A Comparison of Anticonvulsants in the Treatment of Impulsive Aggression.

This study compared the behavioral effects of 3 anticonvulsants in impulsive aggressive men. In a double-blind, placebo-controlled, parallel groups design, participants were randomly assigned to 1 of 4 6-week treatments: phenytoin (n = 7), carbamazepine (n = 7), valproate (n = 7), or placebo (n = 8). The efficacy measure was the average aggression score, a global severity index from the Overt Aggression Scale (J. M. Silver & S. C. Yudofsky, 1991). Analysis showed a significant reduction in impulsive aggression during all 3 anticonvulsant conditions compared with placebo. However, the treatment effect during carbamazepine administration was slightly delayed compared with phenytoin and valproate. These findings suggest that increased use of anticonvulsants could make a significant impact in the control of impulsive aggression in both mental health and criminal justice settings. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clarithromycin-carbamazepine interaction: a case report

We report a clinically relevant interaction between a new macrolide antibiotic, clarithromycin, and carbamazepine (CBZ). In a patient receiving CBZ monotherapy, 10-day antibiotic treatment increased CBZ concentration despite concomitant CBZ dose reduction and doubled the CBZ concentration/dose ratio. Concentration of the CBZ epoxide (CBZ-E) metabolite was reduced, suggesting that the interaction occurs at a metabolic level.     

Protein-reactive metabolites of carbamazepine in mouse liver microsomes

The character of reactive metabolites formed from carbamazepine (CBZ) was sought in incubations of [14C]CBZ in hepatic microsomes prepared from adult female mice of a strain (SWV/Fnn) susceptible to CBZ-induced teratogenicity. The formation of radio-labeled protein adducts was used as an index of reactive metabolite exposure. A dependence on cytochrome P450 was shown by a requirement for NADPH and inhibition by carbon monoxide, 1-aminobenzotriazole, piperonyl butoxide, and stiripentol. The addition of ascorbic acid, caffeic acid, N-acetylcysteine, and glutathione decreased the rate of binding of the radiolabel from [14C]CBZ to microsomal protein by more than 50%. The addition of glutathione transferases diminished protein adduct formation beyond that seen with glutathione alone. Evidence for the formation of an arene oxide was sought through the use of inhibitors of epoxide hydrolases, including cyclohexene oxide, chalcone oxides (with the addition of cytosol as appropriate), and by the addition of recombinant human soluble and microsomal epoxide hydrolases and recombinant rat microsomal epoxide hydrolase. The microsomal epoxide hydrolases decreased the velocity of 14C-labeled protein adduct formation by approximately 23%, whereas inhibitors had no effect, most likely because of the low native activity of microsomal epoxide hydrolase in mice. Both DT-diaphorase and catechol-O-methyltransferase diminished 14C-labeled protein adduct formation by 54% and 45%, respectively. The data suggest that the major reactive metabolites formed from CBZ by adult female SWV/Fnn liver microsomes are quinones and arene oxides.     

Recent advances in the pharmacotherapy of epilepsy

The therapeutic options for the treatment of epilepsy have expanded during the 1990s. Since 1993, four novel agents (felbamate, gabapentin, lamotrigine, and topiramate) have been approved by the US Food and Drug Administration, primarily for adjunctive treatment of partial seizures. In addition, a water-soluble pro-drug of phenytoin, fosphenytoin, and a sustained-release preparation of carbamazepine have been introduced. The novel anticonvulsants represent a potential improvement for patients whose seizures are incompletely controlled or who experience significant adverse effects with older anticonvulsants. Felbamate, lamotrigine, and topiramate appear to have a broad spectrum of action in seizure control, but felbamate use is limited by the potential for serious adverse effects. Gabapentin, lamotrigine, and topiramate are all well tolerated. Gabapentin has no known drug interactions, whereas lamotrigine and topiramate have limited interactions compared with older agents. The sustained-release preparation of carbamazepine may decrease the incidence of adverse effects and increase patient compliance. Fosphenytoin offers a safer method for intravenous administration of phenytoin and the added flexibility of intramuscular administration. Taken together, these recent advances in treatment may bring about improved efficacy and decreased adverse effects for many patients with epilepsy.     

Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites using Xenopus

Potential mechanisms of trichloroethylene-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay--Xenopus). Early Xenopus laevis embryos were exposed to trichloroethylene for 96 h in two separate definitive concentration-response assays with and without an exogenous metabolic activation system (MAS) and inhibited MAS. The MAS was treated with either carbon monoxide or cyclohexene oxide to modulate mixed-function oxidase (MFO) or epoxide hydrolase activity, respectively. Trichloroethylene metabolites: dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid were also evaluated in two separate definitive, static renewal tests. Addition of the MAS decreased the 96 h LC50 and EC50 (malformation) of trichloroethylene 1.8-fold and 3.8-fold, respectively. Addition of the carbon monoxide inhibited MAS decreased the developmental toxicity of activated trichloroethylene to levels approximating that of the parent compound. Cyclohexene oxide-inhibited MAS substantially increased the developmental toxicity of trichloroethylene. In addition, each of the metabolites tested were significantly less developmental toxic than the parent compound, trichloroethylene. Results indicate that a highly embryotoxic epoxide intermediate, trichloroethylene oxide, formed as the results of MFO mediated metabolism may play a significant role in the developmental toxicity of trichloroethylene in vitro.     

Recent progress in development of psychotropic drugs (4)--Anticonvulsants: an overview on the mechanisms of action

Conventional anticonvulsants can be classified into three types according to their mechanisms of action: (1) those which act on voltage-dependent Na+ channels such as phenytoin, (2) those which act on T-type Ca2+ channels such as ethosuximide, and (3) those which enhance GABA receptor-mediated inhibitory neurotransmission such as phenobarbital or valproate. However, recent studies on experimental models of epilepsy have suggested that the neural mechanisms underlying experimental epileptogenesis are based on: (1) increments in cellular excitability through changes in the function of Na(+)- or Ca2+ channels, (2) desinhibition or inhibition failure, and (3) enhancement of excitatory amino acid receptor-mediated excitatory neurotransmission. These findings might help us to understand the recently developed anticonvulsants and vice versa. In this review, newly developed anticonvulsants are categorized according to the neural mechanisms underlying epileptogenesis, particularly actions on excitatory and inhibitory neurotransmission.     

A severe case of Moebius syndrome with calcification on the fourth ventricular floor

Disturbance of metabolism of trace elements and antioxidants are investigated in epileptic patients with long-term therapy of anticonvulsants. One hundred and fifteen subjects including healthy controls, untreated epileptic patients, and phenytoin (PHT)- or carbamazepine (CBZ)-treated epileptic patients were recruited in this study. Serum malondialdehyde was measured as an index of extracellular lipid peroxidation. The levels of serum copper (S-Cu), serum zinc, copper/zinc superoxide dismutase (CuZn-SOD), and reduced glutathione in the serum were monitored simultaneously. The results showed that malondialdehyde, S-Cu, and CuZn-SOD levels in the serum all were significantly increased, but the glutathione level was significantly decreased, in all the epileptic patients with PHT monotherapy compared with those of the controls. However, no significant differences of these parameters in the epileptic patients with CBZ monotherapy were found except for a mild elevation of the activity of serum CuZn-SOD. We conclude that compared with PHT monotherapy, the CBZ monotherapy induced less disturbance in trace element metabolism, antioxidants, and lipid peroxidation in the serum of epileptic patients.     

An investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from naphthalene by human liver microsomes

Chemically reactive epoxide metabolites have been implicated in various forms of drug and chemical toxicity. Naphthalene, which is metabolized to a 1,2-epoxide, has been used as a model compound in this study in order to investigate the effects of perturbation of detoxication mechanisms on the in vitro toxicity of epoxides in the presence of human liver microsomes. Naphthalene (100 microM) was metabolized to cytotoxic, protein-reactive and stable, but not genotoxic, metabolites by human liver microsomes. The metabolism-dependent cytotoxicity and covalent binding to protein of naphthalene were significantly higher in the presence of phenobarbitone-induced mouse liver microsomes than with human liver microsomes. The ratio of trans-1,2-dihydrodiol to 1-naphthol was 8.6 and 0.4 with the human and the induced mouse microsomes, respectively. The metabolism-dependent toxicity of naphthalene toward human peripheral mononuclear leucocytes was not affected by the glutathione transferase mu status of the co-incubated cells. Trichloropropene oxide (TCPO; 30 microM), an epoxide hydrolase inhibitor, increased the human liver microsomal-dependent cytotoxicity (19.6 +/- 0.9% vs 28.7 +/- 1.0%; P = 0.02) and covalent binding to protein (1.4 +/- 0.3% vs 2.8 +/- 0.2%; P = 0.03) of naphthalene (100 microM), and reversed the 1,2-dihydrodiol to 1-naphthol ratio from 6.6 (without TCPO) to 2.6, 0.6 and 0.1 at TCPO concentrations of 30, 100 and 500 microM, respectively. Increasing the human liver microsomal protein concentration reduced the cytotoxicity of naphthalene, while increasing its covalent binding to protein and the formation of the 1,2-dihydrodiol metabolite. Co-incubation with glutathione (5 mM) reduced the cytotoxicity and covalent binding to protein of naphthalene by 68 and 64%, respectively. Covalent binding to protein was also inhibited by gestodene, while stable metabolite formation was reduced by gestodene (250 microM) and enoxacin (250 microM). The study demonstrates that human liver cytochrome P450 enzymes metabolize naphthalene to a cytotoxic and protein-reactive, but not genotoxic, metabolite which is probably an epoxide. This is rapidly detoxified by microsomal epoxide hydrolase, the efficiency of which can be readily determined by measurement of the ratio of the stable metabolites, naphthalene 1,2-dihydrodiol and 1-naphthol.     

Impaired biotin status in anticonvulsant therapy

In 264 epileptics undergoing long-term therapy with anticonvulsants, significantly reduced plasma biotin levels were found compared with a normal control group: 74% of the epileptics had biotin levels of 250 ng/L or less. In patients undergoing single-drug therapy, the mean plasma biotin levels for those treated with sodium valproate were higher than for those treated with phenytoin, primidone, or carbamazepine. The observed reduction in biotin levels might be a factor influencing the efficacy of these three anticonvulsants.     

Isolation and characterization of cDNA encoding chicken egg yolk aminopeptidase Ey

Twenty-five to 40 percent of patients with epilepsy continue to have seizures despite optimal treatment with traditional antiepileptic drugs. Treatment with standard anticonvulsants such as phenytoin, carbamazepine, valproic acid and phenobarbital is often complicated by side effects and by failure to adequately control seizures. Up to 61 percent of patients with seizures report having side effects with antiepileptic drugs. After a 15-year hiatus since the last new antiepileptic drug was marketed, five new drugs have been approved by the U.S. Food and Drug Administration for the control of seizures. Three of these, gabapentin, lamotrigine and topiramate, are approved for use in adults with partial seizures with or without generalization. Felbamate is approved for the above indication and also for use in children with Lennox-Gastaut syndrome, a rare childhood seizure disorder. Felbamate and lamotrigine have the potential of significant side effects and should be prescribed by physicians experienced in managing patients with complicated epilepsy. Fosphenytoin is a parenteral prodrug of phenytoin that is more tolerable than parenteral phenytoin.     

A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels

Phenytoin, carbamazepine, and lamotrigine are anticonvulsants frequently prescribed in seizure clinics. These drugs all show voltage-dependent inhibition of Na+ currents, which has been implicated as the major mechanism underlying the antiepileptic effect. In this study, I examine the inhibition of Na+ currents by mixtures of different anticonvulsants. Quantitative analysis of the shift of steady state inactivation curve in the presence of multiple drugs argues that one channel can be occupied by only one drug molecule. Moreover, the recovery from inhibition by a mixture of two drugs (a fast-unbinding drug plus a slow-unbinding drug) is faster, or at least not slower, than the recovery from inhibition by the slow-unbinding drug alone. Such kinetic characteristics further strengthen the argument that binding of one anticonvulsant to the Na+ channel precludes binding of the other. It also is found that these anticonvulsants are effective inhibitors of Na+ currents only when applied externally, not internally. Altogether these findings suggest that phenytoin, carbamazepine, and lamotrigine bind to a common receptor located on the extracellular side of the Na+ channel. Because these anticonvulsants all have much higher affinity to the inactivated state than to the resting state of the Na+ channel, the anticonvulsant receptor probably does not exist in the resting state. Thus, there may be correlative conformational changes for the making of the receptor on the extracellular side of the channel during the gating process.     

Tacrolimus metabolite cross-reactivity in different tacrolimus assays

OBJECTIVES: Tacrolimus (FK506) is an immunosuppressive drug with great clinical promise. There is a controversy regarding the role of tacrolimus metabolites in immunosuppression and toxicity, and immunoassays and immunophilin binding assays have not been adequately tested for metabolite cross-reactivity. Methods are limited to HPLC and HPLC-MS for quantifying the parent drug. Mixed lymphocyte culture assay (MLC) is the preferred functional bioassay for the measurement of parent drug and active metabolites but it is not practical for routine laboratory use. Due to differences in assay methods and reagent specificity, the concentration of tacrolimus in a given specimen may vary among different assay kit manufacturers. The objective of this study was to evaluate the degree of cross-reactivity or interference of the three first-generation tacrolimus metabolites [13-O-demethyl (M-I), 31-O-demethyl (M-II) and 15-O-demethyl (M-III)] among two different tacrolimus immunoassays (Immunoassay: PRO-Trac II FK506, Abbott IMx tacrolimus-II); and the radioreceptor assays (RRA) using minor immunophilins (14, 37, and 52 kDa immunophilins) and tacrolimus binding protein (FKBP12). METHODS: First-generation tacrolimus metabolites (M-I, M-II, and M-III) spiked in drug-free whole blood were assayed with RRA using three minor immunophilins (14, 37, and 52 kDa) and two commercial immunoassay procedures (Incstar PRO-Trac II tacrolimus, Abbott IMx tacrolimus II). The results were compared to previously published FKBP-12 RRA data and their immunosuppressive potency. RESULTS AND CONCLUSION: The first generation tacrolimus metabolites (M-I, M-II, and M-III) were tested using concentrations of 10 and 20 ng/mL. The significance of the metabolite interference (% of the total interference) was calculated based on the relative concentration of each metabolite present at steady-state trough concentrations in renal transplant recipients (22). Metabolite I, which has no functional immunosuppressive activity showed minimal interference compared to M-II and M-III in all assays except the 14 kDa RRA. The Incstar PRO-Trac II tacrolimus assay showed the least M-I interference. Metabolite-II, which has a pharmacologic potency similar to the parent drug, showed a significant interference in the immunoassays and significant interference in radioreceptor assays. Metabolite III, which is pharmacologically inactive, produces 3-10% interference in the different assays if its presence in the blood is 6% of the parent drug. The total interference from these three metabolites was greater in the immunoassays than in the receptor assays. Receptor assays for tacrolimus provide results closer to the target value than do immunoassays.     

Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy

Carbamazepine and its epoxide in plasma were measured by liquid chromatography in 25 patients treated with a mean dose of carbamazepine of 12.5 +/- 3.3 mg/kg body weight. The mean concentrations of parent drug and metabolite were 5.4 +/- 2.5 mug/ml and 1.10 +/- 0.42 mug/ml, respectively. A singificant correlation was found between the plasma concentrations of the two compounds (r = 0.64; p less than 0.001), but marked interindividual variation existed in the ratio of carbamazepine to carbamazepine to epoxide. Based on simultaneous measurements in plasma and cerebrospinal fluid, the unbound fraction of carbamazepine in plasma was of the order of 20% as compared to 45% for the epoxide. Thirteen ambulant patients suffering from partial epilepsy with complex symptomatology, who were already being treated with phenytoin in optimal doses (plasma level 14-20 mug/ml) were also given carbamazepine. At plasma levels of the latter of about 5 mug/ml there was no further reduction in the frequency of partial or generalized epileptic seizures. In five patients the dose was increased to produce plasma concentrations of 7 - 8 mug/ml. There was still no improvement and side-effects were seen in three patients.     

Positive and negative psychotropic effects of lamotrigine in patients with epilepsy and mental retardation

PURPOSE: To describe significant positive or negative psychotropic effects of lamotrigine (LTG) observed in epilepsy patients with mental retardation (MR). METHODS: Seven mentally retarded epilepsy patients, [5 with Lennox-Gastaut syndrome (LGS)] who experienced significant behavioral improvements or worsening after addition of LTG to their medication regimen were studied. RESULTS: LTG produced behavioral improvements in 4 patients. Patient 1, a 14-year-old girl, had LTG added to valproate (VPA) and thioridazine, resulting in diminished lethargy, less hyperactivity, and more appropriate speech. In a 17-year-old boy (patient 2) LTG added to VPA, phenytoin (PHT), and gabapentin (GBP) lessened irritability and hyperactivity. In patient 3, a 41-year-old woman, LTG added to PHT, VPA, and carbamazepine (CBZ) diminished lethargy and enhanced her social interactions. In patient 4, a 27-year-old man, LTG monotherapy diminished irritability and hyperactivity. Adverse behavioral effects were noted in 3 patients. In patient 5, a 43-year-old man, LTG added to PHT, phenobarbital (PB), lorazepam, sertraline, and thioridazine produced irritability, hyperactivity, and poor cooperation. In patient 6, a 29-year-old woman, LTG added to VPA produced frequent screaming, temper tantrums, increased rocking movements, and hyperactivity. In patient 7, a 29-year-old man, LTG added to VPA and PHT resulted in severe exacerbation of baseline behaviors, including self-injurious activity, temper tantrums, and failure to obey simple instructions. CONCLUSIONS: In some patients with epilepsy and MR, LTG has significant positive or negative effects on behavior.     

Morphological variations of the human gastric mucosa after omeprazole treatment: a scanning electron microscopic study

The effects of antiepileptic drugs on cognitive function in 48 healthy volunteers were assessed using event-related potentials (ERP) and the Attention Index included in the Wechsler Memory Scale, revised edition (WMS-R). The study was conducted over 1 week, using a double-blind design. Four drugs, carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and zonisamide (ZNS) were tested. Using an auditory oddball task, ERP measurements were made under two conditions with different tone intensities: Condition 1 used 70 db SPL; and Condition 2 used 30 db SPL. Results showed that CBZ prolonged target N1 and P3 latencies in Condition 1, and reduced frequent N1 amplitude in Condition 2, which suggests that CBZ may cause a change in sensory memory and prolong stimulus evaluation time. It is suggested that under a low stimulus intensity level, the sensory function itself was affected. Phenytoin was found to prolong target N1 latency in Condition 2, which also indicates a change in the sensory memory function. However, VPA did not significantly affect ERP components, except for the shortened frequent N1 latency, which could not be explained due to the limited information. It was found that ZNS augmented P3 amplitude in Condition 2, and reduced scores on the Attention Index. It is suggested that the augmentation of P3 amplitude was caused by the reduction of processing negativity as a result of the detrimental effect of ZNS on subjects' attention. However, the apparent difference between the ERP and behavioral indices suggests that caution should be exercised in assessing the results obtained only from ERP measurements.     

Clinical case report: multiple idiosyncratic adverse effects of antiepileptic drugs in trisomy 9p

We report the case of a mentally retarded 30 y.o. patient with partial trisomy of chromosome 9, affected by epilepsy. Following treatment with antiepileptic drugs (AEDs), the patient developed several rare complications: after beginning therapy with phenytoin, the patient developed pseudolymphoma; after monotherapy with carbamazepine (CBZ), the patient thereafter developed myoclonic jerks of upper and lower limbs upon awakening; after one year of treatment with valproate (VPA) the patient developed clinical and immuno-haematological signs of SLE. Gradual withdrawal of AED, obtained clinical remission. The possibility that the chromosomal abnormality of the patient was responsible for the three rare complications observed during AED therapy is considered.     

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.     

Linear palmo-plantar porokeratotic hamartoma

We report a case of 30-year-old man with generalized seizure, who had received phenytoin (PHT) for more than 6 years, but developed decrease in sperm count and motility. After PHT had been discontinued and valproate (VPA) had been administered for 3 months, his sperm activity became normalized. The decrease in sperm motility was the most important cause of his infertility. Sperm motility has been reported to be inversely correlated with the ratio of the concentrations of antiepileptic drugs in the plasma and semen. In our case, the ratio was 0.21 for PHT and 0.08 for VPA. We wish to emphasize the importance of measuring the concentration of antiepileptic drugs in the semen of infertile young males if they are on anticonvulsants.     

Central effects of clonazepam

The effects of oral administration of clonazepam, a new benzodiazepine derivative (F. Hoffmann-La Roche), on the central nervous system were compared with those of diazepam and several anticonvulsants in mice and rats. 1) Clonazepam exhibited a moderate inhibitory effect on the locomotor activity observed with open-field situation in mice and no effect in rats, while it inhibited markedly the rearing behavior in both animals, the duration of action being approximately six hours. 2) Clonazepam potentiated the methamphetamine-induced hyper-locomotor activity in mice whereas trimethadione had no effect. 3) Clonazepam inhibited with a moderate potency the conditioned avoidance response and response to a fixed-ratio (FR 20) schedule of food reinforcement in rats, the potency being a little weaker than that of diazepam. 4) The muscle relaxant effect of clonazepam determined by the traction test was slightly more potent as compared with that of diazepam. Thiopental hypnosis was markedly potentiated after clonazepam. 5) The clonic (CL), tonic-flexor (TF) and extensor convulsions (TE) induced by pentetrazol were strongly inhibited after clonazepam in mice, anticonvulsant potency against CL and TE of clonazepam being approximately 23 and 21 times stronger than that of diazepam, 3333 and 3846 times that of trimethadione, and over 3047 and 178 times that of phenytoin, respectively. Clonazepam reduced markedly CL and TE elicited by bemegride with about 12 to 14 times stronger potency than diazepam. On the contrary, the anticonvulsant effect of clonazepam against TE of maximal electroshock seizure evoked by supramaximal current was weak, the potency being 0.71 times weaker than that of phenacemide, 0.14 times than phenytoin and 0.24 times than phenobarbital. By the combined administration of clonazepam with other anticonvulsants such as trimethadione and phenytoin against pentetrazol convulsion, and phenacemide, phenytoin and phenobarbital against maximal electroshock seizure, the antagonistic effect of these anticonvulsants was potentiated by 4 to 5 times. 6) The acute toxicity (LD50) of clonazepam was weak but that of phenacemide or phenytoin was potentiated to a certain degree by combined administration with clonazepam. The results suggest that clonazepam has a psychopharmacological profile similar to that of benzodiazepines with a particularly potent anticonvulsant effect on pentetrazol and bemegride convulsions, and the anticonvulsant effect is synergic with that of other anticonvulsants.     

Biotransformation and toxicity of halogenated benzenes

1. Multiple potentially harmful metabolites can be distinguished in the metabolic activation of halogenated benzenes: epoxides, phenols, benzoquinones and benzoquinone-derived glutathione conjugates. 2. The role of these (re-) active metabolites in the toxic effects induced by halogenated benzenes such as hepatotoxicity, nephrotoxicity, porphyria and thyroid toxicity is discussed. 3. Evidence is presented suggesting that the formation of reactive benzoquinone metabolites rather than the traditional epoxides is linked to halogenated benzene-induced hepatotoxicity. 4. A crucial role for the benzoquinone-derived glutathione adducts in halogenated benzene-induced nephrotoxicity is clearly established. 5. Although metabolic activation appears to be involved in porphyria, the nature of the ultimate porphyrinogenic metabolite has not been elucidated yet. 6. Disturbances in thyroid hormone (and retinoid) homeostasis can be (at least partially) explained by the formation of halogenated phenol metabolites. 7. In conclusion, for a relevant prediction of the ultimate fate of a compound in a living organism, one should know the chemical characteristics and reactivity of the parent compound and its metabolites, together with insight into the formation mechanism of each of the suspected metabolites, and an understanding of the interaction between a specific chemical (reactive) structure and its target molecule.