Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type II hypercholesterolaemia

BACKGROUND: Hypercholesterolaemia is a risk factor for coronary heart disease (CHD). Clinical studies have shown that lowering elevated serum total cholesterol (TC) levels, and particularly low density lipoprotein-cholesterol (LDL-C) levels, reduces the frequency of coronary morbidity and deaths, whereas high serum levels of high density lipoprotein-cholesterol (HDL-C) protect against CHD. Policosanol is a cholesterol-lowering drug purified from sugar cane wax with a therapeutic dosage range from 5-20 mg/day. Atorvastatin is an HMG-CoA reductase inhibitor which across its dosage range (10-80 mg/day) has shown significantly greater lipid-lowering effects than all previously marketed statins. OBJECTIVE: This study was undertaken to compare the efficacy and tolerability of policosanol with atorvastatin in older patients with type II hypercholesterolaemia. PATIENTS AND METHODS: This randomised, single-blind, parallel-group study was conducted in older patients (60-80 years) with type II hypercholesterolaemia. After 4 weeks on a cholesterol-lowering diet, 75 patients were randomised to policosanol or atorvastatin 10mg tablets taken once daily with the evening meal for 8 weeks. An interim and final check-up were performed at 4 and 8 weeks, respectively, after treatment was initiated. RESULTS: At 4 (p < 0.0001) and 8 (p < 0.00001) weeks, policosanol 10 mg/day significantly lowered serum LDL-C levels by 17.5 and 23.1%, respectively compared with baseline; corresponding values for atorvastatin were 28.4 and 29.8%. At study completion, policosanol significantly (p < 0.0001) reduced serum TC (16.4%), LDL-C/HDL-C ratio (25.5%) and TC/HDL-C ratio (19.3%), as well as (p < 0.001) triglyceride levels (15.4%). Atorvastatin significantly (p < 0.0001) decreased serum TC (22.6%), LDL-C/HDL-C (26.2%) and TC/HDL-C (19.8%) ratios, as well as (p < 0.001) triglyceride levels (15.5%). Atorvastatin was significantly more effective than policosanol in reducing LDL-C and TC, but similar in reducing both atherogenic ratios and triglyceride levels. Policosanol, but not atorvastatin, significantly (p < 0.05) increased serum HDL-C levels by 5.3%. Both treatments were well tolerated. At study completion, atorvastatin mildly, but significantly (p < 0.05) increased creatine phosphokinase (CPK) and creatinine, whereas policosanol significantly reduced AST and glucose (p < 0.01) and CPK (p < 0.05) levels. All individual values, however, remained within normal limits. Three atorvastatin but no policosanol patients withdrew from the study because of adverse events: muscle cramps (1 patient), gastritis (1 patient) and uncontrolled hypertension, abdominal pain and myalgia (1 patient). Overall, no policosanol and seven atorvastatin patients (18.9%) reported a total of nine mild or moderate adverse events during the study (p < 0.01). CONCLUSIONS: This study shows that policosanol (10 mg/day) administered for 8 weeks was less effective than atorvastatin (10 mg/day) in reducing serum LDL-C and TC levels in older patients with type II hypercholesterolaemia. Policosanol, but not atorvastatin, however, significantly increased serum HDL-C levels, whereas both drugs similarly reduced atherogenic ratios and serum triglycerides. Policosanol was better tolerated than atorvastatin as revealed by patient withdrawal analysis and overall frequency of adverse events. Nevertheless, further studies must be conducted in larger sample sizes and using dose-titration methods to achieve target lipid levels in order to reach wider conclusions.     

Fosinopril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in essential hypertension.

Fosinopril is a phosphinic acid prodrug which, after oral administration, undergoes rapid hydrolysis to its active diacid, the angiotensin converting enzyme (ACE) inhibitor fosinoprilat. Unlike other ACE inhibitors, fosinoprilat has a compensatory dual route of elimination and is cleared by the liver and kidneys. Thus, in patients with diminished renal function increased hepatic clearance of fosinoprilat is noted and, similarly, in patients with diminished hepatic function increased renal clearance seems to occur. Because of this compensatory elimination, fosinopril therapy for all patients can begin with the same recommended dosage. Fosinopril 10 to 40mg administered once daily is an effective antihypertensive regimen that has shown efficacy similar to that of enalapril 5 to 10 mg/day, propranolol 80 to 160 mg/day, hydrochlorothiazide 25 to 50 mg/day and sustained release nifedipine 40 mg/day in preliminary clinical trials. Generally, fosinopril is well tolerated and adverse events associated with the drug are usually mild and similar to those associated with other ACE inhibitors. Thus, fosinopril appears to be a useful alternative to certain 'established' agents used for treating patients with essential hypertension.     

Atorvastatin: safety and tolerability

Importance of the field: Atorvastatin is the most widely used statin administered in a variety of settings, including primary and secondary prevention of cardiovascular events, in the elderly, in patients with chronic kidney disease and in diabetic patients. Therefore, the safety and tolerability of atorvastatin is of paramount importance.

Areas covered in this review: We searched MEDLINE for literature published between 1997 and 2010 on the safety and tolerability of atorvastatin. We retrieved data from randomized controlled trials, meta-analyses, post-marketing studies, reports to regulatory bodies and case reports of rare adverse events.

What the reader will gain: The reader will gain insight into the incidence, severity, prevention and management of the major adverse effects of atorvastatin (i.e., liver function abnormalities and muscle-related side effects) overall and in special populations.

Take home message: The existing data suggest that atorvastatin is generally well tolerated across the range of its therapeutic dosage (10 – 80 mg/day).     

Perindopril/indapamide 2/0.625 mg/day: a review of its place in the management of hypertension

The fixed low-dose combination of the ACE inhibitor perindopril and the non-thiazide diuretic indapamide has been evaluated in the management of patients with mild to moderate hypertension. Combination therapy aims to improve overall therapeutic efficacy while minimising adverse effects. In well-designed multicentre clinical trials, perindopril/indapamide at doses ranging from 2/0.625 to 8/2.5 mg/day was significantly more effective than placebo in achieving adequate blood pressure (BP) control. A similar reduction in supine BP was observed when combined perindopril/indapamide 2/0.625 mg/day was compared with losartan 50 mg/day or atenolol 50 mg/day. Similar reductions in 24-hour ambulatory BP were also seen with perindopril/indapamide 2/0.625 mg/day and irbesartan 150 mg/day. However, response and normalisation rates were significantly higher with combination therapy than with losartan or irbesartan monotherapy. Combined perindopril/indapamide 2/0.625 mg/day therapy effectively reduced BP in elderly patients aged 65 to 85 years to a significantly greater extent than either atenolol 50 mg/day or placebo. Supine BP was also normalised in approximately two-thirds of patients in a small noncomparative trial in patients with hypertension and renal impairment. Low-dose perindopril/indapamide 2/0.625 mg/day was well tolerated in clinical trials; the most common adverse events were headache and cough. Hypokalaemia, associated with the use of diuretics, occurred with a higher incidence with combined perindopril/indapamide 2/0.625 mg/day therapy than with either atenolol 50 mg/day or placebo. Perindopril/indapamide 2/0.625 mg/day has shown efficacy in well designed comparative trials with atenolol, losartan and irbesartan including elderly patients and patients with renal impairment. Studies comparing this dosage of perindopril/ indapamide with other combination therapies would be beneficial in allowing the place of perindopril/indapamide to be more accurately determined. The fixed-low dose combination of perindopril/indapamide provides a promising and well tolerated treatment option in the management of patients with mild to moderate hypertension.     

Overview of the tolerability of gefitinib (IRESSA) monotherapy : clinical experience in non-small-cell lung cancer.

Cytotoxic chemotherapy treatment options for patients with non-small-cell lung cancer (NSCLC) have limited efficacy and are often associated with significant toxicity. Therefore, there is an unmet need for novel drugs that are not only effective in treating this disease but are also well tolerated. Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks the signal transduction pathways implicated in cancer cell growth and survival. It has recently been approved for the treatment of advanced/refractory NSCLC. This review presents the tolerability data from phase I and II gefitinib monotherapy trials, along with data from the worldwide 'Expanded Access Programme' and post-marketing use of gefitinib.Gefitinib was found to be generally well tolerated at the approved dosage of 250 mg/day; the most commonly reported adverse drug reactions (ADRs) were mild to moderate skin rash and diarrhoea, which were manageable and non-cumulative. Other ADRs observed with the use of gefitinib included: dry skin, pruritus, acne, nausea, vomiting, anorexia, asthenia and asymptomatic elevations in liver transaminase levels. Well recognised adverse effects seen with cytotoxic chemotherapy (such as bone marrow depression, neurotoxicity and nephrotoxicity) were not observed. Although the frequency and severity of ADRs increased with the dosage across the range studied (50-1000 mg/day), few patients required dosage reductions or the withdrawal of treatment, and those who did usually received gefitinib >or=600 mg/day.Thus, the available data indicate that gefitinib is well tolerated in patients with a range of solid tumours, including locally advanced or metastatic NSCLC.     

Rosuvastatin

Abstract

Rosuvastatin (Crestor®), an HMG-CoA reductase inhibitor (statin), has a favorable pharmacologic profile, including its selective uptake by hepatic cells, hydrophilic nature, and lack of metabolism by cytochrome P450 (CYP) 3A4 isoenzyme. This last property means that the potential for CYP3A4-mediated drug interactions and, as a consequence, adverse events is low in those requiring concomitant therapy with a statin and agents metabolized by CYP3A4. In a broad spectrum of adult patients with dyslipidemias, oral rosuvastatin 5–40mg once daily effectively and rapidly improved lipid profiles in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks’ duration. After 12 weeks’ treatment, rosuvastatin was significantly (all p < 0.05) more effective at milligram equivalent dosages than atorvastatin, pravastatin, and simvastatin in improving the overall lipid profiles of patients with hypercholesterolemia (intent-to-treat analyses). Moreover, overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein-cholesterol (LDL-C) goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of these other statins after 12 weeks’ treatment in pooled analyses. Rosuvastatin treatment for up to 52 weeks was generally well tolerated in patients with dyslipidemias in clinical trials. The most commonly reported treatment-related adverse events were myalgia, constipation, asthenia, abdominal pain, and nausea; these were mostly transient and mild. The incidence of proteinuria or microscopic hematuria with rosuvastatin 10 or 20 mg/day was <1% versus <1.5% with rosuvastatin 40 mg/day; these events were mostly transient and not associated with acute or progressive deterioration in renal function at recommended dosages. Importantly, very few patients experienced elevations in serum creatine phosphokinase (CPK) levels of over 10-fold the upper limit of normal (0.2–0.4% of patients) or treatment-related myopathy (≤0.1%) [i. e. muscle aches or weakness plus the same elevated serum CPK levels] at dosages of 5–40 mg/day. In conclusion, rosuvastatin treatment effectively and rapidly improves the lipid profile in patients with a broad spectrum of dyslipidemias. In those with hypercholesterolemia (including high-risk patients), rosuvastatin was more efficacious than and generally as well tolerated as atorvastatin, simvastatin, and pravastatin, with significantly more rosuvastatin recipients achieving their NCEP ATP III target LDL-C levels. Thus, rosuvastatin has emerged as a valuable choice for first-line treatment in the management of low- to high-risk patients requiring lipid-lowering drug therapy.

Pharmacodynamic Properties

Rosuvastatin is a single enantiomeric hydroxy acid that is administered as the calcium salt. The drug has a relatively low lipophilicity. Rosuvastatin has a high affinity for the active site of HMG-CoA reductase activity. In in vitro and in vivo studies, rosuvastatin typically inhibits HMG-CoA reductase and cholesterol synthesis to a significantly greater extent than other statins. Rosuvastatin is selectively taken up by hepatic cells in vitro and in vivo, with minimal uptake by nonhepatic cells. Rosuvastatin has a high affinity for the predominantly hepatic organic anion transport protein C. Rosuvastatin increases clearance of plasma low-density lipoprotein-cholesterol (LDL-C) by upregulation of hepatic LDL-C receptors and affects LDL production by decreasing hepatic production of very low-density lipoprotein. In healthy volunteers, rosuvastatin 10 mg/day reduced serum LDL-C (44.2%), total cholesterol (31.8%), triglycerides (22.7%), and apolipoprotein (Apo) B (35.3%). Rosuvastatin was equally effective in lowering serum LDL-C following morning or evening administration. Non-lipid-lowering effects, such as improvements in endothelial function, anti-inflammatory effects, vasculo-protective and cardio/cerebro-protective effects, and improvements in neural function have been reported in in vivo and in vitro studies.

Pharmacokinetic Properties

The Pharmacokinetic properties of rosuvastatin are dose-proportional, with little or no accumulation after repeated administration. Maximum rosuvastatin plasma concentrations of 19–25 μg/L are reached 3–5 hours after administration of a single oral dose of rosuvastatin 40mg in healthy volunteers. The absolute bioavailability of rosuvastatin is approximately 20%. Food decreases the rate of rosuvastatin absorption by 20%, but the extent of absorption remains unchanged. At steady state, the mean volume of distribution of rosuvastatin is approximately 134L. Rosuvastatin is reversibly bound to plasma proteins (88%). Rosuvastatin undergoes very limited metabolism (≈10% of radiolabelled drug recovered as metabolites from urine), with metabolism primarily occurring via cytochrome P450 (CYP) 2C9. N-desmethyl rosuvastatin is the major metabolite. Rosuvastatin undergoes predominantly biliary excretion, with 90% of a single oral dose of radioactive rosuvastatin recovered in the feces (92% as the parent compound). The plasma elimination half-life of rosuvastatin after a single oral dose of rosuvastatin 40mg is 18 24 hours. There were no clinically relevant changes in the pharmacokinetics of rosuvastatin with differences in patient age or gender, time of administration, or mild to moderate renal impairment. However, plasma concentrations of rosuvastatin were increased in patients with severe renal impairment. Rosuvastatin maximum plasma concentration and area under the plasma concentration-time curve values were increased in patients with mild to moderate hepatic impairment. Coadministration of rosuvastatin and ketoconazole, erythromycin, itraconazole (inhibitors of CYP3A4), fenofibrate, fluconazole (metabolized by CYP2C9 and CYP2C19), or digoxin had no clinically relevant effect on the pharmacokinetics of rosuvastatin. Coadministration of rosuvastatin and warfarin increased the International Normalized Ratio. Concomitant rosuvastatin plus cyclosporine or gemfibrozil resulted in a clinically relevant increase in systemic exposure to rosuvastatin. Administration of antacid 2 hours after rosuvastatin avoided clinically relevant decreases in plasma concentrations of rosuvastatin. Administration of contraceptives (ethinyl estradiol and norgestrel) and rosuvastatin increased the plasma concentrations of ethinyl estradiol and norgestrel by 26% and 34%.

Therapeutic Efficacy

Treatment with oral rosuvastatin 5–40mg once daily effectively and rapidly improved lipid profiles across a broad spectrum of patients with dyslipidemias in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks’ duration. In well-designed trials of 6–12 weeks’ duration in patients with hypercholesterolemia, rosuvastatin (5 and 10 mg/day) recipients achieved significantly (all p < 0.05) greater improvements in plasma LDL-C and total cholesterol levels than those receiving atorvastatin 10 mg/day, pravastatin 20 mg/day or simvastatin 20 mg/day, according to primary endpoint intent-to-treat analyses. All other aspects of the lipid profile improved to the same or a greater extent with rosuvastatin treatment than with these other statins, including increases in plasma high-density lipoprotein-cholesterol (HDL-C) levels and reductions in plasma Apo B, triglycerides, and non-HDL-C levels. As assessed in individual trials and pooled analyses, these improvements were in turn reflected in significantly greater improvements in lipid ratios of atherogenic to non-atherogenic lipid components (e. g. LDL-C: HDL-C, non-HDL-C: HDL-C, Apo B: Apo A1 ratios) with rosuvastatin treatment relative to other statins. Notably, rosuvastatin treatment proved effective, irrespective of the patient’s age, gender, postmenopausal status, and/or the presence of type 2 diabetes mellitus with or without metabolic syndrome, hypertension, atherosclerosis, and/or obesity. Pooled analyses indicated that overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of other statins after 12 weeks’ treatment, with 80% of rosuvastatin 10 mg/day recipients achieving their goals. Rosuvastatin 10 mg/day was significantly (all p < 0.05) more effective than simvastatin 20 mg/day or pravastatin 20 mg/day based on individual NCEP ATP III goals: LDL-C target <100 mg/dL 63%, 22%, and 5% of patients achieved target, respectively; LDL-C target <130 mg/ dL 89%, 74%, and 40%; and LDL-C target <160 mg/dL 99%, 90%, and 88%. Relative to atorvastatin 10 mg/day recipients, significantly more rosuvastatin 10 mg/day recipients achieved their target of <100 mg/dL (60% vs 19% in the atorvastatin group; p < 0.05), although response rates were not statistically different in those with targets of <130 mg/dL (88% vs 80%) or <160 mg/dL (96% vs 91%). Results of the STELLAR (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin) trial confirmed data from these pooled analyses. In the 16-week MERCURY I (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) trial, patients who switched from previous statin treatment to rosuvastatin 10 mg/day achieved significantly (all p < 0.0001) greater reductions in plasma LDL-C than those who continued to receive atorvastatin 10 mg/day (46.2% vs 38.5% reduction), simvastatin 20 mg/day (45.6% vs 37.4%) or pravastatin 40 mg/day (46.6% vs 32.4%). Improvements in lipid parameters that were observed after switching to rosuvastatin were generally reflected in significantly (all p ≤ 0.0001) greater reductions in lipid ratios for LDL-C: HDL-C, non-HDL-C: HDL-C, and Apo B: Apo A1. Furthermore, significantly more patients who switched to rosuvastatin 10 mg/day at 8 weeks achieved NCEP ATP III LDL-C targets than those who remained on existing treatment. In difficult-to-treat patient populations, such as those with type 2 diabetes with mixed dyslipidemia, combining rosuvastatin with fenofibrate enhanced reductions in plasma triglyceride levels versus rosuvastatin monotherapy. However, combining rosuvastatin 40 mg/day with niacin extended-release (ER) 1 g/day had no additional benefit in terms of reduction in atherogenic lipid parameters to those achieved with the equivalent dosage of rosuvastatin monotherapy in patients with Fredrickson type IIb or IV hyperlipidemia, although mean plasma HDL-C levels increased by a significantly greater extent with rosuvastatin 10 mg/day plus niacin ER 2 g/ day than with rosuvastatin 40 mg/day monotherapy (11% vs 24%; p < 0.001).

Tolerability

Rosuvastatin was generally well tolerated in clinical trials of up to 1 year’s duration, with tolerability data based on pooled analyses and extension phases of these trials. Overall, in clinical trials the most commonly reported adverse events possibly or probably related to rosuvastatin treatment were myalgia, constipation, asthenia, abdominal pain, and nausea (incidence not reported). Most adverse events were of mild intensity and transient, with 3.7% of 10 275 rosuvastatin recipients discontinuing treatment because of a drug-related adverse event. No rosuvastatin-related deaths occurred during participation in clinical trials. A few rosuvastatin recipients have developed proteinuria (<1% of patients receiving rosuvastatin 10 or 20 mg/day and <1.5% of 40 mg/day recipients) and microscopic hematuria, with these effects generally being mild, mostly transient, possibly tubular in origin, and not associated with acute or progressive deterioration in renal function. There was usually no change or a decrease in mean serum creatinine levels from baseline with rosuvastatin 10–40 mg/day treatment for up to 96 weeks. Notably, in controlled clinical trials with rosuvastatin 5–40 mg/day, 0.2–0.4% of patients experienced elevations in serum creatine phosphokinase (CPK) levels of over 10-fold the upper limit of normal, whereas ≤0.1% of recipients experienced treatment-related myopathy (i. e. muscle aches or weakness plus elevated serum CPK levels of over 10-fold the upper limit of normal); these incidences were similar to those reported with other statins. In clinical trials, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria occurred with rosuvastatin treatment at the higher-than-recommended 80mg dose. Overall, rosuvastatin 10–40 mg/day had a similar tolerability profile to that of atorvastatin 10–80 mg/day, simvastatin 10–80 mg/day, or pravastatin 10–40 mg/day in controlled clinical trials (nature and incidence of adverse events not reported), with 2.9%, 3.2%, 2.5%, and 2.5% of recipients, respectively, discontinuing treatment because of a treatment-related adverse event. As with rosuvastatin 10 or 20 mg/day, less than 1% of patients experienced a positive dipstick test for proteinuria at the final visit with atorvastatin 10–80 mg/day, simvastatin 10–80 mg/day, and pravastatin 10–40 mg/day, with a numerically higher incidence (<1.5%) in those receiving rosuvastatin 40 mg/day. In addition, rare cases (0.2% of patients) of clinically relevant elevations in serum ALT levels have occurred with rosuvastatin ≤80 mg/day, atorvastatin ≤80 mg/day, simvastatin ≤80 mg/ day, or pravastatin ≤40 mg/day. Rosuvastatin (40 mg/day) was as well tolerated as niacin ER (2 g/day) monotherapy in patients with mixed dyslipidemia, with numerically fewer rosuvastatin (n = 46) than niacin ER recipients (n = 72) experiencing treatment-related adverse events (28.3% vs 59.7%). The most common treatment-related adverse events in the rosuvastatin and niacin ER monotherapy groups were flushing (0% vs 43.1%), pruritus (0% vs 13.9%), rash (0% vs 6.9%), paresthesia (0% vs 2.8%), and myalgia (6.5% vs 1.4%). Limited data also indicate that rosuvastatin (5 or 10 mg/day) plus fenofibrate (201 mg/day) combination therapy was as well tolerated as treatment with the same dosages of the individual agents in a 24-week study.

Dosage and Administration

Rosuvastatin is indicated for the treatment of patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson type IIa and IIb) as an adjunct to diet. The recommended dosage is 5–40mg once daily. Rosuvastatin 40 mg/day should only be administered to patients unable to achieve LDL-C goals with 20 mg/day. The drug may be taken without regard to food, with the dosage individualized based on the patient’s response, LDL-C goal, presence of other comorbid conditions, and/or whether the individual is receiving concomitantly administered drugs. Rosuvastatin is also indicated in patients with elevated triglyceride levels (Fredrickson type IV) as an adjunct to diet (recommended dosages not reported in US prescribing information), and in those with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments such as LDL apheresis. Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy. Liver function tests should be performed before treatment commences and at key timepoints throughout the treatment. Dosage reduction should be considered for those receiving rosuvastatin 40 mg/day with persistent unexplained proteinuria. Rosuvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases, and in pregnant women and breastfeeding mothers.     

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.     

Fenofibric Acid

? Fenofibric acid activates peroxisome proliferator-activated receptor α to modify fatty acid and lipid metabolism. Fenofibric acid is the first member of the fibric acid derivatives (fibrates) class approved for use as combination therapy with HMG-CoA reductase inhibitors (statins). ? In three randomized, double-blind, multicenter, phase III trials in adult patients with mixed dyslipidemia, up to 12 weeks’ treatment with once-daily fenofibric acid 135 mg plus a low- or moderate-dose statin (atorvastatin 20 or 40 mg, rosuvastatin 10 or 20 mg, or simvastatin 20 or 40 mg) improved high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels to a significantly greater extent than statin monotherapy, and improved low-density lipoprotein cholesterol (LDL-C) levels to a significantly greater extent than fenofibric acid monotherapy. ? In a 52-week, open-label, multicenter, extension study, HDL-C, TG, and LDL-C levels continued to improve, or were maintained, during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg). ? Once-daily fenofibric acid 135 mg plus a statin was generally as well tolerated as monotherapy with fenofibric acid 135 mg/day or the corresponding statin dosage in the three phase III trials in patients with mixed dyslipidemia. The incidence of adverse events was similar between the combination therapy group and both monotherapy groups. ? In the extension trial, once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg) for up to 52 weeks was generally well tolerated.     

Ziprasidone: a review of its use in schizophrenia and schizoaffective disorder

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily, at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin concentrations. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. CONCLUSIONS: Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.     

Spotlight on ziprasidone in schizophrenia and schizoaffective disorder

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin levels. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. CONCLUSIONS: Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.     

Titration comparative study of TOPINA Tablets in patients with localization related epilepsy: double-blind comparative study by rapid and slow titration methods

To compare the tolerability and efficacy of two titration methods (rapid and slow titration) for TOPINA Tablets with different dosages and periods of escalation, a double-blind comparative study was conducted in patients with localization-related epilepsy. A total of 183 patients were randomized to either rapid titration (initial dosage 100 mg/day increased by 100-200 mg at weekly intervals) or to slow titration (initial dosage 50 mg/day increased in 50 mg/day increments at weekly intervals). TOPINA Tablets were administered for 12 weeks to the maximum dosage of 400 mg/day. The incident of adverse events leading to treatment interruptions or withdrawals was 18.9% in rapid titration and 14.8% in slow titration, with no statistical significance (p = 0.554). The incident of adverse events and adverse reactions of slow titration was slightly lower than that of rapid titration. The common adverse events and adverse reactions reported in the two titration methods were comparable and were well tolerated. On the other hand, the efficacy of slow titration, percent reduction in seizure rate and responder rate, was comparable with that of rapid titration. In conclusion, there were no significant differences of therapeutic response to TOPINA Tablets between the two titration methods.     

Anidulafungin

Anidulafungin is a novel antifungal agent which, like other echinocandins, inhibits beta-(1,3)-D-glucan synthase and disrupts fungal cell-wall synthesis. It has marked antifungal activity against a broad spectrum of Candida spp. and Aspergillus spp., including amphotericin B- and triazole-resistant strains. In clinical trials, anidulafungin has primarily been evaluated in patients with oesophageal and invasive candidiasis. Preliminary data are emerging for other indications such as invasive aspergillosis. In a large, multicentre, double-blind, double-dummy, randomised trial in patients with oesophageal candidiasis, intravenous anidulafungin 50 mg/day was as effective as oral fluconazole 100 mg/day regarding end-of-treatment rates of endoscopic cure and clinical and microbiological success. Duration of treatment was approximately 2-3 weeks, and patients in both groups received a loading dose of study drug (twice the daily maintenance dose) on day 1. Anidulafungin is generally well tolerated. Across the dosage range 50-100 mg/day, adverse events appear not to be dose- or infusion-related. In the largest clinical trial to date, the most common treatment-related adverse events were phlebitis/thrombophlebitis, headache, nausea, vomiting and pyrexia.     

Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia

Fluvastatin sodium (Lescol, Novartis Pharmaceutical Corp., East Hanover, NJ, U.S.A.), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor that limits cholesterol biosynthesis, is available as a 40-mg immediate-release formulation capsule. An extended-release formulation for once-daily administration has been developed for patients with primary hypercholesterolemia who may benefit from doses higher than 40 mg/day. This phase I study evaluated the safety, tolerability, and pharmacokinetics of a new fluvastatin extended-release formulation at doses ranging from 80-640 mg/day in 40 hypercholesterolemic patients. After a 2-week dietary stabilization phase, patients (Fredrickson type IIa/IIb), 18-55 years of age, were randomly assigned to four groups to receive oral fluvastatin extended-release (80, 160, 320, or 640 mg) or matching placebo once daily for 13 days. Fluvastatin extended-release was generally safe and well tolerated at doses of 80-320 mg/day. Within this dose range, linear pharmacokinetics was observed after single and multiple dosing. At 640 mg, fluvastatin extended-release was not well tolerated. Six of the seven actively treated patients at this dose experienced adverse events, including diarrhea, headache, and clinically relevant elevations in serum transaminase concentrations. In addition, nonlinear pharmacokinetics, possibly due to saturation of first-pass metabolism, was observed at this dose, causing higher than expected serum drug concentrations. Once-daily administration of fluvastatin extended-release at doses of 80-320 mg/day was generally safe and well tolerated in patients with primary hypercholesterolemia over a 13-day dosing period.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

Pregabalin: in the treatment of generalised anxiety disorder

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, is a structural analogue of GABA, although it is not active at GABA receptors, nor does it acutely alter GABA uptake or degradation.black triangle Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels in CNS tissues and acts as a presynaptic modulator of the excessive release, in hyperexcited neurons, of various excitatory neurotransmitters. Binding of pregabalin to the alpha2-delta subunit appears necessary for its demonstrable anxiolytic, analgesic and anticonvulsant activities in animal models.black triangle Oral pregabalin, typically at dosages of 300-600 mg/day, was superior to placebo and similar to lorazepam 6 mg/day, alprazolam 1.5 mg/day and venlafaxine 75 mg/day in improving anxiety and depressive symptoms in patients with moderate-to-severe generalised anxiety disorder (GAD). Pregabalin had a rapid onset of anxiolytic activity relative to alprazolam and venlafaxine, which was evident after 1 week. Additionally, pregabalin (initial dosage 450 mg/day) was effective for the prevention of relapse of GAD over 34 weeks. Pregabalin was well tolerated during dosage escalation to fixed dosages (maximum 600 mg/day) over 7 days. Dizziness and somnolence, usually of mild to moderate severity, were the most common adverse events.black triangle The drug was not associated with a clinically significant medication withdrawal syndrome during a 1-week taper following 4 or 6 weeks' double-blind treatment.     

Candesartan

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II receptor antagonist. Candesartan binds selectively and non-competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II. Clinical trials have demonstrated its efficacy at a dose range of 2 to 32 mg once daily in hypertension of all grades, heart failure, in reducing urinary albumin excretion in diabetes mellitus and in coexisting hypertension and renal failure. Pharmacokinetic properties of candesartan cilexetil in elderly patients are not significantly different from those in younger individuals. Hepatic impairment does not change pharmacokinetics of candesartan cilexetil at doses up to 12 mg/day. No dose adjustment is necessary in patients with mild or moderate renal impairment. Tolerability of candesartan cilexetil is not much different from that of placebo. All adverse events are usually of mild to moderate severity and not dose-related. The most common adverse events were headache, upper respiratory tract infection, back pain, and dizziness. The incidence of these adverse effects, as well as of cough, was similar in patients treated with candesartan cilexetil or placebo. The incidence of adverse events in long-term trials was not different from that in short-term trials. Tolerability of candesartan cilexetil does not differ with either age or gender.     

Quinapril: a further update of its pharmacology and therapeutic use in cardiovascular disorders

Quinapril is rapidly de-esterified after absorption to quinaprilat (the active diacid metabolite), a potent angiotensin converting enzyme (ACE) inhibitor. Quinapril produces favourable haemodynamic changes, and improves ventricular and endothelial function in patients with various cardiovascular disorders; these effects are mediated through the binding of quinaprilat to both tissue and plasma ACE. Quinapril 10 to 40 mg/day provided effective blood pressure control in most patients with essential hypertension in clinical trials, but some patients required dosages of 80 mg/day and/or concomitant diuretic therapy. In general, quinapril provided similar blood pressure control to other standard antihypertensive therapies including other ACE inhibitors, calcium antagonists and beta-adrenoceptor antagonists in comparative clinical trials. Combined therapy with quinapril and hydrochlorothiazide had a significantly greater antihypertensive effect than either drug as monotherapy in two well designed studies. Quinapril has also been shown to reduce microalbuminuria in patients with hypertension and/or diabetes mellitus. In patients with congestive heart failure, quinapril 相似文献   

Lansoprazole: an update of its place in the management of acid-related disorders

Lansoprazole is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against Helicobacter pylori in vitro. Current therapy for peptic ulcer disease focuses on the eradication of H. pylori infection with maintenance therapy indicated in those patients who are not cured of H. pylori and those with ulcers resistant to healing. Lansoprazole 30 mg combined with amoxicillin 1g, clarithromycin 250 or 500mg, or metronidazole 400 mg twice daily was associated with eradication rates ranging from 71 to 94%, and ulcer healing rates were generally >80% in well designed studies. In addition, it was as effective as omeprazole- or rabeprazole-based regimens which included these antimicrobial agents. Maintenance therapy with lansoprazole 30 mg/day was significantly more effective than either placebo or ranitidine in preventing ulcer relapse. Importantly, preliminary data suggest that lansoprazole-based eradication therapy is effective in children and the elderly. In the short-term treatment of patients with gastro-oesophageal reflux disease (GORD), lansoprazole 15, 30 or 60 mg/day was significantly more effective than placebo, ranitidine 300 mg/day or cisapride 40 mg/day and similar in efficacy to pantoprazole 40 mg/day in terms of healing of oesophagitis. Lansoprazole 30 mg/day, omeprazole 20 mg/day and pantoprazole 40 mg/day all provided similar symptom relief in these patients. In patients with healed oesophagitis. 12-month maintenance therapy with lansoprazole 15 or 30 mg/day prevented recurrence and was similar to or more effective than omeprazole 10 or 20 mg/day. Available data in patients with NSAID-related disorders or acid-related dyspepsia suggest that lansoprazole is effective in these patients in terms of the prevention of NSAID-related gastrointestinal complications, ulcer healing and symptom relief. Meta-analytic data and postmarketing surveillance in >30,000 patients indicate that lansoprazole is well tolerated both as monotherapy and in combination with antimicrobial agents. After lansoprazole monotherapy commonly reported adverse events included dose-dependent diarrhoea, nausea/vomiting, headache and abdominal pain. After short-term treatment in patients with peptic ulcer, GORD, dyspepsia and gastritis the incidence of adverse events associated with lansoprazole was generally < or = 5%. Similar adverse events were seen in long-term trials, although the incidence was generally higher (< or = 10%). When lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole adverse events included diarrhoea, headache and taste disturbance. In conclusion, lansoprazole-based triple therapy is an effective treatment option for the eradication of H. pylori infection in patients with peptic ulcer disease. Preliminary data suggest it may have an important role in the management of this infection in children and the elderly. In the short-term management of GORD, lansoprazole monotherapy offers a more effective alternative to histamine H2-receptor antagonists and initial data indicate that it is an effective short-term treatment option in children and adolescents. In adults lansoprazole maintenance therapy is also an established treatment option for the long-term management of this chronic disease. Lansoprazole has a role in the treatment and prevention of NSAID-related ulcers and the treatment of acid-related dyspepsia; however, further studies are needed to confirm its place in these indications. Lansoprazole has emerged as a useful and well tolerated treatment option in the management of acid-related disorders.     

Effects of Low-Dose Atorvastatin and Rosuvastatin on Plasma Lipid Profiles

BACKGROUND AND OBJECTIVE: Despite the favorable effects of reduction of low-density lipoprotein-cholesterol (LDL-C) levels in decreasing the risk of coronary heart disease, many patients treated with lipid-lowering HMG-CoA reductase inhibitors (statins) do not achieve goal LDL-C levels. This may be due to high doses of statins prescribed that could potentially induce adverse effects and compromise patient safety and compliance with considerable expense in the long-term. We compared the actions of rosuvastatin and atorvastatin, administered at the low dosages of 10 and 20 mg/day, respectively, in reducing plasma LDL-C levels and their effects on other components of the atherogenic lipid profile in patients with primary hypercholesterolemia. METHODS: In this randomized, parallel group, open-label clinical study, 106 patients with LDL-C >200 mg/dL were treated with rosuvastatin 10 mg/day (group A; n = 52), or atorvastatin 20 mg/day (group B; n = 54) for 48 weeks. RESULTS: At 48 weeks, rosuvastatin 10 mg/day was associated with a significantly greater reduction in plasma LDL-C levels compared with atorvastatin 20 mg/day (-44.32% vs -30%; p < 0.005). Compared with atorvastatin, rosuvastatin also produced a greater reduction in plasma total cholesterol, triglycerides, and non-high-density lipoprotein-cholesterol (non-HDL-C) levels (p < 0.005). Plasma HDL-C levels were not affected significantly, independent of the drug used. CONCLUSION: In high-risk patients with primary hypercholesterolemia, rosuvastatin 10 mg/day was more efficacious than atorvastatin 20 mg/day in reducing plasma LDL-C levels, enabling goal LDL-C levels to be achieved and improving other lipid parameters. Both treatments were well tolerated over 48 weeks.