The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus.

AIM: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase-4 (DPP4) inhibitor, in patients with type 2 diabetes. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled, 4-week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A(1c) (HbA(1c)) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once-daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. RESULTS: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC(0-2 h) by approximately 20% (+0.11 +/- 0.50, -2.08 +/- 0.51, -1.73 +/- 0.49 and -1.88 +/- 0.48 mmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC(0-2 h) of intact glucagon-like peptide-1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 +/- 2.83, 11.63 +/- 2.86, 16.42 +/- 2.72 and 15.75 +/- 2.71 pmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA(1c) was lower in all dose groups; the placebo-corrected change in the groups receiving 400 mg PHX1149 was -0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149-treated and placebo subjects. CONCLUSIONS: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.

Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension.

Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n = 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n = 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > or = 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-to-moderate hypertension.

Cefdinir versus cephalexin for the treatment of skin and skin-structure infections. The Cefdinir Adult Skin Infection Study Group.

Because of increasing resistance to older antimicrobial agents, newer drugs need to be evaluated for the treatment of skin and skin-structure infections (SSSIs). This double-masked, randomized, comparative, multicenter study enrolled patients aged 13 years or older with SSSIs to receive either cefdinir 300 mg BID or cephalexin 500 mg QID for 10 days. Nine hundred fifty-two patients (474 in the cefdinir group and 478 in the cephalexin group) took part, primarily white males between 18 and 65 years of age. There were two follow-up visits, with efficacy determined at the test-of-cure visit, 7 to 16 days posttherapy. Many patients were not microbiologically assessable, primarily because of negative cultures at study admission. Patients who required surgical intervention (e.g., incision and drainage) at the site of infection more than 24 hours after the initiation of drug therapy were defined as treatment failures. Significantly more isolated pathogens were resistant to cephalexin than to cefdinir. In the 178 efficacy-assessable cefdinir-treated patients, the rate of pathogen eradication was 93% (200/215), and the rate of successful clinical response was 88% (157/178), compared with 89% (221/247) and 87% (177/204), respectively, in the 204 efficacy-assessable cephalexin-treated patients. Using confidence-interval analysis, the microbiologic and clinical response rates of the cefdinir-treated patients were statistically equivalent to those of the cephalexin-treated patients. At the follow-up visits, patients were questioned about any adverse events occurring since their previous visit. Any untoward symptom occurring during or within 2 days after completion of drug treatment was considered an adverse reaction if the investigator judged it to be definitely, probably, or possibly related to the study drug. One hundred twenty-three (26%) cefdinir-treated patients and 77 (16%) cephalexin-treated patients experienced at least one adverse reaction, a statistically significant difference. Study drug was discontinued for adverse reactions in 20 (4%) cefdinir-treated patients and 13 (3%) cephalexin-treated patients; in the two groups, 10 and 7 patients, respectively, were discontinued for diarrhea. Cefdinir taken BID was as effective as cephalexin taken QID in the treatment of mild-to-moderate SSSIs and was well tolerated by most patients. The increased antibacterial activity of cefdinir must be balanced against the higher rate of diarrhea seen in patients treated with this drug.

Efficacy and safety of aliskiren and amlodipine combination therapy in patients with hypertension: a randomized, double-blind, multifactorial study.

Most patients with hypertension need more than one drug to achieve blood pressure (BP) control. This randomized, double-blind, multifactorial study evaluated whether combinations of aliskiren and amlodipine provided superior BP reductions to component monotherapies in patients with hypertension (mean sitting diastolic BP (msDBP) 95-<110 mm Hg). Overall, 1688 patients were randomized to once-daily monotherapy with aliskiren 150 or 300 mg or amlodipine 5 or 10 mg, combination therapy with one of four corresponding aliskiren/amlodipine doses, or placebo for 8 weeks. At week 8 end point, aliskiren/amlodipine combinations provided significant msDBP reductions from baseline of 14.0-16.5 mm Hg, compared with reductions of 8.0 and 10.2 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 11.0 and 13.8 mm Hg for amlodipine 5 and 10 mg, respectively (P<0.05). Aliskiren/amlodipine combinations provided reductions in mean sitting systolic BP 20.6-23.9 mm Hg, compared with decreases of 10.7 and 15.4 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 15.8 and 21.0 mm Hg for amlodipine 5 (P< or =0.001) and 10 mg (P=NS), respectively. Aliskiren/amlodipine combination therapy provides greater BP lowering than either agent alone, hence offering an effective treatment option for patients with hypertension.

A randomized placebo-controlled trial comparing the efficacy of etoricoxib 30 mg and ibuprofen 2400 mg for the treatment of patients with osteoarthritis.

OBJECTIVE: We compared the efficacy of etoricoxib 30 mg to placebo and ibuprofen 2400 mg for the treatment of osteoarthritis (OA) of the hip and knee. DESIGN: In this 12-week, randomized, double-blind, placebo- and active-comparator-controlled trial, 548 patients (median age 63 years) with OA of the hip or knee were randomized to receive placebo, etoricoxib 30 mg q.d., or ibuprofen 800 mg t.i.d. Demonstration of etoricoxib's efficacy vs placebo and comparison of its efficacy to ibuprofen were assessed using three co-primary endpoints: Western Ontario and McMaster's University Osteoarthritis Index (WOMAC) Pain Subscale (WOMAC-PS); WOMAC Physical Function Subscale (WOMAC-PFS); and Patient Global Assessment of Disease Status (PGADS). Each primary endpoint utilizes a 0-100 mm visual analog scale. To demonstrate comparable efficacy of etoricoxib vs ibuprofen, the 95% confidence intervals (CIs) for the difference in the least squares (LS) mean change over 12 weeks for all three co-primary endpoints had to fall within +/-10 mm. Safety and tolerability data were collected throughout the study. RESULTS: Mean baseline values for the three co-primary endpoints ranged from 62.52 to 70.14 mm. Both etoricoxib and ibuprofen demonstrated superior (P< or =0.002) efficacy for all primary endpoints. The LS mean (mm) changes (95% CI) over 12 weeks for etoricoxib and ibuprofen, respectively, compared to placebo were given as follows: WOMAC-PS: -11.66 (-16.31, -7.01) and -7.62 (-12.30, -2.94); WOMAC-PFS: -10.15 (-14.74, -5.57) and -7.23 (-11.85, -2.61); PGADS: -11.65 (-16.81, -6.50) and -8.11 (-13.30, -2.92). The efficacy of etoricoxib 30 mg was comparable to ibuprofen 2400 mg. All treatments were similarly well tolerated. CONCLUSION: Treatment with etoricoxib 30 mg q.d. provides superior efficacy vs placebo and comparable clinical efficacy vs ibuprofen 2400 mg (800 mg t.i.d.) for the treatment of OA of the hip and knee.

Effectiveness of a single topical application of 10|x% trolamine salicylate cream in the symptomatic treatment of osteoarthritis.

This study was designed to evaluate the effectiveness in relief of pain and rigidity of a 10|X% trolamine salicylate cream compared with a placebo cream identical in smell and appearance, for subjects with osteoarthritis in their hands. This was a one-application, randomized, double-blind, placebo-controlled, parallel study conducted in 81 patients. Pain and stiffness were assessed in the morning upon subjects' awakening (baseline) and at 30, 45, and 120 min after a 4-min rubbing application. Analgesic response was determined using the sum of pain intensity differences (SPID) and the sum of stiffness intensity differences (SSID); the sum across the observation points derived from a pain/stiffness rating scale. Trolamine salicylate was significantly superior to the placebo in improving SPID (p = 0.0492) and in improving SSID scores for both hands (p = 0.0283). Treatment differences in absolute pain and stiffness scores were significant (p |Ml 0.05) at 45 min after application. A 10|X% trolamine salicylate cream was shown to be safe and effective for the temporary relief of minor pain and stiffness associated with osteoarthritis in the hands. This formulation has no smell or counter-irritating properties; patient acceptability was good.

Oral sumatriptan in the treatment of recurrent headache.

BACKGROUND: Sumatriptan is effective for the treatment of acute migraine. However, headache may recur in about 30% of patients within 24 hours of successful treatment. OBJECTIVE: To evaluate the efficacy of oral sumatriptan, 100 mg, in the treatment of headache recurring within 24 hours of achieving headache resolution with subcutaneous sumatriptan, 6 mg. STUDY DESIGN: Subcutaneous sumatriptan was administered for up to 12 migraine attacks in a randomized, double-blind, parallel-group study. Patients whose headache was completely resolved 90 minutes after subcutaneous dosing received either oral sumatriptan or placebo at the onset of recurrent headache. Patients whose headache was not completely resolved were offered rescue medication, including sumatriptan. Patients rated headache severity for 24 hours. SETTING: Fifteen US outpatient clinics. MAIN OUTCOME MEASURE: Percentage of patients with relief of recurrent headache and adverse events. RESULTS: Approximately 90% of patients achieved relief of headache (severe or moderate headache reduced to mild or no headache) by 90 minutes after unblinded subcutaneous administration of sumatriptan. Efficacy rates were at least 80% regardless of whether the headache fulfilled the International Headache Society criteria for migraine. About 64% of patients achieved complete relief. Oral sumatriptan, 100 mg, relieved moderate or severe recurrent headache within 4 hours in up to 81% of patients. Oral sumatriptan administered as rescue medication to patients not headache-free did not relieve persistent headache. The incidence, pattern, and severity of adverse events after combined subcutaneous and oral administration of sumatriptan were similar to those after subcutaneous administration alone. CONCLUSIONS: Oral sumatriptan was consistently effective in the treatment of headache recurrence.

Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial.

BACKGROUND: Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB389IL-2 have shown benefit to patients with psoriasis. OBJECTIVE: We examined the safety and efficacy of DAB389IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. METHODS: Patients were randomized to receive either placebo or 5, 10, or 15 microg/kg daily of DAB389IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. RESULTS: Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB389IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physician's Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 microg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. CONCLUSION: Our findings are consistent with the potential antipsoriatic activity of DAB389IL-2 demonstrated in an earlier study. However, DAB389IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis.