Vera Lucia Lanchote

Pharmacokinetics of combined treatment with praziquantel and albendazole in neurocysticercosis

AIMS Neurocysticercosis is the most common cause of acquired epilepsy in the world. Antiparasitic treatment of viable brain cysts is of clinical benefit, but current antiparasitic regimes provide incomplete parasiticidal efficacy. Combined use of two antiparasitic drugs may improve clearance of brain parasites. Albendazole (ABZ) has been used together with praziquantel (PZQ) before for geohelminths, echinococcosis and cysticercosis, but their combined use is not yet formally recommended and only scarce, discrepant data exist on their pharmacokinetics when given together. We assessed the pharmacokinetics of their combined use for the treatment of neurocysticercosis. METHODS A randomized, double-blind, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ and PZQ in 32 patients with neurocysticercosis was carried out. Patients received their usual concomitant medications including an antiepileptic drug, dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug (phenytoin or carbamazepine). Subjects had sequential blood samples taken after the first dose of antiparasitic drugs and again after 9 days of treatment, and were followed for 3 months after dosing. RESULTS Twenty-one men and 11 women, aged 16 to 55 (mean age 28) years were included. Albendazole sulfoxide concentrations were increased in the combination group compared with the ABZ alone group, both in patients taking phenytoin and patients taking carbamazepine. PZQ concentrations were also increased by the end of therapy. There were no significant side effects in this study group. CONCLUSIONS Combined ABZ + PZQ is associated with increased albendazole sulfoxide plasma concentrations. These increased concentrations could independently contribute to increased cysticidal efficacy by themselves or in addition to a possible synergistic effect.

Enantioselective analysis of metoprolol in plasma using high-performance liquid chromatographic direct and indirect separations: applications in pharmacokinetics

Direct enantioselective separation on chiral stationary phases and indirect separation based on the formation of diastereomeric derivatives were developed and compared for the HPLC analysis of R(+) and S(-)-metoprolol in human plasma. Plasma samples prepared using solid-phase extraction columns or liquid-liquid extraction were directly analyzed on a Chiralpack AD or on a Chiralcel OD-H columns, respectively. S-(-)-menthyl choroformate was also used to yield diastereomeric derivatives resolved on a RP-8 column. The methods were employed to determine plasma concentrations of metoprolol enantiomers in a pharmacokinetic study of single dose administration of racemic metoprolol to a healthy Caucasian volunteer phenotyped as extensive metabolizer of debrisoquine. The correlation coefficients among enantioselective metoprolol plasma concentrations (5-223 ng/ml) obtained by the three methods were equal or higher than 0.99. The direct method that employed the chiral column Chiralpak AD may be considered the most sensitive, although the three methods demonstrated interchangeable use in the pharmacokinetic investigation.

Simultaneous determination of albendazole sulfoxide enantiomers and albendazole sulfone in plasma

A high-performance liquid chromatographic method has been developed for the simultaneous determination of albendazole sulfoxide (ABZSO) enantiomers and albendazole sulfone (ABZSO2) in human plasma. The resolution of ABZSO enantiomers and ABZSO2 was obtained on a Chiralpak AD column using hexane-isopropanol-ethanol (81:14.25:4.75, v/v/v) as the mobile phase. The drugs were detected by fluorescence (lambda(exc) = 280 nm, lambda(em) = 320 nm). The drugs were extracted from 500 microl plasma with ethyl acetate, and after solvent evaporation, the residues were dissolved in the mobile phase and chromatographed. The method was precise and accurate for the three compounds, as judged by the coefficients of variation and relative errors observed. Linear standard curves were obtained in the concentration range of 5-2500 ng/ml for ABZSO enantiomers and 1-500 ng/ml for ABZSO2. A typical plasma concentration-time profile is presented for one patient under treatment for neurocysticercosis.

Determination of mitragynine in rat plasma by LC-MS/MS: application to pharmacokinetics.

This study used for the first time LC-MS/MS for the analysis of mitragynine (MIT), a mu-opioid agonist with antinociceptive and antitussive properties, in rat plasma. Mitragynine and the internal standard (amitriptyline) were extracted from plasma with hexane-isoamyl alcohol and resolved on a Lichrospher RP-SelectB column (9.80 and 12.90 min, respectively). The quantification limit was 0.2 ng/mL within a linear range of 0.2-1000 ng/mL. The method was applied to quantify mitragynine in plasma samples of rats (n=8 per sampling time) treated with a single oral dose of 20 mg/kg. The following pharmacokinetic parameters were obtained (mean): maximum plasma concentration: 424 ng/mL; time to reach maximum plasma concentration: 1.26 h; elimination half-life: 3.85 h, apparent total clearance: 6.35 L/h/kg, and apparent volume of distribution: 37.90 L/kg.

Enantioselective kinetic disposition of albendazole sulfoxide in patients with neurocysticercosis

The enantioselectivity of the kinetic disposition of albendazole sulfoxide (ASOX) was investigated in 18 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h). Serial blood samples were collected on the eighth day of treatment during the last dose interval, with prorogation up to 12 h. Albendazole sulfone (ASON) and enantiomers of ASOX were analyzed in plasma samples by HPLC using a Chiralpak AD column and detection by fluorescence. The pharmacokinetic parameters showing statistically significant differences between the (+) ASOX and (-) ASOX enantiomers are presented as respective means (95% CI) as follows: maximum plasma concentration, Cmax = 301.6 (179.7-423.5) vs 54.9 (21.9-87.9) ng.ml-1; elimination half-life, t1/2 = 5.2 (4.1-6.3) vs 3.3 (2.8-3.8) h, area under the plasma concentration-time curve, AUCss0-8 = 1719.2 (978.6-2459.8) vs 261.4 (102.9-419.8) ng.h.ml-1 and apparent clearance, Cl/fm = 5.8 (3.8-7.8) vs 54.0 (35.2-72.7) l.h-1.kg-1. The mean value of 9.2 (7.6-10.9) for the AUC0-8(+)-ASOX/AUC0-8(-)-ASOX ratio demonstrated plasma accumulation of the (+) enantiomer. Sulfone formation capacity, expressed by the AUCss0-8 ratio ASON/ASOX + ASON, was 8.0 (7.0-8.9). The present data indicate enantioselectivity in the kinetic disposition of ASOX in patients with neurocysticercosis.

Therapy for neurocysticercosis: pharmacokinetic interaction of albendazole sulfoxide with dexamethasone.

Albendazole is considered the drug of choice for neurocysticercosis. It is frequently used in combination with dexamethasone to prevent the acute inflammatory reaction due to cysticercal death. It has been reported that dexamethasone increases the plasma level of albendazole sulfoxide, the active metabolite of albendazole. The pharmacokinetic interaction of albendazole sulfoxide with dexamethasone, associated or not with cimetidine, was investigated in 24 patients with active intraparenchymal brain cysticercosis. Eight of these patients received albendazole alone, eight received it in combination with dexamethasone, and eight received it in combination with both dexamethasone and cimetidine. The pharmacokinetic parameters maximum plasma concentration, time to maximum plasma concentration, absorption half-life, and absorption rate constant did not differ between groups, suggesting that the formation of albendazole sulfoxide was not altered by the administration of dexamethasone, combined or not with cimetidine. There were significant differences, however, in the parameters plasma concentration-time curve, oral clearance, elimination half-life, and elimination rate constant, suggesting that dexamethasone, combined or not with cimetidine, decreases the rate of elimination of albendazole sulfoxide.

Ethanol Consumption Enhances Endothelin-1-Induced Contraction in the Isolated Rat Carotid

We investigated the mechanisms involved in the enhancement of endothelin (ET)-1 vascular reactivity induced by ethanol consumption. Ethanol intake for 2, 6, and 10 weeks enhanced the ET-1-induced contractile response of endothelium-intact but not endothelium-denuded rat carotid rings independently of the treatment duration. Conversely, phenylephrine-induced contraction was not affected by ethanol intake. The contraction induced by IRL1620 [succinyl-(Glu9,Ala11,15)-ET-1-(8-21)], a selective ETB agonist, was increased after treatment with ethanol in endothelium-intact but not in endothelium-denuded carotid rings. Moreover, ET-1- and IRL1620-induced relaxation was reduced in endothelium-intact phenylephrine-precontracted rings from ethanol-treated rats. Acetylcholine-induced relaxation was not affected by ethanol treatment. NG-Nitro-l-arginine methyl ester, 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one, indomethacin, and tetraethylammonium reduced the relaxation induced by IRL1620 in carotid glands from control but not ethanol-treated rats. The mRNA levels for ETA and ETB receptors were not altered by ethanol consumption. However, ethanol treatment reduced the protein expression of ETB receptors. Furthermore, immunohistochemical assays showed reduced immunostaining for endothelial ETB receptors after treatment with ethanol. We conclude that ethanol consumption enhances ET-1-induced contraction in the rat carotid and that this response is not different among the three periods of treatment used in this study. Finally, the potentiation of ET-1-induced vascular reactivity is probably caused by reduced expression of relaxing endothelial ETB receptors.

HPLC screening and GC-MS confirmation of triazine herbicides residues in drinking water from sugar cane area in Brazil

The extensive use of chlorotriazines as selectiveherbicides in agriculture and their relatively highpersistence imply that these compounds are now presentin the environment, contaminating surface and groundwater. In European countries, United States andCanada, the drinking water ordinance demands a limitedconcentration of 0.5 μg L-1 for the sum of allpesticides and 0.1 μg L-1 with respect to eachcompound, implying on the necessity of sensitive andselective analytical methods. In the present study wedescribe two methods for the analysis of atrazine,simazine and ametryn residues in surface and groundwater collected from the Espraiado Stream watershed,Ribeirão Preto region, SP, Brazil. The HPLC methodused for sample screening was based on herbicideextraction with dichloromethane:isopropanol (9:1, v/v)followed by reversed-phase chromatography (RP-8) withdetection at 220 nm. The presence of herbicides wasconfirmed by GC-MS after ethyl acetate extraction. Atotal of 250 samples collected at different sites fromOctober 1995 to July 1996 were analyzed. Ametrynresidues were detected in 17 samples but almost alwaysat concentrations below those maximum levels recommended by international agencies of environmental control.

Simultaneous HPLC analysis of tricyclic antidepressants and metabolites in plasma samples

A sensitive, selective and rapid reverse-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of imipramine, desipramine, amitriptyline and nortriptyline in human plasma. The procedure consisted of extracting the drugs and the internal standard (clomipramine) from 1 ml plasma with hexane:isoamyl alcohol (99:1, v/v) in alkaline medium. A newly marketed column, LiChrospher 60 RP-select B (dp 5 microns) of Merck was employed. The mobile phase, consisting of acetonitrile/0.25 N sodium acetate buffer at pH 5.5 (50:50, v/v), was delivered at a flow rate of 1.0 ml/min, and detection at 254 nm. The precision, linearity and limit of quantification of the method were within acceptable limits. The method was considered adequate and has, therefore, been used in routine analysis for the therapeutic control of depressed patients.

Enantioselective analysis of praziquantel and trans-4-hydroxypraziquantel in human plasma by chiral LC-MS/MS: application to pharmacokinetics.

A simple enantioselective method for the determination of praziquantel (PZQ) and trans-4-hydroxypraziquantel (4-OHPZQ) in human plasma was developed and validated by high-performance liquid chromatography/mass spectrometry. The plasma samples were prepared by liquid-liquid extraction using a mixture of methyl-tert-butylether/dichloromethane (2:1, v/v) as extraction solvent. The direct resolution of PZQ and 4-OHPZQ enantiomers was performed on a Chiralpak AD column using hexane-isopropanol (75:25, v/v) as the mobile phase. Diazepam was used as internal standard. The method described here is simple and reproducible. The quantitation limit of 1.25ng/ml for each PZQ enantiomer and of 12.5ng/ml for each 4-OHPZQ enantiomer permits the use of the method in studies investigating the kinetic disposition of a single dose of 1.5g racemic PZQ. Enantioselectivity in the kinetic disposition of PZQ and 4-OHPZQ was observed in the clinical study, with the demonstration of a higher proportion of the (+)-(S)-PZQ and (-)-(R)-4-OHPZQ enantiomers in plasma.