Rat BM-MSCs secretome alone and in combination with stiripentol and ISRIB, ameliorated microglial activation and apoptosis in experimental stroke.

BACKGROUND: Stroke, a devastating neurological emergency, is the leading cause of worldwide mortality and functional disability. Combining novel neuroprotective drugs offers a way to improve the stroke intervention outcomes. In the present era, the combination therapy has been proposed as a plausible strategy to target multiple mechanisms and enhance the treatment efficacy to rescue stroke induced behavioral abnormalities and neuropathological damage. In the current study, we have investigated the neuroprotective effect of stiripentol (STP) and trans integrated stress response inhibitor (ISRIB) alone and in combination with rat bone marrow derived mesenchymal stem cells (BM-MSCs) secretome in an experimental model of stroke. MATERIALS & METHODS: Stroke was induced in male Wistar rats (n = 92) by temporary middle cerebral artery occlusion (MCAO). Three investigational agents were selected including STP (350 mg/kg; i.p.), trans ISRIB (2.5 mg/kg; i.p.) and rat BM-MSCs secretome (100 µg/kg; i.v). Treatment was administered at 3 hrs post MCAO, in four doses with a 12 hrs inter-dose interval. Post MCAO, neurological deficits, brain infarct, brain edema, BBB permeability, motor functional and memory deficits were assessed. Molecular parameters: oxidative stress, pro inflammatory cytokines, synaptic protein markers, apoptotic protein markers and histopathological damage were assessed. RESULTS: STP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, significantly improved neurological, motor function and memory deficits along with significant reduction in pyknotic neurons in the brain of post MCAO rats. These results were correlating with significant reduction in pro-inflammatory cytokines, microglial activation and apoptotic markers in the brain of drug treated post MCAO rats. CONCLUSION: STP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, might be considered as potential neuroprotective agents in the acute ischemic stroke (AIS) management.

Neuroprotective effect of bone marrow-derived mesenchymal stem cell secretome in 6-OHDA-induced Parkinson's disease.

Aim: The aim of the study was to evaluate the neuroprotective effect of bone marrow stem cell secretome in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Materials & methods: Secretome prepared from mesenchymal stem cells of 3-month-old rats was injected daily for 7 days between days 7 and 14 after 6-OHDA administration. After 14 days, various neurobehavioral parameters were conducted. These behavioral parameters were further correlated with biochemical and molecular findings. Results & conclusion: Impaired neurobehavioral parameters and increased inflammatory, oxidative stress and apoptotic markers in the 6-OHDA group were significantly modulated by secretome-treated rats. In conclusion, mesenchymal stem cell-derived secretome could be further explored for the management of Parkinson's disease.

Safety and efficacy of lopinavir/ritonavir combination in COVID-19: A systematic review, meta-analysis, and meta-regression analysis.

BACKGROUND: Being protease inhibitors and owing to their efficacy in SARS-CoV, lopinavir + ritonavir (L/R) combination is being used in the management of COVID-19. In this systematic review and meta-analysis, we have evaluated the comparative safety and efficacy of L/R combination. MATERIALS AND METHODS: Comparative, observational studies and controlled clinical trials comparing L/R combination to standard of care (SOC)/control or any other antiviral agent/combinations were included. A total of 10 databases were searched to identify 13 studies that fulfilled the predefined inclusion/exclusion criteria. RESULTS: No discernible beneficial effect was seen in the L/R group in comparison to SOC/control in terms of "progression to more severe state" (4 studies, odds ratio [OR]: 1.446 [0.722-2.895]), "mortality" (3 studies, OR: 1.208 [0.563-2.592]), and "virological cure on days 7-10" (3 studies, OR: 0.777 [0.371-1.630]), while the L/R combination arm performed better than the SOC/control arm in terms of "duration of hospital stay" (3 studies, mean difference (MD): -1.466 [-2.403 to - 0.529]) and "time to virological cure" (3 studies, MD: -3.272 [-6.090 to - 0.454]). No difference in efficacy was found between L/R versus hydroxychloroquine (HCQ) and L/R versus arbidol. However, in a single randomized controlled trail (open label), chloroquine (CQ) performed better than L/R. The combination L/R with arbidol may be beneficial (in terms of virological clearance and radiological improvement); however, we need more dedicated studies. Single studies report efficacy of L/R + interferon (IFN, either alpha or 1-beta) combination. We need more studies to delineate the proper effect size. Regarding adverse effects, except occurrence of diarrhea (higher in the L/R group), safety was comparable to SOC. CONCLUSION: In our study, no difference was seen between the L/R combination and the SOC arm in terms of "progression to more severe state," "mortality," and virological cure on days 7-10;" however, some benefits in terms of "duration of hospital stay" and "time to virological cure" were seen. No significant difference in efficacy was seen when L/R was compared to arbidol and HCQ monotherapy. Except for the occurrence of diarrhea, which was higher in the L/R group, safety profile of L/R is comparable to SOC. Compared to L/R combination, CQ, L/R + arbidol, L/R + IFN-α, and L/R + IFN-1ß showed better efficacy, but the external validity of these findings is limited by limited number of studies (1 study each).

COVID-19 pandemic: A review based on current evidence.

In December 2019, severe acute respiratory syndrome-coronavirus-2, a novel coronavirus, initiated an outbreak of pneumonia from Wuhan in China, which rapidly spread worldwide. The clinical characteristics of the disease range from asymptomatic cases or mild symptoms, which include nonspecific symptoms such as fever, cough, sore throat, headache, and nasal congestion to severe cases such as pneumonia, respiratory failure demanding mechanical ventilation to multi-organ failure, sepsis, and death. As the transmission rate is quite alarming, we require an effective therapeutic strategy to treat symptomatic patients and adopt the preventive measures in order to contain the infection and prevent community transmission. Coronavirus disease 2019 (COVID-19) pandemic is a public health emergency of international concern, hence repurposing of the drugs is an attractive and a feasible option because PK/PD profile, toxicity profile, and drug interactions are already known. This review emphasizes on the different aspects of COVID-19 such as the epidemiology, etiopathogenesis, diagnosis, and preventive measures to be adopted in order to fight this pandemic. It also highlights upon the ethics preparedness and challenges faced by a developing country like India during such an outbreak. The review focuses on the various approaches adopted till date for developing effective therapeutic strategies including combination of drugs, vaccine therapy, and convalescent plasma therapy to combat this viral outbreak.

Athlete Biological Passport: Need and Challenges.

The Athlete Biological Passport programme was initiated in 2009 by the World Anti-Doping Agency for making the anti-doping programme more effective and stronger. There are three modules in this ABP programme: haematological, steroidal and endocrinological. Currently, the first two modules have been implemented. The newer products such as recombinant human erythropoietin, recombinant proteins, and peptides are similar to those produced naturally. Hence, detection of these substances even with advanced techniques is difficult. Therefore, the concept of ABP came into existence which is based on longitudinal monitoring of biological markers and their variations over a period of time. The ABP does not rely upon the detection of a particular prohibited substance but it reflects the changes in biological markers collated over an athlete's career. Hence, athletes can be monitored through constant interpretation of the passport data. There are many advantages with the implementation of this programme; however, there are various issues which may lead to false interpretation of passport data that must be taken into consideration.

Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: A systematic review and meta-analysis.

Following the demonstration of the efficacy of hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 in vitro, many trials started to evaluate its efficacy in clinical settings. However, no systematic review and meta-analysis have addressed the issue of the safety and efficacy of hydroxychloroquine (HCQ) in coronavirus disease 2019. We conducted a systematic review and meta-analysis with the objectives of evaluation of safety and efficacy of HCQ alone or in combination in terms of "time to clinical cure," "virological cure," "death or clinical worsening of disease," "radiological progression," and safety. RevMan was used for meta-analysis. We searched 16 literature databases out of which seven studies (n = 1358) were included in the systematic review. In terms of clinical cure, two studies reported possible benefit in "time to body temperature normalization" and one study reported less "cough days" in the HCQ arm. Treatment with HCQ resulted in less number of cases showing the radiological progression of lung disease (odds ratio [OR], 0.31, 95% confidence interval [CI], 0.11-0.9). No difference was observed in virological cure (OR, 2.37, 95% CI, 0.13-44.53), death or clinical worsening of disease (OR, 1.37, 95% CI, 1.37-21.97), and safety (OR, 2.19, 95% CI, 0.59-8.18), when compared with the control/conventional treatment. Five studies reported either the safety or efficacy of HCQ + azithromycin. Although seems safe and effective, more data are required for a definitive conclusion. HCQ seems to be promising in terms of less number of cases with radiological progression with a comparable safety profile to control/conventional treatment. We need more data to come to a definite conclusion.

Antibiotics for prophylaxis of spontaneous bacterial peritonitis: systematic review & Bayesian network meta-analysis.

BACKGROUND: Various antibiotic regimens are used for primary and secondary prevention of spontaneous bacterial peritonitis (SBP). A systematic review and network meta-analysis to compare various antibiotics regimens for primary and secondary prevention of SBP were done. METHODS: We did a comprehensive literature search using various databases (i.e. MEDLINE via Ovid and PubMed, Embase, Cochrane Central Register of Controlled Trials and others) from inception to 26th October 2019 using various keywords. Only randomised studies which evaluated the role of antibiotics in adult cirrhotic patients with ascites for primary or secondary prophylaxis of SBP were included. The primary outcome was occurrence/recurrence of SBP episode and other outcomes assessed were extra-peritoneal infections and reduction in mortality. We did random-effects network meta-analysis using a Bayesian approach, and calculated odds ratios (ORs) and 95% credible intervals (CrI); agents were ranked using rank probabilities. RESULTS: We found total 1701 records in our systematic database search and out of these 17 randomised trials were found eligible for network meta-analysis. For primary prevention of SBP, the odds ratio (95% CrI) for norfloxacin daily was 0.061 (0.0060, 0.33) and for rifaximin daily was 0.037 (0.00085, 0.87) and norfloxacin and rifaximin alternate month was 0.027 (0.00061, 0.61) when compared to placebo or no comparator. For the secondary prevention of SBP, rifaximin daily had odds of 0.022 (0.00011, 0.73). CONCLUSION: Rifaximin is useful for both primary and secondary prevention of SBP whereas norfloxacin daily and alternate norfloxacin and rifaximin are useful for primary prophylaxis.