A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG).

BACKGROUND: Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an anti-rabies monoclonal antibody cocktail. METHODS: This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with World Health Organization (WHO) category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the 2 arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥0.5 IU/mL on day 14. RESULTS: A total of 308 patients were equally randomized into the 2 arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and 94.37% in the HRIG arm. The geometric mean of rapid fluorescent foci inhibition test titers in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. CONCLUSIONS: This study confirmed that TwinrabTM is noninferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with 1 WHO approved vaccine regimen (Essen). CLINICAL TRIALS REGISTRATION: CTRI/2017/07/009038.

Comparison of anti-inflammatory effect of atorvastatin with rosuvastatin in patients of acute coronary syndrome.

OBJECTIVES: To compare anti-inflammatory effect of atorvastatin and rosuvastatin in patients of acute coronary syndrome. MATERIALS AND METHODS: The study was a prospective, open-labeled, randomized and single-center study conducted on 100 patients of acute coronary syndrome. Patients were assigned to atorvastatin 40 mg daily or rosuvastatin 20 mg daily for 4 weeks. C-reactive protein (CRP) levels, lipid profiles, erythrocyte sedimentation rate (ESR) and adverse effects were measured at beginning and at the end of 4 weeks. RESULTS: Baseline parameters and clinical profile did not differ between the two groups. CRP levels significantly decreased from beginning to the end of 4 weeks in both atorvastatin and rosuvastatin groups (from 35.48 to 23.07 mg/l and from 35.88 to 19.91 mg/l respectively, both P < 0.001). However, there was significant difference between the levels of CRP in patients of the rosuvastatin group as compared to the atorvastatin group (19.91 ± 6.32 vs 23.07 ± 7.47, P < 0.05). In addition, both the drugs were associated with a reduction in total cholesterol, LDL levels and ESR at the end of 4 weeks as compared to the beginning (P < 0.001 for all comparisons). CONCLUSION: Both atorvastatin (40 mg) and rosuvastatin (20 mg) are effective in decreasing CRP and LDL cholesterol levels even in a short duration of 4 weeks. Rosuvastatin was found to be more effective in decreasing CRP levels.

Assessment of raloxifene, estradiol-17ß, dl-ormeloxifene and levormeloxifene on thrombin activity.

Abstract Background: Cancer is one of the leading causes of morbidity and mortality globally. Cancer-associated thrombosis is well established in clinical settings, and thrombin has been found to induce angiogenesis at cancer sites. This establishes a link between cardiovascular diseases and cancer, where cancer and thrombin have been intricately associated. Various selective estrogen receptor modulators (SERMs) have been reported to exhibit anticancer activity. Therefore, we investigated estradiol-17ß and SERMs dl-ormeloxifene (centchroman), raloxifene and levormeloxifene (l-centchroman) for their anticancer effects and their effect on thrombin activity. Methods: Anticancer activity was assessed against PC-3 cell line by flow cytometry following treatment with estradiol-17ß and SERMs at 10 nM-1 mM concentrations. The cells were stained with propidium iodide and the percentage of cells in the sub-G0/G1 region was considered apoptotic. Thrombin inhibitory effect was evaluated by thrombin inhibition assay in vitro following incubation with 100 nM-3 mM concentrations of estradiol-17ß or various SERMs. Further, the effect of estradiol-17ß and SERMs on endogenous thrombin generation potential (ETP) was assessed by thrombin generation assay on rat plasma in vitro. Results: These compounds exhibited >90% cell death in PC-3 cell lines at 1 mM concentration except estradiol-17ß. Neither estradiol-17ß, dl-ormeloxifene and levormeloxifene showed any thrombin inhibitory or enhancing activity in thrombin inhibition assay, nor did they show any effect on ETP on rat plasma in vitro. However, raloxifene inhibited thrombin activity in a concentration-dependent manner. Raloxifene decreased ETP of the plasma at 3 and 1 mM,which is equivalent to that of 30-100 U/mL of heparin. Interestingly, raloxifene increased thrombin generation at lower concentrations and it inhibited thrombin generation at higher concentrations. Conclusions: These observations suggest that dl-ormeloxifene, estradiol-17ß and levormeloxifene do not possess thrombin inhibitory activity. Raloxifene possesses thrombin modulatory effect in addition to its anticancer activity, and this observation may help us in understanding the thromboembolic complications associated with raloxifene.

Effect of ormeloxifene, a nonsteroidal once-a-week oral contraceptive, on systemic hemodynamics in adult female rats.

OBJECTIVE: To investigate the short-term effects of ormeloxifene on systemic hemodynamics, coagulation profile, and serum antioxidant activity in vivo in comparison with raloxifene. MATERIALS AND METHODS: Colony-bred adult female Sprague-Dawley rats were randomized into 19 groups of 10 each and received either ormeloxifene or raloxifene (0.25, 1.25, or 3 mg/kg/day) for 7, 15, or 30 days by the oral route. Animals of control group received vehicle (gum-acacia in distilled water) alone in a similar manner. Systemic hemodynamics and serum total antioxidant activity were assessed 24 h after the last treatment. RESULTS: There was no significant effect of ormeloxifene administered at these doses and schedules on hemodynamic parameters or antioxidant activity, except for increase in amplitude of R wave in rats treated with 3 mg/kg/day dose for 30 days. This effect with raloxifene was evident only 7 days after treatment at this dose. Overall response was, however, almost similar with both the agents. CONCLUSION: The findings demonstrate comparable pharmacological profile of ormeloxifene and raloxifene on short-term administration to rats. Based on changes observed in the ECG (R wave), long-term studies may lead to justifiable comparison of beneficial and harmful effects of ormeloxifene and raloxifene in relation to cardiovascular effects.