The new generation of antiepileptic drugs: unresolved questions.
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Anticonvulsants↗
Biomedical subjects
B E Gidal
Publications and source records attributed to B E Gidal.
Diet- and valproate-induced transient hyperammonemia: effect of L-carnitine.
Hyperammonemia is an adverse effect of valproate (VPA) treatment. In particular, transient hyperammonemia has been reported to occur in VPA-treated patients after protein-rich meals. This phenomenon may occur secondary to a VPA-mediated carnitine insufficiency. We sought to confirm that protein ingestion would result in transient hyperammonemia and to determine whether supplementation with L-carnitine would prevent this effect. We studied the effect of consumption of a standardized protein-rich meal (45 g protein) before (phase I) and after (phase II) administration of L-carnitine 50 mg/kg/day for 7 days in 11 epileptic children (13.3 +/- 2.3 years of age) receiving VPA. Venous blood was obtained during fasting (baseline) and at 2 and 4 hours after the protein-rich meal for analysis of ammonia (NH3), and VPA concentrations. Mean VPA trough concentrations did not differ significantly at any time. After protein ingestion, 2-hour NH3 concentration increased by 86% (P < .05) from baseline in phase I as compared with a 38% increase in phase II. In both phases I and II, 4-hour NH3 concentrations decreased toward baseline values. We conclude that (1) modest protein ingestion can result in significant transient increases in NH3 in VPA-treated children, (2) significant increases may occur in patients with normal fasting NH3 concentrations, (3) these increases can be significantly attenuated by L-carnitine supplementation, and (4) these changes do not appear to be related to changes in VPA concentration.
Administration, Oral↗
Lamotrigine pharmacokinetics in patients receiving felbamate.
Drug interactions can significantly complicate the management of patients receiving multiple medications. It is essential therefore that potential pharmcokinetic interactions be evaluated as new antiepileptic medications are introduced. Lamotrigine (LTG) is a recently marketed medication whose pharmacokinetics are significantly influenced by concomitant drugs. Felbamate (FBM), another relatively new antiepileptic agent has been associated with multiple interactions including both enzyme induction and inhibition. The purpose of the present pilot study was to evaluate potential differences in lamotrigine kinetics in six patients concomitantly receiving FBM compared to five patients receiving lamotrigine as monotherapy. There was no statistically significant differences in either apparent LTG oral clearance (0.026 +/- 0.005 vs. 0.024 +/- 0.01 l/kg per h, respectively), or in mean elimination half-life (33.7 +/- 7.5 vs. 40.2 +/- 15.05 h, respectively). Oral clearance values in our patients are also consistent with data reported previously in the literature. Data from this pilot study suggest that a marked effect of FBM upon lamotrigine pharmacokinetics is unlikely.
Adult↗
Effect of lamotrigine on carbamazepine epoxide/carbamazepine serum concentration ratios in adult patients with epilepsy.
Although lamotrigine (LTG) appears to have a low propensity to cause pharmacokinetic interactions with other medications, it has been suggested that LTG may interfere with the elimination of carbamazepine 10,11-epoxide (CBZE), the active metabolite of carbamazepine (CBZ). Evidence for this pharmacokinetic interaction is inconclusive and conflicting, however. We evaluated CBZ apparent oral clearance and the steady-state CBZE/CBZ serum concentration ratios in nine patients (30.8 +/- 7.7 years) with epilepsy prior to and following the initiation of adjunctive treatment with LTG. Overall, CBZ oral clearance was unchanged following the introduction of LTG (5.58 +/- 1.60 vs. 5.81 +/- 1.74 1/h, P = 0.630). Likewise, CBZE to CBZ serum concentration ratios were not significantly different (0.241 +/- 0.082 vs. 0.232 +/- 0.082, P = 0.782). These observations suggest that the addition of LTG did not result in a significant pharmacokinetic interaction involving either CBZ or CBZE.
Administration, Oral↗
Optimized high-performance liquid chromatographic method for determination of lamotrigine in serum with concomitant determination of phenytoin, carbamazepine, and carbamazepine epoxide.
Lamotrigine (LG), phenytoin (PY), carbamazepine (CM), and carbamazepine epoxide (CE) are measured with an optimized procedure that uses thin sorbent extraction disks and a highly selective, sterically protected bonded silica high-performance liquid chromatography (HPLC) column. Routinely, serum (200 microliters at pH 6.8 with cyheptamide as internal standard) is applied to an Empore octyl (C8) solid-phase extraction disk to isolate the drugs. a water wash removes interferences, and the retained drugs are eluted with a small volume of solvent. The eluate is directly injected onto a Zorbax Stable Bond cyanopropyl HPLC column with quantification at 214 nm. Evaporation-concentration steps are unnecessary. Overall, for all drugs, between-run precision coefficients of variation (n = 16 each) ranged from 2.1% to 4.9% at concentrations from 0.75 to 20.5 mg/l; extraction recoveries fell within a range of 96% to 110% at concentrations of 2, 10, and 30 mg/l tested for each drug; the lowest limit of detection was 0.15 to 0.35 mg/l. The analytical response was linear for each drug > 80 mg/l (LG) and > 50 mg/l (PY, CM, and CE). Optimization graphs are presented to illustrate the rationale for selection of test parameters for a robust method. In addition, a comparison study between two commercial laboratories demonstrates accuracy problems associated with LG testing.
Anticonvulsants↗
The concentration-effect relationship with lamotrigine (LTG)
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Anticonvulsants↗
Effects of aspirin on platelet aggregation in smokers and nonsmokers.
OBJECTIVE: To assess the relative antiaggregatory ability of aspirin on platelets of smoking and nonsmoking healthy volunteers. DESIGN: Prospective, randomized, crossover study. SETTING: Tertiary-care teaching institution. SUBJECTS: Eighteen healthy smoking and nonsmoking male volunteers. INTERVENTIONS: Each subject received aspirin 325 mg or ticlopidine 250 mg bid as an active control for 7 days in a crossover manner separated by a 1-month washout period. Whole blood platelet aggregation was measured on four occasions, twice at baseline and once after each drug treatment. OUTCOME MEASUREMENT: Whole blood ex vivo platelet aggregation in terms of impedance (omega) and adenosine triphosphate (ATP) release (nmol), as assessed using Lumi-aggregometry. RESULTS: Aspirin was associated with significantly less ATP release in both smokers (p = 0.01) and nonsmokers (p = 0.003). No significant differences in platelet aggregation were found between smokers and nonsmokers at baseline or with any treatment phases. Sixty-seven percent and 17% of volunteers receiving ticlopidine and aspirin, respectively, reported adverse effects. CONCLUSIONS: Twice-daily administration of aspirin for 7 days to healthy volunteers was well tolerated and also reduced platelet aggregation significantly regardless of smoking status.
Adenosine Triphosphate↗
Melatonin: therapeutic use in sleep disorders.
OBJECTIVE: To review the use of melatonin in sleep disorders, including jet lag, shift work disorder, insomnia, and sleep cycle disorders in neurologically impaired patients. DATA SOURCE: A MEDLINE search (1966 to April 1996) was performed that included clinical studies and reviews on melatonin in the English language. References used in those articles were also screened for additional information. STUDY SELECTION: All published trials were considered for inclusion in this review, with an emphasis placed on more recently published studies (last 5 years). DATA SYNTHESIS: There is significant evidence that links the hormone melatonin to circadian sleep cycles in humans. It has been suggested that in situations where the endogenous melatonin concentration is reduced (advancing age) or the normal circadian cycle is disrupted (jet lag, shift work, blind patients), supplementation with exogenous melatonin may improve both sleep duration and quality. Limited data from generally short-term trials and anecdotal reports suggest that melatonin may be effective in several of these sleep disorders. Melatonin use in jet lag appears to decrease jet lag symptoms and hasten the return to normal energy levels. Melatonin may be helpful in rotating shift schedules to improve sleep quality and maintain normal circadian rhythm. In some patients with insomnia, melatonin appears to induce sleep onset. The optimal dosage and timing of drug administration is still unclear. CONCLUSIONS: Although there is some evidence that melatonin may have modest efficacy, especially in insomnia, jet lag, and sleep disorders in neurologically impaired patients, adequate long-term studies examining both efficacy and toxicity are lacking. In addition, further studies evaluating dose-response relationships and drug interactions are warranted.
Adult↗
Effect of a high-protein meal on gabapentin pharmacokinetics.
The anticonvulsant gabapentin is transported across biological membranes via the L-amino acid transport system (System-L). Absorption of gabapentin is saturable, and in-vitro data have previously demonstrated that both L-leucine and L-phenylalanine may compete with the intestinal transport of gabapentin. The purpose of this study therefore was to determine whether a high-protein meal would interfere with gabapentin absorption. Ten healthy volunteers received in a randomized, cross-over design, a single 600-mg dose of gabapentin in the fasting state and after a high-protein meal consisting of 80 gm total protein (4.1 g phenylalanine, 8.2 g leucine and 4.2 g isoleucine), 52 g carbohydrate, and 9 g fat. Plasma gabapentin concentrations were measured by HPLC at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 30 h. Calculated pharmacokinetic parameters included Cmax' Tmax' AUC and T1/2. In addition, a pharmacodynamic assessment (using visual analog scales) of gabapentin-related adverse effects was performed at 2 h post drug ingestion and was compared between study phases. Statistical analysis included Student's t-test for paired data, with significance assigned at P < 0.05. Cmax was significantly increased by 36% (3.87 +/- 1.15 vs 5.28 +/- .97 micrograms/ml, P = 0.002), and Tmax tended to be shorter (3.9 +/- 1.8 vs 2.8 +/- .35 h, P = 0.10), after the high-protein meal. Although AUC was increased by 11%, this did not achieve statistical significance. Despite significantly higher plasma concentrations at 2 h, subjects reported significantly fewer adverse effects after the high-protein meal. Potential mechanisms to explain these unexpected findings may be that the large amino acid load delivered with the high-protein meal enhanced gabapentin absorption via trans-stimulation, the process by which acutely increased intestinal luminal amino acid concentrations result in an acute up regulation in System-L activity. Conversely, the decrease in perceived adverse CNS effects of gabapentin following the high-protein meal may reflect CNS competition for System-L transport.
Acetates↗
Bidirectional interaction of valproate and lamotrigine in healthy subjects.
OBJECTIVE: To evaluate the steady-state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady-state therapeutic doses of valproate. METHODS: This was an open-label, randomized, three-way crossover study of 18 normal male volunteers. Subjects received oral valproate (500 mg Depakote twice a day) throughout the study. Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) for 1 week each, with a 2-week washout period between lamotrigine treatment periods. Valproate and lamotrigine trough plasma samples were determined by a capillary gas chromatography method and immunofluorometric assay, respectively. Urine samples were assayed for 11 valproate metabolites by gas chromatography/mass spectrometry. RESULTS: When compared to other studies in which lamotrigine was administered with no concurrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug. The addition of lamotrigine was associated with a small but significant 25% decrease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pentenoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E),4-diene-valproate], was unaffected by lamotrigine administration. CONCLUSIONS: As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.
Analysis of Variance↗
Evaluation of carbamazepine and carbamazepine-epoxide protein binding in patients undergoing epilepsy surgery.
Carbamazepine (CBZ) serum concentrations increase after epilepsy surgery. A possible mechanism may be acute changes in protein binding, specifically those involving the acute phase reactant alpha(1)-acid glycoprotein (AAG). We prospectively evaluated 16 adults (11 receiving CBZ) with epilepsy (mean age 30 +/- 9.9 years, 8 women and 8 men) undergoing temporal lobe resections and characterized AAG, albumin, CBZ, and CBZ-epoxide (CBZ-E) free fractions over time. AAG, ALB, CBZ, and CBZ-E free fractions were determined before surgery (baseline) and on postoperative days 1-5, 14, and 30. AAG was measured with a radial immunodiffusion assay method, CBZ and CBZ-E serum concentrations were determined by high-performance liquid chromatography (HPLC). Free fractions of CBZ and CBZ-E were calculated as the ratio of unbound (determined after ultracentrifugation) to total serum drug concentrations. Statistical analysis included analysis of variance (ANOVA) and Student's t test for paired data when appropriate, with significance assigned at p<0.05. All data are mean +/- SD. AAG concentrations increased significantly from baseline 61.9 +/- 21.3 mg/dl), peaking at postoperative day 3 (116.8 +/- 20.6 mg/gl) and decreasing to baseline levels between days 14 and 30. CBZ serum concentrations were significantly increased in the immediate postoperative period (day 3), but albumin concentrations and CBZ and CBZ-E free fractions did not differ significantly between baseline and the postoperative time points. Temporal lobe resection results in an acute phase reaction which is manifested in part by significant changes in AAG. Although CBZ and CBZ-E total serum concentrations increased significantly in the immediate postoperative period, epilepsy surgery did not appear to result in significant overall changes in drug binding to plasma proteins.
Adult↗
Changes in interleukin-6 concentrations following epilepsy surgery: potential influence on carbamazepine pharmacokinetics.
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Adult↗
Current developments in neurology, Part I: Advances in the pharmacotherapy of headache, epilepsy, and multiple sclerosis.
When caring for patients with disorders of the central nervous system such as migraine headaches, epilepsy, or MS, clinicians are faced with increasingly complex pharmacotherapeutic options. Pharmacotherapeutic strategies directed toward prevention, reversal, or cure of these diseases are hampered by an incomplete understanding of the underlying pathophysiology. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some seemingly overwhelming questions for these devastating illnesses.
Adjuvants, Immunologic↗
Potential interaction between warfarin and dicloxacillin.
OBJECTIVE: To report a case and retrospective review of seven patients who experienced a decrease in prothrombin time during concomitant administration of warfarin and dicloxacillin. CASE SUMMARY: A 41-year-old man receiving warfarin 22 mg/wk with a final baseline prothrombin time (PT) of 20.7 sec was prescribed dicloxacillin 500 mg qid for 10 days. Plasma collected for PT determinations was also used to measure trough warfarin R- and S- enantiomer concentrations. The PT and S- and R-warfarin concentrations decreased 17%, 25%, and 20%, respectively, on day 5 after initiation of dicloxacillin. For the retrospective review, the mean PT decreased 17.0% (range 10.5-25.9%) as soon as 4 days after the initiation of dicloxacillin. DISCUSSION: Our observations, which are consistent with those of two previously published reports, suggest a close temporal relationship between the administration of dicloxacillin and a decreased anticoagulant effect of warfarin. Limited data from our patient further suggest that this may result from declines in systemic warfarin concentrations. The time course of the fall of PTs appears to occur within 4-5 days; return of the PT to baseline after dicloxacillin administration is stopped appears to take up to 3 weeks. Until further controlled studies are conducted to confirm this interaction, clinicians should be aware that patients may be at risk for a decreased anticoagulant effect of warfarin when dicloxacillin is given concomitantly. CONCLUSIONS: Careful monitoring of international normalized ratios and titration of the warfarin dosage is recommended on initiation and for 3 weeks after discontinuation of dicloxacillin in patients receiving warfarin.
Adult↗
Current developments in neurology, Part II: Advances in the pharmacotherapy of Alzheimer disease, Parkinson's disease, and stroke.
Disorders of the central nervous system provide innumerable challenges to the clinician. Often the underlying pathophysiology is not completely understood, thus preventing the design of treatment strategies aimed at correcting the underlying process. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some of these seemingly over-whelming questions for these devastating illnesses.
Alzheimer Disease↗
Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies.
Consistent with expectations based on human in vitro microsomal experiments, administration of fluconazole (400 mg/day) for 6 days to six human volunteers significantly reduced the cytochrome P450 (P450)-dependent metabolic clearance of the warfarin enantiomers. In particular, P4502C9 catalyzed 6- and 7-hydroxylation of (S)-warfarin, the pathway primarily responsible for termination of warfarin's anticoagulant effect, was inhibited by approximately 70%. The change in (S)-warfarin pharmacokinetics caused by fluconazole dramatically increased the magnitude and duration of warfarin's hypoprothrombinemic effect. These observations indicate that co-administration of fluconazole and warfarin will result in a clinically significant metabolically based interaction The major P450-dependent, in vivo pathways of (R)-warfarin clearance were also strongly inhibited by fluconazole. 10-Hydroxylation, a metabolic pathway catalyzed exclusively by P4503A4, was inhibited by 45% whereas 6-, 7-, and 8-hydroxylations were inhibited by 61, 73, and 88%, respectively. The potent inhibition of the phenolic metabolites suggests that enzymes other than P4501A2 (weakly inhibited by fluconazole in vitro) are primarily responsible for the formation of these metabolites in vivo as predicted from in vitro kinetic studies. These data suggest that fluconazole can be expected to interact with any drug whose clearance is dominated by P450s 2C9, 3A4, and other as yet undefined isoforms. Overall, the results strongly support the hypothesis that metabolically based in vivo drug interactions may be predicted from human in vitro microsomal data.
Adult↗
Immunotherapy in multiple sclerosis, Part 2.
The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits.
Adult↗
Immunotherapy in multiple sclerosis, Part 1.
The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits.
Adrenal Cortex Hormones↗