M Asif A Siddiqui's research while affiliated with Health New Zealand and other places

Doxepin binds with high specificity and affinity to the histamine HI receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises H receptors, which is believed to promote the initiation and maintenance of sleep. In three large, well designed, phase III trials in adult or elderly patients with chronic primary insomnia, oral, low-dose doxepin 3 or 6 mg once daily improved wake time after sleep onset, total sleep time and sleep efficiency to a significantly greater extent than placebo. Significant between-group differences in polysomnographic sleep recordings that favoured low-dose doxepin were evident after a single administration of the drug. Other efficacy measures, including patient-reported sleep quality, also favoured low-dose doxepin over placebo. Symptom control was maintained for up to 12 weeks of low-dose doxepin administration and there was no evidence of physical dependence or worsening insomnia after doxepin withdrawal. Oral, low-dose doxepin 6 mg was also significantly more effective than placebo in a large, well designed trial modelling transient insomnia in healthy adults, according to polysomnographic recordings (e.g. in latency to persistent sleep). Oral, low-dose doxepin was generally well tolerated in clinical trials.

Etoricoxib is a selective cyclo-oxygenase (COX)-2 inhibitor, approved in Europe for the symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis. Etoricoxib provided similar symptomatic relief to nonselective NSAIDs in patients with these conditions, and to celecoxib in patients with osteoarthritis. The drug was associated with fewer uncomplicated upper gastrointestinal (GI) adverse events than nonselective NSAIDs, and was noninferior to diclofenac in terms of the rate of thrombotic cardiovascular (CV) events. Etoricoxib may be considered as a treatment option for patients requiring NSAID therapy, particularly those at risk of upper GI events, after careful consideration of significant risk factors for CV events (including uncontrolled hypertension). As with all NSAIDs, the potential GI and CV risks of treatment with etoricoxib should be weighed against the potential benefits in individual patients, and it should be administered at the lowest effective dose for as short a duration as possible.

Etoricoxib is a selective cyclo-oxygenase (COX)-2 inhibitor, approved in Europe for the symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis. Etoricoxib provided similar symptomatic relief to nonselective NSAIDs in patients with these conditions, and to celecoxib in patients with osteoarthritis. The drug was associated with fewer uncomplicated upper gastrointestinal (GI) adverse events than nonselective NSAIDs, and was noninferior to diclofenac in terms of the rate of thrombotic cardiovascular (CV) events. Etoricoxib may be considered as a treatment option for patients requiring NSAID therapy, particularly those at risk of upper GI events, after careful consideration of significant risk factors for CV events (including uncontrolled hypertension). As with all NSAIDs, the potential GI and CV risks of treatment with etoricoxib should be weighed against the potential benefits in individual patients, and it should be administered at the lowest effective dose for as short a duration as possible.

Lisdexamfetamine dimesylate is a long-acting amfetamine prodrug that requires in vivo hydrolysis to gradually release active d-amfetamine. It is approved in the US for the treatment of attention-deficit hyperactivity disorder (ADHD) in adults and in children aged 6—12 years. ▴ In a study in adult stimulant abusers, oral lisdexamfetamine 50 or 100 mg showed less ‘likability’ response than immediate-release d-amfetamine 40 mg on the Drug Rating Questionnaire-Subject (DRQS) Liking scale. However, there was no significant difference between lisdexamfetamine 150 mg and d-amfetamine 40 mg. ▴ In a randomized, double-blind, phase III trial in adult patients with ADHD, oral lisdexamfetamine 30, 50 or 70mg/day for 4 weeks caused a significantly greater improvement in ADHD-Rating Scale (ADHD-RS) total score than placebo; significant between-group differences favouring lisdexamfetamine were evident after 1 week. ▴ Lisdexamfetamine was generally well tolerated in adult patients with ADHD, with most treatment-emergent adverse events being of mild to moderate severity and consistent with the known effects of psychostimulants.

Oral pregabalin, a calcium channel α2δ-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia. Pharmacological Properties Pregabalin selectively binds with high affinity to the α2δ subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems. This modulates calcium influx in presynaptic nerve terminals to reduce excessive release of several excitatory neurotransmitters. Pregabalin demonstrates beneficial effects on the key symptoms and co-morbidities associated with fibromyalgia (i.e. pain, anxiety and sleep). Oral pregabalin is absorbed rapidly (peak plasma concentrations occur within 1.5 hours) and exposure is dose proportional. Metabolism of pregabalin is negligible, with most of the drug being excreted unchanged in the urine. In healthy volunteers, the mean apparent elimination half-life is 6.3 hours. Clearance of pregabalin is directly related to creatinine clearance; dosage adjustments are required in patients with impaired renal function. Therapeutic Efficacy Oral pregabalin was generally associated with improvements from baseline in mean pain scores in short-term, randomized, double-blind, placebo-controlled, multicentre trials in patients with fibromyalgia. In three 8-, 13- or 14-week trials conducted in the US, relative to placebo recipients, pregabalin 450 or 600 mg/day recipients demonstrated significant improvements from baseline in endpoint mean pain numerical rating scale (NRS) scores (primary endpoint), with pregabalin 300 mg/day recipients also showing significant improvements in two of the trials. Mean pain NRS scores for all pregabalin arms were significantly different from those with placebo as early as week 1, with significant improvements generally sustained through most or all weeks of the treatment period in the pregabalin 300, 450 and 600 mg/day arms. Improvements from baseline in Fibromyalgia Impact Questionnaire (additional co-primary endpoint) total scores in the pregabalin 450 and 600 mg/day groups were significantly better than those in the placebo groups in the 14-week trial, but there was no significant difference between placebo and any of the pregabalin groups in the 13-week trial. Patient-rated overall status, as assessed by response on the Patient Global Impression of Change scale (additional co-primary end-point), improved in patients with fibromyalgia receiving pregabalin 300, 450 or 600 mg/day in the 13- and 14-week US trials. Relative to placebo, pregabalin 300, 450 and 600 mg/day was associated with improvements in several sleep parameters in the short-term trials. Significant differences between pregabalin and placebo were reported for only some of the other secondary endpoints and were generally not consistent across trials. Continued treatment with pregabalin was effective in prolonging the efficacy of open-label pregabalin in patients with fibromyalgia who had shown initial response to open-label pregabalin. In the FREEDOM trial, patients who had an initial response to pregabalin during a 6-week open-label phase were randomized to a further 26 weeks of treatment with their optimized dosage of pregabalin or placebo. Based on Kaplan-Meier estimates, the time to loss of therapeutic response was significantly longer in the pregabalin 300–600 mg/day group than in the placebo group. Sensitivity analyses, which tested the validity of the primary assumptions, confirmed the superiority of pregabalin over placebo. Tolerability The tolerability profile of pregabalin in patients with fibromyalgia is consistent with the known adverse effects the drug. Although adverse events were frequently reported in the pregabalin and placebo groups in clinical trials in patients with fibromyalgia, most events were of mild to moderate intensity and were often of limited duration. The treatment-emergent adverse events most frequently associated with pregabalin were dizziness and somnolence. These events were generally reported shortly after the initiation of pregabalin therapy, were mild to moderate in intensity and occurred more frequently at higher dosages, but led to discontinuation of pregabalin therapy in only some patients.

Amlodipine/atorvastatin (Caduet®) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate. In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes. Pharmacologic Properties Amlodipine is a dihydropyndine calcium channel blocker that inhibits extracellular calcium influx into vascular smooth muscle via blockade of L-type calcium channels causing relaxation of vascular smooth muscle leading to a reduction in BP. Atorvastatin is an HMG-CoA reductase inhibitor that impedes mevalonic acid formation, which subsequently reduces cholesterol formation and increases the rate of low-density lipoprotein-cholesterol (LDL-C) clearance from plasma. The combined administration of amlodipine and atorvastatin may have an additive or potentially synergistic beneficial effect on atherosclerotic plaque formation and some molecular markers of endothelial function. Administration of the fixed-dose combined amlodipine/atorvastatin tablet does not alter the rate or extent of absorption of either agent. Oral amlodipine peak plasma concentrations (Cmax) are achieved in 6–12 hours. Amlodipine undergoes hepatic metabolism with an elimination half-life (t½β) of ≈30–50 hours. Oral atorvastatin is rapidly absorbed, with Cmax occurring within 1–2 hours. Atorvastatin is metabolized to active ortho- and para-hydroxylated derivatives, which are equipotent to the parent drug in vitro. Active metabolites account for about 70% of the lipid-lowering activity in plasma. Cytochrome P450 (CYP) 3A4 is involved in the metabolism of atorvastatin. The parent drug and its metabolites undergo hepatic metabolism, with t½β values of ≈14 hours and 20–30 hours. Therapeutic Efficacy In hypertensive patients with average or below-average LDL-C values in ASCOT-LLA, significantly fewer of those randomized to atorvastatin plus an antihypertensive regimen (either amlodipine or atenolol based) experienced a nonfatal myocardial infarction or fatal coronary heart disease (CHD; primary endpoint) than those randomized to placebo plus an antihypertensive regimen. In a prespecified 2×2 factorial analysis of data from ASCOT-LLA, the risk of nonfatal myocardial infarction and fatal CHD was reduced more in patients receiving atorvastatin plus amlodipine-based treatment than in those receiving atorvastatin plus atenolol-based treatment. Amlodipine plus atorvastatin once daily demonstrated greater antihypertensive efficacy than atorvastatin alone, and better lipid-lowering efficacy than amlodipine alone, in two randomized, double-blind, placebo-controlled, multicenter studies in patients with hypertension and dyslipidemia. In one study, after 8 weeks of therapy, the percentages of patients who achieved both their BP and LDL-C goals in the groups receiving amlodipine 5 mg plus atorvastatin 10 mg, amlodipine 5 mg plus placebo, atorvastatin 10 mg plus placebo, and placebo plus placebo were 45.5%, 8.3%, 28.6%, and 3.5%, respectively. After a further 12 weeks of nonblind, titration-to-goal treatment with varying dosages of combined therapy, the percentage of patients achieving both goals increased to 67.1%. In titration-to-goal, noncomparative, prospective, multicenter studies in hypertensive patients with dyslipidemia, the percentage of patients achieving both their BP and LDL-C goals after 14–16 weeks’ treatment with any of 8 fixed-dose combination tablets of amlodipine/atorvastatin once daily ranged from 50.6% to 62.9%. In two prospective subgroup analyses, the proportions of patients with diabetes achieving both goals were 28.6% and 43.6%, and those for patients with metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Panel III) were 45.5% and 55.3%. Tolerability The fixed-dose combination of amlodipine/atorvastatin is generally well tolerated in patients with hypertension with or without dyslipidemia, with an overall tolerability profile similar to those of each single agent. In clinical trials, the most common treatment-related adverse events associated with amlodipine and atorvastatin administered as a fixed-dose combination or concomitantly as separate agents were peripheral edema, myalgia, and sinusitis. Most adverse events were mild to moderate in severity. In a large, double-blind trial, the rate of treatment discontinuation for any reason was 7.7% in the amlodipine 5 mg plus atorvastatin 10 mg group, 7.0% in the amlodipine 5 mg group, 7.5% in the atorvastatin 10 mg group, and 9.6% in the placebo group.

Amlodipine/atorvastatin (Caduet) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate. In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes.

Oral pregabalin, a calcium channel alpha(2)delta-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.

(1) Biologics have had a tremendous impact on the management of rheumatoid arthritis.(2) Three new biologics have been approved or filed for approval for the treatment of rheumatoid arthritis in the last 2 years: abatacept, rituximab, and tocilizumab.(3) The utility of the newer biologics against the background of existing, well established biologics (infliximab, etanercept, adalimumab, and anakinra) has not been evaluated systematically.

Imatinib is a protein-tyrosine kinase inhibitor with antitumour effects in patients with gastrointestinal stromal tumour (GIST) that is indicated for the treatment of unresectable and/or metastatic GIST and as adjuvant therapy in patients with KIT-positive GIST. Imatinib binds to and inhibits KIT and platelet-derived growth factor receptor (PDGFR)-α tyrosine kinases, interfering with their downstream tumourogenic processes. Cell lines with KIT mutations that are common in patients with GIST were sensitive to imatinib at low in vitro concentrations. Patients with exon 11 KIT mutations were significantly more likely to have partial tumour responses and longer overall survival (OS) and were significantly less likely to have progression of disease than patients with exon 9 KIT mutations or no detectable KIT or PDGFR mutations. In a large (n>700) randomized, double-blind, placebo-controlled, multinational trial (ACOSOG [American College of Surgeons Oncology Group] Z9001), patients who received 1 year of adjuvant treatment with oral imatinib 400mg/day after surgical resection of GIST had significantly longer recurrence-free survival than placebo recipients, with an overall hazard ratio of 0.35 (95% CI 0.22, 0.53) [primary endpoint]. At the time of reporting, there was no significant between-group difference in OS. In patients with GIST who received adjuvant imatinib in this trial, adverse events were mostly of mild or moderate severity; the imatinib treatment group had an almost 2-fold higher rate of US National Cancer Institute Common Toxicity Criteria grade 3 or 4 adverse events than the placebo group.