Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients.

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with type 2 diabetes.

BACKGROUND: There are few data on the role of lipid lowering in the primary prevention of coronary heart disease (CHD) in diabetic patients. This paper describes the design of a collaborative clinical trial between Diabetes UK, the NHS Research and Development Directorate and Pfizer UK, that addresses this question. METHODS: The Collaborative AtoRvastatin Diabetes Study (CARDS) is a multicentre, randomized, placebo-controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with Type 2 diabetes. The primary objective is to investigate whether treatment with the hydroxymethylglutaryl coenzyme A reductase inhibitor, atorvastatin, reduces the incidence of major cardiovascular events. At entry patients have at least one other risk factor for CHD in addition to diabetes, namely current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. At randomization patients have been selected for a serum low-density lipoprotein (LDL) cholesterol concentration < or = 4.14 mmol/l (160 mg/dl) and triglycerides < or = 6.78 mmol/l (600 mg/dl). Randomization was completed in June 2001. Patients will be followed until 304 primary endpoints have accrued (expected date early 2005). The trial includes 2838 men and women aged 40-75 years. This report describes the design and administration of the study and reviews the evidence to date of the effectiveness of lipid-lowering therapy in Type 2 diabetes. CONCLUSIONS: The case for lipid-lowering therapy for the primary prevention of CHD in diabetes has not been demonstrated. CARDS will provide essential information on the extent of any benefits and adverse effects of lipid-lowering therapy in diabetic patients without prior CHD.

Gabapentina en la neuralgia postherpética: estudio controlado con placebo, doble ciego y aleatorizado / Gabapentin in postherpetic neuralgia: a ran domised, double blind and placebo controlled study

Se llevó a cabo un estudio multicéntrico controlado con placebo, doble ciego y aleatorizado, de 7 semanas de duración, para evaluar la eficacia y la seguridad de la gabapentina a dosis de 1.800 ó 2.400 mg.día- 1 en el tratamiento de la neuralgia postherpética. Un total de 334 hombres y muj e res de al menos 18 años (media 73) recibieron gabapentina 1.800 ó 2.400 mg al día o un placebo en tres tomas fraccionadas, con una pauta de ajuste forzado de dosis. La variable de valoración principal fue el cambio en la puntuación diaria media del dolor registrada en un diario (semana basal frente a semana final). Las variables secundarias fueron la puntuación semanal media de interferencia en el sueño; el Short Form-McGill Pain Questionnaire (SF-MPQ); la Clinician Global Impression of Change y la P a t i e n t Global Impression of Change (CGIC/PGIC); la S h o r t F o rm-36 Health Survey (SF-36). A partir de la semana 1, las puntuaciones de dolor mostraron una mejoría significativamente mayor con la gabapentina: la diferencia entre el valor final y el basal fue de -34,5 por ciento para la dosis de 1.800 mg, -34,4 por ciento para la dosis de 2.400 mg, en comparación con -15,7 por ciento para el grupo de placebo. La diferencia respecto al placebo fue de un 18,8 por ciento para la dosis de 1.800 (intervalo de confianza del 95 por ciento, 10,9-26,8 por ciento; p < 0,01) y del 18,7 por ciento para la dosis de 2.400 mg (10,7-26,7 por ciento; p < 0,01). Los diarios de interferencia en el sueño mostraron un patrón similar. Hubo diferencias significativas favorables a la gabapentina en cuanto al número de pacientes que notificaron una reducción superior al 50 por ciento en la intensidad del dolor, en la CGIC y en la PGIC, en las puntuaciones sensitiva y total del SF-MPQ (ambas dosis), en la escala análoga visual del dolor del SF-MPQ (solamente para la dosis de 2.400 mg) y en los dominios de vitalidad, dolor corporal y salud mental del SF-36. La gabapentina fue, en general, bien tolerada. Las reacciones adversas más frecuentes fueron el mareo y la somnolencia, en especial durante la fase de ajuste. Así pues, este estudio confirma el papel de la gabapentina como tratamiento eficaz y bien tolerado de la neuralgia postherpética. ©2001 International Association for the Study of Pain. Publicado por Elsevier Science B.V. Reservados todos los derechos. (AU)

Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study.

A multicentre double blind, randomised, placebo controlled 7-week study evaluated the efficacy and safety of gabapentin 1800 or 2400 mg/day in treating postherpetic neuralgia. Three hundred and thirty-four men and women aged at least 18 years (mean 73) received gabapentin 1800 or 2400 mg daily or placebo in three divided doses with a forced titration schedule. The primary outcome measure was change in average daily pain diary score (baseline week v final week). Secondary outcomes included mean weekly sleep interference score; Short Form-McGill Pain Questionnaire (SF-MPQ); Clinician and Patient Global Impression of Change (CGIC/PGIC); Short Form-36 Health Survey (SF-36). From week 1, pain scores showed a significantly greater improvement with gabapentin: the final difference v baseline was -34.5% for the 1800 mg dose, -34.4% for the 2400 mg dose compared with -15.7% for the placebo group. The difference vs. placebo was 18.8% for the 1800 mg dose (95% confidence interval 10.9-26.8%; P<0.01) and 18.7% for the 2400 mg dose (10.7-26.7%; P<0.01). Sleep interference diaries showed a similar pattern. There were significant differences in favour of gabapentin for number of patients reporting >50% reduction in their pain intensity, in the CGIC and PGIC, in the sensory and total scores of the SF-MPQ (both doses), in the visual analogue scale of pain of the SF-MPQ (2400 mg only) and in the vitality, bodily pain and mental health domains of the SF-36. Overall gabapentin was well tolerated. The most common adverse events were dizziness and somnolence, particularly during the titration phase. Thus, this study confirms the role of gabapentin as an efficacious and well-tolerated treatment for postherpetic neuralgia.

Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study.

The efficacy and safety of gabapentin as add-on therapy for refractory partial seizures in 237 children, aged 3 to 12 years were evaluated over a 6-month period. All children received gabapentin at 24 to 70 mg/kg/day. Efficacy variables included the percent change in seizure frequency and the responder rate (defined as those patients who showed >50% reduction in seizure frequency). For all partial seizures, the median percent change in seizure frequency was -34% and the overall responder rate was 34%. Simple partial seizures showed a median reduction of -53%; complex partial seizures, -38%; and secondarily generalized tonic-clonic seizures, -35%. Thirteen patients (5%) withdrew during the 6-month period because of adverse events. Concurrent antiepileptic medication remained unchanged in 185 patients (78%), was decreased in 27 (11%), and increased in 25 (11%) patients. This 6-month follow-up study has demonstrated that gabapentin was well tolerated and appeared to show a sustained efficacy in a large population of children with refractory partial and secondarily generalized tonic-clonic seizures.

An assessment of the efficacy of atorvastatin in achieving LDL cholesterol target levels in patients with coronary heart disease: a general practice study.

Adherence to evidence-based guidelines for the secondary prevention of coronary heart disease (CHD) has been shown to be poor in a number of surveys. In this open-label, non-comparative 17-week trial, 399 patients with existing CHD and LDL cholesterol concentration > 3.4 mmol/l (130 mg/dl) were treated with atorvastatin 10 mg daily. After 5 weeks, the dose of atorvastatin was adjusted according to a patient's LDL cholesterol level. Of the 379 patients remaining in the study after five weeks of treatment, dose titration was not required for 355 patients (94%) who had reached the target LDL cholesterol of < or = 3.4 mmol/l. Of the 23 patients titrated to higher doses, 11 achieved the target LDL cholesterol after treatment for 17 weeks. Atorvastatin was well tolerated during the course of the study. Achieving LDL cholesterol targets without the need for dose titration simplifies clinical management and should encourage better adherence to evidence-based recommendations for secondary prevention of CHD.

An assessment of the efficacy of atorvastatin in treating patients with dyslipidaemia to target LDL-cholesterol goals: the atorvastatin matrix study.

A total of 531 patients from 57 hospital centres across the UK, who had previously been treated with lipid-lowering agents in combination or alone, in whom the degree of cholesterol reduction was insufficient to achieve European Atherosclerosis Society target levels, were treated with atorvastatin over a 12-week period. The dose of atorvastatin (10, 20 or 80 mg/day) was determined by assignment of risk based on entry level cholesterol levels and the presence of other established CHD risk factors. Atorvastatin was successful in achieving target LDL-cholesterol levels in 86% of mild risk patients, 88% of moderate risk patients and 52% of high risk patients. Compliance with atorvastatin was 96% and treatment was well tolerated. This study demonstrates that atorvastatin is effective in achieving target lipid levels in a large proportion of patients and that the dose required can be predicted by an assessment of the patient's risk profile.

The incidence of first-dose hypotension with quinapril in patients with mild to moderate hypertension.

A total of 2242 patients with mild to moderate hypertension (diastolic pressure 95-120 mmHg) were randomised on a double-blind basis to receive a single dose of placebo, 5 mg quinapril or 10 mg quinapril. Patients were identified who: (a) met the blood pressure (BP) criteria for first-dose hypotension (sitting or standing systolic BP < 100 mmHg, or a fall in systolic BP > or = 20 mmHg on standing); (b) had symptoms suggestive of hypotension; and (c) met the BP criteria and had symptoms. In all three classifications there were no statistically significant differences between the incidences in placebo and combined active treatment groups, or between those in the two quinapril groups. No associated serious adverse events were reported. In the low-risk population studied, it would appear that the incidence of first-dose hypotension with quinapril is similar to placebo and is not dose-related.