Biomedical subjects

Meir Bialer

Publications and source records attributed to Meir Bialer.

44 records · Page 3Linked to original sources

PubMed2003

Analysis of topiramate and its metabolites in plasma and urine of healthy subjects and patients with epilepsy by use of a novel liquid chromatography-mass spectrometry assay.

A novel liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for quantification of topiramate (TPM) and its metabolites 10-hydroxy topiramate (10-OH-TPM), 9-hydroxy topiramate (9-OH-TPM), and 4,5-O-desisopropylidene topiramate (4,5-diol-TPM) in plasma and urine. The method uses 0.5 mL of plasma or 1 mL of urine that is extracted with diethyl ether and analyzed by LC-MS. Positive ion mode detection enables tandem mass spectrometric (MS/MS) identification of the aforementioned four compounds. Calibration curves of TPM, 4,5-diol-TPM, 9-OH-TPM, and 10-OH-TPM in plasma and urine were prepared and validated over the concentration range of 0.625 to 40 microg/mL using TPM-d(12) as an internal standard. Calibration curves were linear over this concentration range for TPM and its metabolites. Accuracy and precision ranged in urine from 83% to 114% and 4% to 13% (%CV), respectively, and in plasma from 82% to 108% and 6% to 13%, respectively. The applicability of the assay was evaluated by analyzing plasma samples from a healthy subject who received a single oral dose of TPM (200 mg) and urine samples from 11 patients with epilepsy treated with TPM (daily dose between 100 to 600 mg) alone or with other antiepileptic drugs. Only TPM was detected and quantified in the plasma samples, and its concentration ranged between 0.7 and 4.3 microg/mL. The concentrations of TPM and 10-OH TPM were quantifiable in all urine samples and ranged from 20 to 300 microg/mL for TPM and from 1 to 50 microg/mL for 10-OH-TPM. The metabolites 4,5-diol-TPM and 9-OH-TPM were also detected in all urine samples, but their concentrations were quantifiable only in 4 patients. An unidentified peak in the chromatograms obtained from patients' urine was attributed to 2,3-O-desisopropylidene topiramate (2,3-diol-TPM). Due to a lack of reference material of 2,3-diol TPM and the similar MS/MS spectrum with 4,5-diol-TPM, the calibration curves of 4,5-diol-TPM were used for the quantification of its isomer 2,3-diol-TPM. Based on these determinations, the apparent 2,3-diol-TPM-to-TPM concentration ratio in patients' urine ranged from 0.05 to 0.51 and the 10-OH-TPM-to-TPM ratio ranged from 0.02 to 0.17. In conclusion, a novel LC-MS method for the assay of TPM and four of its metabolites in plasma and urine was developed. Its utilization for analysis of urine samples from patients with epilepsy showed that the method was suitable for analysis of TPM and its metabolites in clinical samples. Two quantitatively significant TPM metabolites (10-OH-TPM and 2,3-diol-TPM) and two quantitatively minor metabolites (9-OH-TPM and 4,5-diol-TPM) were detected and quantified in urine samples from patients with epilepsy.

Adult↗

PubMed2003

Therapeutic drug monitoring of the newer antiepileptic drugs.

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.

Anticonvulsants↗

PubMed2003

New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet?

PURPOSE OF REVIEW: Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar disorders. The use of VPA is limited by its two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity, and it is the least potent of the established AEDs. Consequently, there is an incentive to develop a second-generation VPA. A successful, second-generation VPA would need to possess the following characteristics: broad-spectrum antiepileptic activity; better potency than VPA; and lack of teratogenicity and hepatotoxicity. These characteristics would give such a drug the potential to be utilized in epilepsy and other CNS disorders. RECENT FINDINGS: Intensive research has been carried out in order to develop a second-generation VPA that would be more potent and safer than VPA. Amide derivatives of VPA have shown particular value as potential follow-up compounds and have better in-vivo performance than VPA. Several CNS-active valproylamides are more potent as antiepileptics than VPA, they possess broad-spectrum antiepileptic activity, and have been found to be nonteratogenic in animal models. The amide analogues of VPA that emerged from structure-pharmacokinetic-pharmacodynamic relationship studies as promising second-generation compounds are: N-methyl-tetramethylcyclopropane carboxamide, (2S,3S)-valnoctamide, (R)-propylisopropyl acetamide and valproyl glycinamide. SUMMARY: At present there are three compounds in clinical trials in patients with epilepsy that can be regarded as second-generation VPA: valproyl glycinamide, 3-methylbutanamide or isovaleramide and SPD421 (DP-VPA). For any one of these second-generation valproic acids to become a successful follow-up compound to VPA, it has to fulfil the above criteria and also possess favorable pharmacokinetics.

Amides↗

PubMed2002

Anticonvulsant profile and teratogenicity of N-methyl-tetramethylcyclopropyl carboxamide: a new antiepileptic drug.

PURPOSE: The studies presented here represent our efforts to investigate the anticonvulsant activity of N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity. METHODS: The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague-Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acid-induced neural tube defects. RESULTS: In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES- and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice. CONCLUSIONS: The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential.

Acoustic Stimulation↗

PubMed2002

Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients.

PURPOSE: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment. METHODS: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations. RESULTS: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (+/-SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 +/- 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 microM (11% inhibition) and 900 microM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy CONCLUSIONS: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT.

Adolescent↗

PubMed2002

New antiepileptic drugs currently in clinical trials: is there a strategy in their development?

In designing and developing antiepileptic drugs (AEDs), attention should be paid to the desirable pharmacokinetic properties of potential new agents so that molecules are designed to achieve the desired pharmacodynamic and pharmacokinetic profiles. A review of current compounds in development or in clinical trials shows that several promising agents have incorporated pharmacokinetic-based design into their development process. This is particularly true for new AEDs that are second-generation or follow-up compounds of existing AEDs.

Anticonvulsants↗

PubMed2002

Pros and cons for the development of new antiepileptic drugs.

There continues to be an escalation in the number of new antiepileptic drugs, with many recently marketed drugs and many more entering clinical trials. This growth begs the question as to whether we need additional antiepileptic drugs. We consider the answer to this question from the medical perspective and also from the viewpoint of the pharmaceutical industry, health providers and from a more global, international perspective. There is undoubtedly a medical need for new antiepileptic drugs, and despite growing competition, the antiepileptic drug market remains profitable. However, in health services with limited resources, it is important that this expense is not offset by failure to research more appropriate use of existing antiepileptic drugs that may have a greater impact on healthcare. This is especially true for developing countries where resources would be much better spent on prevention and closing the treatment gap (the difference between those who can be treated and those who are treated).

Anticonvulsants↗

PubMedDate not supplied

Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII).

The Seventh Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT VII) took place in Villasimius, Sardinia, Italy from the 9th to 13th May 2004. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference,whose main themes included advances in pathophysiology of drug resistance, new AEDs in pediatric epilepsy syndromes, modes of AED action and spectrum of adverse effects and a re-appraisal of comparative responses to AED combinations. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on second-generation AEDs. This article summarizes the information presented on drugs in development, including atipamezole, BIA-2-093, fluorofelbamate, NPS 1776, pregabalin, retigabine, safinamide, SPM 927, stiripentol, talampanel,ucb 34714 and valrocemide (TV 1901). Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine,topiramate, vigabatrin, zonisamide, new oral and parenteral formulations of valproic acid and SPM 927 and the antiepileptic vagal stimulator device are also presented.

Adult↗