UGT2B7_-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study.

Lamotrigine (LTG) is metabolized by UGT1A4 but UGT2B7 also contributes to its glucuronidation. The aim of this study was to determine whether UGT2B7_- 161C>T and UGT2B7_372A>G polymorphisms contribute to the intersubject variability in LTG concentration-to-dose ratio (LTG-CDR) in epileptic patients. Fifty-three white epileptic patients attending the Neuropediatric and Neurology Services at the Marqués de Valdecilla University Hospital, in whom LTG serum concentration was to be measured for pharmacokinetic monitoring, were selected according to predefined criteria for LTG-CDR evaluation.

Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy.

Epilepsy drug-resistance may depend on the metabolism of antiepileptic drugs (AEDs), transport to the epileptic focus and/or target sensitivity. Furthermore, drug response depends on multiple characteristics of the patient, the epilepsy, and the antiepileptic drugs used. We have investigated the association between polymorphisms related to antiepileptic drug metabolism (CYP2C9, CYP2C19, and UGT), transport (ABCB1), and targets (SCN1A) both in a crude analysis and after adjusting by clinical factors associated with drug-resistance, and stratifying by patient age or aetiology of epilepsy.

[P-glycoprotein and human immunodeficiency virus infection].

P-glycoprotein (PGP) is a membrane protein and product of the MDR-1 gene, which acts as an efflux pump for several drugs, such as protease inhibitors (PI) used in HIV. Numerous studies in vitro, in experimental animals, and in patients have analyzed the relationships between PGP and the pharmacokinetic and pharmacodynamic properties of antiretroviral agents, with differing conclusions. In addition, studies focusing on the impact of single nucleotide polymorphisms in the MDR-1 gene, mainly C3435T in exon 26 and G2677A/G2677T in exon 21, on antiretroviral plasma concentrations, efficacy and adverse effects, have reported varying results, which have been attributed to the influence of other polymorphisms, such as cytochrome P450.

Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics.

Objective: It has been suggested that sustained-release valproate (VPA) formulations may be more effective and better tolerated than conventional VPA due to better compliance and lower fluctuations in VPA serum concentrations, but comparative trials with conventional VPA in children are scarce. This randomized and crossover trial compared the efficacy (complete control of seizures), the tolerability, and the patient (or parents) preference of conventional VPA twice daily (CVbid) with those of sustained-release chrono VPA twice daily (ChVbid), once daily in the morning (ChVom) or once daily in the evening (ChVoe) in monotherapy.

Methods: The study was carried out in 48 children (29 girls), aged 5-14 years, with newly diagnosed partial epilepsy (n=26), or idiopathic generalized epilepsy (n=22).

10-Hydroxycarbazepine serum concentration-to-oxcarbazepine dose ratio: influence of age and concomitant antiepileptic drugs.

This study was done to evaluate the association between patient age and the concomitant use of enzyme-inducing antiepileptic drugs (AEDs) and oxcarbazepine (OXC) concentration-to-dose ratio (CDR) by a multivariate analysis. The influence of patient age and concomitant AEDs on the trough steady-state serum concentration of 10-hydroxycarbazepine (OHC) normalized to 1 mg/kg body weight of OXC or concentration-to-dose ratio (OHC-OXC-CDR) was assessed by analysis of covariance. Samples were collected from 106 patients (90% outpatients), aged 1-80, who were receiving OXC either alone (n = 41) or in combination with other AEDs (n = 65).

Beneficial interaction between vigabatrin and valproate against seizures induced by pentylenetetrazole in mice.

The anticonvulsant effects of adding a non-protective dose of vigabatrin (VGB) to increasing single doses of sodium valproate (VPA) against seizures induced by 110 mgkg(-1) of pentylenetetrazole (PTZ) or by 4.5 mgkg(-1) of picrotoxin (PIC) were compared in CD1 mice with those of VPA alone and vice versa. Neurotoxicity was evaluated by the rotarod test.

Association between patient age and gabapentin serum concentration-to-dose ratio: a preliminary multivariate analysis.

Objectives: To evaluate the association between patient age and gabapentin (GBP) concentration-to-dose ratio by a multivariate analysis.

Methods: The association between patient age and the trough steady-state serum concentration of gabapentin (GBP) normalized to 1 mg/kg body weight or concentration-to-dose ratio (CDR) was retrospectively assessed by analysis of covariance. Potential confounding factors considered were GBP dosage, the number of GBP doses per day, and the presence of concomitant antiepileptic drugs (AEDs).

Topiramate serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and monitoring implications.

The influence of age and concomitant antiepileptic drugs (AEDs) on the trough steady-state serum concentration of topiramate, normalized to 1 mg/kg body weight or concentration-to-dose ratio (TPM-CDR), was assessed using multivariate methods in samples from 94 epileptic patients (38 under 11 years and 56 over 11 years of age), most of whom were outpatients receiving either just TPM (n = 20) or TPM in combination with other AEDs (n = 74). Analysis of the covariance showed that the age of the patients was influential (P < 0.001) and also showed a difference in TPM-CDR between the non-inducers group (TPM or TPM + lamotrigine or valproate) and the inducers group (TPM + carbamazepine, phenobarbital, or phenytoin) (P < 0.

Is the interaction between felbamate and valproate against seizures induced by 4-aminopyridine and pentylenetetrazole in mice beneficial?

We compared the effects of adding a non-protective dose of valproate (VPA) to increasing single doses of felbamate (FBM) with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by 14 mg kg(-1) of 4-aminopyridine (4-AP) and by 110 mg kg(-1) of pentylenetetrazole (PTZ), and neurotoxicity by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate in the whole brain.

Pharmacokinetics of an ultralong sustained-release theophylline formulation when given twice daily in elderly patients with chronic obstructive pulmonary disease: monitoring implications.

The steady-state pharmacokinetics of an ultralong sustained release formulation of theophylline (Unilong) twice daily (bid) in elderly hospitalized patients suffering from chronic obstructive pulmonary disease (COPD) have been studied in order to establish guidelines for monitoring. The study was carried out in 37 patients (33 men), aged 60-87 years. Samples were collected from 0 to 12 h after the morning dose on day 9 of treatment with 250 mg bid (n=25) or 375 mg bid (n=12).

Synergistic interaction between felbamate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice.

We compared the effects of adding a nonprotective dose of felbamate to increasing single doses of lamotrigine with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by both 14 mg/kg of 4-aminopyridine and 110 mg/kg of pentylenetetrazole, and neurotoxic effects were evaluated by the rotarod test. Changes in anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate concentrations in the whole brain were also assessed.

Synergistic interaction between valproate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice.

We compared the effects of adding a non-protective dose of valproate to increasing doses of lamotrigine with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by both 4-aminopyridine and pentylenetetrazole, and neurotoxic effects were evaluated by the rotarod test. Changes in anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate concentrations in the whole brain were also assessed.

Factors influencing cyclosporine blood concentration-dose ratio.

Objective: To analyze the trough cyclosporine concentration-dose ratio (CDR) and its relationship to some commonly available factors such as cyclosporine dosage, patient age, grade of obesity, posttransplant days, serum creatinine, serum bilirubin, and serum cholesterol by multiple linear regression.

Methods: The study was performed on 866 samples from 90 transplant recipients (25 kidney, 25 heart, 17 bone marrow, 13 liver, 10 simultaneous pancreas-kidney).

Results: The results show differences between transplants both in cyclosporine CDR variability (expressed by the coefficients of variation) and in the capability of those factors to explain this variability (expressed by the coefficient of determination).