PubMed Health⌕ Search

Biomedical subjects

M Bialer

Publications and source records attributed to M Bialer.

At least 55 records · Page 3Linked to original sources
PubMed1997

Prenatal diagnosis of pseudothalidomide syndrome in consecutive pregnancies of a consanguineous couple.

Pseudothalidomide syndrome is a rare autosomal recessive condition characterized by tetraphocomelia, craniofacial abnormalities and postnatal growth restriction. We report the prenatal sonographic findings of pseudothalidomide syndrome in three consecutive pregnancies of a consanguineous couple. In the last pregnancy, the correct diagnosis was made sonographically at 11 weeks of pregnancy. The combination of transabdominal and transvaginal ultrasound examinations revealed a large cystic hygroma extending over the lower back. The lower extremities were markedly shortened with no identifiable bones below the level of the femora. The humeri on both sides were shortened; ulnae were small with no identifiable radii. The pregnancy was terminated by dilatation and curettage and diagnosis confirmed at 12 weeks of pregnancy. In conclusion, fetuses with pseudothalidomide syndrome may exhibit characteristic findings in the first trimester of pregnancy which can be detected using ultrasound.

Abnormalities, Multiple↗
PubMed1996

Pharmacokinetic and pharmacodynamic analysis of (E)-2-ene valproyl derivatives of glycine and valproyl derivatives of nipecotic acid.

GABA is a major inhibitory neurotransmitter in mammals, whose uptake in glial cells is inhibited by nipecotic acid. In addition to GABA, glycine is an important inhibitory neurotransmitter. Valproic acid (VPA) is one of the four established antiepileptics and (E)-2-ene valproic acid ((E)-2-ene VPA) is its major active metabolite. The described structure-pharmacokinetic-pharmacodynamic relationship (SPPR) study explored the possibility of utilizing valproyl derivatives of glycine and nipecotic acid as new antiepileptics. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following conjugation products were investigated: (E)-2-ene valproyl glycinamide (between (E)-2-ene VPA and glycinamide) and valproyl nipecotic acid and valproyl nipecotamide (between VPA and nipecotic acid). Out of the investigated compounds only (E)-2-ene valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic and pharmacodynamic profile. (E)-2-ene valproyl glycinamide was more potent than VPA and showed an activity and a safety margin similar to those of its analogous compound valproyl glycinamide. The investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDSs) of glycine or nipecotic acid, but, rather, acted as drugs on their own. (E)-2-ene valproyl glycinamide was partially excreted unchanged in the urine (fe = 7.4%), while its urinary metabolite was (E)-2-ene valproyl glycine. Unlike the new antiepileptic tiagabine, in which nipecotic acid is attached to 4, 4-di-(3-methylthien-2-yl)-3-butenyl and yields an active compound, the conjugation between nipecotic acid or its amide and VPA yielded inactive entities. In contrast to nipecotic acid, the conjugation between VPA or (E)-2-ene VPA and glycinamide gave two active compounds with similar pharmacokinetic and pharmacodynamic profiles.

Animals↗
PubMed1996

Progress report on new antiepileptic drugs: a summary of the Third Eilat Conference.

The Third Eilat Conference on New Antiepileptic Drugs was held at the Royal Beach Hotel from May 27 to May 30, 1996. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss critical issues in drug development, new antiepileptic drugs (AEDs) in development, progress reports and recent findings of newly marketed AEDs, the use of AEDs in special populations and their utilization in non-epileptic disorders. Over the last seven years, six new AEDs have been introduced worldwide and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate and vigabatrin. Drugs in development include those at an advanced stage, such as remacemide and tiagabine, as well as those just entering clinical trials, such as rufinamide (CGP 331010) and levetiracetam (ucb LO59). The following is a summary of the presentations for drugs in development and recent findings on newly marketed drugs.

Acetamides↗
PubMed1996

Pharmacokinetic analysis and antiepileptic activity of tetra-methylcyclopropane analogues of valpromide.

PURPOSE: The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetramethylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. METHODS: The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). RESULTS: The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their nonactive acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. CONCLUSIONS: In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the beta position to the carbonyl, such as in the case of TMCD, or a substitution in the alpha and in the beta positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.

Animals↗
PubMed1996

The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine.

Following the introduction of felbamate, gabapentin, lamotrigine, oxcarbazepine and vigabatrin in the early 1990s, other new antiepileptic drugs have been advancing in clinical development. Those most extensively evaluated to date include topiramate, zonisamide and tiagabine. Topiramate, licensed recently in the UK, acts multifactorially through the blockade of sodium channels and kainate/AMPA receptors, enhancement of gamma-aminobutyric acid (GABA)ergic transmission and inhibition of carbonic anhydrase. It is well absorbed from the gastrointestinal tract and negligibly bound to plasma proteins. When used as a monotherapy, topiramate is eliminated primarily in the urine in an unchanged form with a half-life of 20 to 30 hours; elimination is faster in patients receiving concurrent medication with enzyme-inducing anticonvulsants, in whom the extent of biotransformation becomes more prominent. Zonisamide, which has been commercially available in Japan for some years, also has a multifactorial mode of action, possibly involving the blockade of sodium channels, T-type calcium channels and inhibition of carbonic anhydrase. It is rapidly absorbed, 50% bound to plasma proteins and is eliminated predominantly by biotransformation; zonisamide has a half-life of 50 to 70 hours in monotherapy patients, or 25 to 35 hours in patients comedicated with enzyme-inducing anticonvulsants. Tiagabine, a nipecotic acid derivative which inhibits GABA reuptake, is rapidly and completely absorbed after oral intake. It is highly (96%) bound to plasma proteins and it is eliminated primarily by cytochrome P450 3A-mediated oxidation, with a half-life of about 7 hours in healthy volunteers. Tiagabine metabolism is also enhanced by concurrent medication with enzyme-inducing anticonvulsants, resulting in a need to use dosages larger than those required in monotherapy or valproic acid (sodium valproate)-treated patients. Additional investigational antiepileptic agents included in this article are rufinamide (CGP 33101), fosphenytoin, levetiracetam, losigamone, remacemide and stiripentol. All these drugs have undergone early characterisation with respect to pharmacokinetic features and interaction potential.

Anticonvulsants↗
PubMed1996

Disposition of valpromide, valproic acid, and valnoctamide in the brain, liver, plasma, and urine of rats.

Valpromide (VPD) and valnoctamide (VCD) are amide derivatives of valproic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent models, both VPD and VCD are more potent as anticonvulsants than VPA. However, in humans, VPD served as a prodrug to VPA, whereas VCD acts as a drug on its own, which is not biotransformed to its corresponding acid--valnoctic acid (VCA). The present study investigates the pharmacokinetics (PKs of VPD and VCD in rats by monitoring the levels of these two amide isomers in the brain, liver, plasma, and urine of rats. The disposition of VPD and VCD was analyzed in a comparative manner with that of VPA. The following PK parameters were obtained for VPD and VCD, respectively: clearance, 6.1 and 3 ml/min/kg; volume of distribution (Vss), 0.63 and 0.58 liter/kg; half-life (t1/2), 42 and 94 min; and mean residence time (MRT), 102 and 196 min. The clearance of VCD in rats was half of that of VPD, and their Vss was similar. Therefore, VCD, t1/2, and MRT were twice as long as those of VPD.PK analysis of VPD and VCD liver and brain levels gave similar major PK parameters to those obtained from the plasma data. VPD underwent hepatic biotransformation to VPA, which persisted in the liver and brain for a longer period than VPD. The fraction metabolized of VPD to VPA was 42%. The brain was not found to be a metabolic site of the VPD-VPA biotransformation. Unlike VPD, VCD did not undergo amid-acid biotransformation to its corresponding acid, but was eliminated by biotransformation to unidentified metabolites. In contrast to VPD and VCD that distributed about evenly between the plasma, liver, and brain, VPA showed different disposition patterns in the plasma, liver, and brain. VCD and VPD distribute better into the brain than VPA, a fact that may contribute to their better anticonvulsant activity.

Amides↗
PubMed1995

Clinical spectrum in homozygotes and compound heterozygotes inheriting cystic fibrosis mutation 3849 + 10kbC > T: significance for geneticists.

We describe patients inheriting cystic fibrosis (CF) mutation 3849 + 10kb > T as homozygotes or compound heterozygotes. Three unrelated homozygotes for this mutation were all pancreatic-sufficient and sweat test-negative or inconclusive. Among the compound heterozygotes, both pancreatic sufficiency and insufficiency, as well as positive and negative/inconclusive sweat test results are reported, expanding the range of clinical expression associated with inheritance of this mutation. 3849 + 10kbC > T is one of several CF mutations that can result in atypical or variant forms of CF. For geneticists, the diagnosis of variant CF has implications for recurrence risk and prognosis counseling of the families of affected individuals, and possibly for CF carrier screening in the general population.

Adolescent↗
PubMed1995

Pharmacokinetic analysis of diethylcarbonate prodrugs of ibuprofen and naproxen.

The pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and naproxen diethythylcarbonate (napdice), two new diethylcarbonate prodrugs of ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicity without adversely affecting their anti-inflammatory activity. In addition the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethylcarbonate esters were rapidly biotransformed to the parent compounds and no ibudice or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice and napdice, was 96% and 74%, respectively, and the rate of absorption was not significantly different from that obtained following oral dosing of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice, with both prodrugs undergoing rapid biotransformation to their parent compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibudice or napidice.

Animals↗
PubMed1995

Criteria to assess in vivo performance of sustained release products: application to diltiazem formulations.

The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zero to infinity), Cmax (peak plasma concentration), and tmax (time to reach Cmax), are suitable to determine the extent and rate of absorption of immediate-release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained-release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean arithmetic time), Cmax/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of Cmax), C(apical) (the arithmetic mean of the concentration within 25% of Cmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of the Css (steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC, Cmax, and tmax were utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respectively. The 90% confidence intervals (Cl) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% Cl over a mean Cmax ratio of 100% were 83-115% (SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 +/- 37% with a 90% Cl of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameter s. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC and Cmax ratio, the 90% Cls associated with the ratio of the proposed criteria, with the exception of C(apical), did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parameters Cmax and tmax for rate of absorption assessment, their utility in bioequivalence would require further examination.

Adult↗
PubMed1995

Progress report on new antiepileptic drugs. A summary of the Second Eilat Conference.

The Second Eilat Conference on New Antiepileptic Drugs was held at the King Solomon's Palace Hotel from October 31 to November 3, 1994. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss new trial designs, drug approval, early use of new antiepileptic drugs, and new drugs in development. Over the last six years, several novel antiepileptic drugs have been introduced worldwide, and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, and vigabatrin. Drugs in development include those at an advanced stage, such as topiramate and tiagabine, as well as those just entering clinical trials, such as remacemide and levetiracetam. The following is a summary of the presentations for drugs in development and newly marketed drugs. The meeting concluded with a presentation, 'Still Searching for the Magic Bullet'.

Anticonvulsants↗
PubMed1995

Pharmacokinetic analysis and antiepileptic activity of N-valproyl derivatives of GABA and glycine.

PURPOSE: To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach. METHODS: The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four conjugation products of valproic acid (VPA), glycine and GABA were investigated: valproyl glycine, valproyl glycinamide, valproyl GABA and valproyl gabamide. RESULTS: Only valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic profile. Valproyl glycinamide was more potent than one of the major antiepileptic agents--VPA and showed a better margin between activity and neurotoxicity. Valproyl glycine and valproyl GABA were partially excreted unchanged in the urine (fe = 50% and 34%, respectively), while the urinary metabolites of the amide derivatives were valproyl glycine and valproyl GABA. CONCLUSIONS: The four investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDS) of glycine or GABA, but acted rather as drugs on their own. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.

Animals↗
PubMed1994

Can we develop improved derivatives of valproic acid?

Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not undergo amide-acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.

Animals↗
PubMed1994

Pharmacokinetic analysis of two new sustained-release products of diltiazem designed for twice- and once-daily treatment.

The pharmacokinetics of two new sustained-release (SR) products of diltiazem, Dilapress 120 mg tablets and Dilapress 240 mg tablets, was analysed and characterized in three different studies, in comparison to the following diltiazem SR formulations: Cardizem Retard, Cardizem SR, and Cardizem CD. Dilapress 120, designated for twice-daily dosing, was found to be bioequivalent to Cardizem SR and to Cardizem Retard with mean (+/- SD) relative bioavailability values of 99 +/- 27% and 113 +/- 38%, respectively. Dilapress 240, designed for once-a-day treatment, was found to have a slower absorption rate than Cardizem SR and its extent of absorption was 56 +/- 19% relative to that of Cardizem SR. However, the bioavailability of Dilapress 240 relative to that of Cardizem CD was 118 +/- 46%, indicating that the bioavailability of Cardizem CD relative to that of Cardizem SR was only 54 +/- 29%. Diltiazem is partially available due to a saturable liver first-pass effect. A high dose of Cardizem SR may partially escape this first-pass effect and, thus, achieve a higher extent of absorption than a slower SR product. Consequently, SR products of diltiazem designed for once-daily treatment may not reach the saturation stage in the liver first-pass effect process that diltiazem is susceptible to. Consequently, a twice-daily SR product of diltiazem cannot serve as a reference for extent of absorption assessments of a once-daily SR product.

Absorption↗
PubMed1994

Pharmacokinetic profile of conjugated verrucarol urinary metabolites in dogs.

The pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg-1). The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32-60% for verrucaryl glucuronides and 32-47% for verrucaryl sulphates. These urinary conjugated metabolites were analysed quantitatively following their enzymatic hydrolysis. The half-life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half-life calculated from the plasma data of the parent compound.

Animals↗
PubMed1994

Prenatal evaluation and in utero platelet transfusion for thrombocytopenia absent radii syndrome.

A fetus with absent radii in both forearms was discovered on routine ultrasound examination performed at 18 weeks of pregnancy. No other significant abnormalities were found, and no signs of haemorrhage were detected. Serial ultrasound examinations revealed no evidence of fetal internal bleeding. At 37 weeks of pregnancy, a CBC obtained by cordocentesis under ultrasound guidance confirmed the diagnosis of thrombocytopenia absent radii (TAR) syndrome. Apheresis platelets were transfused into the umbilical vein to correct the thrombocytopenia and was followed by an uncomplicated delivery. No bleeding was encountered during the remainder of the baby's neonatal course. We conclude that TAR syndrome can be readily identified prenatally on sonogram, and if severe thrombocytopenia is confirmed by cordocentesis, platelets should be transfused to diminish the risk of serious internal bleeding during and immediately after delivery.

Adult↗
PubMed1994

Comparative pharmacokinetic and pharmacodynamic analysis of phthaloyl glycine derivatives with potential antiepileptic activity.

Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents--valproic acid and showed a better margin between activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds' pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers.

The effect of fluvoxamine on the pharmacokinetics of diazepam and metabolically derived N-desmethyl-diazepam was investigated in eight healthy volunteers. Each subject received a single oral dose of diazepam (10 mg) in a control session and on the fourth day of a 16-day treatment with fluvoxamine maleate (100 to 150 mg daily). Compared with the control session, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/ml, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (from 0.40 to 0.14 ml/min/kg; p < 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p < 0.01). Although peak plasma N-desmethyldiazepam levels were similar in the two sessions, the time required for the metabolite to reach a peak was longer during fluvoxamine intake than in the control session (206 versus 62 hours; p < 0.01). N-Desmethyldiazepam area under the plasma concentration-time curve values were also significantly increased during fluvoxamine treatment. These data suggest that fluvoxamine inhibits the biotransformation of diazepam and its active N-demethylated metabolite. The magnitude of this interaction is likely to have considerable clinical significance.

Adult↗