Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation.

Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MAPK activation, TNF-α upregulation and activation of the death receptor-mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest. ABZ-induced SIRT3 degradation elicited ROS-mediated p38 MAPK activation, leading to pyruvate kinase M2-mediated tristetraprolin (TTP) degradation. Inhibition of TTP-mediated TNF-α mRNA decay elicited TNF-α upregulation in ABZ-treated cells. Either the overexpression of SIRT3 or abolishment of ROS/p38 MAPK activation suppressed TNF-α upregulation and rescued the viability of ABZ-treated cells. In contrast to the inhibition of ROS/p38 MAPK pathway, SIRT3 overexpression attenuated tubulin depolymerization and G2/M arrest in ABZ-treated cells. Treatment with a SIRT3 inhibitor induced TNF-α upregulation and cell death without the induction of G2/M arrest in U937 cells. Taken together, our data indicate that ABZ-induced SIRT3 downregulation promotes its microtubule-destabilizing effect, and that the non-mitotic effect of ABZ largely triggers apoptosis of U937 cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Notably, the same pathway is involved in the ABZ-induced death of HL-60 cells.

Zataria multiflora would attenuate the hepatotoxicity of long-term albendazole treatment in mice with cystic echinococcosis.

Hepatic injury is the major limitation of long-term albendazole administration in patients with cystic echinococcosis (CE), which could give rise to cessation of treatment. The objective of the present study was to evaluate the protective effects of Zataria multiflora aromatic water (AW) against the hepatic injury induced by long-term albendazole treatment in mice with CE. Fifty healthy BALB/c female mice were infected intraperitoneally by injection of 1500 protoscoleces per animal. Five months after infection, the infected animals were divided into five treatment groups including Z. multiflora (40ml/l in drinking water for 90days), albendazole (200mg/kg/day for 90days), Z. multiflora+albendazole 200 (40ml/l Z. multiflora and 200mg/kg/day albendazole for 90days), Z. multiflora+albendazole100 (40ml/l Z. multiflora and 100mg/kg/day albendazole for 90days), and untreated (control) group. At the end of the treatment period, anesthesia was performed and blood samples were collected directly from the heart prior to euthanasia. Liver variables and oxidative stress markers were measured in the blood serum samples. A decrease in serum liver enzyme activity in the both Z. multiflora+albendazole groups was observed when compared to control, Z. multiflora and albendazole groups; however, the results for Z. multiflora+albendazole 100 were significant (p<0.007) and superior compared to those for Z. multiflora+albendazole 200. No significant differences for oxidative stress markers were observed between the different groups. The results of the present study revealed that a combined therapy with Z. multiflora AW and albendazole is effective against hepatic injury induced by CE and/or long term albendazole administration in mice with cystic echinococcosis.

Formation and characterization of Langmuir and Langmuir-Blodgett films of Newkome-type dendrons in presence and absence of a therapeutic compound, for the development of surface mediated drug delivery systems.

Organic macromolecules with dendrimeric architectures are polymeric materials potentially useful as nanocarriers for therapeutic drugs. In this work, we evaluate a series of Newkome-type dendrons in Langmuir and Langmuir-Blodgett films as platforms capable of interacting with a potential antitumoral agent. The nanocomposite is proposed as model for the development of surface mediated drug delivery systems. We were successful in the formation and characterization of pure (dendrons) and composite (drug-dendron) stable and reproducible monolayers, and their transfer to solid substrates. A detailed study of topographic characteristics of the generated surfaces by atomic force microscopy was conducted. Furthermore, we probed dendron monolayer films as anchorage surfaces for mammalian cells. Normal cell attachment and proliferation on the surfaces were observed. No evident cytotoxic effects were detected, demonstrating the adequate biocompatibility of the surfaces.

Short-Term Effects of Albendazole on the Oxidative Stress Markers and Hematological Parameters in Tissues of African Catfish Clarias gariepinus.

Albendazole (ABZ) is a typical broad-spectrum benzimidazole drug used for the treatment of parasitic worm infestations in humans and animals. The present study investigated the oxidative stress biomarkers and hematological parameters in juvenile African Catfish (also known as Sharptooth Catfish) Clarias gariepinus exposed to ABZ for 96 h. Fish were exposed to 0 (control) 20, 40, and 60 mg/L ABZ. The liver and gill tissues were sampled at regular intervals of 24 h, and the results showed significant concentration- and time-dependent increases in the values of lipid peroxidation but reductions in glutathione peroxidase, catalase, superoxide dismutase, and glutathione reductase in both tissues. Erythrocytes were sampled to evaluate hematological parameters. The results showed significant concentration- and time-dependent increases in white blood cells but no significant differences in mean cellular hemoglobin. Hemoglobin values, red blood cell counts, packed cell volume, mean cell volume, and mean cellular hemoglobin concentration decreased significantly over the experimental period. The activities of lymphocytes and neutrophils increased significantly, whereas there were no significant differences in basophils, eosinophils, and monocytes among the treatment groups. Albendazole should be used with caution, as sublethal concentrations induced oxidative stress in the liver and gill tissues along with hematological changes that were more evident in liver cells. Received November 20, 2015; accepted May 4, 2015.

Efficacy of osthole for Echinococcus granulosus in vitro and Echinococcus multilocularis in vivo.

Echinococcosis is a zoonotic infection caused by cestode species of the genus Echinococcus; in addition, this zoonosis has long been neglected as a parasitic disease and has limited treatment options. Clinical drugs such as benzimidazole derivatives have limited treatment efficacy. The current study evaluated a novel drug, osthole, with low toxicity and high activity against Echinococcus in vitro and in vivo. The results in vitro indicated that the viability of Echinococcus granulosus protoscoleces in the group treated with osthole (120µM) decreased by 100% within 3days. In vivo experiments were conducted using parasite-infected mice. For this purpose, three groups of infected mice were treated daily for 6 weeks with albendazole (ABZ, 100mg/kg, positive control group), osthole (100mg/kg, experimental group), or honey/PBS (100mg/kg, negative control group), respectively. The osthole- and ABZ-treated groups presented a significant reduction in wet weight of metacestodes, increase in the level of interleukin (IL)-4 and the percentage of eosinophils compared with the control group. Osthole exhibited a high activity against echinococcosis in vivo. In addition, the toxicity of osthole was evaluated via an in vitro 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, as well as via morphological observation and calculation of liver and kidney function indexes in vivo. No obvious toxic effects of osthole were observed in our study. Therefore, this novel drug may be a promising alternative to benzimidazole in anti-echinococcosis chemotherapy.

Copper(II) oxide nanoparticles augment antifilarial activity of Albendazole: In vitro synergistic apoptotic impact against filarial parasite Setaria cervi.

Mass treatment of lymphatic filariasis with Albendazole (ABZ), a therapeutic benzimidazole, is fraught with serious limitations such as possible drug resistance and poor macrofilaricidal activity. Therefore, we need to develop new ABZ-based formulations to improve its antifilarial effectiveness. CuO nanoparticles were used as an adjuvant with ABZ to form ABZ-CuO nanocomposite, which was characterized by UV-vis spectroscopy, FT-IR, AFM and SEM. Antifilarial activity of nanocomposite was evaluated using relative motility assay and dye exclusion test in dark and under UV light. ROS generation, antioxidant levels, lipid peroxidation and DNA fragmentation in nanocomposite treated parasites were estimated. Biophysical techniques were employed to ascertain the mode of binding of nanocomposite to parasitic DNA. Nanocomposite increases parasite mortality as compared to ABZ in dark, and its antifilarial effect was increased further under UV light. Elevated ROS production and decline of parasitic-GST and GSH levels were observed in nanocomposite treated worms in dark, and these effects were pronounced further under UV light. Nanocomposite leads to higher DNA fragmentation as compared to ABZ alone. Further, we found that nanocomposite binds parasitic DNA in an intercalative manner where it generates ROS to induce DNA damage. Thus, oxidative stress production due to ROS generation and consequent DNA fragmentation leads to apoptosis in worms. This is the first report supporting CuO nanoparticles as a potential adjuvant with ABZ against filariasis along with enhanced antifilarial activity of nanocomposite under UV light. These findings, thus, indicate that development of ABZ-loaded nanoparticle compounds may serve as promising leads for filariasis treatment.

Combined subacute toxicity of copper and antiparasitic albendazole to the earthworm (Eisenia fetida).

Copper (Cu) is one of the most common metal contaminants, and albendazole (ABZ) is a veterinary drug with a high efficacy against helminthes. It is believed that the two may co-exist in soil. In this study, the combined subacute toxicity of Cu exposure (0, 80, 120, 160 mg kg(-1)) and ABZ exposure (0, 3, 9 mg kg(-1)) in earthworms (Eisenia fetida) were observed using three approaches, namely chronic growth and reproduction, antioxidant enzyme activity, and earthworm Cu residue. The results have shown that the toxicity of Cu on cocoon hatching success and biomass was alleviated by presence of low concentrations of ABZ (3 mg kg(-1)) during a 56-day exposure period. However, the sensitivity of the earthworms' reproduction to Cu increased with the presence of high concentrations of ABZ (9 mg kg(-1)), indicating a reduction beginning at a Cu concentration of 80 mg kg(-1), in the cocoon number, hatching success, and biomass. In addition, the three enzyme activities exhibited different responsive patterns, indicating inducement in the catalase and glutathione peroxidase, and inhibition in the superoxide dismutase, which were dependent on the exposure times and concentrations. In regard to the earthworm Cu residue, when increasing Cu exposure concentrations, the internal Cu concentrations tended to level off, exhibited a linear pattern at the Cu concentration range of 40 to 120 mg kg(-1), and showed a stable trend above 120 mg kg(-1). The results of the present study can potentially provide important information regarding the combined toxicity of the veterinary drugs and the heavy metals in soil.

Reproductive responses of the earthworm (Eisenia fetida) to antiparasitic albendazole exposure.

Albendazole (ABZ) is a veterinary drug with a high efficiency against helminths. Here reproductive responses of earthworms Eisenia fetida to ABZ exposure (0, 1, 3, 6, 9 and 12 mg kg(-1) soil dry weight) were investigated for 56 d in chronic reproduction test, and deformed sperm were counted and morphological alterations in the seminal vesicles were qualitatively assessed by light and transmission electron microscopy. Results have showed that cocoon number of earthworms was more sensitive to low concentrations of ABZ than cocoon hatching success and hatching survival, showing a significant dose-related decrease in cocoon number at 3, 6, 9 and 12 mg kg(-1). In short-time exposure of 14 d, the sperm deformity (%) of earthworms increased at 6, 9 and 12 mg kg(-1), and the microstructural alteration in seminal vesicles was also observed at these concentrations, whereas ultrastructural alteration of germ cells, particularly morphology of mitochondria, was observed at 3 mg kg(-1) and above, suggesting the high sensitivity of germ cell ultrastructure to low concentrations of ABZ in short-time exposure. The results can provide important information for prediction of ecologically significant toxic effects.

Isolation and identification of Paenibacillus sp. FM-6, involved in the biotransformation of albendazole.

A strain, designated as FM-6, was isolated from fish. Based on the results of phenotypic, physiological characteristics, genotypic and phylogenetic analysis, strain FM-6 was finally identified as Paenibacillus sp. When albendazole was provided as the sole carbon source, strain FM-6 could grow and transform albendazole. About 82.7 % albendazole (50 mg/L) was transformed by strain FM-6 after 5 days incubation at 30 °C, 160 rpm. With HPLC-MS method, the transforming product of albendazole was researched. Based on the molecular weight and the retention time, product was identified as albendazole sulfoxide and the transforming pathway of albendazole by strain FM-6 was proposed finally. The optimum temperature and pH for the bacterium growth and albendazole transformation by strain FM-6 were both 30 °C and 7.0. Moreover, the optimum concentration of albendazole for the bacterium growth was 50 mg/L. Coupled with practical production, 50 mg/L was the optimum concentration of albendazole transformation for strain FM-6. This study highlights an important potential use of strain FM-6 for producing albendazole sulfoxide.

Gene expression responses in different regions of Eisenia fetida with antiparasitic albendazole exposure.

Albendazole (ABZ) is a veterinary drug with a high efficiency against parasite. The aim of this research is to investigate and characterize the response of gene expression in different regions of earthworms Eisenia fetida in relation to ABZ exposure. In this research, the earthworms were exposed to ABZ at 0, 10, 30, 90, and 270 mg/kg concentrations for 42 days. Within the initial 14-day exposure, the expression levels of two target genes (mitochondrial large ribosomal subunit (l-rRNA) and heat shock protein (HSP90)) in different regions of earthworms were affected significantly by the different exposure concentrations of ABZ, but the growth rates were similar among the ABZ and control groups. With longer exposure time, growth rates decreased significantly after 28 days of exposure at 90 and 270 mg/kg. These results of target genes expression suggest that, at low ABZ concentrations, the middle region of earthworms is more sensitive to ABZ than the anterior and posterior regions. In the middle region, the l-rRNA expression of the ABZ-exposed groups was significantly lower than the control group, with a reduction to 23%, 25% and 31% for 10, 30 and 90 mg/kg ABZ concentrations, respectively (P<0.01). In contrast, the HSP90 expression of the ABZ groups (full range of 10 to 270 mg/kg) in the middle region increased 4.1-8.7 folds over the control group (P<0.01). In the anterior and posterior regions, the expression of the two target genes at 10mg/kg did not differ significantly among the ABZ and control groups (P>0.05), except for l-rRNA in the posterior region. The characterization and understanding of target genes expression in different regions of earthworms can provide important information on predictive early reading on the pollution of ABZ residue in soils.

Relative potency of albendazole and its sulfoxide metabolite in two in vitro tests for developmental toxicity: the rat whole embryo culture and the mouse embryonic stem cell test.

The benzimidazole carbamate albendazole (ABZ), a potent anthelmintic, is a teratogenic compound in rats. At present it is unclear to which degree this effect is caused by the parent compound or its major metabolite, albendazole sulfoxide (ASO). Both substances were studied separately and in combinations to mimic incomplete bioactivation in two in vitro tests: mouse embryonic stem cell test (EST) and rat whole embryo culture (WEC). In both assays, ABZ and mixtures with ASO induced detrimental effects at lower concentrations compared to ASO alone. While ABZ caused half-maximal effects on cardiomyocyte differentiation at a mean concentration of 0.26 µM (EST) and dysmorphogenic development of rat embryos at 3.7 µM (WEC), effective concentrations of ASO were similar in both assays (10-13 µM). By using WEC and EST we demonstrate that ABZ exhibits stronger inherent embryotoxic potency although ASO might be the proximate teratogen in vivo because of higher plasma concentrations.

Albendazole causes stage-dependent developmental toxicity and is deactivated by a mammalian metabolization system in a modified zebrafish embryotoxicity test.

The zebrafish embryotoxicity test has previously been combined with an external metabolic activation system (MAS) to assess developmental toxicity of metabolites produced by maternal metabolism. Due to toxicity of MAS the exposure was limited to one early and short period. We have modified the method and included additional testing time points with extended exposure durations. Using the anthelmintic drug albendazole as a model substance, we demonstrated stage-dependent toxic effects at three windows of zebrafish embryo development, i.e. 2-3, 12-14 and 24-28h post fertilization, and showed that MAS, by metabolic deactivation, reduced the toxicity of albendazole at all time points. Chemical analysis confirmed that albendazole was efficiently metabolized by MAS to the corresponding sulfoxide and sulfone, which are non-toxic to zebrafish embryos. To conclude, the modified zebrafish embryotoxicity test with MAS can be expanded for assessment of metabolites at different developmental stages.

Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos.

Albendazole (ABZ) is used as an anthelmintic drug in humans and animals. ABZ has been shown to cause developmental toxicity in experimental animals, however it is not clear if this is caused by the parent compound or a metabolite. Zebrafish embryos were exposed from 1 to 144hpf (hours post fertilization) to investigate the developmental toxicity of ABZ, the first metabolite albendazole sulphoxide and the subsequent metabolites albendazole sulphone (ABZSO(2)) and albendazole-2-aminosulphone (ABZSO(2)NH(2)). The results showed that ABZ caused malformations of head and tail and embryonic lethality from 0.3µM. In contrast, the metabolites did not display developmental toxicity at any tested concentration. Dechorionation did not influence the developmental toxic potential of ABZ and ABZSO, indicating that bioavailability was not a limiting factor. Chemical analysis showed that at sublethal concentrations, most of ABZ was metabolized to ABZSO. The results demonstrate that in zebrafish embryos ABZ rather than ABZSO displays developmental toxicity.

Evaluation of potential embryo toxicity of albendazole sulphoxide in CF1 mice.

Benzimidazole compounds are used in both humans and animals for controlling helminth parasites. Albendazole has teratogenic effects attributed to its active metabolite albendazole sulphoxide. The aim of this work was to evaluate the effect of the latter compound when administered to pregnant CF1 mice during the preimplantation period. Females were superovulated by intraperitoneal injection of 10 IU of eCG and 10 IU of hCG (48h later) and were paired with males of proven fertility. Albendazole sulphoxide (200 mg/kg) was orally administered by gavages at day 1, 2 or 3 of pregnancy; the control group received only the vehicle (carboxymethylcellulose). Females were killed by cervical dislocation at day 4 of pregnancy and embryos were flushed from uteri with Ham F10 media supplemented with bovine serum albumin (0.4%). Number of collected embryos per female, percentage of morphologically normal embryos, differentiation rate and number of cells per embryos were recorded. The variables were analyzed on a per litter basis by Kruskal-Wallis test. There was no effect of albendazole sulphoxide on parameters evaluated (P>0.05). We conclude that the preimplantation mouse embryo development was not significantly affected by albendazole sulphoxide.

Evaluation of potential embryo toxicity of albendazole sulphoxide in CF1 mice

Benzimidazole compounds are used in both humans and animals for controlling helminth parasites. Albendazole has teratogenic effects attributed to its active metabolite albendazole sulphoxide. The aim of this work was to evaluate the effect of the latter compound when administered to pregnant CF1 mice during the preimplantation period. Females were superovulated by intraperitoneal injection of 10 IU of eCG and 10 IU of hCG (48h later) and were paired with males of proven fertility. Albendazole sulphoxide (200 mg/kg) was orally administered by gavages at day 1, 2 or 3 of pregnancy; the control group received only the vehicle (carboxymethylcellulose). Females were killed by cervical dislocation at day 4 of pregnancy and embryos were flushed from uteri with Ham F10 media supplemented with bovine serum albumin (0.4%). Number of collected embryos per female, percentage of morphologically normal embryos, differentiation rate and number of cells per embryos were recorded. The variables were analyzed on a per litter basis by Kruskal-Wallis test. There was no effect of albendazole sulphoxide on parameters evaluated (P>0.05). We conclude that the preimplantation mouse embryo development was not significantly affected by albendazole sulphoxide.

[Ecotoxicolgical effects of albendazole on Eisenia fetida].

By using artificial soil test, the effects of different concentration albendozole on Eisenia foetida's growth, survival, reproduction, and activities of superoxide dismutase (SOD), glutathione-sulfurtransferase (GST-S) and acetylcholine esterase (AchE) were studied. Low concentration (5 mg x kg(-1)) albendazole inhibited the reproduction of E. foetida significantly (P < 0.05), and 7 mg x kg(-1) of albendazole had significant effects on the growth and survival of E. foetida. When the albendazole concentration reached to 10 mg x kg(-1), the mortality of E. foetida was as high as 53%. There was a significant dose-response relationship between the exposure concentration of albendazole and the inhibition rate of E. foetida's growth and reproduction. After 21 days' albendazole exposure, the SOD and GST-S activities were affected significantly, but no significant dose-response relationship was observed. Albendazole exposure had less effects on AchE activity. In sum, albendazole had direct toxicity on soil animals, with a potential ecological risk.

Effects of albendazole sulphoxide on embryonic, foetal and placental parameters in Wistar rats / Efectos de albendazol sulfóxido sobre parámetros embrionarios, fetales y placentarios en ratas Wistar

The aim of this work was to evaluate the effect of albendazole sulphoxide (ABZSO), administered to Wistar rats during pregnancy on embryonic, foetal and placental parameters. A colpocytological control was performed daily and detection of spermatozoa in the vaginal smear was considered as day 0 of pregnancy. For the preimplantational study, ABZSO (10 mg/kg) was orally administered at day 2 of pregnancy; at day 4 the embryos were collected. For the postimplantational study, ABZSO (10 mg/kg) was orally administered by gavages at day 2, 6 or 10 of pregnancy (G2, G6 and G10 Groups respectively); the control group was administered the same volume of carboxymethylcellulose vehicle used to prepare the drug suspension. Fetuses were obtained from pregnant rats sacrificed on day 20 of gestation. Maternal body weight gains were analyzed using the one-way ANOVA test. Embryonic and foetal variables were analized on a per litter basis by the Kruskal-Wallis test. Skeletal anomalies were analyzed using an X² test. The significance level accepted was established at P<0.05. In the preimplantational analysis, the cleavage rate was lower in the experimental group (P<0.05). In the postimplantational analysis there were no differences in the net weight increase among females of the different groups (P>0.05). The number of fetuses and the foetal vesicles weight were lower in the G10 group (P<0.05). This group showed the highest percentage of resorptions (P<0.05) and fetuses morphologically abnormal. An increase in the number of bones affected in fetuses of G6 and G10 groups was observed. The most common malformations were at vertebral, costal and head level. Weights and placental diameters were lower in the G10 group (P<0.05). We conclude that ABZSO at the dose used in this study affects the cleavage rate in preimplantational embryo development, without interrupting pregnancy. Furthermore; the developmental toxicity is related to day of administration.

El objetivo de este trabajo fue caracterizar los efectos de albendazol sulfóxido (ABZSO) durante la gestación de ratas Wistar, sobre parámetros embrionarios, fetales y placentarios. Se efectuó colpocitología diaria de las hembras considerándose día 0 de gestación el día de aparición de espermatozoides en vagina. Estudio preimplantacional: ABZSO (10 mg/kg) fue dosificado oralmente el día 2 de gestación; el día 4 de gestación se realizó la recolección de embriones. Estudio post-implantacional: ABZSO (10 mg/kg) fue dosificado oralmente los días 2, 6 ó 10 de gestación (Grupos G2, G6 y G10, respectivamente). Hembras controles recibieron carboximetilcelulosa, vehículo usado para solubilizar la droga. Las hembras fueron sacrificadas al día 20 de gestación. Variables embrionarias y fetales fueron analizadas sobre la base de las camadas mediante test de Kruskal-Wallis; ganancia de peso de las madres por ANOVA y porcentaje de fetos con alteraciones esqueléticas mediante X2. Estudio preimplantacional: la tasa de recolección embrionaria, el número de embriones recolectados y el porcentaje de diferenciación fueron similares entre grupos (P>0,05). La velocidad de clivaje fue menor en el grupo experimental (P<0,05). Estudio post-implantacional: la ganancia de peso de las madres no difirió entre grupos (P>0,05), el número de fetos y el peso de las vesículas fetales fueron menores en el grupo G10 (P<0,05). Los porcentajes de reabsorciones y de fetos con características morfológicas anormales fueron mayores en el grupo G10 (P<0,05). Las alteraciones esqueléticas fueron mayores en los grupos G6 y G10 (P<0,05) observándose con mayor frecuencia en vértebras, costillas y cabeza. Pesos y diámetros placentarios fueron menores en el grupo G10 (P<0,05). Se concluye que, bajo las condiciones del presente estudio, el ABZSO administrado en la etapa preimplantacional afecta la velocidad de clivaje sin detener la gestación mientras que su efecto en el desarrollo post-implantacional...

Albendazole-cyclodextrin complex: enhanced cytotoxicity in ovarian cancer cells.

BACKGROUND: Over recent years, we have identified a potentially new indication for albendazole (ABZ) namely that of an anticancer agent. Our recent data indicate that besides regional use, the drug is quite likely to be useful as a systemic anticancer agent. However, with extremely low solubility, ABZ has to be prepared in a biocompatible solubilized form before any systemic evaluation is possible. The present study aimed at preparing soluble ABZ and evaluating its in vitro antiproliferative efficacy and toxicity. EXPERIMENTAL DESIGN: Using beta-cyclodextrins (CDs), various formulations of ABZ were prepared and tested in cell culture for antiproliferative efficacy, cell integrity and cell toxicity against human ovarian cancer cell lines 1A9, OVCAR-3 and SKOV-3. Hepatocytes isolated from patients undergoing liver tumor resection were used for toxicity evaluations. RESULTS: Treatment of tumor cells with ABZ-CD + citric acid (CA) solution led to dose-dependent inhibition of cell proliferation. Compared to an ethanolic solution of ABZ, ABZ-CD + CA increased the antiproliferative efficacy of ABZ. Furthermore, in contrast to the ethanolic solution, ABZ-CD-CA complex profoundly (p<0.001) reduced the number of OVCAR-3 colonies formed. Fresh human hepatocytes exposed for 3 days to the highest ABZ concentration used in the study (1 microM), revealed no drug toxicity. CONCLUSION: Complexation of ABZ with beta-cyclodextrin leads to the formation of an ABZ solution with potent antiproliferative effects. This solution may find clinical value as an intravenous anticancer agent.

Membrane-water partitioning, membrane permeability, and baseline toxicity of the parasiticides ivermectin, albendazole, and morantel.

A comparative hazard assessment of the antiparasitics ivermectin, albendazole, and morantel was performed, with a particular focus on bioavailability and uptake into biological membranes. The experimentally determined liposome-water distribution ratio at pH 7 (D(lipw) (pH 7)) of the positively charged morantel was 100 L/kg lipid. The D(lipw) (pH 7) of albendazole was 3,000 L/kg lipid. The membrane permeability determined with the parallel artificial membrane permeability assay was consistent with predictions from a quantitative structure-activity relationship (QSAR) for morantel but 14-fold lower than predicted for albendazole, which can be rationalized because neutral albendazole is, in fact, zwitterionic and the large dipole moment hinders permeation through hydrophobic membranes. An unusually large molecule, ivermectin was suspected to show decreased bioaccumulation because of its bulkiness, but experimental determination of solubility showed that it was 40-fold less soluble than expected from a QSAR between solubility and the octanol-water partition coefficient. In contrast, its membrane permeability appeared to be typical for a compound of the given hydrophobicity, but it was not possible to determine the membrane-water partition coefficient because of its low solubility and high affinity to the dialysis membrane of the experimental device. The D(lipw) (pH 7) for ivermectin of 2,700 L/kg lipid was calculated with a QSAR model. Morantel and albendazole were baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri and a test for inhibition of photosynthesis in green algae. Only ivermectin exhibited a specific effect toward algae, but the excess toxicity was not very pronounced and might be biased by the uncertainty of the estimated hydrophobicity descriptor. Overall, we did not find any unexpected effect on nontarget endpoints.