Anti-inflammatory effects of varespladib methyl in diabetic patients with acute coronary syndrome.

PURPOSE: Secretory phospholipase A(2) group IIA (sPLA(2-)IIA) concentration and activity are associated with increased risk of cardiovascular events in acute coronary syndrome (ACS) patients. This study evaluated baseline differences in sPLA(2)-IIA concentration and other inflammatory markers in ACS patients with and without diabetes, and the inflammatory biomarker response to selective sPLA(2) inhibition. METHODS: The effects of the sPLA(2) inhibitor varespladib methyl 500 mg daily and placebo on serial changes in inflammatory and lipid biomarkers were examined in 624 ACS patients who were treated with standard of care including atorvastatin 80 mg daily. RESULTS: Compared with non-diabetic patients, diabetic patients had higher baseline concentrations of sPLA(2)-IIA (p = 0.0066), hs-CRP (p = 0.0155), and IL-6 (p = 0.009). At 8 weeks of treatment (primary endpoint), varespladib methyl reduced median sPLA(2)-IIA levels by -83.6% in diabetic patients and by -82.4% in non-diabetic patients (p = 0.33). Median hs-CRP and IL-6 levels were reduced in both varespladib methyl-treated diabetic and non-diabetic patients, but these differences were not statistically significantly different at 8 weeks (p = 0.57 and p = 0.97 respectively). CONCLUSIONS: Varespladib significantly reduces the post-ACS inflammatory response in those with and without diabetes. These responses were greater in diabetic subjects compared to non-diabetic subjects.

The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial.

BACKGROUND AND PURPOSE: Inhibition of von Willebrand factor offers a novel approach to prevention of stroke and myocardial ischemia but has not yet been demonstrated to show efficacy on clinically relevant end points. ARC1779 is an aptamer that inhibits the prothrombotic function of von Willebrand factor by binding to the A1 domain of von Willebrand factor and thereby blocking its interaction with glycoprotein. Phase 1 studies suggest it inhibits platelet aggregation with less increase in bleeding than conventional antiplatelet agents. The effect of ARC 1779 on cerebral emboli immediately after carotid endarterectomy was investigated in a randomized clinical trial. METHODS: Patients undergoing carotid endarterectomy were randomized double-blind to ARC1779 or placebo administered intravenously. Transcranial Doppler recording, to detect cerebral embolic signals, was performed in the first 3 hours postoperatively. The primary end point was time to first embolic signals. RESULTS: Thirty-six patients were recruited, 18 in each arm. The Kaplan-Meier median time to first embolic signals was 83.6 minutes for ARC1779 compared with 5.5 minutes for placebo. Using Cox proportional hazards embolic signals occurred statistically significantly later on ARC1779 (P=0.007). Reduced embolic signals counts were correlated with inhibition of von Willebrand factor activity (P=0.03). Increased perioperative bleeding and anemia were seen with ARC1779. CONCLUSIONS: von Willebrand factor inhibition reduces thromboembolism in humans. It may play a role in treatment of stroke and myocardial ischemia. The extent to which bleeding complications occur in nonoperated patients needs to be assessed in further studies. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00742612.

A multicentre, randomised, double-blind, single-dose study assessing the efficacy of AMC/DCBA Warm lozenge or AMC/DCBA Cool lozenge in the relief of acute sore throat.

BACKGROUND: Clinically proven over-the-counter (OTC) treatment options are becoming increasingly important in the self-management of acute sore throat. The aim of this study was to determine the analgesic and sensorial benefits of two different amylmetacresol/2,4-dichlorobenzyl alcohol (AMC/DCBA) throat lozenge formulation variants, AMC/DCBA Warm lozenge and AMC/DCBA Cool lozenge, compared with an unflavoured, non-medicated placebo lozenge in the relief of acute sore throat due to upper respiratory tract infections. METHODS: In this multicentre, randomised, double-blind, single-dose study, 225 adult patients with acute sore throat were randomly assigned to receive either one AMC/DCBA Warm lozenge (n = 77), one AMC/DCBA Cool lozenge (n = 74) or one unflavoured, non-medicated lozenge (matched for size, shape and demulcency; n = 74). After baseline assessments, patients received their assigned lozenge and completed four rating assessments at 11 timepoints from 1 to 120 minutes post dose. Analgesic properties were assessed by comparing severity of throat soreness and sore throat relief ratings. Difficulty in swallowing, throat numbness, functional, sensorial and emotional benefits were also assessed. RESULTS: Both the AMC/DCBA Warm and AMC/DCBA Cool lozenge induced significant analgesic, functional, sensorial and emotional effects compared with the unflavoured, non-medicated lozenge. Sore throat relief, improvements in throat soreness and difficulty in swallowing, and throat numbness were observed as early as 1-5 minutes, and lasted up to 2 hours post dose. Sensorial benefits of warming and cooling associated with the AMC/DCBA Warm and AMC/DCBA Cool lozenge, respectively, were experienced soon after first dose, and in the case of the latter, it lasted long after the lozenge had dissolved. Emotional benefits of feeling better, happier, less distracted and less frustrated were reported in those taking either of the AMC/DCBA throat lozenge variants, with no differences in adverse events compared with the unflavoured, non-medicated lozenge. CONCLUSIONS: AMC/DCBA Warm and AMC/DCBA Cool lozenges are well-tolerated and effective OTC treatment options, offering functional, sensorial and emotional benefits to patients with acute sore throat, over and above that of the rapid efficacy effects provided. TRIAL REGISTRATION: ISRCTN: ISRCTN00003567.

A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single-tablet combination of ibuprofen/paracetamol for postoperative dental pain.

Combination analgesia is often recommended for the relief of severe pain. This was a double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single-dose study designed to compare the efficacy and tolerability of a novel single-tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination, and a paracetamol/codeine combination, using the dental impaction pain model. Subjects with at least 3 impacted third molars and experiencing moderate to severe postoperative pain were randomised to receive: 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg; 2 tablets of ibuprofen 200 mg/codeine 12.8mg; 2 tablets of paracetamol 500mg/codeine 15mg; or placebo. Results for the primary endpoint, the sum of the mean scores of pain relief combined with pain intensity differences over 12hours, demonstrated that 1 and 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically significantly more efficacious than 2 tablets of placebo (P<0.0001) and paracetamol/codeine (P⩽0.0001); furthermore, 2 tablets offered significantly superior pain relief to ibuprofen/codeine (P=0.0001), and 1 tablet was found noninferior to this combination. Adverse events were uncommon during this study and treatment emergent adverse events were statistically significantly less frequent in the groups taking the ibuprofen/paracetamol combination compared with codeine combinations. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics currently indicated for strong pain. A single-tablet combination of ibuprofen 200mg/paracetamol 500mg provides highly effective analgesia, comparable or superior to other combination analgesics indicated for strong pain.

Clinical effects of initial 6 months monotherapy with bisoprolol versus enalapril in the treatment of patients with mild to moderate chronic heart failure. Data from the CIBIS III Trial.

PURPOSE: To assess the clinical effects and safety profile of initial monotherapy with either bisoprolol or enalapril in elderly patients with heart failure (HF). METHODS: In CIBIS III, 1010 patients with mild to moderate HF and age>or=65 years were randomized to monotherapy with either bisoprolol or enalapril for 6 months. RESULTS: Bisoprolol had a similar effect as enalapril on the combined end-point of all-cause mortality or hospitalization (HR 1.02; p=0.90), as well as on each of the individual end-points. A trend towards fewer sudden deaths was observed with bisoprolol (NS). On the other hand, more cases of worsening HF requiring hospitalization or occurring while in hospital were observed in the bisoprolol group (HR 1.67; p=0.03). The two groups were similar with regard to treatment cessations and early introduction of the second drug. CONCLUSIONS: Bisoprolol and enalapril had a similar effect on the combined end-point of mortality or hospitalization during 6 months monotherapy. However, more worsening HF events were observed in the bisoprolol group.

Ibuprofen versus paracetamol in pediatric fever: objective and subjective findings from a randomized, blinded study.

OBJECTIVE: The main objective of this study was to compare the single-dose efficacy of 15 mg/kg paracetamol (acetaminophen) versus 10 mg/kg ibuprofen in a general practice setting. METHODS: Children from the age of 3 months to 12 years with a fever of non-serious origin were randomized to receive either ibuprofen or paracetamol. The first dose was given double-blind, using a double-dummy technique. Tympanic temperature was measured at baseline and over the following 8 hours. The second and subsequent doses were administered open-label for up to 3 days by parents at home. At the end of the double-blind and the open-label periods, parents were asked to subjectively rate the efficacy of the product and state whether they would treat their child with the product again. The primary endpoint of the study was the area under the temperature reduction curve expressed as an absolute difference from baseline, from 0 to 6 hours (AUC(0-6)). Secondary efficacy endpoints included a variety of objective and subjective measures. RESULTS: No statistically significant differences in the primary endpoint or any of the objective secondary endpoints were observed. Both agents were equally well tolerated. Compared with parents in the paracetamol group, significantly more parents in the ibuprofen group rated the drug as very efficacious, and reported that they would use the drug again in both the double-blind and open-label phases of the study. CONCLUSIONS: Ibuprofen at a dose of 10 mg/kg and paracetamol at a dose of 15 mg/kg have equivalent efficacy and tolerability; parental opinion in favor of ibuprofen could be explained by additional benefits of ibuprofen that were not measured in this trial and helped allay their anxiety over the treatment of their child.

Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial.

OBJECTIVES: We sought to evaluate the safety and efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). BACKGROUND: Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex that has the potential to reduce ischemic complications mediated by thrombin generation. METHODS: A total of 203 patients were randomized 4:1 to double-blinded intravenous rNAPc2 or placebo every 48 h for a total of 1 to 3 doses in 8 ascending panels (1.5 to 10 microg/kg). All patients received aspirin, unfractionated heparin (UFH), or enoxaparin and early catheterization; clopidogrel and glycoprotein IIb/IIIa blockers were encouraged. Two subsequent open-label panels evaluated 10 mug/kg rNAPc2 with half-dose UFH (n = 26) and no UFH (n = 26). The primary end point was the rate of major plus minor bleeding. Pharmacokinetics, pharmacodynamics, continuous electrocardiography, and clinical events were assessed. RESULTS: Recombinant NAPc2 did not significantly increase major plus minor bleeding (3.7% vs. 2.5%; p = NS) despite increasing the international normalized ratio in a dose-related fashion (trend p < or = 0.0001). Higher-dose rNAPc2 (> or =7.5 microg/kg) suppressed prothrombin fragment F1.2 generation compared with placebo and reduced ischemia by >50% compared to placebo and lower-dose rNAPc2. Thrombotic bailout requiring open-label anticoagulant occurred in 5 of 26 patients treated without UFH, but none in the half-dose UFH group (19% vs. 0%; p = 0.051). CONCLUSIONS: In patients with nSTE-ACS managed with standard antithrombotics and an early invasive approach, additional proximal inhibition of the coagulation cascade with rNAPc2 was well tolerated. rNAPc2 doses > or =7.5 microg/kg suppressed F1.2 and reduced ischemia, though some heparin may be necessary to avoid procedure-related thrombus formation. (Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32; http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1; NCT00116012).