Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.

PURPOSE: Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy. METHODS: The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG. RESULTS: Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free. CONCLUSIONS: This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.

Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures.

The results of a multicentre, randomised, double-blind, placebo controlled, crossover trial of lamotrigine as add-on therapy in patients with partial seizures poorly controlled by established antiepileptic drugs (AEDs) are presented. The study consisted of two 12 week treatment periods each followed by a four week washout period. During the lamotrigine treatment phase, patients received 150 mg or 300 mg daily dose depending on their concomitant AEDs to achieve concentrations in the range 1-3 mg/L. Forty one patients were entered at four centres and all patients entered completed the study. There was a highly significant (p < 0.001) decrease in total seizure counts on lamotrigine compared with placebo. Overall, 22% of patients experienced at least a 50% reduction in the total numbers of all seizures types on lamotrigine, compared with none on placebo. When the total numbers of partial seizures (simple and complex partial) were analysed there was also a significant (p < 0.05) reduction in seizure counts on lamotrigine compared with placebo. When total numbers of secondarily generalised seizures were compared the trend for a reduction in this seizure type did not achieve significance (0.05 < p < 0.1). Concomitant AED plasma concentrations were virtually unchanged. It is concluded that lamotrigine is an effective AED in the treatment of therapy-resistant partial seizures.

The pharmokinetics of isradipine in hypertensive subjects.

In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0-8) were 6.0 ng.ml-1, 1.5 h and 15.1 h.ng.ml-1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0-8) were 3.7 ng.ml-1, 1.2 h and 12.2 h.ng.ml-1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.

Timing of blood pressure measurements in determining anomalies in duration of effect of an antihypertensive drug: assessment of isradipine.

Analysis of an antihypertensive drug trial, which involved measurements of blood pressure (BP) during visits to the clinic at a set time of day, showed that the initial dosage titration procedure had been inadequate in some patients. Plasma drug concentration-time curves and corresponding BP values suggested that control of BP was closely related to plasma drug concentration and that the duration of drug effect was shorter than the dosage interval of 12 h. This interpretation was supported by measurements of BP and drug concentrations taken at steady state, before and 2 h after taking the drug. Measurements of ambulatory BP revealed that some patients whose doses had been titrated at peak plasma drug concentrations had high BP at the time of trough plasma drug concentrations, whereas some of those titrated at trough times were hypotensive at peak times. Adjustment of antihypertensive therapy should entail observations of BP at times coincident with both peak and trough concentrations of the drug concerned, and can be facilitated by ambulatory BP monitoring.

Naproxen dose and concentration: response relationship in rheumatoid arthritis.

Information on the relationship between the plasma concentration of nonsteroidal anti-inflammatory drugs (NSAIDs) and clinical response in rheumatoid arthritis is sparse. As a result treatment is often relatively empirical. Standard doses are prescribed and an apparent lack of response leads either to the prescription of another drug, or an increase in the dose beyond that recommended. This study investigated 18 patients given three doses (500, 1000 and 1500 mg/day) of naproxen in a randomized double-blind design for 12 days at a time. Using a linear modelling approach we found that three out of four clinical response measurements improved linearly with increasing naproxen trough concentrations, suggesting that most patients will achieve an improvement in symptoms if the dose of naproxen is increased up to 1500 mg/day. However, since trough naproxen concentrations show a less than proportional increase with increasing dose (due to saturation of binding sites on plasma albumin), the improvement in response will be less dramatic as the dose is increased.

Quantitation of dose and concentration-effect relationships for fenclofenac in rheumatoid arthritis.

Response to non-steroidal anti-inflammatory drugs (NSAIDs) is not usually assessed on the basis of concentration measurements: identification of a concentration-effect relationship has proved difficult to achieve. Dose and concentration-effect relationships of fenclofenac have been determined in a group of 18 patients with rheumatoid arthritis at three dose levels (600, 1200 and 1800 mg day-1). The study was double-blind and treatments were randomised according to a Latin square design. A multiple linear regression technique (GLIM) was used in the analysis. The best model to describe the change in effect in terms of dose and concentration incorporated an average slope and an individual subject intercept for each effect measurement. On average, an improvement in grip strength of 20 mm Hg could be obtained with an increase in fenclofenac (trough) concentration of 100 micrograms ml-1.