Dinora F. González-Esquivel

Interaction between Grapefruit Juice and Praziquantel in Humans

ABSTRACT After a single oral dose of praziquantel with 250 ml of grapefruit juice, the area under the concentration-time curve and the maximum concentration in plasma of praziquantel (Cmax) were significantly increased (Cmax for water treatment, 637.71 ± 128.5 ng/ml; and Cmax for grapefruit juice treatment, 1,037.65 ± 305.7 ng/ml, P < 0.05). No statistically significant differences were found in the time to maximum concentration of drug in plasma or elimination half-life.

Plasma Level Monitoring of Oxcarbazepine in Epileptic Patients

BACKGROUND Despite the wide use of oxcarbazepine (OXC) there is little data concerning the usefulness of plasma level monitoring with this drug in Mexican patients with epilepsy. The purpose of the present study was to determine whether OXC levels correlate with dose, age, weight, or drugs used concomitantly. METHODS Plasma levels of the antiepileptic drug OXC were evaluated in 214 patients with epilepsy. In each patient, plasma MHD (10-hydroxycarbazepine, the main metabolite of OXC) concentration was determined. Additionally, plasma protein binding was determined in 30 patients and affinity to red blood cells (RBCs) was evaluated in 50 patients. RESULTS Our results showed that the mean plasma level of MHD was 15.34 microg/mL, mean protein binding ranged between 30-40%, and the mean RBC concentration was 18.38 microg/mL. A relationship between dose/weight and plasma concentration was found (r = 0.5149, p <0.001). In addition, a linear relationship between plasma and RBC concentration was established (r = 0.8806, p <0.0001). CONCLUSIONS These results suggest that for OXC, routine RBC concentrations are not necessary to make drug adjustments.

In Vitro Effects of Albendazole Sulfoxide and Praziquantel against Taenia solium and Taenia crassiceps Cysts

ABSTRACT We investigated the minimum exposure times of prazicuantel (PZQ) and albendazole sulfoxide (ABZSO) required for their activities against Taenia cysts in vitro as well as the 50 and 99% effective concentrations. The results showed that although the effects of both drugs are time and concentration dependent, ABZSO acts much slower and is less potent than PZQ.

Role of Redox Status in Development of Glioblastoma

Glioblastoma multiforme (GBM) is a highly aggressive neoplasia, prognosis remains dismal, and current therapy is mostly palliative. There are no known risk factors associated with gliomagenesis; however, it is well established that chronic inflammation in brain tissue induces oxidative stress in astrocytes and microglia. High quantities of reactive species of oxygen into the cells can react with several macromolecules, including chromosomal and mitochondrial DNA, leading to damage and malfunction of DNA repair enzymes. These changes bring genetic instability and abnormal metabolic processes, favoring oxidative environment and increase rate of cell proliferation. In GBM, a high metabolic rate and increased basal levels of reactive oxygen species play an important role as chemical mediators in the regulation of signal transduction, protecting malignant cells from apoptosis, thus creating an immunosuppressive environment. New redox therapeutics could reduce oxidative stress preventing cellular damage and high mutation rate accompanied by chromosomal instability, reducing the immunosuppressive environment. In addition, therapies directed to modulate redox rate reduce resistance and moderate the high rate of cell proliferation, favoring apoptosis of tumoral cells. This review describes the redox status in GBM, and how this imbalance could promote gliomagenesis through genomic and mitochondrial DNA damage, inducing the pro-oxidant and proinflammatory environment involved in tumor cell proliferation, resistance, and immune escape. In addition, some therapeutic agents that modulate redox status and might be advantageous in therapy against GBM are described.

The distribution of 10-hydroxy carbazepine in blood compartments.

The distribution of 10-hydroxy carbazepine (MHD), the main metabolite of oxcarbazepine (OXC), was investigated in plasma and red cells. After the oral administration of 600mg of OXC to nine healthy volunteers, blood samples were withdrawn for the next 56h and packed red cells were separated from plasma by centrifugation. Also, in vitro studies of plasma binding of MHD were carried out by a dialysis technique. Results showed that the in vitro protein binding was low. The mean bound concentration ranged from 37 to 40%; however, an affinity of MHD to red corpuscles was found. These observations indicate that MHD red blood cell concentrations together with plasma measurements could be useful in cases of inefficacy or toxicity in order to make the appropriate drug adjustments.

Clinical pharmacokinetics of albendazole in children with neurocysticercosis.

The pharmacokinetics of albendazole sulphoxide, the main metabolite of albendazole, were studied in eight children with brain cysticercosis. Albendazole was given as a single oral dose of 15 mg per kg body weight (Zentel suspension; Smith Kline & Beecham, Philadelphia, PA). Blood samples were taken during 24 h and analyzed by high performance liquid chromatography. Plasma levels showed great interindividual variation. Maximum plasma levels for albendazole sulphoxide ranged from 0.2–1.0 μg/mL. A double peak was found in four children. The half-life for albendazole sulphoxide was from 2.3–8.3 hours and mean residence time values were from 5.1–13.6 hours. These values are shorter than those found in adults. The results suggest that when treating children with neurocysticercosis, albendazole should be administered three times a day rather than twice daily as is currently done in Mexico.

Single dose pharmacokinetics of HEPP, a new anticonvulsant in normal healthy volunteers.

The pharmacokinetics and the dose proportionality of a new anticonvulsant compound, HEPP (D,L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropionamide) was studied in healthy male volunteers as part of the pharmacological evaluation for new drugs. Study was performed administering doses of 250, 375, 500 and 625 mg of HEPP to six male volunteers. Blood and urine samples were collected for 72 h postdose and analysed by HPLC. Results showed that in man HEPP is rapidly absorbed from the gastrointestinal tract. Tmax values were between 1.5 and 6.0 h. Plasma mean terminal half‐life after the different doses ranged between 15.83 and 27.62 h with an overall harmonic mean value of 22.8. The mean AUC0–∞ and Cmax increased linearly with doses of 250, 375 and 500 mg but not with the dose of 625 mg. The amount of unchanged drug excreted in urine was between 3 and 6% of administered dose which shows an extensive metabolism of the drug.

Plasma levels of clozapine and norclozapine in Mexican schizophrenia patients.

The aim of the present study was to determine the prescribing practice for clozapine (CAS 5786-21-0) as well as the plasma levels of clozapine and its main metabolite norclozapine (CAS 6104-71-8) in Mexican patients. A prospective study was performed in 69 in and out psychotic patients taking clozapine. Blood samples were taken at steady state. Plasma concentrations of clozapine and norclozapine were determined by HPLC. The results showed that the mean daily dose administered was 250 mg/d. Plasma levels showed a large interindividual variability. Mean plasma levels were 411.3 +/- 328.12 ng/mL, for clozapine and 172.0 +/- 129.9 ng/mL for norclozapine. When data were compared with those reported in other populations, it was found that although the dose was lower than that reported in Caucasians, the plasma levels were similar. As a result, the predictive models for the estimation of clozapine concentration in Caucasians were not appropriate for application in Mexican patients. The findings suggest ethnic differences in the ratio dose/plasma levels of clozapine in Mexican patients. Further studies are required to expand the observations.

Comparison of a high‐performance liquid chromatography method for quantification of carbamazepine with chemiluminescent microparticle immunoassay

Carbamazepine is an antiepileptic drug widely used for the treatment of epilepsy. In the National Institute of Neurology, monitoring has been performed using the technique chemiluminescent microparticle immunoassay (CMIA) in an automated way during the last five years. The aim of this study was to develop a simple and rapid HPLC analytical method coupled to DAD-UV detection for the determination of plasma concentrations of carbamazepine and compare its feasibility with those used in routine analysis. The developed HPLC method was fully validated and the applicability of the proposed method was verified through the analysis of plasma samples of patients and later compared with the quantification of the same plasma samples with the CMIA method. The limit of quantification obtained was 0.5 μg/mL. The mean value for recovery was 99.05% and the coefficient of variation (CV) was 5.6%. The precision and accuracy of this method were within the acceptable limits; inter- and intraday CV values were <10%. The correlation between the CMIA method and the developed HPLC method was very good (r ≈ 0.999). A Bland-Altman plot showed no significant bias between the results. The HPLC-DAD method may be an alternative to determine and monitoring the carbamazepine levels in human plasma or serum. Copyright

3-Hydroxykynurenine and 3-Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture

Copper is an integral component of various enzymes, necessary for mitochondrial respiration and other biological functions. Excess copper is related with neurodegenerative diseases as Alzheimer and is able to modify cellular redox environment, influencing its functions, signaling, and catabolic pathways. Tryptophan degradation through kynurenine pathway produces some metabolites with redox properties as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HANA). The imbalance in their production is related with some neuropathologies, where the common factors are oxidative stress, inflammation, and cell death. This study evaluated the effect of these kynurenines on the copper toxicity in astrocyte cultures. It assessed the CuSO4 effect, alone and in combination with 3-HK or 3-HANA on MTT reduction, ROS production, mitochondrial membrane potential (MMP), GHS levels, and cell viability in primary cultured astrocytes. Also, the chelating copper effect of 3-HK and 3-HANA was evaluated. The results showed that CuSO4 decreased MTT reduction, MMP, and GSH levels while ROS production and cell death are increasing. Coincubation with 3-HK and 3-HANA enhances the toxic effect of copper in all the markers tested except in ROS production, which was abolished by these kynurenines. Data suggest that 3-HK and 3-HANA increased copper toxicity in an independent manner to ROS production.