Search

The study of genetic and metabolic etiologies of pediatric stroke, both vascular and metabolic, allows an understanding of the causes of acute focal neurologic deficits in childhood. Here, the mendelian and mitochondrial genetic causes of pediatric stroke syndromes are reviewed. This approach elucidates the etiology of childhood stroke and illustrates many of the genetic risk factors that are found in adult-onset cerebrovascular disease. Therefore, the study of childhood stroke serves as a model to elucidate the potential risk factors for all stroke. Ultimately this will serve to develop a more rational preventive and therapeutic approach for all cerebrovascular disease.

Purpose: The purpose of this study was to evaluate the in vitro inhibitory potency of various amide analogues and derivatives of valproic acid toward human microsomal epoxide hydrolase (mEH)., Methods: mEH inhibition was evaluated in human liver microsomes with 25 microM (S)-(+)-styrene oxide as the substrate. Inhibitory potency expressed as the median inhibitory concentration (IC50) was calculated from the formation rate of the enzymatic product, (S)-(+)-1-phenyl-1,2-ethanediol., Results: Inhibitory potency was directly correlated with lipophilicity and became significant for amides with a minimum of eight carbon atoms. Branched eight-carbon amides were more potent inhibitors than their straight chain isomer, octanamide. N-substituted valproylamide analogues had reduced or abolished inhibition potency with the exception of valproyl hydroxamic acid being a potent inhibitor. Inhibition potency was not stereoselective in two cases of chiral valpromide isomers. Valproyl glycinamide, a new antiepileptic drug currently undergoing phase II clinical trials and its major metabolite valproyl glycine were weak mEH inhibitors. Acid isomers of valproic acid were not potent mEH inhibitors., Conclusions: The structural requirements for valproylamide analogues for potent in vitro mEH inhibition are: an unsubstituted amide moiety; two saturated alkyl side chains; a minimum of eight carbons in the molecule.

Purpose: The purpose of this study was to evaluate there existed stereoselective effects in the pharmacokinetics, anticonvulsant activity, microsomal epoxide hydrolase (mEH) inhibition, and teratogenicity of the two enantiomers of propylisopropyl acetamide (PID), a CNS-active chiral amide analogue of valproic acid., Methods: Racemic PID, as well as the individual enantiomers, were intravenously administered to six dogs in order to investigate the stereoselectivity in their pharmacokinetics. Anticonvulsant activity was evaluated in mice (ip) and rats (oral), mEH inhibition studies were performed in human liver microsomes, and teratogenicity was evaluated in an inbred susceptible mice strain., Results: Following intravenous administration to dogs of the individual enantiomers, (R)-PID had significantly lower clearance and longer half-life than (S)-PID, however, the volumes of distribution were similar. In contrast, following intravenous administration of racemic PID, both enantiomers had similar pharmacokinetic parameters. In rats (oral), (R)-PID had a significantly lower ED50 in the maximal electroshock seizure test than (S)-PID; 16 and 25 mg/kg, respectively. PID enantiomers were non-teratogenic and did not demonstrate stereoselective mEH inhibition., Conclusions: (R)-PID demonstrated better anticonvulsant activity, lower clearance and a longer half-life compared to (S)-PID. When racemic PID was administered, the clearance of (S)-PID was significantly reduced, reflecting an enantiomer-enantiomer interaction.

Purpose: The purpose of this study was to evaluate the structure-pharmacokinetic-pharmacodynamic relationships of a series of N-alkyl and N,N-dialkyl derivatives of the new antiepileptic drug (AED), valproyl glycinamide (VGD)., Methods: The following compounds were synthesized: N-methyl VGD (M-VGD), N,N-dimethyl VGD, N-ethyl VGD, N,N-diethyl VGD (DE-VGD), and N,N-diisopropyl VGD. These compounds were evaluated for anticonvulsant activity, neurotoxicity, and pharmacokinetics., Results: After i.p. administration to mice in the maximal electroshock seizure test (MES), DE-VGD had an ED50 value comparable to that of VGD (145 and 152 mg/kg, respectively), whereas in the subcutaneous metrazol test (sc Met) model, M-VGD had a slightly lower ED50 than VGD (108 and 127 mg/kg, respectively). After oral administration to rats, M-VGD had an MES-ED50 similar to that of VGD (75 and 73 mg/kg, respectively). Of the N-alkyl VGD derivatives studied, M-VGD had the best pharmacokinetic profile: the lowest clearance (5.4 L/h), the longest half-life (1.8 h), and the lowest liver-extraction ratio (14%). N,N-dialkylated VGD derivatives underwent two consecutive N-dealkylations, whereas N-alkylated derivatives underwent a single N-dealkylation process, yielding VGD as a major active metabolite., Conclusions: M-VGD had the most favorable pharmacodynamic and pharmacokinetic profile of the investigated N-alkyl VGD derivatives. VGD was found to be a major active metabolite of M-VGD and to be less neurotoxic than M-VGD. Therefore VGD rather than one of the investigated N-alkyl VGD derivatives should be considered for development as a new AED.

The active entity of the new antiepileptic drug, oxcarbazepine (OXC), is 10-hydroxycarbazepine (MHD). In humans, OXC undergoes rapid presystemic (first-pass) metabolic reduction to MHD. MHD is a chiral molecule with an asymmetric carbon at position 10. Previous reports have shown that in humans, the first-pass metabolic reduction of OXC into MHD is stereoselective, resulting in a 1-to-4 AUC ratio of R(-) and S(+) enantiomers. The objective of the current study was to investigate whether the pharmacokinetics of MHD was stereoselective. Racemic MHD was thus administered intravenously (i.v.) and orally to six dogs, and plasma samples were analyzed by a stereospecific, high-performance liquid chromatographic (HPLC) assay. We found that R(-)-MHD had a clearance similar to that of S(+)-MHD; however, a difference was found between the volume of distribution (Vd) and consequently, between the half-lives of the two MHD enantiomers. The main pharmacokinetic parameters of R(-)- and S(+)-MHD were as follows: A terminal half-life (t1/2) of 2.2 +/- 0.4 hours for R(-)-MHD and of 3.8 +/- 0.3 hours for S(+)-MHD; a clearance (CL) of 7.8 +/- 1.3 L/h for R(-)-MHD and of 8.6 +/- 2.1 L/h for S(+)-MHD; a Vd of 25 +/- 6 L for R(-)-MHD and of 47 +/- 14 L for S(+)-MHD; and a Vd at steady state (V(ss)) of 22.8 +/- 3.6 for R(-)-MHD and of 29.9 +/- 4.1 for S(+)-MHD. After its oral administration to dogs, the absolute bioavailability was 78.4 +/- 20.9% for R(-)-MHD and 78.5 +/- 27.3% for S(+)-MHD; t1/2 was 2.7 +/- 0.6 hours for R(-)-MHD and 4.1 +/- 0.8 hours for S(+)-MHD. These results showed stereoselectivity in the volume of distribution and consequently, the t1/2 of S(+)-MHD was longer than that of R(-)-MHD after both i.v. and oral administration to dogs.

Purpose: The goal of this study was to develop a new method, based on robust pharmacokinetic (PK) parameters, for determining t(max) (time of peak plasma concentration) and the magnitude of difference between the absorption (k(a)) and elimination (k) rate constants in the one compartment body model with first order input and output., Methods: The function F(X) that describes the ratio of the AUC (area under the curve) from MRT (mean residence time) to infinity and the AUC from zero to MRT as a function of ratio between the first-order absorption and elimination constants (X) was derived and its limits were determined. Similarly, the function G(X) that describes the ratio between MRT and t(max) was derived and its limits were determined., Results: The functions F(X) and G(X) depend only on the ratio between k and k(a). Thus, the different values of the functions F(X) (a-values) and G(X) (b-values) were calculated as a function of the ratio k/k(a). A table with 1% increments of the relevant b-value for every a-value was derived. The appropriate t(max) was thus calculated from the quotient MRT and the relevant b-value. A useful application of the new method to a drug product with prolonged absorption and long half life was presented., Conclusions: A new method that allows the calculation of t(max) and the k/k(a) ratio and derivation of a simple criterion of the equality between k and k(a) has been developed. This method is applicable to the one compartment open body model with first order absorption and elimination and is not based on single point parameters but on robust pharmacokinetic parameters such as AUC and MRT.

Propylisopropyl acetamide (PID), an amide analogue of the major antiepileptic drug valproic acid (VPA), possesses favorable anticonvulsant and CNS properties. PID contains one chiral carbon atom and therefore exists in two enantiomeric forms. The purpose of this work was to synthesize the two PID enantiomers and evaluate their enantiospecific teratogenicity. Enantioselective synthesis of PID enantiomers was achieved by coupling valeroyl chloride with optically pure (4S)- and (4R)-benzyl-2-oxazolidinone chiral auxiliaries. The two oxazolidinone enolates were alkylated with isopropyl triflate, hydrolyzed, and amidated to yield (2R)- and (2S)-PID. These two PID enantiomers were obtained with excellent enantiomeric purity, exceeding 99.4%. Unlike VPA, both (2R)- and (2S)-PID failed to exert teratogenic effects in NMRI mice following a single 3 mmol/kg subcutaneous injection. From this study we can conclude that individual PID enantiomers do not demonstrate stereoselective teratogenicity in NMRI mice. Due to its better anticonvulsant activity than VPA and lack of teratogenicity, PID (in a stereospecific or racemic form) has the potential to become a new antiepileptic and CNS drug., (Copyright 1999 Wiley-Liss, Inc.)

Trisomy 16, once thought to result uniformly in early pregnancy loss, has been detected in chorionic villus samples (CVS) from on-going pregnancies and was initially ascribed to a second, nonviable pregnancy. Prenatally detected trisomy 16 in CVS and its resolution to disomy has led to the reexamination of the viability of trisomy 16. This study evaluates 11 cases of mosaic trisomy 16 detected through second trimester amniocentesis. In 9 of the 11 cases, amniocenteses were performed in women under the age of 35 because of abnormal levels of maternal serum alpha-fetoprotein (MSAFP) or maternal serum human chorionic gonadotropin (MShCG). The other two amniocenteses were performed for advanced maternal age. Five of the 11 pregnancies resulted in liveborn infants, and six pregnancies were electively terminated. The liveborn infants all had some combination of intrauterine growth retardation (IUGR), congenital heart defects (CHD), or minor anomalies. Two of them died neonatally because of complications of severe congenital heart defects. The three surviving children have variable growth retardation, developmental delay, congenital anomalies, and/or minor anomalies. In the terminated pregnancies, the four fetuses evaluated by ultrasound or autopsy demonstrated various congenital anomalies and/or IUGR. Cytogenetic and fluorescent in situ hybridization studies identified true mosaicism in 5 of 10 cases examined, although the abnormal cell line was never seen in more than 1% of cultured lymphocytes. Placental mosaicism was seen in all placentas examined and was associated with IUGR in four of seven cases. Maternal uniparental disomy was identified in three cases. Mosaic trisomy 16 detected through amniocentesis is not a benign finding but associated with a high risk of abnormal outcome, most commonly IUGR, CHD, developmental delay, and minor anomalies. The various outcomes may reflect the diversity of mechanisms involved in the resolution of this abnormality. As 80% of these patients were ascertained because of the presence of abnormal levels of MSAFP or MShCG, the increased use of maternal serum screening should bring more such cases to clinical attention.

We describe the clinical phenotype in four males from three families with duplication (X)(qter-->q27::p22.3-->qter). This is an unusual duplication of the distal long arm segment, Xq27-qter, onto the distal short arm of the X chromosome at Xp22.3, as shown by fluorescent in situ hybridization analysis with multiple X-specific probes. The patients are young male offspring of three unrelated, phenotypically normal carrier women. The affected males have similar clinical manifestations including severe growth retardation and developmental delay, severe axial hypotonia, and minor anomalies. Such clinical similarity in three unrelated families demonstrates that this chromosome abnormality results in a new and distinct clinical phenotype. Replication studies, performed on two of the mothers, provided evidence that inactivation of the abnormal X chromosome permitted the structural abnormality to persist in these families for a generation or more in females without phenotypic expression.

Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled-release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time-concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), t(apical), and C(apical) (the arithmetic mean of the POT times and concentrations within 25% of Cmax, respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve., Methods: These proposed parameters were used in two recent (single and multiple dose) two-way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab., Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time-concentration curves as assessed by visual inspection and the proposed parameters., Conclusions: The additional parameters examined may supplement the traditional single-point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption-rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

We report case of a subclavian artery pseudoaneurysm in a patient with type IV Ehlers-Danlos Syndrome. A 16-year-old boy underwent successful repair of a subclavian artery pseudoaneurysm that occurred after a cervical hyperextension injury. Subsequent workup included skin biopsy and fibroblast culture, which were consistent with a diagnosis of type IV Ehlers-Danlos Syndrome. This condition is a dominantly inherited connective tissue disorder, which in this patient was found to be caused by a spontaneous point mutation in the COL3A1 gene that encodes the chains of type III procollagen. The clinical, genetic, and molecular characteristics of type IV Ehlers-Danlos Syndrome are briefly reviewed.

Recently, there has been considerable discussion regarding the classification of drugs as a function of their therapeutic index, defined as the ratio between the upper and lower limits of the therapeutic range. Pharmacologic agents with a therapeutic index < 2 are classified as "narrow therapeutic index" (NTI) drugs. One of the agents classified as an NTI drug is carbamazepine. These recent developments led us to evaluate critically the evidence supporting the classification of carbamazepine as an NTI drug to address an old question: "Does carbamazepine have a narrow therapeutic plasma concentration range?"

Valproyl glycinamide (TV 1901-VPGD) is a new antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant activity and a safety margin in mice similar to those of VPGD. Following i.v. administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8 +/- 1.1 Lh-1 (mean +/- SD), a volume of distribution (Vss) of 15 +/- 2 L, and a half-life (t1/2) of 1.9 +/- 0.3 h. DIGD had Cl, Vss, and t1/2 values of 10 +/- 0.8 Lh-1, 19 +/- 3 L, and 1.6 +/- 0.2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized (fm): 59 +/- 5% (VCGD) and 62 +/- 15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values. Both VCGA and DIGA had higher Cl and lower Vss values than VCGD and DIGD and therefore their mean t1/2 values were 0.43 +/- 0.02 and 0.30 +/- 0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (fe) of 60 +/- 9 and 55 +/- 7%, respectively. The improved pharmacokinetic profile of VCGD and DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokinetic-pharmacodynamic relationship (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 improved pharmacokinetic profile.

Purpose: To investigate the disposition of valproyl glycinamide and valproyl glycine in rats and to compare it with that of valproic acid (VPA) and valpromide which were studied previously., Methods: The study was carried out by monitoring the brain and liver levels of valproyl glycinamide and valproyl glycine (as a function of time after iv dosing) in addition to the regular pharmacokinetic (PK) monitoring of plasma and urine levels of these compounds., Results: The following PK parameters were obtained for valproyl glycinamide and valproyl glycine, respectively: clearance, 7.1 and 16 ml/ min/kg; volume of distribution (Vss), 0.78 and 0.41 l/kg; half-life, 1.1 and 0.37 h; and mean residence time, 1.8 and 0.4 h. The ratios of AUCs of valproyl glycinamide of liver to plasma and brain to plasma were 0.70 and 0.66, respectively. The ratios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively., Conclusions: Valproyl glycinamide distributes better in the brain than VPA, a fact which may contribute to its better anticonvulsant activity. Valproyl glycine was barely distributed in the brain, a fact which may explain its lack of anticonvulsant activity. In addition to the liver, the brain was found to be a minor metabolic site of the biotransformation of valproyl glycinamide to valproyl glycine.

Objective: To investigate the pharmacokinetics of the four stereoisomers of valnoctamide, a mild tranquilizer endowed with anticonvulsant properties., Methods: Racemic valnoctamide, 400 mg, was administered orally to seven healthy subjects and to six patients with epilepsy stabilized with long-term carbamazepine therapy. In the patients with epilepsy, valnoctamide kinetics was also reassessed after 8-day oral dosing at a dosage of 600 mg daily. Plasma samples were assayed by gas chromatography-mass spectrometry with use of a capillary column coated with chiral stationary phase that enabled baseline resolution of the four stereoisomers, designated hereafter as A, B, C, and D (where A and C, together with B and D, represent enantiomeric pairs)., Results: In healthy subjects, stereoisomers A, C, and D showed similar kinetics, with an apparent oral clearance (CL/F) of about 4 1/2 L/hr, a half-life (t1/2) of about 10 hours, and an apparent volume of distribution (VSS/F) of about 65 L. However, stereoisomer B showed a much higher clearance (8.7 +/- 0.9 L/hr) and a shorter t1/2 (5.8 hours). For all stereoisomers, CL/F values in patients with epilepsy were about tenfold higher than those found in healthy subjects. Compared with healthy subjects, patients with epilepsy also showed shorter t1/2 values and higher VSS/F values for each of the stereoisomers. After 7-day dosing, CL/F values at steady state were lower than those determined in the same patients after a single dose., Conclusions: Valnoctamide exhibits enantioselectivity and diastereoselectivity, an observation that may have important practical implications if pharmacodynamic differences between stereoisomers are also found. The observed pharmacokinetic differences between healthy subjects and patients with epilepsy are likely to be related to induction of metabolism of valnoctamide stereoisomers by carbamazepine.

Purpose: To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics., Methods: The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives., Results: Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid-VPA-HA, N-(1-hydroxyethyl)-valpromide-HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(1-methoxyethyl) valpromide and N-(1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied., Conclusions: In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.

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.

The fragile X mutation is diagnosed from the structure of the FMR1 gene in blood cell DNA. An estimated 12 to 41% of affected males are mosaics who carry both a "full mutation" allele from which there is no gene expression and a "premutation" allele which has normal gene expression. We compared the DNA in blood cells and skin fibroblasts from four mosaic fragile X males to see if there was a difference in the relative amounts of premutation and full mutation alleles within the tissues of these individuals. Two of these males showed striking differences in the ratio of premutation to full mutation in different tissues while the other two showed only slight differences. These observations conform with the widely accepted hypothesis that the fragile X CGG repeat is unstable in somatic tissue during early embryogenesis. Accordingly, the mosaicism in brain and skin, which are both ectodermal in origin, may be similar to each other but different from blood which is not ectodermal in origin. Thus, the ratio of full mutation to premutation allele in skin fibroblasts might be a better indicator of psychological impairment than the ratio in blood cells.

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.

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.

Amniocytes isolated from two pregnancies at risk for fatty acid oxidation defects were incubated with stable isotopically labelled palmitate, in the presence of L-carnitine, to probe that pathway. The labelled acylcarnitines were then quantitated using tandem mass spectrometry. Amniocytes from a pregnancy at risk for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency produced a characteristic acylcarnitine profile with increased levels of octanoylcarnitine and decanoylcarnitine, indicative of MCAD deficiency. DNA analysis confirmed that the fetus was homozygous for the MCAD A985G mutation. Acylcarnitine and DNA analysis of the infant's blood obtained post-partum confirmed MCAD deficiency. Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect produced increased levels of long-chain acylcarnitines consistent with a deficiency in very-long-chain acyl-CoA dehydrogenase (VLCAD). Measurements of the enzymatic activity confirmed VLCAD deficiency in amniocytes. Acylcarnitine profiles of the infant's blood obtained post-partum in addition to enzyme activities measured in fibroblasts confirmed VLCAD deficiency. The successful prenatal diagnosis of VLCAD and MCAD deficiencies using in vitro probes of fatty acid oxidation in fibroblasts suggests that this approach can potentially recognize many mitochondrial fatty acid oxidation defects even if no prior diagnosis is determined in the family at risk.

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.

A new case with a de novo translocation involving the long arms of chromosomes Y and 9 i.e. 46, X, t(Y;9) (q11.2;q22) was noted in a phenotypically normal male as revealed by GTG technique and subsequently confirmed using dual color whole chromosome painting probes. Since the Yq11.2 region was involved in the translocation the fecundity status of the individual has been questioned. Previous cases with (Y;autosomal) translocations have produced males with azoospermia, a variety of male gamete deformities and idiopathic sterility. The azoospermic factor (AZF) on the distal Yq11 band, which apparently controls spermatogenesis, may have been adversely affected due to a microdeletion, rearrangement or complete loss as a result of the translocation mechanism. Testicular histological and fertility tests of the proband at a postpubescent age will reveal the status. The sex determining region (SRY) on the Yp, which has been equated with the testis determining factor (TDF), is believed to be intact. Dual color whole chromosome painting probes, which served as an important adjunct to GTG banding, increased the degree of certainty for the characterization of the involved translocation. A concise review of balanced (Y ; autosome) translocation cases are annotated here.

A 28-week fetus with hydrops and bilateral pleural effusions underwent drainage of both pleural spaces via a single-needle supradiaphragmatic insertion technique. The traditional approach was not feasible due to a persistently unfavorable fetal position. The dependent pleural effusion was drained by a needle which coursed through the nondependent pleural effusion. The needle traversed the midline pleura through an avascular plane. Thereafter the needle was withdrawn into nondependent pleural effusion which was drained. Both lungs expanded with favorable neonatal outcome.

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.

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.

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.

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.

The investigation of pathogenic mitochondrial DNA (mtDNA) mutations has revealed a complex relation between patient genotype and phenotype. For unknown reasons, some mtDNA mutations produce specific clinical manifestations such as chronic progressive external ophthalmoplegia; myoclonic epilepsy and ragged-red fiber disease (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). To enhance our understanding of the association between genotype and phenotype, we investigated a patient with mitochondrial encephalomyopathy and severe cerebral calcifications for a mtDNA mutation. There was a deletion of one of three T:A nucleotide pairs in the tRNALeu(UUR) gene of the mtDNA involving positions 3271 to 3273. Pedigree analysis suggested that this mutation may have occurred spontaneously in the proband. This analysis represents the smallest mtDNA deletion observed to date and is the first deletion identified within a mitochondrial tRNA. This observation emphasizes the importance of delineating the precise mutation responsible for an oxidative phosphorylation disease for patient diagnosis as well as for genetic counseling of maternal lineage relatives.

We report on a so-called rare variant where a G-positive band was sandwiched within the secondary constriction (qh) region of chromosome 9 and is apparently different from previous cases when characterized by the fluorescence in situ hybridization technique. The major differences included duplication of beta-satellite and satellite III DNA sequences and bands 9q13-->q21.1, without duplication or inversion of the alphoid sequences. Based on the reported cases, at least four types of variations can be accounted for. A variety of mechanisms have been proposed to describe the origin of a G-positive band within the 9qh region, which appears to be similar when studied by routine cytogenetic techniques but differs by molecular methods. It is hypothesized that the clinical consequences depend upon the size of the G-positive band(s) duplicated, and a genetic inactivation mechanism might have some sort of influence during the so-called heterochromatinization process. It appears that heterochromatin, once thought to be composed of junk DNA, may have some role after all in suppression of gene(s) and/or spreading of inactivation, if genes are embedded within the heterochromatic region. Apparently, the mixture of different types of DNA creating patches of genetic debris have become a fundamental hidden treasure, where genetically active chromatin could be inactivated without dire consequences. The variable nature of heterochromatin has resulted in cytogenetic heteromorphisms of a number of human chromosomes. Their characterization by molecular techniques is becoming imperative, because fetal wastage have occurred in many situations where variant chromosomes were wrongly identified as chromosomal abnormalities.

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.

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.

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)

Two phenotypically abnormal liveborns in whom trisomy 16 mosaicism was diagnosed prenatally by amniocentesis are described. Analysis of a percutaneous umbilical blood sample in one case revealed a normal chromosomal complement. Ultrasound examinations performed at the time of amniocentesis were normal. Serial sonography during the late second and third trimesters demonstrated progressive intrauterine growth retardation (IUGR) in both fetuses and a cardiac defect in one. At birth, both infants had dysmorphic features and multiple congenital anomalies. Trisomy 16 mosaicism was confirmed postnatally in both infants in skin fibroblasts; however, peripheral blood samples contained only chromosomally normal cells. The two mosaic trisomy 16 cases described in this report, together with the five confirmed cases reported previously, demonstrate the need for caution in the counselling of patients when trisomy 16 mosaicism is diagnosed prenatally in amniotic fluid samples. Such cases potentially can result in the birth of dysmorphic infants with significant birth defects, growth retardation, and possible developmental disabilities.

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.

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.

Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.

During the past few years a major increase has taken place in the number of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin, oxcarbazepine and lamotrigine, were recently approved in several European countries. Two other drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharmacokinetics of the following 10 new antiepileptic drugs: felbamate, flunarizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripentol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gabapentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted mainly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal. About 50% of felbamate is excreted unchanged, with the rest eliminated by metabolism. The remaining drugs are eliminated by metabolic processes such as glucuronidation (lamotrigine), deglycine formation (remacemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarbazepine and remacemide have high hepatic clearance and are biotransformed to hydroxy and deglycine metabolites, respectively, with the activity of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass effect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokinetically as their original design intended. Gabapentin is not effective as a chemical drug delivery system for gamma-aminobutyric acid (GABA), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, but does not act as a drug on its own. Nevertheless, these 2 agents demonstrate efficacy in extensive preclinical and clinical trials. Although the pharmacokinetics features of these drugs are important, these features are secondary to their pharmacodynamic properties--i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.

The pharmacokinetics of doxorubicin (DOX) encapsulated in liposomes containing polyethylene glycol-derivatized distearoylphosphatidylethanolamine (PEG/DSPE) were investigated in rodents and dogs. The plasma levels of DOX obtained with PEG/DSPE-containing liposomes were consistently higher than those without PEG/DSPE or when PEG/DSPE was replaced with hydrogenated phosphatidylinositol (HPI). Despite the inclusion of PEG/DSPE in liposomes, there was a significant drop in the plasma levels of DOX when the main phospholipid component, hydrogenated phosphatidylcholine, was replaced with lipids of lower phase transition temperature (dipalmitoylphosphatidylcholine, egg phosphatidylcholine), indicating that phase transition temperature affects the pharmacokinetics of liposome-encapsulated DOX. In beagle dogs, clearance was significantly slower for DOX encapsulated in PEG/DSPE-containing liposomes than in HPI-containing liposomes, with distribution half-lives of 29 and 13 hr, respectively. In both instances, almost 100% of the drug measured in plasma was liposome-associated. The apparent volume of distribution was only slightly above the estimated plasma volume of the dogs, indicating that drug leakage from circulating liposomes is insignificant and that the distribution of liposomal drug is limited mostly to the intravascular compartment in healthy animals.

The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4-butanediol divalproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4-butanediol.

The pharmacokinetics of five monoester prodrugs of valproic acid (VPA) were investigated: propyl valproate (P-VPA), butyl valproate (B-VPA), isobutyl valproate (IB-VPA), isoamyl valproate (IA-VPA), and hexyl valproate (H-VPA). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPA and valpromide (VPD). The pharmacokinetics of VPA and its five ester derivatives were determined after intravenous administration of equivalent doses (400 mg of VPA) to six dogs. The five ester prodrugs of VPA were biotransformed to VPA; the biotransformation was complete for P-VPA, B-VPA, and H-VPA but was only partial for IB-VPA and IA-VPA. Because of the rapid conversion of the prodrugs to the parent drug, levels of VPA in plasma after administration of the prodrugs peaked at 6-26 min after dosing and did not yield an in vivo sustained-release dosage profile. Of the five ester prodrugs of VPA, only P-VPA demonstrated anticonvulsant activity. P-VPA also was less neurotoxic than VPA and VPD; therefore, it has a better protective index.

The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be "stable" to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the beta position of its chemical structure. A "stable" valpromide analogue must have either two substitutions at the beta position, such as in the case of TBD, or a substitution in the alpha and beta positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.

We restudied a family with X-linked mental retardation (XLMR) originally reported in abstract form by Davis et al. [1981]. All 8 living affected males were examined. Characteristics included severe mental retardation, spastic paraplegia, dysarthria, muscle wasting, scoliosis, broad shallow pectus excavatum, long face, large ears with minor modeling anomalies, foot deformities, joint contractures, and neck drop. Stature, OFC, testicular volume, high resolution chromosome and fragile X studies, and plasma amino acids were all normal. Their manifestations closely resemble those of a large family with XLMR originally reported by Allan et al. [1944] and restudied by Stevenson et al. [1990]. This condition has been termed the Allan-Herndon-Dudley syndrome (AHDS). As AHDS has been mapped to Xq21, mapping studies were undertaken to determine if this family maps to the same location. These studies demonstrate tight linkage to Xq21, with a maximum lod score of 2.88 obtained with probe pX65H7 (DXS72). Multipoint analysis located the mutant gene quite close to pX65H7 (multipoint Z = 4.14), slightly more proximal in Xq21 than was suggested by the data from the original AHDS family. It appears likely that this family is the second reported family with AHDS.

Epilepsy is a chronic disease that requires long term therapy, and most of the established antiepileptic drugs (the exception is phenobarbital) must be administered several times daily. This results in compliance problems and fluctuations in plasma concentrations which may lead to subtherapeutic and potentially toxic levels. Development of sustained release formulations of the existing antiepileptic agents may improve antiepileptic therapy. At present, only the following 4 major drugs are used for the treatment of epilepsy: phenobarbital, phenytoin, carbamazepine and valproic acid. Of these, only the latter 2 are suitable candidates for sustained release formulations. This review, therefore, focuses on the evaluation and clinical implications of sustained release formulations of valproic acid and carbamazepine.

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2-2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 x 100-mg immediate-release tablets, (b) 2 x 300-mg sustained-release theophylline tablets, and (c) 2 x 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P greater than 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.

The hydrolysis of diltiazem in biological fluids: whole blood, plasma, and gastric fluid was investigated under conditions considered close to the physiological situation. The most significant rate of hydrolytic degradation was found in whole blood (half-life of 27 h), followed by plasma (half-life of 88 h), while the least significant degradation rate was observed in gastric fluid (half-life 153 h). The kinetic profiles of diltiazem hydrolysis indicate that hydrolytic degradation in the biological fluids makes a minimal contribution to the clearance and disposition of the drug.

The pharmacokinetics of valproic acid (VPA) were compared in dogs with those of the prodrugs ethyl valproate (E-VPA), trichloroethyl valproate (T-VPA), and valproyl valproate (V-VPA). Valproic acid, E-VPA, T-VPA, and V-VPA were administered intravenously and orally to six dogs at equimolar doses. The three VPA prodrugs were rapidly converted to VPA. The biotransformation was complete in the case of E-VPA and T-VPA but was only partial in the case of V-VPA. Because of the rapid conversion to the parent drug, after administration of the prodrugs, VPA plasma levels did not yield a sustained-release profile. Further, the anticonvulsant activity of prodrugs was compared in mice to that of VPA and valpromide (VPD). The anticonvulsant activity of E-VPA, T-VPA, and V-VPA was less than that of VPA.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked muscular dystrophy characterized by early contractures, progressive muscle weakness, and atrial arrhythmias. Recent reports suggest that there may be additional cardiac problems in affected males and that carrier females may also show ECG abnormalities. We restudied two large families with EDMD in order to determine the extent of these problems. We examined 10 affected males and interviewed 2 others. The 3 affected males less than 20 years old had no ECG changes. All affected men of 35 years or older had arrhythmias. One had more severe arrhythmias when asleep, indicating the usefulness of continuous 24-h ECG monitoring in the evaluation of males affected with EDMD. Two required pacemakers, 4 had already had a pacemaker placed, and 4 other affected men with pacemakers had died prior to this study. One affected man with a pacemaker developed ventricular bigeminy and another developed congestive heart failure. Thus of 10 affected males with pacemakers, 6 had additional cardiac symptoms and 4 have died. Males with EDMD may survive longer with a ventricular pacemaker, but this may increase the likelihood that they will develop cardiomyopathy and ventricular arrhythmias. Of 34 carrier females examined, 6 had arrhythmias typical of EDMD. Two required a pacemaker. The risk of arrhythmia increased with age. Results from one family should be extrapolated to another with caution, as there appears to be significant interfamilial variation. We suggest careful cardiologic follow-up of EDMD patients and regular cardiac evaluations for older carrier females.

Valpromide has been used as an antiepileptic and antipsychotic drug for the past 25 years in several European countries. Unlike its corresponding acid, valproic acid, whose pharmacokinetics have been quite extensively reviewed, and despite years of clinical use, it appears that no reviews have been written on the pharmacokinetics of valpromide. This article summarises and analyses its pharmacokinetics from various aspects, with a special emphasis on the differences between valpromide and valproic acid. In humans, valpromide is a prodrug of valproic acid. Despite their chemical similarity, the pharmacokinetics of the 2 drugs in humans are quite distinct. Compared with valproic acid. valpromide has a very short half-life (mean +/- SD: 0.84 +/- 0.33h; n = 6), a high clearance value (70 +/- 31 L/h) and a large volume of distribution (75 +/- 13L). Despite its rapid biotransformation to valproic acid, valpromide has some special characteristics, such as its inhibition of the enzyme epoxide hydrolase which is responsible for the metabolism of carbamazepine-10, 11-epoxide. This review discusses the pharmacokinetics of valpromide, the interactions between it and other drugs such as carbamazepine and amitriptyline, and its antiepileptic and antipsychotic activities.