A comprehensive hepatitis C viral kinetic model explaining cure.

We propose a model that characterizes and links the complexity and diversity of clinically observed hepatitis C viral kinetics to sustained virologic response (SVR)-the primary clinical end point of hepatitis C treatment, defined as an undetectable viral load at 24 weeks after completion of treatment)-in patients with chronic hepatitis C (CHC) who have received treatment with peginterferon alpha-2a +/- ribavirin. The new attributes of our hepatitis C viral kinetic model are (i) the implementation of a cure/viral eradication boundary, (ii) employment of all hepatitis C virus (HCV) RNA measurements, including those below the lower limit of quantification (LLOQ), and (iii) implementation of a population modeling approach. The model demonstrated excellent positive (99.3%) and negative (97.1%) predictive values for SVR as well as high sensitivity (96.6%) and specificity (99.4%). The proposed viral kinetic model provides a framework for mechanistic exploration of treatment outcome and permits evaluation of alternative CHC treatment options with the ultimate aim of developing and testing hypotheses for personalizing treatments in this disease.

Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females.

INTRODUCTION: Ibandronate is a potent, nitrogen-containing bisphosphonate that is licensed as a once-monthly oral preparation and is currently in clinical development as a novel intermittent intravenous (i.v.) injection in osteoporosis. Ibandronate pharmacokinetic (PK) data were used to develop a PK model that could ultimately be incorporated into a PK pharmacodynamic (PD) model to assist the ibandronate development program through computer-assisted trial design. This manuscript reports the use of non-linear mixed-effects modeling to characterize the PK of ibandronate, to examine the possible influence of ethnicity on the disposition of ibandronate and to develop an appropriate population PK model for ibandronate. METHODS: A retrospective, cross-study population PK analysis was performed using PK data from five phase I studies with i.v. ibandronate (0.125 - 2.0 mg) conducted in Caucasian and Japanese healthy male volunteers, postmenopausal Caucasian women without osteopenia and postmenopausal Japanese women with osteopenia. The following covariates were investigated to establish their influence on the central volume of distribution (V1) and drug clearance (CL): age, body weight, gender, disease status (healthy versus osteopenic), creatinine clearance (CLCR), and ethnicity (Japanese versus Caucasian). Serum concentrations of ibandronate were quantified by GC-MS or ELISA, and data were modeled using non-linear mixed-effects modeling implemented by the software program NONMEM. RESULTS: The PK of ibandronate was adequately described by a linear 3-compartment model. Disease status, body weight, gender and CLCR significantly influenced ibandronate CL (10 34%) and the latter 3 also influenced V1 (20 29%). Ethnicity was not a determinant for ibandronate PK in the final model. Although gender was the most influential covariate, differences in V1 and CL between the sexes were modest (29 and 34%, respectively) and the overall effects on ibandronate exposure (Cmax and AUC) were not clinically relevant. The final model described the observed PK of ibandronate well, and all PK parameters were estimated with an acceptable degree of precision (SE < 13%). CONCLUSION: The PK of i.v. ibandronate was well described by a linear 3-compartment population PK model that included disease status, body weight, gender and CLCR as covariates, but without greatly affecting ibandronate exposure (Cmax and AUC). Ethnicity did not influence ibandronate PK and was not included in the final model.

Interaction between saquinavir soft-gel and rifabutin in patients infected with HIV.

AIMS: To evaluate the potential pharmacokinetic interaction between the HIV protease inhibitor saquinavir and rifabutin. METHODS: Fourteen HIV-infected patients provided full steady-state pharmacokinetic profiles following administration of rifabutin alone (300 mg once daily) or saquinavir soft-gel formulation (1200 mg three times daily) plus rifabutin (300 mg once daily) in this open label, partially randomized study. RESULTS: Coadministration of saquinavir and rifabutin resulted in a reduction in saquinavir AUC(0,8 h) and C(max)(0,8 h) of 47% (95% CI 30, 60%) and 39% (95% CI 11, 59%), respectively. Rifabutin AUC(0,24 h) and C(max)(0,24 h) was increased by an average of 44% (95% CI 17, 78%) and 45% (95% CI 14, 85%), respectively. Saquinavir in combination with rifabutin was well tolerated. Gastrointestinal intolerance and asymptomatic increases in liver enzymes were the only adverse events of note. CONCLUSIONS: Administration of rifabutin with saquinavir may decrease the efficacy of this HIV protease inhibitor.

The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients.

OBJECTIVE: The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily. METHODS: In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily. In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily. Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment. RESULTS: In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82). In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively. When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment. CONCLUSION: Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients. The effects observed in patients, however, appear to be less pronounced. The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance.

The effect of warfarin on the pharmacokinetics and pharmacodynamics of napsagatran in healthy male volunteers.

OBJECTIVE: The effect of oral warfarin on the pharmacokinetics and pharmacodynamics of the synthetic direct thrombin inhibitor napsagatran was investigated. METHODS: In an open, randomised, two-way crossover study, 12 healthy male volunteers were infused napsagatran (80 micrograms/min) for 48 h. Each subject was administered 25 mg warfarin (Coumadin) at the start of the infusion in either the first or second treatment period. Sampling was performed regularly over the treatment period and 24 h thereafter for measurement of plasma levels of napsagatran, activated partial thromboplastin time (APTT) and prothrombin time (PT). RESULTS: The pharmacokinetic parameters of napsagatran were not significantly influenced by co-administration of warfarin. Napsagatran administration was followed by increases in APTT and PT. Co-administration of warfarin increased the AUEC (area under the effect curve) calculated for the period 0-48 h (corrected for baseline) for APTT by 45% (95% CI: 28-65%) and for PT by 438% (95% CI: 272-678%) compared to the treatment with napsagatran alone. CONCLUSION: Warfarin has no effect on the pharmacokinetics of napsagatran, but has a marked influence on the pharmacodynamic parameters (APTT, PT) of napsagatran. In clinical practice, this interaction between the two compounds should be taken into account. The PT cannot be used to monitor the effect of oral anticoagulants during the switch from this group of direct thrombin inhibitors to full oral anticoagulant therapy.

Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients.

PURPOSE: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. METHODS: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. RESULTS: Based on the primary pharmacokinetic parameter, AUC(0-infinity) of 5'-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the t(max) for the two formulations (median 2.1 versus 2.0 h). The estimate for C(max) was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5'-DFUR reached the systemic circulation and the rate at which 5'-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC(0-infinity) and C(max) of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC(0-infinity) and C(max) of intact drug and for C(max) of FBAL, which were higher in females than in males. CONCLUSION: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites.

Capecitabine (Xeloda) is a rationally designed oral, tumor-selective fluoropyrimidine carbamate aimed at preferential conversion to 5-fluorouracil (5-FU) within the tumor. Because capecitabine is extensively metabolized by the liver, it is important to establish whether liver dysfunction altered the pharmacokinetics of capecitabine and its metabolites. This was investigated in 14 cancer patients with normal liver function and in 13 with mild to moderate disturbance of liver biochemistry due to liver metastases. They received a single oral dose of capecitabine (1255 mg capecitabine/m2) with serial blood and urine samples collected up to 72 h after administration. Concentrations of capecitabine and its metabolites were determined in plasma by high-performance liquid chromatography or liquid chromatography coupled to mass spectrometry and in urine by 19F-nuclear magnetic resonance spectroscopy. Although plasma concentrations of capecitabine, 5'-deoxy-5-fluorouridine, 5-FU, dihydro-5-FU, and alpha-fluoro-beta-alanine were, in general, higher in patients with liver dysfunction, the opposite was found for 5'-deoxy-5-fluorocytidine. These effects were not clinically significant. Total urinary recovery of capecitabine and its metabolites was 71% of the administered dose in patients with normal hepatic function and 77% in patients with hepatic impairment. The absolute bioavailability of 5'-deoxy-5-fluorouridine was estimated as 42% in patients with normal hepatic function and 62% in patients with impaired hepatic function. In summary, mild to moderate hepatic dysfunction had no clinically significant influence on the pharmacokinetic parameters of capecitabine and its metabolites. Although caution should be exercised when capecitabine is administered to patients with mildly to moderately impaired hepatic function, there is no need for, a priori, adjustment of the dose.

Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers.

AIMS: This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44-3888. METHODS: The study consisted of three parts. Part I was an open ascending-dose study to determine target effect ranges of sibrafiban. Part II, a double-blind, placebo-controlled, parallel-group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double-blind, placebo-controlled, ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban. RESULTS: At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were non-linear because of the saturable binding to the glycoprotein IIb-IIIa receptor. Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml-1. At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation was about 20-30%. At the higher doses, ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation (prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre-set level of acceptance. CONCLUSIONS: With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44-3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.

Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients.

PURPOSE: In the present study the possible influence of the antacid Maalox on the pharmacokinetics of capecitabine (Xeloda) and its metabolites was investigated in cancer patients. METHODS: A total of 12 patients with solid, predominantly metastatic tumors of various origin received a single oral dose of 1250 mg/m2 of capecitabine (treatment A), a single oral dose of 1250 mg/m2 of capecitabine followed immediately by 20 ml of Maalox (treatment B), and a single oral dose of 1250 mg/m2 of capecitabine followed 2 h later by 20 ml of Maalox (treatment C) in an open, randomized, three-way cross over fashion. Serial blood and urine samples were collected for up to 24 h after each administration. Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry and in urine using nuclear magnetic resonance spectroscopy. RESULTS: Administration of Maalox either concomitantly with capecitabine or delayed by 2 h did not influence the time to peak plasma concentrations (Cmax) or the elimination half-lives of capecitabine and its metabolites. Unexpectedly, moderate increases in the Cmax and AUC0-infinity values obtained for capecitabine and 5'-deoxy-5-fluorocytidine were observed when Maalox was given together with capecitabine. However, these increases, which ranged between 10% and 31%, were not statistically significant (P > 0.05) and are not of clinical significance. There was no indication of consistent changes in the plasma concentrations of the other metabolites 5'-deoxy-5'-fluorouridine (5'-DFUR), 5-fluorouracil, and alpha-fluoro-beta-alanine. The Cmax and AUC0-infinity values recorded for these three metabolites increased and decreased in a stochastic manner. The magnitude of these changes was low (<13%) and not statistically significant. The primary statistical analysis of the AUC0-infinity obtained for 5'-DFUR provided a P value of 0.4524 and clearly indicated no significant difference between the treatments. The addition of Maalox had no influence on the overall urinary recovery or the proportion of the dose recovered as capecitabine or its metabolites from urine. CONCLUSION: At the dose used in this study, the effect of concomitantly delivered Maalox on the extent and rate of gastrointestinal absorption of capecitabine is not clinically significant. Therefore, there is no need to adjust the dose or timing of capecitabine administration in patients treated with Maalox.

Increased potency and decreased elimination of lamifiban, a GPIIb-IIIa antagonist, in patients with severe renal dysfunction.

Activation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (i.v.). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for half-maximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the antiplatelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly.

Effect of cilazapril on glucose tolerance and lipid profile in hypertensive patients with non-insulin-dependent diabetes mellitus.

Hypertension frequently complicates diabetes mellitus and is associated with an increased incidence of cardiovascular and microvascular complications. Angiotensin-I converting enzyme (ACE) inhibitors are effective antihypertensive agents and it has been suggested that they may improve glucose tolerance. We performed a double-blind, randomized study comparing treatment for 8 weeks with cilazapril, a new ACE inhibitor, or placebo on metabolic variables in 22 hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients. At week 8 no significant changes in fasting plasma glucose, fasting plasma insulin, haemoglobin A1 and plasma lipids had occurred. The areas under the glucose [placebo (mean +/- SD): 10.7 +/- 3.27 and 10.6 +/- 2.53; cilazapril: 11.9 +/- 3.23 and 12.1 +/- 2.9 mmol/l per 180 min at 0 and 8 weeks, respectively] and insulin curve [placebo (median and range): 47.4 (31.4-165.1) and 65.3 (16.8-190.8); cilazapril: 51.1 (23.8-132.0) and 57.6 (29.0-150.1) mU/l per 180 min at 0 and 8 weeks, respectively] after a standardized oral liquid test meal were unaltered. A significant decrease in mean arterial blood pressure was observed after cilazapril (122 +/- 8.6 and 106 +/- 8.3 mmHg at 0 and 8 weeks, respectively), in contrast to placebo (122 +/- 6.7 and 120 +/- 6.9 mmHg at 0 and 8 weeks, respectively). In conclusion, cilazapril does not affect metabolic control in hypertensive NIDDM patients, whereas it effectively reduces blood pressure.

The effects of anti-hypertensive medication on learning and memory.

1. The aim of the study was to investigate whether there were differential effects of three different anti-hypertensive medications (cilazapril, atenolol, nifedipine) on cognitive function. 2. A sub-group of patients participating in a large clinical trial of these three drugs, randomly allocated between the three drug conditions, received cognitive assessment at two points before the commencement of treatment and then after 12 and 24 weeks of treatment. Seventy-six patients began treatment, and 55 completed the full course. 3. Tests of learning and memory were designed specially for the study, with a different but comparable version administered on each assessment occasion, in a fixed order. 4. No significant differences between drug groups were found in any index of learning or memory, at any testing occasion. The results were the same whether or not treatment non-completers were included in the analysis.

Quality of life with three antihypertensive treatments. Cilazapril, atenolol, nifedipine.

A multicenter, randomized double-blind study of 6 months' duration was performed in 540 patients (average age 54 years, 57% male) with mild-to-moderate essential hypertension to determine the relative effects on quality of life of cilazapril, atenolol, and nifedipine retard. Quality of life was assessed by using both a self-administered and an interviewer-administered questionnaire; the assessment included a complaint score (symptoms checklist), Health Status Index, assessment of work satisfaction, Psychological General Well-being Index, Profile of Mood States subscales, and life satisfaction assessment. Psychomotor function was measured by the Reitan Trail Making test B. At the end of the trial, diastolic blood pressure had fallen by an average of 15 mm Hg in all three groups, but significantly (p = 0.01) more patients taking cilazapril required the addition of a diuretic (36%) compared with those taking atenolol (25%) or nifedipine retard (24%). No significant differences in quality of life were observed between cilazapril and atenolol during the trial. Symptomatic complaints increased on nifedipine retard (p = 0.02) and contributed to a higher discontinuation rate (21% discontinued treatment compared with 13% and 14% taking atenolol and cilazapril, respectively, p = 0.04). However, a possible improvement in the fatigue subscale (p = 0.04) was also observed on nifedipine retard. The 95% confidence intervals showed that none of the drugs in this trial produced an effect equivalent to that previously reported between captopril and methyldopa in the Psychological General Well Being Index or between captopril and methyldopa or propranolol in Trail Making test B.(ABSTRACT TRUNCATED AT 250 WORDS)

Epilepsy and employment, marital, education and social status.

Employment, marital, educational and social status in epileptic patients attending a seizure clinic were assessed. A total of 343 patients were evaluated. The social group, employment and marital status did not compare favourably with the overall population. Forty per cent of patients belonged to social group five and six compared with 14% of the population. Thirty three per cent of male patients aged 20 years or more were married, compared with 65% in the community. The corresponding statistics for females were 46% and 73% respectively. The male unemployment rate of 34% compared poorly with the unemployment rate of 13% for the period during which the study data was collected. Patients with lower educational attainments were significantly more likely to have poor seizure control (P less than 0.001), or required polypharmacy. A similar situation was found between seizure control and social status, with poor seizure control occurring in patients in social group six.

Serum bilirubin levels with antiepileptic drugs.

The incidence of reduced bilirubin levels in 168 outpatients with epilepsy, compared with levels in 69 controls, has been investigated. Highly significant (p less than 0.001) reductions in average bilirubin levels were noted for carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and multiple drug groups. A marginally significant (p less than 0.05) reduction in bilirubin levels occurred in patients treated with valproate (VPA) which, unlike the other drugs, has not been shown to induce hepatic enzymes.

Withdrawal of anticonvulsant drugs in patients free of seizures for two years. A prospective study.

We discontinued anticonvulsant drugs in 92 patients who had been free of seizures during two years of treatment with a single drug. All the patients had epilepsy that had previously been untreated, and had been randomly assigned to receive carbamazepine, phenytoin, or sodium valproate. Thirty-one patients relapsed, and 61 remained free of seizures. The mean duration of the follow-up in the patients remaining free of seizures was 35 months (range, 6 to 62). There was no significant difference between the relapse rate among adults (35 percent) and that among children (31 percent). Our results suggest that the number of seizures a patient had before control was achieved, the number of drugs tried as single-drug therapy, and the type of treatment withdrawn all influenced the outcome. Among the various types of seizures, complex partial seizures with secondary generalization carried the worst prognosis. In comparison, the risk of relapse was 65 percent lower in patients with generalized seizures and 97 percent lower in patients with complex or simple partial seizures in the absence of secondary generalized attacks. Among the four electroencephalographic classes, class 4 (abnormal before treatment and unchanged before withdrawal) carried the worst prognosis. The risk of relapse was 94 to 99 percent lower in patients in the other three electroencephalographic classes. Among the three anticonvulsants, withdrawal of sodium valproate carried the worst prognosis. In comparison, the odds of relapsing were 28 percent lower after withdrawal of phenytoin and 85 percent lower after withdrawal of carbamazepine. We conclude that withdrawal of anticonvulsant medication should be considered in patients free of seizures for two years.

Adjunctive therapy in resistant epilepsy.

It is now established that the overall prognosis for epilepsy is good and that remission will occur in at least 75% of patients following adequate treatment with monotherapy. Patients who fail to respond to monotherapy, who are not suitable for surgery, and who continue to have frequent seizures may have to be considered for an alternative drug regimen. A review of the literature indicates that complete seizure control with adjunctive treatment is rare, but improved seizure control can be obtained in up to 40% of patients. In a study of clobazam as adjunctive treatment, 60% (N = 20) of our patients responded to treatment initially and 33% maintained an improvement over an 18-month period. In 31 patients who failed to respond to carbamazepine as monotherapy, primidone (N = 16) or valproate (N = 15) were prescribed as adjunctive treatment. One patient obtained complete freedom from seizures and 14 (45%) had a greater than 50% reduction in seizure frequency. Suggested indications for the use of additive treatment in epilepsy are discussed.

A comparative study of the relative effects of anticonvulsant drugs and dietary folate on the red cell folate status of patients with epilepsy.

In a survey of the red cell folate status of 200 patients with epilepsy, compared to 72 controls, we found that median red cell folate levels were reduced significantly in patients treated with phenytoin (p less than 0.01) or carbamazepine (p less than 0.001) alone. Patients taking more than one drug had reduced levels also (p less than 0.001), but in patients treated with sodium valproate alone there was no significant decrease in red cell folate levels compared to controls. Twenty-two per cent of patients in the group taking more than one drug had reduced levels of red cell folate compared with 17 per cent of those taking carbamazepine alone, 13 per cent of those taking phenytoin only, and 9 per cent of those taking sodium valproate only. Dietary folate intake was significantly reduced in all the patient groups compared with controls (p less than 0.001 for the carbamazepine and phenytoin groups, p less than 0.01 for the polypharmacy and sodium valproate groups); a significant correlation between red cell folate levels and dietary folate was not established. Significant negative relationships were established between carbamazepine dose (r = -0.35, p less than 0.01) or serum level (r = -0.27, p less than 0.05) and red cell folate level in patients on one drug only. The correlation between dose or serum level of phenytoin and red cell folate level was also negative but did not reach significance. Our findings show that all anticonvulsant drugs interfere with folate metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy.

The biochemical parameters associated with vitamin D metabolism, calcium, 25-hydroxy-vitamin D (25OHD) and alkaline phosphatase levels were assessed in 226 out-patients with epilepsy. Patients were grouped depending on the drug treatment; carbamazepine, phenytoin, phenobarbitone and sodium valproate used alone as monotherapy and a combination of these drugs as polytherapy. The most severe alterations occurred in the polytherapy group. Hypocalcaemia was more severe in the phenobarbitone monotherapy group than the carbamazepine or the phenytoin groups. No patient on sodium valproate monotherapy had subnormal levels of calcium (less than 2.1 mmol/l). 25OHD levels were similarly reduced in the carbamazepine, phenytoin and the phenobarbitone groups with no reduction in the sodium valproate group. Significant elevations in alkaline phosphatase levels were evident in all patient groups except the sodium valproate group. This study confirms biochemical evidence for anticonvulsant osteomalacia when the enzyme-inducing drugs are used, the degree of severity depending on the drug regimen.