Pramipexole extended release (ER) is a non-ergolinic dopamine receptor agonist available for use as a once-daily oral treatment for the signs and symptoms of early and advanced idiopathic Parkinson's disease. Once-daily pramipexole ER and three times-daily pramipexole immediate release (IR) have similar exposure over 24 hours. The ER formulation is associated with fewer fluctuations in plasma pramipexole concentrations over this period. Pramipexole ER improved the symptoms of Parkinson's disease in three well designed trials in adults with early or advanced disease, as measured by changes from baseline in the sum of the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III subtotal scores. In a 9-week study, the majority of patients with early Parkinson's disease who were receiving stable pramipexole IR treatment were successfully switched to pramipexole ER. Relative to placebo at week 18, pramipexole ER 0.375-4.5 mg (of the salt) once daily significantly decreased the sum of the UPDRS parts II and III subtotal scores from baseline in two trials in patients with early or advanced Parkinson's disease, and also reduced the percentage of off-time during waking hours in patients with advanced disease. The efficacy of pramipexole ER was maintained after 33 weeks of treatment in the trials in patients with early or advanced Parkinson's disease. Pramipexole ER was generally well tolerated in patients with Parkinson's disease, with the rate of adverse events being generally similar to that with pramipexole IR.

Paliperidone, the major active metabolite of the atypical antipsychotic risperidone, is available in an oral extended-release (ER) formulation (Invega(R)) and is indicated for the acute and maintenance treatment of schizophrenia in adults in the US and the EU. Once-daily paliperidone ER provides stable plasma drug concentrations over a 24-hour period and may be initiated at therapeutically effective dosages without the need for titration. Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end to a significantly greater extent than placebo in 6-week, double-blind trials in patients with acute symptoms of schizophrenia. The significant improvement in PANSS total score was seen after 4 days of treatment in some trials and paliperidone ER was effective against both positive and negative symptoms of the disease. End of treatment clinical response rates were significantly higher in paliperidone ER recipients than in those who received placebo. The efficacy of paliperidone ER was maintained with longer-term treatment (up to 52 weeks) in open-label extensions of placebo-controlled trials. When compared with quetiapine, paliperidone ER was associated with significantly greater improvements in PANSS total scores from baseline at 2 weeks (primary endpoint) in patients with acute schizophrenia, and at 6 weeks. The two drugs did not significantly differ in terms of clinical response rates. In the only trial to evaluate paliperidone ER for the prevention of symptom recurrence, paliperidone ER recipients had a significantly longer time to recurrence than did placebo recipients, as well as significantly less deterioration of symptom severity. In a 6-month, open-label trial in patients with non-acute schizophrenia, PANSS total scores, PANSS subscale scores and all five Marder factor scores did not significantly differ between paliperidone ER and olanzapine, but were significantly reduced from baseline at endpoint in both treatment groups. In adults with non-acute schizophrenia who were previously unsuccessfully treated with other oral antipsychotics and switched to paliperidone ER, PANSS total scores, PANSS subscale scores and all five Marder factor scores were significantly decreased from baseline at week 26 or endpoint. Paliperidone ER was generally well tolerated during short- and longer-term use and had a tolerability profile generally similar to that of its parent drug, risperidone. There were no unexpected tolerability findings during treatment of up to 52 weeks in duration. Paliperidone ER appeared to have little pro-arrhythmic potential and little effect on plasma glucose, lipid or insulin levels, but increased plasma prolactin levels over both short- and longer-term treatment periods. Clinically significant gains in bodyweight were seen in 15% of patients treated with paliperidone ER during the extension phase of placebo-controlled trials. Pooled analyses revealed that extrapyramidal symptoms occurred in approximately a quarter of the p...

Dalfampridine extended release (ER) is an orally administered formulation of dalfampridine (fampridine, 4-aminopyridine), a potassium channel antagonist indicated for the improvement in walking ability in patients with multiple sclerosis (MS). Oral dalfampridine ER improved walking ability in patients with MS in three randomized, double-blind trials of up to 15 weeks' duration. In a phase II trial, percentage improvements in walking speed on the Timed 25-Foot Walk (T25FW) test (primary endpoint) were not significant versus baseline or placebo during treatment with dalfampridine ER 10, 15 or 20 mg twice daily. However, according to a post hoc analysis, response rates were significantly higher with dalfampridine ER than placebo, with a consistent mean improvement in walking speed of 25-29% seen in the pooled results from dalfampridine ER responders during the double-blind treatment period. In two phase III trials, the proportion of timed walk responders (primary endpoint) was significantly greater with dalfampridine ER 10 mg twice daily than with placebo, with improvements in walking speed of approximately 25% seen during dalfampridine ER treatment amongst timed walk responders. Interim results of noncomparative extensions of the two phase III trials showed that consistent improvements in walking speed were sustained above baseline for up to 2.5 years of dalfampridine ER treatment. Oral dalfampridine ER 10 mg twice daily was generally well tolerated in patients with MS, according to the results of the three randomized, double-blind, placebo-controlled trials.

Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300 mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2 (mild to moderate) hypertension, alone or in combination with other antihypertensives, including HCTZ, valsartan or amlodipine.

Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30-week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment-experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia.