS) coating enhances oral drug delivery of NPs. In this study, the efficacy of ABZ-SO-loaded CS-PGLA NPs in the treatment of CE was evaluated in laboratory mice. ABZ-SO-loaded CS-PGLA NPs were prepared by nanoprecipitation and characterized by dynamic light scattering method and scanning electron microscopy. Thirty mice were intraperitoneally infected by 1000 protoscoleces of Echinococcus granulosus. Ten months later, the mice were allocated into 3 groups: groups 1 and 2 were treated with ABZ-SO and ABZ-SO-loaded CS-PGLA NPs, respectively, and the mice in group 3 remained untreated as the control group. The drugs were administered by gavage for 45 days at a daily dose of 10 mg/kg. Finally, all mice were opened and the cysts were collected, counted, weighed, and measured separately. The therapeutic effect of ABZ-SO in the number, weight, and volume of the cysts were not statistically significant compared with those in ABZ-SO-loaded CS-PGLA NPs and the control group. However, the therapeutic effect of ABZ-SO-loaded CS-PGLA NPs in the weight and volume of cysts were statistically significant when compared with that in the control group (p ˂ 0.05). In conclusions, this study revealed that ABZ-SO-loaded CS-PGLA NPs could enhance the therapeutic efficacy of ABZ-SO in the treatment of CE in laboratory mice.

Efficacy of novel albendazole salt formulations against secondary cystic echinococcosis in experimentally infected mice.

In this study, we evaluated the efficacy, expressed as a mean weight decrease of the whole echinococcal cyst mass, of novel benzimidazole salt formulations in a murine Echinococcus granulosus infection model. BALB/c mice were intraperitoneally infected with protoscoleces of E. granulosus (genotype G1). At 9 months post-infection, treatment with albendazole (ABZ), ricobendazole (RBZ) salt formulations, and RBZ enantiomer salts (R)-(+)-RBZ-Na and (S)-(-)-RBZ-Na formulations were initiated. Drugs were orally applied by gavage at 10 mg kg-1 body weight per day during 30 days. Experimental treatments with benzimidazole sodium salts resulted in a significant reduction of the weight of cysts compared to conventional ABZ treatment, except for the (S)-(-)-RBZ-Na enantiomer formulation. Scanning electron microscopy and histological inspection revealed that treatments impacted not only the structural integrity of the parasite tissue in the germinal layer, but also induced alterations in the laminated layer. Overall, these results demonstrate the improved efficacy of benzimidazole salt formulations compared to conventional ABZ treatment in experimental murine cystic echinococcosis.

In vitro nitazoxanide exposure affects energetic metabolism of Taenia crassiceps.

Nitazoxanide (NTZ) is a broad-spectrum drug used in intestinal infections, but still poorly explored in the treatment of parasitic tissular infections. This study aimed to evaluate the in vitro responses of the energetic metabolism of T. crassiceps cysticerci induced by NTZ. The organic acids of the tricarboxylic acid cycle, products derived from fatty acids oxidation and protein catabolism were analyzed. These acids were quantified after 24 h of in vitro exposure to different NTZ concentrations. A positive control group was performed with albendazole sulfoxide (ABZSO). The significant alterations in citrate, fumarate and malate concentrations showed the NTZ influence in the tricarboxylic acid (TCA) cycle. The non-detection of acetate confirmed that the main mode of action of NTZ is effective against T. crassiceps cysticerci. The statistical differences in fumarate, urea and beta-hydroxybutyrate concentrations showed the NTZ effect on protein catabolism and fatty acid oxidation. Therefore, the main energetic pathways such as the TCA cycle, protein catabolism and fatty acids oxidation were altered after in vitro NTZ exposure. In conclusion, NTZ induced a significant metabolic stress in the parasite indicating that it may be used as an alternative therapeutic choice for cysticercosis treatment. The use of metabolic approaches to establish comparisons between anti parasitic drugs mode of actions is proposed.

Albendazole Sulfoxide Plasma Levels and Efficacy of Antiparasitic Treatment in Patients With Parenchymal Neurocysticercosis.

BACKGROUND: The efficacy of albendazole therapy in patients with parenchymal neurocysticercosis (NCC) is suboptimal. Plasma levels of albendazole sulfoxide (ASOX), the active metabolite of albendazole, are highly variable among patients. We hypothesized that high ASOX plasma levels during albendazole therapy may be associated with an increased antiparasitic efficacy. METHODS: ASOX plasma levels were measured at treatment day 7 in 118 patients with parenchymal NCC enrolled in a treatment trial. The relationships between increasing ASOX plasma levels with the proportion of cysts resolved and the proportion of patients with complete cyst resolution (evaluated by 6-month brain magnetic resonance) were assessed. RESULTS: There was a trend toward a higher proportion of cysts resolved and a higher proportion of patients cured with increasing quartiles of ASOX plasma levels. In patients with 3 or more brain cysts, the regression analysis adjusted by the concomitant administration of praziquantel (PZQ) showed a 2-fold increase in the proportion of cysts resolved (risk ratio [RR], 1.98; 95% confidence interval [CI], 1.01-3.89; P = .048) and 2.5-fold increase in the proportion of patients cured (RR, 2.45; 95% CI, .94-6.36; P = .067) when ASOX levels in the highest vs the lowest quartile were compared. No association was found in patients with 1-2 brain cysts. CONCLUSIONS: We suggest an association between high ASOX plasma levels and increased antiparasitic efficacy in patients with parenchymal NCC. Nonetheless, this association is also influenced by other factors including parasite burden and concomitant administration of PZQ. These findings may serve to individualize and/or adjust therapy schemes to avoid treatment failure.

Factors Associated With Cysticidal Treatment Response in Extraparenchymal Neurocysticercosis.

Extraparenchymal neurocysticercosis is the most severe form of cysticercosis, and response to treatment is suboptimal. We sought to determine how demographic and clinical characteristics and albendazole sulfoxide concentrations were related to cysticidal treatment response. We conducted a longitudinal study of 31 participants with extraparenchymal vesicular parasites who received the same treatment, albendazole 30 mg/kg/day for 10 days with dexamethasone 0.4 mg/kg/day for 13 days, followed by a prednisone taper. Response to treatment was determined by parasite volumes before and 6 months after treatment. Eight participants (25.8%) had a complete treatment response, 16 (51.6%) had a treatment response > 50% but < 100%, and 7 (22.6%) had a treatment response < 50%. Complete treatment response was significantly associated with higher concentrations of albendazole sulfoxide (P = .032), younger age (P = .032), fewer cysts (P = .049) and lower pretreatment parasite volume (P = .037). Higher number of previous cysticidal treatment courses was associated with a noncomplete treatment response (P = .023). Although the large proportion of participants with less than a complete response emphasizes the need to develop more efficacious pharmacologic regimens, the association of albendazole sulfoxide concentrations with treatment response highlights the importance of optimizing existing therapeutic regimens. In addition, the association of treatment response with parasite volume emphasizes the importance of early diagnosis.

Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer.

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-ß-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.

In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone.

BACKGROUND: The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites. OBJECTIVE: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites. METHODS: In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method. RESULTS: CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments. CONCLUSION: Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy.

A benzimidazole derivative (RCB15) in vitro induces the alternative energetic metabolism and glycolysis in Taenia crassiceps cysticerci.

The emergence of resistance to albendazole has encouraged the search for effective alternatives for cysticercosis and other parasitosis treatment. RCB15 is a benzimidazole derivative that may be used against such diseases. The aim of this study was to determine the in vitro effect of RCB15 on the alternative energetic pathways of Taenia crassiceps cysticerci. The cysticerci were in vitro exposed to albendazole sulphoxide (ABZSO) or RCB15 at different concentrations during 24h. The cysticerci extract and the culture medium were analyzed through spectrophotometry and high performance liquid chromatography as to detect glucose, urea, creatinine and organic acids of the energetic metabolism. The drugs did not influence the protein catabolism. Fatty acids oxidation was enhanced through significantly higher acetate concentrations in the groups treated with RCB15 and ABZSO. Beta-hydroxybutyrate concentrations were decreased which indicates the use of fatty acids towards acetyl-CoA synthesis. There was a decrease in glucose uptake and pyruvate concentrations. The absence of lactate indicates the use of pyruvate in gluconeogenesis. Therefore it is possible to conclude that RCB15 enhanced the alternative energetic pathways of cysticerci in vitro exposed to different concentration, with emphasis on the fatty acids catabolism.

Hot melt extrusion versus spray drying: hot melt extrusion degrades albendazole.

The purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ-polymer binary mixtures generated from Flory-Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80 °C for 5 min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80 °C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon® VA 64, degraded at 180 °C and 140 °C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot melt extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and polymers (Kollidon® VA 64, Soluplus® and Eudragit® E PO) were studied. The spray-dried ABZ with methanesulfonic acid and Kollidon® VA 64 substantially improved non-sink dissolution in acidic media as compared to bulk ABZ (8-fold), physical mixture of ABZ:Kollidon® VA 64 (5.6-fold) and ABZ mesylate salt (1.6-fold). No degradation was observed in the spray-dried product for up to six months and less than 5% after one-year storage. In conclusion, amorphous ABZ solid dispersions in combination with an acid and polymer can be prepared by spray drying to enhance dissolution and shelf-stability, whereas those made by melt extrusion are degraded.

A benzimidazole derivative (RCB20) in vitro induces an activation of energetic pathways on Taenia crassiceps (ORF strain) cysticerci.

Human cysticercosis caused by Taenia crassiceps is unusual; however, it is an useful experimental model for cysticercosis studies. Benzimidazole derivatives are important antihelminthic drugs widely used against helminths. A novel compound 6-chloro-5-(1-naphthyloxy) -2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative less polar and more lipophilic. The aim of this study was to detect the effect of the RCB20 on the in vitro energetic metabolism of T. crassiceps cysticerci. For this, products of the metabolism both produced and secreted/excreted (S/E) by the parasite were detected through spectrophotometry and high performance liquid chromatography after exposure to 6.5 and 13 µM of RCB20 and albendazole sulfoxide (ABZSO). There was a gradual increase in the concentrations of glucose not uptaken by parasites exposed to both concentrations RCB20 and ABZSO. There was a higher concentration of all the organic acids related to the tricarboxilic acid cycle int the parasites exposed to RCB20. The structural differences between RCB20 and ABZSO result in different targets within the parasite and in a greater induction of the energetic pathways, such as the glycolysis and the TCA cycle. RCB20 is a good candidate as a substitute for anthelminthic benzimidazoles due to a differentiated site of action with similar outcome.

Nitazoxanide induces in vitro metabolic acidosis in Taenia crassiceps cysticerci.

Nitazoxanide (NTZ) is a broad-spectrum anti-parasitic drug used against a wide variety of protozoans and helminthes. Albendazole, its active metabolite albendazole sulfoxide (ABZSO), is one of the drugs of choice to treat both intestinal and tissue helminth and protozoan infections. However little is known regarding their impact on the metabolism of parasites. The aim of this study was to compare the in vitro effect of NTZ and ABZSO in the glycolysis of Taenia crassiceps cysticerci. The cysticerci were treated with 1.2; 0.6; 0.3 or 0.15 µg/mL of NTZ or ABZSO. Chromatographic and spectrophotometric analyses were performed in the culture medium and in the cysticerci extract. Regarding the glucose concentrations was possible to observe two responses: impair of the uptake and gluconeogenesis. The pyruvate concentrations were increased in the ABZSO treated group. Lactate concentrations were increased in the culture medium of NTZ treated groups. Therefore it was possible to infer that the metabolic acidosis was greater in the group treated with NTZ than in the ABZSO treated group indicating that this is one of the modes of action used by this drug to induce the parasite death.

Scolicidal and apoptotic activities of albendazole sulfoxide and albendazole sulfoxide-loaded PLGA-PEG as a novel nanopolymeric particle against Echinococcus granulosus protoscoleces.

Treatment failures of human cystic echinococcosis (CE) with albendazole (ABZ) have attributed to its low solubility and poor drug absorption rate, resulting in low drug level in plasma. The scolicidal effects of ABZ-loaded liposome nanoparticles have recently evaluated; however, these particles have several challenges due to their low encapsulated load. This investigation was designed to evaluate and compare in vitro apoptotic activities of ABZ sulfoxide (ABZs) and ABZs-loaded poly(lactic-co-glycolic acid) (PLGA)-PEG against protoscoleces (PSCs). ABZs-loaded PLGA-PEG was prepared by a double-emulsion method (W1/O/W2). Various concentrations of ABZs and ABZs-loaded PLGA-PEG (50, 100, 150, and 200 µg/ml) were experimentally tested against PSC of CE at different exposure times (5, 10, 20, 30, and 60 min). ABZs-loaded PLGA-PEG at concentrations of 150 and 200 µg/ml was able to act at a 100 % scolicidal rate in all exposure times (5 to 60 min), while ABZs at a concentration of 200 µg/ml demonstrated 94, 100, and 100 % mortality rates following 20, 30, and 60 min of exposure times, respectively. The messenger RNA (mRNA) expression of caspase-3 was assessed by semi-quantitative RT-PCR after 15 h of exposure. Caspase-3 mRNA expression was higher in both PSC treated with ABZs and PSC treated with ABZs-loaded PLGA-PEG than that in control groups (P < 0.05). No significant difference was observed between the apoptotic intensity of PSC treated with ABZs and that of PSC treated with ABZs-loaded PLGA-PEG (P > 0.05). DNA fragmentation assay and ultrastructural changes revealed that ABZs and ABZs-loaded PLGA-PEG induced the apoptosis of PSC by activation of caspase-3. The higher permeability and scolicidal rate of ABZs-loaded PLGA-PEG can be addressed as an effectual alternative strategy to improve the treatment of human CE.

Intra-cystic concentrations of albendazole-sulphoxide in human cystic echinococcosis: a systematic review and analysis of individual patient data.

Cystic echinococcosis (CE) is a widespread zoonosis caused by the species complex Echinococcus granulosus. Albendazole (ABZ)-the first-line anthelminthic drug for medical treatment of CE-is metabolized in vivo to the active derivative ABZ-sulphoxide (ABZ-SO). Target-site ABZ-SO concentrations in the hydatid cyst mediate the anthelminthic effect in CE. Primary outcome of this systematic review of individual patient data was the intra-cystic ABZ-SO concentration stratified by cyst size, location, calcification status and use of praziquantel. Studies reporting intra-cystic ABZ-SO concentrations in humans were identified by a systematic search. A pooled analysis of individual patient data was performed to assess intra-cystic concentrations. Pharmacokinetic data of 121 individual cysts were analysed. There was no correlation between plasma and intra-cystic ABZ-SO concentrations (rho = -0.03, p = 0.76). Intra-cystic drug concentrations were also not associated with sex and treatment duration. Use of praziquantel in combination with ABZ was associated with higher plasma (median 540 vs. 240 µg/L; p = 0.04) but not intra-cystic ABZ-SO concentrations (median 220 vs. 199 µg/L; p = 0.36). Relative drug concentrations in hepatic cysts were higher than in other cysts (0.8 vs. 0.4; p = 0.05). Intra-cystic concentrations were higher in calcified than non-calcified cysts (median 897 vs. 245 µg/L; p = 0.03). There was a trend towards higher intra-cystic concentrations in smaller sized cysts (ß = -17.2 µg/L/cm; 95th CI, -35.9 to 1.6; p = 0.07). This study demonstrates that mean intra-cystic drug concentrations are similar to plasma concentrations on a population level. However, in individual patients plasma concentrations are not directly predictive for intra-cystic concentrations. The use of booster drugs was not associated with higher intra-cystic ABZ-SO concentrations in this analysis.

Alternative energy production pathways in Taenia crassiceps cysticerci in vitro exposed to a benzimidazole derivative (RCB20).

Biochemical studies of benzimidazole derivatives are important to determine their mode of action and activity against parasites. The lack of antihelminthic alternatives to treat parasitic infections and albendazole resistance cases make the search for new antiparasitary drugs of utmost importance. The 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative with promising effect. This study evaluated the effect of different concentrations of RCB20 in the alternative energetic pathway of in vitro Taenia crassiceps cysticerci. The parasites were in vitro exposed to 6.5 and 13 µM of RCB20 and albendazole sulfoxide (ABZSO). The quantification of acetate, acetoacetate, ß-hydroxybutyrate, fumarate and propionate was performed by high-performance liquid chromatography. The quantification of urea, creatinine and total proteins was performed by spectrophotometry. The increase in ß-hydroxybutyrate reflects the enhancement of the fatty acid oxidation in the treated groups. Volatile fatty acids secretion, acetate and propionate, was increased in the treated groups. The secretion mechanisms of the treated parasites were impaired due to organic acids increased concentrations in the cysticerci. It is possible to conclude that the metabolic effect on alternative energetic pathways is slightly increased in the parasites treated with RCB20 than the ones treated with ABZSO.

Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery.

[Efficacy of albendazole chitosan microspheres against Echinococcus granulosus infection in mice].

OBJECTIVE: To observe the therapeutic effect of albendazole chitosan microspheres (ABZ-CS-MPs) on cystic echinococcosis in mice. METHODS: Two hundred male kunming mice were each infected by intraperitoneal inoculation of about 5 000 viable protoscoleces of Echinococcus granulosus. Another 20 mice were kept as blank control. After 12 weeks post infection, the mice were randomly divided into four groups named as infection control group (n = 20), ABZ-CS-MPs group, albendazole liposome (L-ABZ) group, and albendazole tablet group. The latter three treatment groups were then each divided into three subgroups (n = 20) by given the dose of 37.5, 75.0, and 150.0 mg/kg for three times per week, respectively. After 12 weeks of treatment, all mice were sacrificed. The weight of hydatid cysts was measured and the inhibition rate were calculated. Mouse liver was observed. The histopathological changes of E. granulosus were observed by microscopy. The concentration of albendazole sulfoxide in plasma and liver tissues was determined by high-performance liquid chromatography. RESULTS: Compared with the other treatment groups, the turbidity of contained fluid, the consolidation level and calcification level of hydatid cysts in ABZ-CS-MPs group were higher. The average weight of hydatid cysts in each treatment group was lower than that of infection control group [(3.19 +/- 2.94) g] (P < 0.05). The cyst weight in 37.5, 75.0, and 150.0 mg/kg ABZ-CS-MPs group [(0.28 +/- 0.28), (0.24 +/- 0.22), and (0.20 +/- 0.19) g, respectively] was lower than that of albendazole tablet groups [(0.77 +/- 0.74), (0.55 +/- 0.42), (0.76 +/- 0.35) g] (P < 0.05). Among the same dosage groups, the inhibition rate in ABZ-CS-MPs group (from low to high dosage sub-group: 91.1%, 92.6%, and 93.7%, respectively) was highest. In 75.0 mg/kg ABZ-CS-MPs group, there were 15 mice with class I (degeneration) and II (necrosis) pathological changes of E. granulosus hydatid. The number of mice with class I and II pathological changes in each dosage ABZ-CS-MPs sub-group and L-ABZ sub-group was more than that of albendazole tablet group (P<0.05). Plasma concentration of albendazole sulfoxide in 75.0 and 150.0 mg/kg ABZ-CS-MPs sub-groups [(0.83 +/- 0.39), (0.80 +/- 0.5) microg/ml] were higher than that of L-ABZ sub-groups [(0.34 +/- 0.03), (0.43 +/- 0.15) microg/ml] and albendazole tablet sub-groups [(0.31 +/- 0.02), (0.40 +/- 0.10) microg/ml] (P < 0.05). Compared with 37.5, 75.0, and 150.0 mg/kg albendazole tablet sub-groups [(0.04 +/- 0.02), (0.07 +/- 0.04), (0.04 +/- 0.0) microg/g], the albendazole sulfoxide concentration in liver tissue was higher in ABZ-CS-MPs sub-groups [(0.33 +/- 0.06), (0.45 +/- 0.31), (0.50 +/- 0.30) microg/g] (P < 0.05). In 37.5 mg/kg dosage sub-group, the albendazole sulfoxide concentration in liver tissue in ABZ-CS-MPs group was higher than that of L-ABZ group [(0.14 +/- 0.19) microg/g] (P < 0.05). CONCLUSION: ABZ-CS-MPs can reduce the weight of hydatid cyst and increase the concentration of al-bendazole sulfoxide in plasma and liver tissue of mice.

Albendazolesulphoxide concentrations in plasma and hydatid cyst and prediction of parasitological and clinical outcomes in patients with liver hydatidosis caused by Echinococcus granulosus.

AIM: To investigate the relationship between plasma and cyst concentrations of albendazolesulphoxide (ASO) and their effects on parasitological findings and disease recurrence in patients with liver hydatidosis. METHODS: The study was conducted at the University Hospital for Infectious Diseases Dr. Fran Mihaljevic, Zagreb, Croatia, between August 2006 and January 2011. Consecutive patients (N=48, age 6-77 years) were treated with albendazole (3×5 mg/kg/d) over 28 days before surgical cyst removal (n=34) or percutaneous evacuation (PAIR) (n=14). Plasma ASO was determined on days 10 and 28 of treatment and cyst concentrations at surgery/PAIR. RESULTS: Disease recurred in 3 surgically treated patients. Variability of ASO concentrations was substantial. Plasma concentrations on day 10 were higher than on day 28 (geometric means ratio [GMR] 2.00; 95%CI 1.38-2.91, P<0.001) and higher than cyst concentrations at the time of treatment (GMR=1.58, 1.01-2.34, P=0.045). Higher cyst (but not plasma) concentrations were independently associated with lower odds of protoscolex motility (OR=0.23, 0.01-0.70, P<0.001) and higher odds of protoscolex destruction (OR=1.17, 1.04-1.46, P<0.001). With adjustment for age and protoscolex motility, higher day 10 plasma concentrations (but not cyst concentrations) were associated with lower odds of disease recurrence (OR=0.49, 0.09-0.97, P=0.035). Plasma concentrations did not predict cyst concentrations. CONCLUSION: Viability of protoscolices progressively decreased with increasing ASO concentrations in the cyst. Data strongly suggested that higher plasma concentrations reduced the risk of disease recurrence.

Enhanced chemoprophylactic and clinical efficacy of albendazole formulated as solid dispersions in experimental cystic echinococcosis.

Cystic echinococcosis is a chronic, complex, and still neglected disease. Although albendazole has demonstrated efficacy, only about one-third of patients experience complete remission or cure and 30-50% of treated patients develop some evidence of a therapeutic response. Different strategies have been developed in order to improve the albendazole water solubility and dissolution rate. The aim of the current work was to investigate the chemoprophylactic and clinical efficacy of an albendazole:poloxamer 188 solid dispersion formulation on mice infected with Echinococcus granulosus metacestodes. Albendazole formulated as solid dispersion had greater chemoprophylactic and clinical efficacy than albendazole alone. The improved in therapeutic efficacy could be a consequence of the increase in the systemic availability of albendazole sulfoxide. The work reported here demonstrates that in vivo treatment with albendazole:poloxamer 188 impairs the development of the hydatid cysts. This new pharmacotechnically based strategy could be a suitable alternative for treating cystic echinococcosis in humans.

Historic of therapeutic efficacy of albendazol sulphoxide administered in different routes, dosages and treatment schemes, against Taenia saginata cysticercus in cattle experimentally infected.

The present study aimed to notify the history of albendazole sulphoxide (ALB-SO) and albendazole (ALBZ) efficacy against Taenia saginata cysticercus (Cysticercus bovis) parasitizing experimentally infected bovines. A total of 11 efficacy trials were performed between the years of 2002 and 2010. In order to perform these trials, animals were individually inoculated with 2×10(4) eggs of T. saginata in each study's day zero (D0). For every trial, a positive control group (untreated infected animals) and a negative control group (animals that were neither infected nor treated) were used. ALB-SO or ALB were administered in the different dosages, in different days of treatments. In a last study with this formulation, this active principle was administered orally, mixed with the mineral supplement, on the 60th DPI, in a dosage of 30mg/kg. In all trials, on the 100th DPI, all animals were euthanized and submitted to the sequenced slicing of 26 anatomical segments (fragments of approximately five millimeters) for the survey of T. saginata cysticercus. With the obtained results it is possible to verify that in the first trials, conducted in 2002, ALB-SO reached, independently of dosage and treatment scheme, efficacies superior to 98% (arithmetic means). The trials conducted in 2005 (2.5mg/kg on the 30th, 60th, and 90th DPI) obtained values of efficacy all inferior to 60%. In 2008, the trials with 2.5 and 7.7mg/kg demonstrated efficacy values inferior to 40%, for both dosages and treatment schemes (30th/60th/90th DPI and 60th DPI). When this formulation was administered orally on the dosage of 30mg/kg on the 60th DPI, the efficacy against T. saginata cysticercus reached 88.28%. ALB administered orally showed efficacy values of 0.0%, 29.88% and 28.64% in the dosages of 5, 10 and 15mg/kg, respectively, using the treatment schemes described above for each dosage. Based on the results of these trials, conducted in an eight year period (2002-2010) using the sequenced slicing method for evaluating the efficacy of the aforementioned formulations against T. saginata cysticercus, it is possible to observe that, amongst the few molecules used in the chemotherapic treatment against T. saginata larvae, ALB-SO, administered in varied routes, dosages and treatment schemes, the studies conducted in 2008, 2009, and 2010, have a low therapeutic efficacy against C. bovis in Brazil, while ALBZ had insignificant efficacy values against T. saginata larvae parasitizing experimentally infected bovines. However, future studies using molecular biology will be necessary to assess whether the difference on the efficacy of the ALB-SO can be related to strain or another specific factor.

In vivo evaluation of the efficacy of albendazole sulfoxide and albendazole sulfoxide loaded solid lipid nanoparticles against hydatid cyst.

Cystic echinococcosis (CE) is caused by the larval stage of Echinococcus granulosus, which in this disease the metacestode develop in visceral organs especially liver and lungs. The disease is present worldwide and affects humans as well as herbivores including cattle, sheep, camels, horses and others. Benzimidazole carbamate derivatives, such as mebendazole and albendazole, are currently used for chemotherapeutic treatment of CE in inoperable patients and have to be applied in high doses for extended periods of time, and therefore adverse side effects are frequently observed. This study was designed to evaluate and compare the in vivo effects of 0.5 mg/kg, BID, albendazole sulfoxide (ricobendazole) and two different therapeutic regimens of 0.5 mg/kg BID and 2 mg/kg every 48 h of albendazole sulfoxide loaded solid lipid nanoparticles. Albendazole sulfoxide loaded solid lipid nanoparticles was prepared by solvent diffusion-evaporation method. Fifty Balb/c mice were infected by intraperitoneal injection of protoscoleces and 8 months post infection, the infected mice were treated for 15 days with the above mentioned regimens. They were then euthanized and the size and weight of the cysts as well as their ultrastructural changes were investigated. Although the cysts showed reduced size and weight in the treated animals but these reductions were not statistically significant. The cysts in the animals which received albendazole sulfoxide loaded SLN every 48 h showed more ultrastructural modification. However, these ultrastructural changes should be supported by further biochemical and molecular studies before introducing it as an efficient therapeutic regimen for treatment of human and animal hydatid disease.