Effect of ezetimibe/simvastatin compared with atorvastatin on lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia.

AIM: To evaluate the effects of the usual starting and next higher doses of ezetimibe/simvastatin and atorvastatin on the cholesterol content of lipoprotein subclasses in patients with type 2 diabetes and hypercholesterolaemia. METHODS: This post hoc analysis compared the effects of treatment with ezetimibe/simvastatin 10/20 mg vs. atorvastatin 10 and 20 mg/day and ezetimibe/simvastatin 10/40 mg/day vs. atorvastatin 40 mg/day on the cholesterol content of lipoprotein subclasses in the modified intent-to-treat (mITT) population (n = 1013) and in subgroups of patients with triglyceride (TG) levels <200 mg/dl (n = 600) and >or=200 mg/dl (2.6 mmol/l) (n = 413). RESULTS: Ezetimibe/simvastatin significantly reduced low-density lipoprotein cholesterol (LDL-C) subclasses LDL(1)-C, LDL(2)-C and LDL(3)-C; real LDL-C (LDL-C(r)); intermediate-density lipoprotein cholesterol (IDL-C), IDL(1)-C, IDL(2)-C; very low-density lipoprotein cholesterol (VLDL-C), VLDL(3)-C; and remnant-like lipoprotein cholesterol (RLP-C) from baseline more than atorvastatin at all dose comparisons (p < 0.01) in the mITT population. Significant improvements were also observed in high-density lipoprotein cholesterol (HDL-C) subclass HDL(3)-C at the ezetimibe/simvastatin 10/20 mg vs. atorvastatin 20 mg and highest dose comparisons (p < 0.001) and in VLDL(1 + 2)-C at the lowest and highest dose comparisons (p < 0.001). Changes in LDL(4)-C and LDL-C subclass patterns (A, B and I) were comparable for both treatments. Generally, similar results were observed for patients with TG levels <200 and >or=200 mg/dl (2.3 mmol). For both treatments, notable differences between TG subgroups were that patients with elevated TGs had smaller reductions in LDL(2)-C, slightly smaller decreases in all IDL subclasses and greater decreases in all VLDL-C subclasses than those with lower TG levels. Frequency of pattern B was also reduced more in patients with higher TGs for both treatments. CONCLUSIONS: Ezetimibe/simvastatin reduced the cholesterol content of most lipoprotein subclasses from baseline with generally similar efficacy in patients with low and high TGs. Despite the different mechanism of action of ezetimibe, the response to ezetimibe/simvastatin and atorvastatin treatment related to these lipoprotein subclasses was generally consistent with the overall effects of these therapies on the major lipid/lipoprotein classes. The clinical significance of these results awaits further study.

Comparison of rizatriptan 5 mg and 10 mg tablets and sumatriptan 25 mg and 50 mg tablets.

This randomized, double-blind, two-attack, placebo-controlled, crossover study explored the efficacy and tolerability of rizatriptan 10 mg compared with sumatriptan 50 mg as well as rizatriptan 5 mg compared with sumatriptan 25 mg in the acute treatment of migraine. Following randomization to one of six possible treatment sequences, patients (n = 1447) treated two sequential attacks, of moderate or severe intensity, separated by at least 5 days. Patients assessed pain severity, migraine-associated symptoms, and functional disability at 0.5, 1, 1.5, and 2 h post treatment. Compared with placebo, all treatments were effective. On the primary endpoint of time to pain relief, rizatriptan 10 mg was not statistically different from sumatriptan 50 mg [odds ratio (OR) 1.10, P = 0.161], and rizatriptan 5 mg was statistically superior to sumatriptan 25 mg (OR 1.22, P = 0.007). In general, rizatriptan 10 mg and 5 mg treatment resulted in improvement compared with the corresponding doses of sumatriptan on measures of pain severity, migraine symptoms, and functional disability and the 5-mg dose reached statistical significance on almost all measures. All treatments were generally well tolerated.

Distribution of therapeutic response in asthma control between oral montelukast and inhaled beclomethasone.

The distribution of responses in study populations provides a novel method of comparing the benefit of two treatments. This 6-week, randomised, placebo-controlled, double-blind study compared the effectiveness of oral montelukast with inhaled beclomethasone in chronic asthma by assessing the distribution and overlap of patient responses to therapy, as measured by a clinical outcome (asthma control days). A total of 730 adult patients with asthma, age 15-65 yrs, with a forced expiratory volume in one second (FEV1) at baseline of 50-85% of predicted and > or = 15% improvement in FEV1 after inhaled beta-agonist were enrolled. After a 2-week placebo run-in period, patients were randomly allocated to receive montelukast (10 mg once daily), inhaled beclomethasone (200 microg twice daily) or placebo. The primary end-point (per cent of asthma control days) was compared between treatments as the overlap in the response distributions. The overlap of the distribution of responses between the montelukast and beclomethasone groups was 89% for per cent asthma control days and 96% for change from baseline in FEV1. The mean (+/-SD) per cent asthma control days in the montelukast and beclomethasone groups was significantly higher than that in the placebo group (placebo 40.0+/-35.8, montelukast 50.7+/-37.1, beclomethasone 57.9+/-36.1). The mean differences between montelukast and placebo, beclomethasone and placebo, and montelukast and beclomethasone were significant. The mean per cent change (+/-SD) from baseline in FEV1 was 12.1+/-18.7 and 13.9+/-20.8 in the montelukast and beclomethasone groups, respectively, and significantly greater than that in the placebo group (6.4+/-20.1); there was no significant difference between the montelukast and beclomethasone groups in mean values or response distribution. There was also no difference among treatment groups in the frequency of adverse experiences. A comparison of the response distribution is an important approach to comparing therapies; montelukast and beclomethasone provided similar response distributions for the end-point of per cent asthma control days over a 6-week treatment period.

A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Rizatriptan Multiple Attack Study Group.

OBJECTIVE: To examine the safety and efficacy of rizatriptan 10 mg PO in the treatment of multiple migraine attacks. BACKGROUND: Rizatriptan is a potent and rapidly absorbed 5-HT1B/1D receptor agonist. Efficacy and general safety have been examined in controlled trials treating single migraine attacks. In the current placebo-controlled study, we report constancy of safety and efficacy of rizatriptan for patients treating four discrete migraine attacks. METHODS: Patients with moderate or severe migraine (n = 473) were randomized to one of five sequence groups, in which each patient was to treat four migraine attacks. Patients in four groups received rizatriptan 10 mg for three of four attacks and placebo for the remaining attack. Patients in the fifth group received rizatriptan 10 mg for four attacks. Headache severity, functional disability, and migraine symptoms were measured immediately before dosing and at 0.5, 1, 1.5, 2, 3, and 4 hours postdose. RESULTS: After the first attack, response rates were 77% for rizatriptan and 37% for placebo (p < 0.001). Similar efficacy of rizatriptan, ranging from a 75 to 80% response, was observed in each of the subsequent attacks with no evidence of tolerance to therapeutic effects. Most patients (93%) responded to rizatriptan 10 mg during the first or second attack. Adverse experiences were generally mild and transient, the most common being dizziness and somnolence. Incidence of adverse experiences per attack decreased after the first attack. CONCLUSIONS: Rizatriptan 10 mg PO is efficacious and generally well tolerated in acute migraine. Its efficacy is maintained throughout the treatment of multiple, discrete migraine attacks.

The efficacy and safety of dorzolamide as adjunctive therapy to timolol maleate gellan solution in patients with elevated intraocular pressure. Additivity Study Group.

PURPOSE: Two parallel, randomized, double-masked, placebo-controlled studies were conducted to assess the efficacy and safety of 2% dorzolamide hydrochloride as adjunctive therapy to 0.5% timolol maleate ophthalmic gellan (gel-forming) solution in patients with elevated intraocular pressure (IOP) that was inadequately controlled with 0.5% timolol maleate gellan solution alone. METHODS: Both studies began with an open-label 2-week run-in period on 0.5% timolol maleate gellan solution once a day. The only variation in method between the two studies was the dosage of 2% dorzolamide. In one study, 202 patients received 0.5% timolol maleate gellan solution once daily plus either 2% dorzolamide or placebo three times daily. In the other study, 181 patients received 0.5% timolol maleate gellan solution once daily plus either 2% dorzolamide or placebo twice daily. RESULTS: After 85 days, additional mean percent reductions in IOP from baseline at morning trough for the groups receiving 2% dorzolamide three times daily and placebo three times daily were 12.5% and 8.4%, respectively. Mean percent reductions for the groups receiving 2% dorzolamide twice daily and placebo twice daily were 13.1% and 6.5%, respectively. Burning and/or stinging on instillation were the only adverse experiences that affected significantly more of the patients receiving 2% dorzolamide twice or three times daily than those receiving placebo. CONCLUSION: When administered concomitantly with 0.5% timolol maleate gellan solution, 2% dorzolamide three times daily or twice daily produced a statistically significant reduction in IOP at morning trough and peak and was generally well tolerated.

Comparison of the efficacy and safety of 2% dorzolamide and 0.5% betaxolol in the treatment of elevated intraocular pressure. Dorzolamide Comparison Study Group.

A multicenter, parallel-design, randomized, double-masked study was conducted to compare the efficacy and safety of 2% dorzolamide with those of 0.5% betaxolol in the treatment of elevated intraocular pressure (i.o.p). A total of 311 adults with ocular hypertension or open-angle glaucoma were randomly allocated to receive either 2% dorzolamide administered topically TID or 0.5% betaxolol administered topically BID plus placebo administered topically QD for 12 weeks. After the washout of previous ocular hypotensive drugs, patients with IOP > or = 23 mm Hg in at least one eye at 10 AM or 4 PM on study day 1 were randomly allocated to receive one of the study treatments. Throughout the study, IOP was measured 2 and 8 hours after instillation of study medication for the morning peak effect (hour 2) and afternoon trough effect (hour 8). After 12 weeks of therapy, the mean change in IOP was not significantly different between the dorzolamide and betaxolol treatment groups at hour 8 (-3.6 mm Hg in both groups) or hour 2 (-5.4 vs -5.3 mm Hg, respectively). The differences between treatments (and 95% CIs associated with these differences) in mean IOP changes from baseline were 0.02 mm Hg (-0.870 to 0.901) for hour 8 and -0.14 mm Hg (-0.959 to 0.685) for hour 2. The ocular adverse experience (AE) most frequently reported by patients was ocular burning and/or stinging, and the most frequently reported nonocular AEs were taste perversion, upper respiratory infection, and headache. Only the incidence of taste perversion was significantly different between treatment groups (14.6% for the dorzolamide group and 0.0% for the betaxolol group). Two percent of patients in each treatment group discontinued the study due to AEs. This study confirmed the similar IOP-lowering effect of 2% dorzolamide and 0.5% betaxolol. Both treatments were generally well tolerated, and their safety profiles were similar.

Two-year safety study of dorzolamide as monotherapy and with timolol and pilocarpine. Dorzolamide Safety Study Group.

PURPOSE: To evaluate the safety of open-label 2.0% dorzolamide as monotherapy and when used with timolol and/or pilocarpine for as long as 2 years. METHODS: The safety of dorzolamide was evaluated in patients with open-angle glaucoma or ocular hypertension over a 2-year period. The incidence of the most common drug-related adverse experiences in the first year was compared with that in the second year using McNemar's test. The ocular hypotensive effect of dorzolamide as monotherapy and with adjunctive therapy was assessed using percent change in intraocular pressure (IOP) from baseline. RESULTS: Of the 304 patients enrolled, 164 (53.9%) continued to receive dorzolamide as monotherapy for 2 years and 140 (46.1%) required add-on therapy. Add-on therapy was initiated by month 6 in 112 of these 140 patients (80%). Of the 304 patients, 202 (66.4%) completed 2 years of therapy. Of the patients who received dorzolamide as monotherapy, drug-related adverse events occurred more frequently during the first year (29.7%) than the second year (13.8%), and the most common ocular drug-related adverse events included conjunctivitis, burning/stinging eye, follicular conjunctivitis, and eyelid edema. After 2 years of therapy, the mean percent decrease in peak IOP was 22.8% for patients receiving dorzolamide monotherapy and 31.2% to 36.0% for patients receiving add-on therapy. CONCLUSION: Dorzolamide was generally well tolerated for up to 2 years as monotherapy and when used with timolol and/or pilocarpine. Drug-related adverse events were less frequent during the second year of monotherapy than during the first year. Most patients who required add-on therapy did so within the first 6 months of initiating dorzolamide therapy.

Efficacy and safety of rizatriptan versus standard care during long-term treatment for migraine. Rizatriptan Multicenter Study Groups.

Rizatriptan is a novel, selective 5-HT1B/1D receptor agonist with a rapid onset of action after oral dosing for the acute treatment of migraine. We conducted a long-term (up to 1 year), multicenter, randomized study in 1831 patients treating more than 46,000 attacks to compare the efficacy and tolerability of rizatriptan 5 mg and 10 mg to standard care medications routinely used for the acute treatment of migraine attacks. Both doses of rizatriptan were highly effective, without evidence of tachyphylaxis. Rizatriptan 10 mg was consistently superior (P < 0.05), both to the 5-mg dose and to standard care, in providing relief in 90% of attacks, with 50% pain-free by 2 hours after dosing. The most common dose-related adverse events were nausea, somnolence, and asthenia/fatigue. Based on this large, multicenter, long-term trial, rizatriptan is an important new oral agent for the acute treatment of migraine.

A comparison of the efficacy and tolerability of dorzolamide and acetazolamide as adjunctive therapy to timolol. Oral to Topical CAI Study Group.

PURPOSE: To compare the efficacy and tolerability of dorzolamide to acetazolamide. METHODS: Following a timolol and acetazolamide run-in, 105 patients with elevated intraocular pressure (IOP) were randomized to dorzolamide or acetazolamide, in addition to timolol, for 12 weeks. RESULTS: More patients receiving acetazolamide discontinued due to clinical adverse experiences than patients receiving dorzolamide; 13 (25%) vs. 1 (2%); p<0.001. The prevalence of systemic adverse experiences for the dorzolamide group dropped by 50% by Week 12, but remained unchanged for the acetazolamide group, as compared to baseline; p<0.001. Ocular burning/stinging was more common in the dorzolamide group (21% vs. 0%; p<0.001). The mean trough IOP at Day 1 and Week 12 were 20.5 mmHg and 21.8 mmHg for the dorzolamide group, and 20.4 mmHg and 20.5 mmHg for the acetazolamide group. The mean peak IOP at Dayl and Week 12 were 18.9 mmHg and 20.0 mmHg for the dorzolamide group, and 18.7 mmHg and 18.6 mmHg for the acetazolamide group. CONCLUSIONS: Mean IOP was slightly lower (by approximately 1 mmHg) with acetazolamide, while dorzolamide demonstrated much better tolerability.

Double-blind, placebo-controlled, dose-finding study of rizatriptan (MK-462) in the acute treatment of migraine.

Rizatriptan (MK-462) is a potent 5HTID receptor agonist. This multicenter, double-blind, placebo-controlled, outpatient study investigated the clinical efficacy, safety, and tolerability of rizatriptan (2.5, 5, and 10 mg) as a function of dose for acute migraine. Patients with moderate or severe migraine (n = 417) were treated with placebo (n = 67), rizatriptan 2.5 mg (n = 75), 5 mg (n = 130), or rizatriptan 10 mg (n = 145). Headache severity, functional disability, and migraine symptoms were measured immediately before dosing (0) and at 0.5, 1, 1.5, 2, 3, and 4 h post-dose. Patients were permitted to take a second dose of test drug at 2 h if their headache pain was moderate or severe (i.e., placebo initially-->rizatriptan 10 mg as optional second dose; rizatriptan 2.5 mg, 5 mg, or 10 mg initially-->placebo as optional second dose). An upward dose-response relationship was observed among placebo, rizatriptan 2.5 mg, 5 mg, and 10 mg in the primary efficacy measure of proportion of patients reporting pain relief, i.e., a change in headache severity to "no pain or mild pain" at 2 h post-dose. The relationship was evident even at the first recorded timepoint, 30 min, and was statistically significant at 1.5 h and beyond. At the primary timepoint of 2 h after the initial dose, the proportion of patients reporting pain relief was 47.6% for rizatriptan 10 mg; 45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and 17.9% for placebo. Seventy percent of patients on rizatriptan 10 mg reported pain relief at 4 h. Patients who took rizatriptan 5 mg and 10 mg were significantly less functionally disabled than those who took placebo at 1.5 and 2 h post-dose. Rizatriptan 10 mg was consistently more effective than 5 mg, although the differences were not statistically significant. The most frequent clinical adverse events were dizziness, somnolence, and asthenia/fatigue. No patients were discontinued for any adverse experiences and there were no serious adverse experiences.

Effects of angiotensin II receptor blockade on N-terminal proatrial natriuretic factor plasma levels in chronic heart failure.

BACKGROUND: Plasma N-terminal proatrial natriuretic factor (N-terminal proANF) has been shown to reflect intraatrial pressures in heart failure patients, and may be used as a biochemical parameter of atrial pressures. It is still unclear how treatment of heart failure influences the relationship between hemodynamic parameters and plasma levels of N-terminal proANF. METHODS AND RESULTS: This double-blind, placebo-controlled study investigated whether 12 weeks of treatment with the angiotensin II receptor blocker losartan influenced N-terminal proANF plasma levels in 129 chronic heart failure patients. After 12 weeks of treatment, N-terminal proANF level was increased in patients given placebo by 344 +/- 1126 pmol/L, whereas in patients given 50 mg losartan, the levels had decreased by 251 +/- 886 pmol/L (P < .01 vs placebo). The change in N-terminal proANF correlated significantly with the corresponding change in pulmonary capillary wedge pressure (r = .53, P < .001). CONCLUSION: The correlation between N-terminal proANF plasma levels and pulmonary capillary wedge pressure at baseline, as well as the correlation between the changes in these parameters during treatment, suggests that plasma N-terminal proANF may be used to monitor effects on left ventricular filling pressures in patients treated with losartan.

The long-term tolerability of enalapril in hypertensive patients with renal impairment.

There has been some concern raised regarding the safe use of ACE-inhibitors in patients with severe renal insufficiency, including the development of hyperkalaemia in these patients. Therefore, the objective of the current analysis was to evaluate the long-term safety of enalapril in patients with severe renal sufficiency and hypertension. Three protocols with similar randomized, double blind, placebo-controlled designs were selected for analysis. A total of 153 patients, enrolled at six sites, were treated for up to 3 years with enalapril; 164 patients served as controls. One protocol used a fixed dose (5 mg/day) of enalapril, while the other two protocols allowed open titration up to 40 mg/day. The primary comparison was between the enalapril and control populations. For the analysis, patients, by treatment, were grouped according to the degree of renal insufficiency (serum creatinine > or < 3 mg/dl) at baseline. The incidence of the most common, as well as important, clinical and laboratory adverse events for this patient population were summarized. In addition, trends in important laboratory adverse events and the incidence of first-dose events, cough and angioedema were evaluated. The incidence of clinical adverse events was similar for both treatment groups, regardless of the severity of renal insufficiency. Seven patients died, four in the control group and three in the enalapril treatment group; none was considered related to treatment. Enalapril appeared to be well-tolerated in this group of patients with severe renal impairment.

Improvement in migraine-specific quality of life in a clinical trial of rizatriptan.

A validated migraine-specific questionnaire (24-h Migraine Quality of Life Questionnaire: 24-h MQoLQ) was used to assess the impact of migraine and migraine therapy on health-related quality of life during an acute migraine attack. Male and female migraineurs aged 18-55 years were randomized to placebo (n=41), rizatriptan 2.5 mg (n=47), 5 mg (n=74), or 10 mg (n=85) in a triple-blind, placebo-controlled clinical trial. Rizatriptan 5 mg and 10 mg were significantly more efficacious than placebo on pain relief and functional disability. After accounting for multiple comparisons to placebo, rizatriptan 10 mg showed significantly better responses compared to placebo on three of five domains of 24-h MQoLQ (social functioning, migraine symptoms, and feelings/concerns). The O'Brien's Rank Sum Test statistic showed a statistically significant overall difference on the 24-h MQoLQ between the 10 mg rizatriptan and placebo groups (p=0.005) and for the overall dose trend (p< or =0.001).

Infarct topography and hemiparesis profiles with cerebral convexity infarction: the Stroke Data Bank.

For the 183 of 1276 patients in the NINDS Stroke Data Bank with convexity infarction in the middle cerebral artery territory, the size of the infarct did not differ between the two sides but the location of the main site of the infarct differed: on the left side, it was centred in the inferior parietal region, and was mid-frontal on the right. There was a good correlation between infarct size and weakness severity whether estimated by overall motor function on one side, arm, or hand alone. There was a poor correlation, however, for lesion location (lower third, middle third or upper third on either side of the Rolandic fissure) and any of the specific syndromes of focal weakness, no two cases sharing the same lesion for the same syndrome and several cases sharing the same lesion with a different syndrome. The findings indicated a difference in weakness syndromes between the two hemispheres and great individual variation of the acute syndrome caused by a given site of focal infarction along the Rolandic convexity. These variations may explain some of the difficulties showing effects of a given therapeutic agent in studies of acute ischaemic stroke. Large sample sizes will be required for the reliable assessment of any treatment using currently popular clinical stroke scales.

Partial characterization of the sialic acid-free forms of alpha-1-acid glycoprotein from human plasma.

Some of the properties of sialic acid-free alpha(1)-acid glycoprotein prepared by mild acid hydrolysis (pH1.6 at 80 degrees for 1hr.) were compared with those of neuraminidasetreated alpha(1)-acid glycoprotein. Chemically, the former contained less fucose (15%) and amide (2%) residues. Physicochemically, it had undergone certain changes primarily pertaining to the secondary structure, so that the specific optical rotation was more negative than that of the latter. A further expression of this change is probably the difference in the pH range of the resolution into two bands on electrophoresis. The resolution of the glycoprotein prepared by mild acid hydrolysis seems to be extended to more acidic pH values both by starch-gel and free moving-boundary electrophoresis. On ultracentrifugation both preparations appeared homogeneous and sedimented with a rate of 3s. Removal of sialyl residues at different pH values, in the range 1-7, showed that 2moles of sialic acid/mole of protein are very strongly bound. The two variants of alpha(1)-acid glycoprotein were isolated from pooled sialic acid-free alpha(1)-acid glycoprotein by preparative starch-gel electrophoresis and from selected blood of normal adults by fractionation by solubility and chromatography. Ultracentrifugal and starch-gel electrophoretic analyses at pH5, with incubation times of 1 or 24hr., demonstrated that no dissociation-association equilibrium (constant sedimentation coefficient and molecular weight) or isomerization (constant apparent electrophoretic mobilities) exist between the two variants. Therefore these variants are not sub-units of native alpha(1)-acid glycoprotein but represent modifications of naturally occurring proteins. Further, it was shown that the difference in the electrophoretic mobilities between the two variants was not due to any difference in amide content. Immunochemically, the two variants share the same determinants.