Summary: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 treatmentresistant 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-tv?o patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 250% 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 250% 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.

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 seizure 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. (7 Neurol Neurosurg Psychiatry 1993;56:448-453) Lamotrigine (3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) is a novel antiepileptic drug (AED) chemically unrelated to the major drugs in current use. In vitro studies have suggested that lamotrigine acts at volt- The study was a multicentre, randomised, double-blind, placebo controlled, crossover trial of lamotrigine in outpatients with refractory partial seizures, as defined by the international classification.8 One of the previous crossover studies which had included 18 patients in the analysis had failed to achieve statistical significance5 and therefore it was decided that 40-50 patients should be entered into this trial to ensure the study has sufficient power to detect a drug effect. Lamotrigine or placebo was added to an existing regime of up to two established AEDs. The trial consisted of five phases ( fig 1). Patients were considered for inclusion into the trial during an initial three month baseline period. Each treatment period of 12 weeks was followed by a four week taper/washout period. Medication was tapered over the first week of the washout period and then patients were given placebo.

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.

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.