Possible Interaction Between Oxcarbazepine and an Oral Contraceptive

The effect of oxcarbazepine (OCBZ) on the kinetics of an oral contraceptive containing ethinyloestradiol (EE) and levonorgestrel (LNG) was investigated in 13 healthy female volunteers who had previously received the contraceptive for at least 3 months. After 15 days of the first study cycle, each subject received, in addition to the oral contraceptive, 300 mg OCBZ on day 16, 300 mg twice daily on day 17, and 300 mg three times daily from day 18 of the first cycle to day 18 of the next menstrual cycle. The area under the curve values for both EE and LNG decreased when OCBZ was given with the oral contraceptive (p = 0.006, analysis of variance). The results indicate that OCBZ, like most antiepileptic drugs (AEDs), decreases the bioavailability of EE and LNG, perhaps by affecting metabolism or protein binding.     

Liver Enzyme Induction and Serum Lipid Levels After Replacement of Carbamazepine with Oxcarbazepine

Summary: We evaluated liver P450 enzyme system induction and serum lipid levels in a prospective follow–up study in 12 male patients with epilepsy after replacing carbamazepine (CBZ) medication with oxcarbazepine (OCBZ). Antipyrine_{1 1/2} increased and antipyrine_CL decreased 2 months after the medication was changed, reflecting normalization of liver P450 enzyme system function. Furthermore, serum total cholesterol levels decreased, but serum concentrations of high-density lipoprotein (HDL)-cholesterol and triglycerides (TG) were unchanged. OCBZ may be the preferable antiepileptic drug (AED) with regard to the effects of the medication on lipid metabolism.     

Do Anticonvulsants Reduce the Efficacy of Oral Contraceptives?

Women in our area with epilepsy who were also taking oral contraceptives were identified. Of 82 patients taking oral contraceptives, 41 had used both anticonvulsants and oral contraceptives for a total of 955 months. Three documented oral contraceptive (pill) failures occurred during this period, whereas the expected number of 0.12 (relative risk, 25; 95% confience interval, 5 to 73). No pill failures were observed in 2,278 months among women with epilepsy who were taking oral contraceptives but who were not taking anticonvulsants at this time. Thus our data support the suggestion that there is an increased rate of pill failure among women taking anticonvulsants. In view of this diminished effectiveness, the advisability of using oral contraceptives rather than one of the other forms of contraception when anticonvulsant medication is being used concurrently may need to be reevaluated.     

Concentrations and Effects of Oral Midazolam are Greatly Reduced in Patients Treated with Carbamazepine or Phenytoin

Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacody-namic aspects of an oral 15–mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration-time curve (AUC) of midazolam (mean 2 SEM) was only 5.7% (0.60 ± 0.16 vs. 10.5 ± 0.6 μg - min/ml), and the peak midazolam concentration was 7.4% (5.2 ± 1.2 vs. 70.4 ± 9.0 μg/ml) of its value in control subjects (p < 0.001). The elimination half-life (t1/2) of midazolam was 1.3 ± 0.2 h in patients and 3.1 ± 0.1 h in controls (p < 0.001). The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects [e.g., the Critical Flicker Fusion Test (CFFT), p < 0.05]. Induction of CYP3A (cytochrome P-450IIIA) enzymes by CBZ and PHT is the most likely explanation of the great difference in the pharmacokinetic and pharmacodynamic profiles of oral midazolam in the two groups.     

Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine

PURPOSE: To characterize the metabolic profile of topiramate (TPM) in humans and to assess the influence of enzyme induction by carbamazepine (CBZ) on the pharmacokinetics and metabolic profile of TPM. METHODS: Twelve healthy subjects received a single oral dose of TPM (200 mg) on two randomized occasions. On one occasion, TPM was administered alone, and on the other, it was given on day 18 of a 24-day treatment with CBZ (maintenance dosage, 600 mg/day). Blood and urine samples were collected for > or = 72 h after dosing. TPM and its metabolites were assayed in plasma and urine by a specific liquid chromatography-mass spectroscopy (LC-MS) method. RESULTS: Mean TPM oral clearance (CL/F) increased from 1.2 L/h (control) to 2.2 L/h after CBZ treatment. Mean TPM half-life decreased from 29 h to 19 h. TPM was excreted extensively in urine both under noninduced (56%) and CBZ-induced conditions (40%). 2,3-O-Des-isopropylidene-TPM (2,3-diol-TPM) was identified as the most prominent urinary metabolite, with a recovery accounting for 3.2% and 7.9% of the TPM dose under noninduced and induced conditions, respectively. Corresponding recovery values for 10-hydroxy-TPM (10-OH-TPM) were 1.2% and 1.8%, respectively. The control AUC(metabolite)/AUC(drug) ratio for 2,3-diol-TPM and 10-OH-TPM were 1.5% and 0.6%, and they increased by threefold and twofold, respectively, after CBZ treatment. CONCLUSIONS: TPM remains appreciably excreted unchanged in urine (41%) under CBZ-induced conditions, even though TPM CL/F increased by twofold. Although 2,3-diol-TPM and 10-OH-TPM were measured in unconjugated form, the significant increases in their AUC and urinary excretion are consistent with the twofold increase in TPM clearance.     

Plasma concentrations of risperidone and olanzapine during coadministration with oxcarbazepine

PURPOSE: Oxcarbazepine (OZC) is a second-generation antiepileptic drug (AED) that also may be used as a mood stabilizer. Unlike carbamazepine (CBZ), which is an inducer of the cytochrome P-450 isoforms and may accelerate the elimination of several therapeutic agents, OXC seems to have only a modest inducing action. The aim of this investigation was to evaluate the effect of a treatment with OXC on plasma concentrations of the new antipsychotics risperidone and olanzapine. METHODS: OXC, at a dosage of 900-1,200 mg/day, was administered for 5 consecutive weeks to 25 outpatients, 10 men and 15 women, aged 25 to 64 years, with bipolar or schizoaffective disorder. Twelve patients were stabilized on risperidone therapy (2-6 mg/day) and 13 on olanzapine (5-20 mg/day). Steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and olanzapine were measured by high-pressure liquid chromatography (HPLC) before addition of OXC and after 5 weeks from the start of adjunctive treatment. RESULTS: OXC caused only minimal and no significant changes in the mean plasma levels of risperidone (from 5.6 +/- 3.6 ng/ml at baseline to 4.8 +/- 2.6 ng/ml at week 5), 9-OH-risperidone (from 23.6 +/- 7.5 to 24.7 +/- 7.4 ng/ml), and olanzapine (from 26.5 +/- 5.7 ng/ml at baseline to 27.8 +/- 5.1 ng/ml). OXC coadministration with either risperidone or olanzapine was well tolerated. CONCLUSIONS: Our findings indicate that OXC does not affect the elimination of risperidone and olanzapine, thus confirming its weak inducing effect on hepatic drug-metabolizing enzymes.     

Comparison of Cognitive Effects of Lamotrigine and Oxcarbazepine in Epilepsy Patients

Background and Purpose

This study compared the cognitive effects of 1 year of treatment with lamotrigine (LTG) and oxcarbazepine (OXC) in epilepsy patients.

Methods

This retrospective study investigated 60 epilepsy patients undergoing neuropsychological tests who were either newly diagnosed or untreated in the preceding 6 months. The cognitive function in 30 patients receiving LTG monotherapy and 30 age-matched patients receiving OXC monotherapy was compared after 1 year. The neuropsychological scores at baseline and all of the epilepsy-relevant variables except seizure type did not differ between the groups. The mean daily dosages of LTG and OXC at 1 year were 93 mg and 825 mg, respectively.

Results

The posttreatment list-learning performance was better in the LTG group than in the OXC group (p<0.05). The incidence of cognitive complaints did not differ between the two groups. The list-learning performance and Trail Making Test scores were better in each group after treatment.

Conclusions

LTG and OXC monotherapies have similar, slightly beneficial effects on cognitive function, and are probably not harmful.     

Women with Epilepsy: Must Contraception and Pregnan Add to the Burden of Epilepsy?

Summary: In addition to seizure control, women with epilepsy face particular complications associated with menstruation, fertility, contraception, pregnancy, and breastfeeding. With traditional long-term antiepileptic drug (AED) therapy there is a risk of menstrual irregularities, contraceptive failure, and adverse pregnancy outcome. Many women intentionally discontinue AED therapy during pregnancy because of concerns about the risk of fetal malformation and effects on fetal growth and development. However, trauma resulting from seizures is the leading cause of maternal and fetal death in women with epilepsy. In addition, mothers are concerned about the presence of AEDs in breast milk and therefore tend to choose bottle feeding. Clearly, a balance must be achieved between seizure control for the mother and exposure of the fetus or infant to AEDs. Tiagabine (TGB) is a new AED which acts by inhibiting uptake of the neurotransmitter γ-aminobutyric acid into glial cells. Animal studies show that TGB has no toxic effects either on reproductive function or on the developing fetus, although there is still insufficient evidence to permit conclusions from human studies. TGB does not induce hepatic metabolism, and a study in healthy volunteers indicates no interaction with oral contraceptives. It is hoped that the availability of new AEDs such as TGB, with the promise of a better safety profile and a lower propensity for drug interactions, will alleviate the burden for women with epilepsy.     

A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy

PURPOSE: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state. METHODS: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS). RESULTS: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug. CONCLUSIONS: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.     

Oxcarbazepine is effective and safe in the treatment of neuropathic pain: pooled analysis of seven clinical studies

Abstract The results of 7 open-label clinical studies on oxcarbazepine (OXC) in different neuropathic pain conditions, sharing the same protocols, were pooled together in order to evaluate whether the results obtained in the individual trials were confirmed in the pooled analysis of this larger sample, providing more evidence for efficacy and tolerability of OXC in these conditions. Eligible patients (>18 years old) with a diagnosis of neuropathic pain were enrolled in seven open-label trials, consisting of a oneweek prospective Screening Phase followed by an eight-week Treatment Phase. Treatment with OXC was initiated at 150 mg/day, and the daily dose was increased by 150 mg/day on a 2–3 day basis to the maximum tolerated dose over four weeks, up to 1800 mg/day. The primary outcome measure was the change in the actual pain rating assessed on the visual analogue scale (VAS) between the end of the Screening Phase and the end of the Treatment Phase. One hundred and thirty-six patients were enrolled in the trials. The mean VAS score dropped from 77.13 at the end of the Screening Phase to 38.41 at the end of the trial for a mean reduction of 50.2%. The percentage of responders (mean VAS score reduction ≥50%) was 49.2%. OXC was well tolerated, with the most common adverse events consisting of vertigo, tremor, somnolence, hypotension and nausea. The results of this analysis suggest that OXC administered as monotherapy is an efficacious and safe option for the symptomatic treatment of pain associated with neuropathies.     

Efficacy, tolerability, and pharmacokinetics of oxcarbazepine oral loading in patients with epilepsy

The rapid achievement of effective levels of antiepileptic drugs (AEDs) is required in patients with epilepsy who have a higher risk of seizures, and oral loading of AEDs may be an important consideration in these patients. We performed the present study to investigate the efficacy and tolerability of oral loading of oxcarbazepine in patients with recurrent seizures, or after temporary discontinuation of AEDs for diagnostic or presurgical evaluation of epilepsy. Forty adult patients were studied and oxcarbazepine was administered orally at a single loading dosage of 30 mg/kg. The plasma levels of oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), were measured, and clinical assessment of adverse events was performed at 2, 4, 6, 8, 10, 12, 16, and 24 h after oral loading of oxcarbazepine. Approximately two-thirds of patients reached effective levels of MHD 2 h after receiving the oral loading, and all patients reached effective levels 4 h after oxcarbazepine administration. Most patients maintained therapeutic MHD levels for at least 16 h. Almost half of the patients experienced adverse events, but all were mild to moderate in severity and resolved spontaneously within 24 h. Our study shows that oral loading of oxcarbazepine is an effective and well-tolerated method for rapidly achieving therapeutic levels of MHD in patients with epilepsy, and is a useful option in selected patients with recurrent seizures, or after temporary discontinuation of AEDs.     

Effect of Topiramate on the Pharmacokinetics of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol in Patients with Epilepsy

Summary: Purpose: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. Methods: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-μg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200f and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. Results: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100–400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC_0–24) values for ethinyl estradiol were 18–30% lower in cycles 2 through 4 compared with cycle 1 (p 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7–33.0% higher (p 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T_max values determined during topiramate therapy were not significantly different from those at baseline. Conclusions: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing 235 μg of ethinyl estradiol.     

Anticonvulsant Action of Oxcarbazepine, Hydroxycarbamazepine, and Carbamazepine Against Metrazol-Induced Motor Seizures in Developing Rats

Summary: Antimetrazol effects of carbamazepine (CBZ, 5, 12.5, 25, or 50 mg/kg), oxcarbazepine (OCBZ, 5, 10, 30, or 60 mg/kg), and hydroxycarbamazepine (HCBZ, the main human metabolite of OCBZ, 10, 30, or 60 mg/kg) were studied in 7–, 12–, 18–, 25–, and/or 90-day-old laboratory rats. No drug tested affected the incidence of minimal (clonic) metrazol seizures (mMs) in animals aged ≥18 days; in rats aged 7 or 12 days in which mMs are rare under control conditions, the incidence of mMs was increased by lower doses of CBZ and HCBZ. All drugs tested specifically abolished the tonic phase of major generalized tonic-clonic seizures (MMs) in a dose-dependent manner. In addition, CBZ and OCBZ were able to suppress all phases of MMs in the two youngest groups (7-and 12-day-old). There were no marked differences among the three drugs tested (CBZ, OCBZ, and HCBZ) on their action against metrazol-induced seizures during ontogenesis of rats; i.e., all these drugs appeared to possess an identical profile of anticonvulsant action.     

A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4

PURPOSE: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. METHODS: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. RESULTS: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36-164; p=0.0022) and 181% (CI: 120-260, p<0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139-187, p<0.0001) (OXCZ) and 222% (CI: 192-257, p<0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16-40, p=0.0018) (OXCZ) and 33% (CI: 18-45, p=0.0020) (CBZ). T1/2 decreased by means of 12% (CI: 6-17, p<0.0014) (OXCZ) and 32% (CI: 25-38, p<0.0001) (CBZ). tmax was not changed in either period. CONCLUSION: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance.     

Pharmacokinetics and safety of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures: A randomized,multicenter, open‐label phase 1 study

Purpose: To characterize the pharmacokinetics of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures (POS); also to evaluate safety and tolerability of topiramate in the dose range of 3–25 mg/kg/day. Methods: In this open‐label phase 1 study, infants (N = 55) with refractory POS receiving at least one concurrent antiepileptic drug (AED) were enrolled. Infants were stratified by age and randomly assigned to one of four topiramate target dose groups (3‐, 5‐, 15‐, or 25 mg/kg/day). Treatment was initiated at 3 mg/kg/day with titration to the target dose by weekly dose escalation. Topiramate was administered daily in two divided doses as oral liquid (5 mg/ml for infants <9 kg or those who could not tolerate solid foods) or sprinkle capsule (25 mg) formulations. Following seven consecutive days of topiramate administration at the target dose, four blood samples were collected from each infant for pharmacokinetic assessments (predose, 1–3, 4–6, and 8–10 h postdose). Key Findings: Fifty‐five infants (mean [SD] age in months: 11.4 [5.79]) with POS were enrolled, of whom 33% had seizures with or without secondary generalization. Complete pharmacokinetic profiles were obtained in 35 infants in whom mean plasma topiramate concentration–time profiles demonstrated linear pharmacokinetics (predose topiramate concentrations [C_trough] and area under the plasma concentration–time curve from time 0 through 12 h [AUC_{12 h}]) of topiramate over the dose range studied). Apparent steady state oral clearance (CL_ss/F) remained similar across all topiramate target dose groups and was independent of creatinine clearance, age, and weight. Mean values for CL_ss/F were approximately twofold greater in infants receiving concomitant enzyme‐inducing AEDs versus enzyme‐inhibiting AEDs. Topiramate was well tolerated and safety findings were consistent with previous reports in children and adults. Most common treatment emergent adverse events (≥10%) were upper respiratory tract infection, fever, vomiting, somnolence, and anorexia. Significance: In infants (1–24 months), topiramate exhibited linear steady state pharmacokinetics over the dose range 3–25 mg/kg/day, and CL_ss/F of topiramate was independent of dose. Moreover, the concomitant enzyme‐inducing AEDs doubled the clearance of topiramate. Topiramate was generally well tolerated as adjunctive therapy at doses up to 25 mg/kg/day.     

A Double-Blind, Placebo-Controlled Study on the Effect of Vigabatrin on In Vivo Parameters of Hepatic Microsomal Enzyme Induction and on the Kinetics of Steroid Oral Contraceptives in Healthy Female Volunteers

Summary: Purpose: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. Methods: Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of ≤= 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-β-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum γ-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 μg ethinyl estradiol and 150 μg levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. Results: VGB treatment had no influence on antipyrine clearance (28 ± 5.6 vs. 30 ± 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 ± 3.5 vs. 14.1 ± 2.1 h), urinary 6–β-hydroxycortisol excretion (488 ± 164 vs. 470 ± 228 nmol/day), 6-β-hydroxycortisol-to-cortisol concentration ratio (6.8 ± 3.1 vs. 6.1 ± 3.1) and serum γ-glutamyltransferase activity (12 ± 3 vs. 11 ± 3 IUIL). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 ± 3.2 vs. 13.9 ± 3.2 h; AUC, 874 ± 301 vs. 939 ± 272 ng/L/h) and levonorgestrel (half-life, 17.7 ± 5.2 vs. 23.1 ± 9.8 h; AUC, 27.5 ± 9.6 vs. 30.0 ± 12.0 μg/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. Conclusions: At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.     

Inhibition of Carbamazepine and Phenytoin Metabolism by Nafimidone, a New Antiepileptic Drug

When nafimidone (NFM), a new antiepileptic drug, was given to six patients already taking carbamazepine (CBZ) and phenytoin (PHT) as part of a late phase I pilot efficacy trial, it reduced CBZ elimination by 76-87% and reduced PHT elimination by 38-77%. CBZ and PHT levels rose within 24 h after NFM was started, and began to decline within 12 h after NFM was stopped. The inhibitory effect on CBZ metabolism persisted throughout the course of 1 year of long-term follow-up in all five patients who continued with the drug after completion of the pilot study. Inhibition of PHT elimination persisted in three of the patients, but PHT elimination returned to baseline rates in the other two patients during long-term follow-up. The inhibition of CBZ and PHT metabolism is probably due to binding of cytochrome P-450 by NFM or a metabolite and thus inhibition of the hepatic microsomal mixed-function oxidase system.     

Effects of an antiandrogenic oral contraceptive on appetite and eating behavior in bulimic women

High androgen levels in women with bulimia nervosa may promote bulimic behavior. The aim of the present study was to investigate the effects of an antiandrogenic oral contraceptive (OC) on appetite and eating behavior in women with bulimia nervosa compared to healthy controls. Twenty-one women with bulimia nervosa and 17 healthy controls matched for age and body mass index participated in the study. Basal and meal-related appetite and secretions of the satiety peptide cholecystokinin (CCK) and the appetite-stimulating peptide ghrelin were studied before and after 3 months of treatment with an antiandrogenic OC (30 microg ethinyl estradiol combined with 3 mg drospirenone). Bulimic behavior was evaluated in relation to changes in hormone levels. Before treatment, bulimic women had higher frequency of menstrual disturbances, acne and hirsutism and higher levels of testosterone but lower meal-related CCK secretion than controls. OC treatment reduced meal-related hunger and gastric distention in bulimics. CCK secretion in response to the meal was unchanged in bulimic women but decreased in the controls. Ghrelin secretion was comparable between groups and did not change in response to OC treatment. The treatment improved bulimic behavior in relation to a decline in testosterone levels in the entire group. Our results support the suggestion that androgens play a role in bulimic behavior. Treatment with an antiandrogenic OC may serve as a new strategy for treatment of bulimia nervosa and particularly in those patients with hyperandrogenic symptoms.     

Cigarette smoking and risk of cerebral sinus thrombosis in oral contraceptive users: a case-control study

Abstract Idiopathic cerebral sinus thrombosis (CST) can cause death and serious neurological disability. It is unknown whether smoking, a major risk factor for arterial stroke, is a risk factor also for CST. This work explored the association between smoking and CST in a hospitalbased, multicentric, case-control study. In order to avoid the confounding effect of the different risk factors for CST, we analysed the homogeneous subgroup of oral contraceptive users. We compared the prevalence of smoking in a group of 43 young women with CST (cases), whose oral contraceptive use was the only known risk factor, with a sample of 255 healthy contraceptive users of similar age (controls). The prevalence of smoking in cases and controls was similar (26% vs. 29%). The age and geographic area-adjusted odds ratio was 0.9; 95% confidence interval, 0.4–1.8; p=0.7. Smoking in oral contraceptive users does not appear to be associated with CST.