Ex Vivo Anthelmintic Activity of Albendazole-Sulphoxide Enantiomers

Bolás‐Fernández, F.; Rama-Iñiguez, Sara; Torrado, J. J.

doi:10.1645/ge-3212rn

Cited by 17 publications

(12 citation statements)

References 24 publications

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“…The anthelmintic effect of ABZSO and its enantiomers on larvae of the nematode Trichinella spiralis determined using an ex vivo model of treatment has been previously reported; (ϩ)-(R)-ABZSO was the most effective form, rendering a significant reduction of larval viability at 100 ng/ml (26). Likewise, (ϩ)-(R)-ABZSO showed a significantly higher activity than (Ϫ)-(S)-ABZSO against Haemonchus contortus using a gerbil (Meriones unguiculatus) infection model.…”

Section: Discussionmentioning

confidence: 82%

In Vitro Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-( R )-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium

Paredes

Lourenço

Marzal

et al. 2013

Antimicrob Agents Chemother

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Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with Taenia N eurocysticercosis (NCC) is a major cause of adult-onset seizures and epilepsy in many areas of the developing world. It is an infection with the larval cyst form of the cestode tapeworm Taenia solium acquired through the accidental ingestion of ova shed in the feces of human tapeworm carriers. The released oncospheres find their way to the bloodstream and are carried throughout the body but develop mostly in the muscles, subcutaneous tissues, and brain. Almost all the symptoms are due to brain involvement (1).Two drugs, the benzimidazole albendazole (ABZ) and the pyrazinoisoquinoline praziquantel (PZQ), are commonly used to treat neurocysticercosis, usually with accompanying immunosuppressive/anti-inflammatory medication (2-4). Albendazole is frequently preferred to praziquantel because it is more widely available, has a lower cost, and normally requires shorter courses of treatment (and hence represents lower hospitalization-associated expenses) for higher efficacy (2, 5-7).In susceptible parasites, the main effect of ABZ is the inhibition of tubulin polymerization into microtubules, but the drug also causes biochemical changes such as inhibition of mitochondrial fumarate reductase, reduced glucose transport, and uncoupling of oxidative phosphorylation, impairing ATP generation (8, 9). Although ABZ has been used since the 1970s (10, 11), it is not completely effective in killing cysts; 12% and 45% of total cysts remain after the usual dosing regimens used with albendazole and praziquantel, respectively (12). Cure rates are unacceptably low for both drugs at about 40% to 50%, so retreatments are often required.After oral administration, the nonchiral ABZ is oxidized in the liver to its active metabolite, albendazole sulfoxide (ABZSO), with one chiral center in the sulfoxide group. The two possible enan- (13), show different pharmacokinetics and affinities for cytosolic proteins from different parasites (28). Kinetic parameters of (ϩ)-(R)-and (Ϫ)-(S)-ABZSO enantiomers in NCC patients treated with ABZ differ in renal excretion (14), accumulation in plasma (15), and, most importantly, distribution in the cerebrospinal fluid (12). Even though the levels of effectiveness of the two enantiomers against a number of other helminths differ, the effect of the isolated enantiomers against T. solium metacestodes (cysts) has not been reported. tiomers, (ϩ)-(R)-and (Ϫ)-(S)-ABZSOA sensitive in vitro system to quantify drug effects on cysts of T. solium has been recently reported (16). In this system, drug sensitivity to both ABZSO and PZQ correlates with the degree of inhibition of alkaline phosphatase (AP) release from cysts, obtained from naturally infected pigs and cultured in vitro (16). Using this system, we compared the anthelmintic effect of the (ϩ)-(R)-and (Ϫ)-(S)-ABZSO enantiomers to effects of the ABZSO racemic mixture and of PZQ. Here we show that the antiparasitic effect of the drug ...

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Section: Discussionmentioning

confidence: 82%

In Vitro Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-( R )-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium

Paredes

Lourenço

Marzal

et al. 2013

Antimicrob Agents Chemother

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“…The kinetic disposition of ASOX is enantioselective in NCC patients treated with ABZ with area under the plasma concentration–time curve ratios of ASOX (+) : ASOX (−) ranging from 7.6 to 10.9 [12]. The antiparasitic activity of racemic ASOX (+)‐ASOX and (−)‐ASOX tested in an ex vivo murine model for Trichinella spiralis infection showed that at lower concentrations only treatment with (+)‐ASOX resulted in a significant reduction in larval viability [13].…”

Section: Introductionmentioning

confidence: 99%

Albendazole‐praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

Lima¹,

Ferreira

Carvalho

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacokinetic interactions between albendazole and praziquantel are based on plasma concentrations of the enantiomeric mixture of both drugs with contradictory data, although the antiparasitic activity arises from (-)-(R)-praziquantel and (+)-albendazole sulfoxide. WHAT THIS STUDY ADDS• The pharmacokinetic interaction between albendazole and praziquantel is enantioselective. Praziquantel increased the plasma concentrations of (+)-albendazole sulfoxide more than those of (-)-albendazole sulfoxide and the administration of albendazole did not change the kinetic disposition of (+)-(S)-praziquantel, but increased the plasma concentration of (-)-(R)-praziquantel. AIMThis study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODSA randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P Յ 0.05. RESULTSThe administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 mg ml -1 h), (-)-ASOX by 358% (0.14 vs. 0.50 mg ml -1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 mg ml -1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 mg ml -1 h). CONCLUSIONSThe pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.

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“…SOABZ exhibits chirality with two enantiomeric forms present in plasma of different animals (Delatour et al 1990a, b;García-Rodríguez et al 2001;2003). These two enantiomeric forms show a different anthelmintic activity (Bolás-Fernández et al 2004). These authors observed, under ex vivo conditions, that (+) SOABZ has higher activity against T. spiralis than its antipode or the racemic form as only the positive form retained its anthelmintic activity up to very low concentration level (0.1 μg/ml in the incubation medium).…”

Section: Discussionmentioning

confidence: 99%

“…In a previous work, it has been shown that SOABZ enantiomers exhibit different pharmacological activity against the larval stages of Trichinella spiralis with the SOABZ (+) being responsible for anthelmintic effectiveness (Bolás-Fernández et al 2004). In the present work, the comparative pattern of ex vivo uptake, diffusion and accumulation of ABZ, SOABZ and its enantiomers by the muscle larvae of T. spiralis was examined.…”

Section: Introductionmentioning

confidence: 99%

Enantiomerical pharmacokinetic prevalence of (+) albendazole sulphoxide in Trichinella spiralis muscle larvae

et al. 2011

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In a previous work, it was demonstrated that (+) albendazole sulphoxide (SOABZ) has higher anthelmintic activity than (-) SOABZ (Bolás-Fernández et al. J Parasitol 90:407-409, 2004). In this work, the pharmacokinetics characteristics of SOABZ and its enantiomeric forms were studied in an ex vivo model system for Trichinella spiralis isolated muscle larvae. To this end, samples of either racemic or purified SOABZ enantiomers were added to the incubation medium. Quantification of either albendazole, racemic SOABZ or its enantiomers was performed by validated HPLC methods and the effect of different SOABZ concentrations in relation to time of contact with the larvae was also analysed. Obviously, higher concentration of SOABZ in the medium leads to higher concentrations of SOABZ inside the larvae which increased in an exponential mode, thus indicating a simple diffusion process. At least 18 h of contact with the drug was required to achieve anthelmintic effects. Besides, after this time, the concentration of (+) SOABZ inside the larvae was significantly higher than that of the (-) SOABZ. From these results, it can be concluded that the higher activity found in the previous work is clearly related to the pharmacokinetic prevalence of (+) enantiomer inside the larvae.

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Ex Vivo Anthelmintic Activity of Albendazole-Sulphoxide Enantiomers

Cited by 17 publications

References 24 publications

In Vitro Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-( R )-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium

In Vitro Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-( R )-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium

Albendazole‐praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

Enantiomerical pharmacokinetic prevalence of (+) albendazole sulphoxide in Trichinella spiralis muscle larvae

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