Hydroxychloroquine's Efficacy as an Antiplatelet Agent Study in Healthy Volunteers: A Proof of Concept Study.

BACKGROUND: With the inflammatory model of atherosclerosis taking center stage, anti-inflammatory drugs hold a promising place in the therapy of cardiovascular disease (CVD). Recent studies showed that hydroxychloroquine (HCQ) was protective against thrombovascular events in lupus erythematosus and traditional cardiovascular risk factors in patients with rheumatoid arthritis. Some preliminary experimental data have shown that it may prevent platelet activation too. OBJECTIVE: To evaluate the antiplatelet activity of HCQ when given alone and in combination with aspirin (ASA) and compare it with ASA alone and ASA plus clopidogrel (CLOP) in healthy human volunteers. METHODS: In part 1 of the study, 8 volunteers were given HCQ for 7 days. In part 2, 12 volunteers were randomly assigned in a 1:1:1 ratio to the 3 groups in which 2 of the 3 treatments, ASA, ASA plus CLOP, and ASA plus HCQ, were given in the 2 treatment periods separated by a 14-day washout period using the incomplete block design. Inhibition of platelet aggregation (IPA) was measured by light transmission aggregometry. RESULTS: When arachidonic acid (AA) was used as agonist, HCQ given alone showed a significant reduction in platelet aggregation (11.0% ± 4.2%, P = .03). The IPA was significantly increased when ASA plus HCQ was compared with ASA alone (31.2% ± 8.1%, P = .002). This synergistic effect was not seen with adenosine diphosphate and collagen as agonists. Levels of serum 11-dehydrothromboxane B2, a stable marker of thromboxane A2 production, were not significantly different between the groups. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values when HCQ was used alone or in combination with ASA. CONCLUSION: This study suggests that HCQ has antiplatelet properties possibly through the AA pathway (downstream to thromboxane A2 production). With possible additional beneficial effects over the traditional CVD risk factors, larger studies in the future might explore HCQ's potential as an antiplatelet agent.

Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug.

Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T 1/2, MRT, and AUC0-∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

Antihypertensive efficacy of metoprolol XL/low dose chlorthalidone (6.25 mg) combination: a randomized, comparative study in indian patients with mild-to-moderate essential hypertension.

OBJECTIVE: High blood pressure is one of the most important risk factors, directly responsible for increasing the cardiovascular morbidity and mortality. The primary objective was to evaluate the efficacy of metoprolol XL/chlorthalidone against metoprolol XL/hydrochlorothiazide with respect to mean fall in systolic and diastolic blood pressure. The secondary objective was to compare the response rates and to evaluate the tolerability of study medications in patients with mild-to-moderate essential hypertension. METHODS: Total 130 eligible patients (65: metoprolol XL 25 mg/chlorthalidone 6.25 mg; 65: metoprolol XL 25 mg/HCTZ 12.5 mg) were enrolled in this randomized, comparative, multicentric, 12-weeks study. Sixty-two patients from each group completed the study. After 4-weeks of treatment, non-responders from chlorthalidone 6.25 mg combination group were shifted to metoprolol XL 50 mg/chlorthalidone 12.5 mg and non-responders from HCTZ 12.5 mg combination group were escalated to metoprolol XL 50 mg/HCTZ 12.5 mg. RESULTS: The study treatment groups were comparable with respect to demography and baseline disease characteristics. Both the starting therapies were comparable with respect to mean fall in SBP (p = 0.788) and DBP (p = 0.939), and response rates (p = 1.0) after 4-weeks of therapy. Also both the step-up therapies showed similar mean fall in SBP (p = 0.277) and DBP (p = 0.507) at the end of 12-weeks. However, significantly more number of patients from chlorthalidone 12.5 mg/metoprolol XL 50 mg group responded to therapy as compared to that from HCTZ 12.5 mg/metoprolol XL 50 mg group (p = 0.045). All the reported adverse events were of mild-to-moderate intensity. There were no clinically significant trends in electrolytes (Na (+), K(+), Cl(-)) and fasting blood sugar, evident across the treatment groups. CONCLUSION: Chlorthalidone in combination with metoprolol XL is as effective and well tolerated as widely used combination of metoprolol XL/HCTZ, thus providing an alternative therapeutic option.

Randomized, multicentre, comparative clinical evaluation of cefuroxime-sulbactam versus amoxicillin-clavulanic acid therapy in the treatment of lower respiratory tract infections.

This randomized, multicentre, comparative study evaluated the efficacy and safety of treatment with cefuroxime-sulbactam compared with amoxicillin-clavulanic acid (co-amoxiclav) in patients with lower respiratory tract infections (LRTIs). The study enrolled 75 adult in-patients with moderate to severe LRTIs. Patients were treated intravenously for 7 - 10 days. The treatment groups were comparable at baseline with respect to demographic and disease characteristics. Efficacy was evaluated in 72 patients. The clinical success rate was statistically superior in patients treated with cefuroxime-sulbactam (100%) compared with patients treated with amoxicillin-clavulanic acid (88%). The bacteriological success rate was 95% and 100% for cefuroxime-sulbactam and amoxicillin-clavulanic acid, respectively, with no significant difference between treatments. Both treatments were safe and well tolerated. One patient in the cefuroxime-sulbactam group reported convulsions, which the investigator considered were probably not related to the study medication. Cefuroxime-sulbactam can be an effective alternative empirical treatment for LRTIs.

Clinical effectiveness of low-dose chlorthalidone (6.25 mg) + atenolol combination in stage I hypertensive patients: a multicenter, randomized, controlled study.

OBJECTIVE: To compare the efficacy and safety of low-dose chlorthalidone + atenolol combination with atenolol and atenolol + amlodipine combination in stage I hypertensive patients uncontrolled on active run-in monotherapy. METHODS: Newly diagnosed stage I hypertensive patients were randomized to active run-in monotherapy either with atenolol 25 mg (98/300) or chlorthalidone 6.25 mg (100/300) or amlodipine 2.5 mg (102/300). A total of 282/300 patients (atenolol 92, chlorthalidone 91, amlodipine 99) completed the active run-in phase successfully. Patients uncontrolled on active run-in monotherapy (atenolol 33, chlorthalidone 45, amlodipine 47) received the study treatment, namely atenolol 50 mg alone, chlorthalidone 6.25 mg+atenolol 25 mg and atenolol 25 mg+amlodipine 2.5 mg, respectively. Efficacy of the therapy was evaluated by BP measurement at weeks 12 and 20 post-therapy. RESULTS: Post-active run-in monotherapies, the study treatment groups showed a significant fall in mean SBP and DBP from baseline (p<0.05). The mean fall in SBP and DBP was comparable for study treatments (atenolol 50 mg, atenolol 25 mg+chlorthalidone 6.25 mg and atenolol 25 mg+amlodipine 2.5 mg) (p=0.337 for SBP and p=0.054 for DBP) at week 12 and (p=0.744 for SBP and p=0.855 for DBP) at week 20; also, the percentage of responders was comparable for the three study treatment groups (p=0.799) indicating that the low-dose chlorthalidone+atenolol combination is noninferior to the high-dose atenolol alone and atenolol+amlodipine combination. No serious laboratory/clinical adverse events were reported in this study. CONCLUSION: Chlorthalidone 6.25 mg in combination with atenolol 25 mg is effective and safe in stage I (JNC 7) essential hypertensive patients. This low dose of chlorthalidone could reduce dose-related concerns over metabolic adverse effects and may lead to wider usage of this proven antihypertensive agent in combination therapy.