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PubMed2000

Anticonvulsant drugs for acute and chronic pain.

BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for neuropathic pain, especially when the pain is lancinating or burning. OBJECTIVES: To evaluate the analgesic effectiveness of anticonvulsant drugs compared to either placebo or other drugs in order to provide evidence-based recommendations for pain management in clinical practice and to identify a clinical research agenda. Adverse effects are also considered. SEARCH STRATEGY: Randomised trials of anticonvulsants in acute, chronic or cancer pain were identified by Medline (Silver Platter 3.0, 3.1 and 3.11) from 1966 to February 1994. In addition, 40 medical journals were hand searched (published between 1950 and 1990). Additional reports were identified from the reference list of the retrieved papers, and contacting investigators. Date of the most recent searches: 1994. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of anticonvulsant drugs in patients, with pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal, for individual studies and for pooled data. MAIN RESULTS: Twenty trials of four anticonvulsants were considered eligible (746 patients). The only placebo-controlled study in acute pain found no analgesic effect of sodium valproate. Three placebo-controlled studies of carbamazepine in trigeminal neuralgia had a combined NNT for effectiveness of 2.6, for adverse effects 3.4, and for severe effects (withdrawal from study) 24. Three placebo-controlled studies of diabetic neuropathy had a combined NNT for effectiveness of 3, for adverse effects 2.5, and for severe effects 20. Three placebo-controlled studies of migraine prophylaxis had a combined NNT for effectiveness of 2.4, for adverse effects 2.4 and for severe effects 39. Phenytoin had no effect in irritable bowel syndrome, and carbamazepine little effect in post-stroke pain. Clonazepam was effective in one study of temporomandibular joint dysfunction. No study compared one anticonvulsant with another. Anticonvulsants fared poorly against other treatments. REVIEWER'S CONCLUSIONS: Although anticonvulsants are used widely in chronic pain surprisingly few trials show analgesic effectiveness. No trial compared different anticonvulsants. There is no evidence that anticonvulsants are effective for acute pain. In chronic pain syndromes other than trigeminal neuralgia anticonvulsants should be withheld until other interventions have been tried.

Acute Disease↗
PubMed2000

Anticonvulsants for women with pre-eclampsia.

BACKGROUND: Pre-eclampsia is a relatively common complication of pregnancy. Anticonvulsants are used in the belief they help prevent eclamptic fits and subsequent poor outcomes for mother and infant. OBJECTIVES: The objective of this review was to assess the effects of anticonvulsants for women with pre-eclampsia on the women and their children. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, and the Cochrane Controlled Trials Register, 1999 Issue 3. SELECTION CRITERIA: Randomised trials comparing anticonvulsants with placebo or no anticonvulsants or comparisons of different anticonvulsants in women with pre-eclampsia. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Nine studies were included. Comparing magnesium sulphate with placebo/no anticonvulsant the relative risk (RR) of eclampsia was 0.33, 95% confidence interval (CI) 0.11 to 1.02. There was no significant difference detected in the risk of caesarean section (RR 1.04, 95% CI 0.92 to 1.17). Magnesium sulphate appeared to be better than phenytoin at reducing the risk of eclampsia (RR 0.05, 95% CI 0.00 to 0.84). However there was an increased risk of caesarean section with magnesium sulphate compared to phenytoin (RR 1.21, 95% CI 1.05 to 1. 41). No statistically significant differences were reported for any other clinically important outcomes. Studies comparing magnesium sulphate and diazepam were too small for any reliable conclusions. REVIEWER'S CONCLUSIONS: There is not enough evidence to establish the benefits and hazards of anticonvulsants for women with pre-eclampsia. If an anticonvulsant is used, magnesium sulphate appears to be the best choice.

Anticonvulsants↗
PubMed1994

The anticonvulsant effect of the broad spectrum anticonvulsant loreclezole may be mediated in part by serotonin in rats: a microdialysis study.

Loreclezole is an experimental anticonvulsant drug. We found previously that several established anticonvulsants increase extracellular serotonin as measured by microdialysis. We have concluded that the increase in extracellular serotonin and the anticonvulsant effect produced by these anticonvulsant drugs are related in a cause and effect manner. To determine if anticonvulsant doses of loreclezole increase extracellular serotonin, we determined anticonvulsant dose-response relationships in genetically epilepsy-prone rats (GEPRs). Then, we administered ED99 doses of loreclezole to GEPRs and determined the effect on extracellular serotonin as measured by microdialysis in the striatum. We conclude that loreclezole produces a dose-related anticonvulsant effect in GEPRs and that anticonvulsant doses of loreclezole increase extracellular serotonin in these animals.

Acoustic Stimulation↗
PubMed2000

Repeated acute testing of anticonvulsant drugs in amygdala kindled rats: increase in anticonvulsant but decrease in adverse effect potential.

PURPOSE: Because preparation of kindled rats is laborious, time-consuming, and expensive, such animals are often used for several experiments in the evaluation of anticonvulsant drugs (AEDs). Furthermore, for comparison with data on new drugs, often "historical" data on standard drugs obtained in previous experiments in other groups of kindled rats are used. Without knowing how factors such as repeated drug testing or seasonal variation in drug responses affect drug potencies in the kindling model, false conclusions and predictions might be drawn from such comparisons. In this study, we examined the anticonvulsant and adverse effects of the three clinically established AEDs carbamazepine (CBZ), phenobarbital (PB), and valproate (VPA) once per month in the same two groups of amygdala-kindled rats over a period of 9 (group 1) or 6 (group 2) consecutive months. To evaluate the possible effect of the season, experiments in group 1 were started in autumn, and experiments in group 2 in spring. METHODS: For quantification of anticonvulsant activity, the focal seizure threshold (threshold for afterdischarges; ADT) was determined after each acute drug treatment and compared with a control ADT determined 2-3 days before. RESULTS: The repeated acute (single-dose) drug testing in the same groups of amygdala-kindled rats led to three pronounced alterations in the animals: (a) a significant decrease in ADT, (b) a marked potentiation of AED effects on ADT, and (c) a striking reduction in ataxia produced by drug treatments. Drug levels in plasma, which were determined in each drug trial, showed only moderate variation over the period of the experiments, so that the observed alterations in drug responses were certainly not due to pharmacokinetic factors. PB and VPA, but not CBZ, showed a more potent anticonvulsant effect when experiments were started in October (group 1) compared with April (group 2), but this difference was rapidly overridden by the marked and progressive potentiation of anticonvulsant activity on repeated drug testing. CONCLUSIONS: These data demonstrate that repeated use of the same kindled rats for acute drug testing significantly alters the sensitivity of the animals to the anticonvulsant and adverse effects of drugs. Because the anticonvulsant potency increases, whereas the adverse effect potential decreases during repeated acute drug testing, this may lead to false-positive data on a test compound. The mechanisms involved in these observations deserve further studies.

Amygdala↗
PubMed2000

Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia.

OBJECTIVES: To assess the benefits and harm of administering anticonvulsants to infants of 37 weeks gestation or more following perinatal asphyxia with the primary aims of prevention of death or subsequent severe neurodevelopmental disability and/or the prevention of seizures. SEARCH STRATEGY: Relevant randomised controlled trials were identified using a combination of electronic database searches (MEDLINE), hand searches and a search of the Neonatal Review Group trials register. SELECTION CRITERIA: All randomised, or quasi-randomised, controlled clinical trials with reported data comparing the following outcomes: mortality, neurodevelopmental disability, neonatal seizures and adverse events, following anticonvulsant therapy in term infants (37 weeks or more), compared to controls with or without placebo, following perinatal asphyxia. DATA COLLECTION AND ANALYSIS: Methodological quality and validity of studies were assessed without consideration of the results. Data relevant to the outcome were extracted and analysed. MAIN RESULTS: Five randomised or quasi-randomised controlled trials which met the selection criteria were identified. No studies were of sufficient methodological quality and size to demonstrate a valid, clinically significant change in the risk of mortality or severe neurodevelopmental disability. A meta-analysis combining three studies comparing barbiturates with conventional therapy following perinatal asphyxia demonstrated no difference in risks of death, severe neurodevelopmental disability, or death or severe neurodevelopmental disability. REVIEWER'S CONCLUSIONS: At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of high quality: randomised control trials with allocation concealment, performance and outcome assessment blinding. Such studies should be of sufficient size, with minimal attrition, to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability, as the primary outcome measures.

Anticonvulsants↗
PubMed2000

The role of technical, biological, and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. VII. Seasonal influences on anticonvulsant drug actions in mouse models of generalized seizures.

Seasonal or circannual rhythms have been reported in various physiologic, biochemical, pharmacological, and toxicological studies in mice and rats despite laboratory conditions with standardized and controlled light cycle, temperature, humidity, and food. This may either be explained by the existence of innate, free-running circannual rhythms or by the existence of seasonally varying environmental factors ('zeitgeber') which are detected by the animals despite controlled laboratory conditions. In the present study, it was evaluated whether circannual rhythms affect the anticonvulsant activity of phenobarbital, carbamazepine, or valproate in two mouse models of generalized seizures, i.e. the threshold for generalized tonic seizures in the maximal electroshock seizure (MES) test and the threshold for different types of generalized seizures induced by the chemical convulsant pentylenetetrazol (PTZ). A study protocol was used with data sampling in separate groups of mice per month (using each group only once) over a period of 13 months beginning and ending in late summer (September), so that data collected in the other seasons could be compared with summer values of 2 subsequent years. With all three anticonvulsants, marked seasonal variation was observed in both seizure models with lowest anticonvulsant efficacy and potency in March and April, i.e. in late winter and early spring. The most marked loss of anticonvulsant activity in this period of the year was observed with valproate. Analysis of drug levels in plasma and brain indicated that the seasonal variation in phenobarbital's and carbamazepine's anticonvulsant effect was predominantly due to alterations in drug metabolism leading to reduced brain levels in March and April, while the seasonal rhythm in valproate's activity appeared to be mainly related to altered pharmacodynamic activity. These findings indicate that the time of the year is an important variable in the experimental evaluation of anticonvulsant drugs. Furthermore, the present data add to the accumulating evidence that endogenous circannual rhythms should be considered during animal experiments under controlled laboratory conditions.

Animals↗
PubMed1979

Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals.

The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).

Animals↗
PubMed1992

Anticonvulsant profile of MDL 27,266: an orally active, broad-spectrum anticonvulsant agent.

The novel anticonvulsant substance MDL 27,266 was tested in a variety of anticonvulsant models to assess its anticonvulsant profile, behavioral toxicity and oral bioavailability. Intraperitoneally (i.p.) administered MDL 27,266 afforded complete protection against sound-induced seizures in DBA/2J and Frings audiogenic-seizure (AGS)-susceptible mice (ED50s: 5.0 and 5.1 mg/kg, respectively). It was also effective following i.p. administration to CF#1 mice against maximal electroshock (MES)-, pentetrazole-, picrotoxin-, quisqualic acid-, and strychnine-induced seizures (ED50s: 24.9, 13.8, 43.3, 8.05, and 60.5 mg/kg, respectively). MDL 27,266, in well tolerated oral doses, prevented the expression of stage 5 behavioral seizures in the corneal-kindled rat and myoclonic seizures in the photosensitive baboon, Papio papio. Chronic administration of MDL 27,266 to AGS-susceptible mice did not markedly affect its anticonvulsant potency or efficacy against sound-induced seizures. These results suggest that MDL 27,266 possesses a broad anticonvulsant profile which most closely approximates that of the broad-spectrum prototype antiepileptic drug valproate.

Animals↗
PubMed1999

Effects of co-administration of anticonvulsant and putative anticonvulsive agents and sub/suprathreshold doses of L-dopa upon motor behaviour of MPTP-treated mice.

The effects of co-administration of the dopamine precursor, L-Dopa, with anticonvulsant and putative anticonvulsive agents upon the motor activity of hypoactive MPTP-treated C57 BL/6 mice were measured in six experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered four to six weeks prior to behavioural testing. Thus, the effects of these agents combined with either a single acute, subthreshold dose (5 mg/kg, s.c.) of L-Dopa, or, with chronically-administered, suprathreshold doses (20 mg/kg, s.c.) of L-Dopa were studied. In the former, lamotrigine, FCE 26743 and L-Deprenyl, injected 60 min before subthreshold L-Dopa (5 mg/kg), each induced an antiparkinsonian action in MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. In the latter, lamotrigine (all three measures of activity at 3 mg/kg), FCE 26743 (locomotion and total activity at 3; rearing at 1 and 3 mg/kg) and L-Deprenyl (locomotion and total activity at 1 and 3mg/kg), but not phenytoin (neither at 1 nor 3 mg/kg), reinstated the motor activity-stimulating effects of the threshold dose of L-Dopa (20 mg/kg) in L-Dopa-tolerant, MPTP-treated mice. Neurochemical analyses confirmed severe DA depletions in MPTP-treated mice. Since neither lamotrigine, FCE 26743 nor L-Deprenyl, nor subthreshold L-Dopa, by themselves increased the motor behaviour of MPTP-treated mice, a synergistic effect of the co-administration is concluded. Further, since the suprathreshold dose of L-Dopa by itself failed to stimulate motor activity in the MPTP mice following chronic (25 daily injections) administrations of the compound, it is suggested that a restorative effect, in combination with lamotrigine, FCE 26743 or L-Deprenyl was evidenced. The potential therapeutic benefits of anticonvulsant or putative anticonvulsive compounds for parkinsonian symptoms are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Two metabolites of anticonvulsant U-54494A: their anticonvulsant activity and interaction with sodium channel.

U-54494A, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamide, has been shown to be a potent and long-acting anticonvulsant without analgesic or sedative effects on intact animals. The persistence of anticonvulsant activity after a decline in its concentration in the brain implies the conversion of the parent drug into active metabolites. In this study, two major metabolites of U-54494A, U-83892E [cis-N-(2-aminocyclohexyl)-3,4-dichlorobenzamide] and U-83894A [cis-N-(2-methylaminocyclohexyl)-3,4-dichlorobenzamide], were identified. The synthetic metabolites displayed anticonvulsant activity against electric shock in experimental animals and blocked voltage-gated sodium channel in N1E-115 neuroblastoma cells in voltage- and use-dependent manner by interacting with the inactivated channels as well as with the channels in the resting state (like the parent compound). These observations may provide one explanation for the long duration of the anticonvulsant activity of the parent compound U-54494A and further underscore the importance of voltage-dependent sodium channels in neuronal excitability, especially during seizures.

Animals↗
PubMed1999

Synthesis, physicochemical properties, anticonvulsant activities and voltage-sensitive calcium channels affinity of N-substituted amides of alpha-(4-phenylpiperazino)-GABA. Part 3: Search for new anticonvulsant compounds.

This paper describes the synthesis and preliminary anticonvulsant evaluation of some GABA analogues i.e. derivatives of 2-(4-phenylpiperazino)- or 2-(4-benzylpiperidino)-GABA (5, 6), N-substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobutyric acid and N-substituted amides of 2-(4-phenylpiperazino)-GABA. N-Substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobutyric acid (7-11) were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of different coupling reagents (2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and carbonyldiimidazole (CDI). N-Substituted benzylamides of 2-(4-phenylpiperazino)-4-aminobutyric acid (12-14) were prepared by hydrazinolysis of amides 9-11. Anticonvulsant activities were determined in mice (for all compounds) and in rats using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The amides (12-14) showed protection against MES and/or scMet seizures in mice. N-(4-Methoxybenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide (13) was the most effective and displayed anticonvulsant activity in both tests at doses of 100-300 mg/kg in mice and at 30 mg/kg in the MES screen in rats. The active compounds (12-14) were tested for their ability to displace [3H]nitrendipine binding sites (voltage-sensitive calcium channel receptors) from rat cortex. Amide 13 was the most active both in pharmacological and biochemical tests. These preliminary results suggest that the anticonvulsant activity of compounds 12-14 may be related to their influence on voltage-sensitive calcium channel receptors.

Aminobutyrates↗
PubMedDate not supplied

[The effect of antidepressants on the experimental anticonvulsant activity and acute toxicity of anticonvulsants].

In the experiments on white mice there was studied the anticonvulsant activity by the test of the maximal electric shock and acute toxicity of anticonvulsants and antidepressants at separate and combined administration. The combined use of anticonvulsants and antidepressants showed the increase of the anticonvulsant activity of phenobarbital with amitriptyline, levomepromazine and lithium oxybutyrate; diphenine and carbamazepine with amitriptyline as well as hexamidine with all antidepressants. The combination of phenobarbital with amitriptyline, levomepromazine and lithium oxybutyrate, diphenine with amitriptyline, hexamidine with amitriptyline and imizine proved to be the safest.

Animals↗
PubMedDate not supplied

[Anticonvulsive activity of anticonvulsants and tranquilizers when used together].

Experiments on mice were made to study anticonvulsive activity of the combinations of 5 tranquilizers (diazepam, chlorodiazepoxide, meprotan, trioxazin, mebicar) and 7 anticonvulsants (phenobarbital, hexamidine, benzonal, diphenin, chloracon, trimetin, carbamazepin) according to the maximal electroshock test. The data obtained form an experimental basis for the combined use of some anticonvulsants and tranquilizers in the treatment of epilepsy, since in a number of cases these combinations permit a significant lowering of the doses of both components without reducing their anticonvulsant activity.

Animals↗
PubMedDate not supplied

Comparison of the anticonvulsant activities of ethosuximide, valproate, and a new anticonvulsant, thiobutyrolactone.

Anticonvulsant properties of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL) were compared with those of the antiepileptic drugs ethosuximide (ESM) and valproate (VPA) by testing their ability to block seizures in mice caused by maximal electroshock (MES), pentylenetetrazol (PTZ), picrotoxin (PICRO), bicuculline (BIC), methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N-methyl-D,L-aspartate (NMDA), aminophylline (AMPH), strychnine (STR), beta-ethyl-beta-methyl-gamma-thiobutyrolactone (beta-EMTBL), and t-butylbicyclophosphorothionate (TBPS). ESM was able to prevent PTZ-, PICRO-, DMCM-, and beta-EMTBL-induced seizures. In contrast, VPA and alpha-EMTBL blocked all of these plus MESTBPS-, and BIC-induced convulsions. Only VPA prevented AMPH-induced seizures. None of the anticonvulsants blocked STR or NMDA seizures. Rotorod testing for acute neurotoxicity demonstrated that ESM was the least toxic and alpha-EMTBL and VPA were equivalent. Animals treated daily with high doses of alpha-EMTBL for a 2-week period appeared healthier and had a higher survival rate than animals treated with VPA in the same manner. After a single intraperitoneal (i.p.) injection, the duration of anticonvulsant action of alpha-EMTBL was 1.3 and 4 times longer than that of ESM and VPA, respectively. These results indicate that alpha-EMTBL has a wide spectrum of anticonvulsant action like VPA but may be less toxic and longer acting. We suggest that alpha-EMTBL is a compound worthy of further testing and development as an antiepileptic drug (AED).

4-Butyrolactone↗
PubMed1999

Synthesis, physicochemical properties, anticonvulsant activities, and GABA-ergic and voltage-sensitive calcium channel receptor affinities of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid. Part 4: Search for new anticonvulsant compounds.

In a search for new anticonvulsant compounds, two series of N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (series A) and alpha-(2-phenylethylamino)-gamma-hydroxybutyric acid (series B), were investigated in maximal electroshock (MES), subcutaneous metrazole, and rotorod toxicity assays. The most potent anticonvulsant compounds were alpha-(benzylamino)-gamma-hydroxybutyric acid N-benzylamide (3) and N-(2-chlorobenzylamide (4) with median effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively. alpha-(4-Phenylpiperazinyl)-gamma-hydroxybutyric acid N-(4-methylbenzyl)amide (17) and alpha-(benzylpiperazinyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)amide (18) were also tested for their ability to potentiate [3H]-muscimol binding and to inhibit [35S]-TBPS binding (as indices of GABA-A receptor potentiation). Amide 17 exhibited activity at the GABA-A complex which may be the mechanism by which the anticonvulsant effect of this compound is mediated. The N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (3-9) were also evaluated for their ability to displace [3H]-nitrendipine from voltage-sensitive calcium channel (VSCC) receptors isolated from rat cortex.

Animals↗
PubMed2000

Anticonvulsant teratogenesis 4: inter-rater agreement in assessing minor physical features related to anticonvulsant therapy.

BACKGROUND: We report on inter-rater agreement in the assessment of newborn infants with respect to a range of minor physical features in a cohort study of the fetal effects of maternal anticonvulsant use during pregnancy. METHODS: Infants from three groups (exposed to anticonvulsants, seizure history but no medication exposure, and unexposed controls) were examined by both a pediatrician/teratologist, who was blinded with respect to the mother's exposure status, and an unblinded research assistant. Agreement on assessments for selected anomalies associated with anticonvulsant therapy was measured by kappa-statistics, as well as by more sensitive log-linear modeling techniques, which allow examination of possible covariate effects on the strength of agreement. Although the physician and research assistant agreed on a high proportion of cases (80-90%), kappa values were modest (0.2-0. 5), partly because of the low prevalence of the anomalies considered. To explore how agreement varies within subgroups, we used recently developed methods for studying agreement based on log-linear models. RESULTS: Log-linear modeling indicated that there was substantial variation in pattern of agreement between different individual research assistants but that other factors (e.g., exposure category, sex, and birthweight) did not appear to be related to agreement. Our results suggest that research assistants with more experience showed the highest degree of agreement with the physicians. CONCLUSIONS: Our results have implications for both clinical practice and epidemiologic research and underline the importance of thorough training of staff in the definitions to be used and also the need for multiple independent assessments of these subtle anomalies.

Abnormalities, Drug-Induced↗
PubMed1997

Search for New Anticonvulsant Compounds, Part 2. Structure-activity relationship studies of new N-substituted amides of alpha-piperazine-gamma-hydroxybutyric acid as active anticonvulsants.

In a search for new anticonvulsants, two series of compounds, viz. derivatives of N-benzylamides of alpha-(4-phenylpiperazine)-gamma-hydroxybutyric acid (A) and derivatives of N-benzylamides of alpha-(4-benzylpiperazine)-gamma-hydroxybutyric acid (B), were investigated. These amides were obtained by aminolysis of 3-(4-phenyl-, or 4-benzylpiperazine)-tetrahydrofuran-2-one with primary arylalkylamines (i.e. 2-phenylethylamine and 2,3,4-substituted derivatives of benzylamine). Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay were employed. All compounds displayed anticonvulsant activity at range of doses 100-300 mg/kg in the MES screens. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two representative compounds of series A and B.

Animals↗
PubMed1996

Triazolines 26: 1-Aryl-5-amido-1,2,3-triazolines, a new group of triazoline anticonvulsants. Effect of 5-substitution on anticonvulsant activity.

Studies in our laboratories have led to the discovery of the delta 2-1,2,3-triazolines as a unique family of anticonvulsant agents hitherto unknown. The anticonvulsant activity of 1,5-diaryl- and 1-aryl-5-pyridyltriazolines was previously reported; this paper describes the evaluation of two series of 1-aryl-5-amido-1,2,3-triazolines, A and B, where the 5-amido groups are (2-oxo-1-pyrrolidino)- (1-8) and (N-methyl-N-acetamido)- (9-15), respectively. The 1-aryl-5-(2-oxo-1-pyrrolidino)-1,2,3-triazolines of the A series, which are uniquely substituted with the pyrrolidinone lactam ring, a cyclic gamma-aminobutyric acid (GABA) structure, seem to function by enhancing inhibitory GABAergic mechanisms. Radioligand binding studies for the two most active triazolines 2 and 7, indicate that both compounds strongly inhibit the specific binding of [3H]GABA to GABAB receptor sites, with Ki = 1.7 and 0.91 microM respectively. The anticonvulsant activity among the various groups of triazolines studied so far appears to be dependent on the 5-substituent groups: 4-pyridyl- >> 2-oxo-1-pyrrolidino- > N-methyl-N-acetamido- > 3-pyridyl > or = aryl approximately 2-pyridyl > 2-quinolyl.

Animals↗