Prescription-based cost analysis of medicines for cardiovascular risk factors at Indian Council of Medical Research-Rational Use of Medicine Centre Hospitals of India.

OBJECTIVES: India has taken several initiatives to provide health care to its population while keeping the related expenditure minimum. Since cardiovascular diseases are the most prevalent chronic conditions, in the present study, we aimed to analyze the difference in prices of medicines prescribed for three cardiovascular risk factors, based on (a) listed and not listed in the National List of Essential Medicines (NLEM) and (b) generic and branded drugs. MATERIALS AND METHODS: Outpatient prescriptions for diabetes mellitus, hypertension, and dyslipidemia were retrospectively analyzed from 12 tertiary centers. The prices of medicines prescribed were compared based on presence or absence in NLEM India-2015 and prescribing by generic versus brand name. The price was standardized and presented as average price per medicine per year for a given medicine. The results are presented in Indian rupee (INR) and as median (range). RESULTS: Of the 4,736 prescriptions collected, 843 contained oral antidiabetic, antihypertensive, and/or hypolipidemic medicines. The price per medicine per year for NLEM oral antidiabetics was INR 2849 (2593-3104) and for non-NLEM was INR 5343 (2964-14364). It was INR 806 (243-2132) for generic and INR 3809 (1968-14364) for branded antidiabetics. Antihypertensives and hypolipidemics followed the trend. The price of branded non-NLEM medicines was 5-22 times higher compared to generic NLEM which, for a population of 1.37 billion, would translate to a potential saving of 346.8 billion INR for statins. The variability was significant for sulfonylureas, angiotensin receptor blockers, beta-blockers, diuretics, and statins (P < 0.0001). CONCLUSION: The study highlights an urgent need for intervention to actualize the maximum benefit of government policies and minimize the out-of-pocket expenditure on medicines.

Strategies to improve antibiotic access and a way forward for lower middle-income countries.

Antibiotics have substantially improved life expectancy in past decades through direct control or prevention of infections. However, emerging antibiotic resistance and lack of access to effective antibiotics have significantly increased the death toll from infectious diseases, making it one of the biggest threats to global health. Addressing the antibiotic crisis to meet future needs require considerable investment in both research and development along with ensuring a viable marketplace to encourage innovation. Fortunately, there has been some improvement in the number of antibiotics approved or in different phases of development through collective global efforts. However, the universal access to these essential novel and generic antibiotics, especially in low- and middle-income countries (LMICs), is challenged by poor economic incentives, regulatory hurdles and poor health infrastructure. Recently, the agenda of securing and expanding access has gained global attention. Several mechanisms are now being proposed and implemented to improve access to essential antibiotics. This review provides an insight into the major barriers to antibiotic access as well as the models proposed and implemented to mitigate accessibility issues. These models include but are not limited to market entry rewards, subscription models and transferable exclusivity vouchers. Further, global access programmes including, Global Antibiotic Research and Development Partnership, Antimicrobial Resistance Action Fund and SECURE Platform are discussed. We also propose the way forward for improving access in LMICs with suggested measures to improve access to generic and novel antibiotics.

Landscape of Push Funding in Antibiotic Research: Current Status and Way Forward.

The growing need for effective antibiotics is attributed to the intrinsic ability of bacteria to develop survival mechanisms. The speed at which pathogens develop resistance is at par or even faster than the discovery of newer agents. Due to the enormous cost of developing an antibiotic and poor return on investment, big pharmaceutical companies are stepping out of the antibiotic research field, and the world is now heading towards the silent pandemic of antibiotic resistance. Lack of investment in research has further led to the anemic antibiotic pipeline. To overcome these challenges, various organizations have come forward with push funding to financially assist antibiotic developers. Although push funding has somewhat reinvigorated the dwindled field of antibiotic development by bearing the financial risks of failure, the landscape is still large and staggered. Most of the funding is funneled towards the early stages; however, to carry the promising compounds forward, equal or more funding is required formid- and late-stage research. To some extent, the complexity associated with accessing the funding mechanisms has led to their underutilization. In the present review, we discuss several major push funding mechanisms, issues in their effective utilization, recent strategies adopted, and a way forward to streamline funding in antibiotic research.

Drug development process and COVID-19 pandemic: Flourishing era of outsourcing.

Traditional drug development is a tedious process with involvement of enormous cost and a high attrition rate. Outsourcing drug development services to contract research organizations (CROs) has become an important strategy for cost and risk reduction, capacity building, and data generation. The therapeutic and operational expertise of these CROs has allowed pharmaceutical industry to reduce in-house infrastructure as well as research capacity. Working with specialized CROs has not only increased the rate of success but also the speed of drug discovery process. Small firms with promising molecules but limited resources and large firms interested in diversifying their dimensions are utilizing the services of efficient CROs. Globally, approximately one-third of the drug development processes are now being outsourced and the data generated by the independent third party are well appreciated during regulatory submissions. In this article, we discuss the international and national trends, outsourcing services and models, key considerations while selecting CRO, and benefits and challenges of outsourcing. Further, we discuss how the technical expertise of competent CROs was utilized when traditional ways of conducting clinical trials were disrupted by the COVID-19 pandemic. Taken together, the increasing health-care demands, COVID-19 pandemic or any other such upcoming health crisis, and recent advances in advanced technologies (machine learning and artificial intelligence, etc.) are likely to fuel global CRO market in the coming years.

Tideglusib Ameliorates Ischemia/Reperfusion Damage by Inhibiting GSK-3ß and Apoptosis in Rat Model of Ischemic Stroke.

OBJECTIVES: Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine protein kinase, gets activated and worsen stroke outcome after ischemia/reperfusion (I/R) injury by inducing inflammation and apoptosis. In this study, tideglusib, a selective irreversible and non-ATP competitive inhibitor of GSK-3ß, was explored in cerebral I/R damage using middle cerebral artery occlusion (MCAo) model in rats. MATERIALS AND METHODS: MCAo was done for 90 min in male Wistar rats (250-280 g) using doccol suture. In pre-treatment group, tideglusib (50 mg/kg) was administered once daily for 2 days and on the day of surgery, 30 min before MCAo. Next day, rats were examined for neurobehavioral parameters and MRI was performed to assess brain damage. In post-treatment group, tideglusib was started at 30 min after MCAo and continued for the next 2 days. After 72 h of MCAo, behavioral parameters and brain damage by MRI were assessed. Further, oxidative stress markers (MDA and GSH), inflammatory cytokines (TNF-α, IL-1ß and IL-10) and expression levels of pGSK-3ß S9, Bcl-2 and Bax were estimated in pre-treatment group. RESULTS: Tideglusib pre-treatment but not post-treatment significantly improved neurobehavioral parameters (p < 0.05) and reduced brain damage (p < 0.01) when compared with MCAo group. I/R induced changes in MDA (p < 0.01), TNF-α and IL-1ß (p < 0.05) were significantly attenuated by pre-treatment. Further, tideglusib pre-treatment ameliorated MCAo induced altered expressions of pGSK-3ß S9, Bcl-2 and Bax. CONCLUSION: The results of our exploratory study indicated prophylactic potential of tideglusib in I/R injury by modulating pGSK-3ß S9, apoptosis and neuro-inflammation.

Dihydromyricetin alleviates cerebral ischemia-reperfusion injury by attenuating apoptosis and astrogliosis in peri-infarct cortex.

OBJECTIVES: In ischemic stroke, reperfusion after thrombolysis is associated with secondary brain damage. Dihydromyricetin (DHM), a flavonoid, has shown neuroprotective effects through anti-oxidant, anti-inflammatory and anti-apoptotic properties. This study investigates the potential of DHM, given postreperfusion in middle cerebral artery occlusion (MCAo) model of stroke in rats. METHODS: MCAo surgery was performed in male Wistar rats. Reperfusion was performed after 90 min of ischemia. DHM (50 and 100 mg/kg) was administered 10-15 min and 2 h postreperfusion followed by daily dosing for 2 more days. Neurobehavioral parameters and infarct size (TTC staining) were assessed after 72 h. The effective dose (100 mg/kg) was then used to study reduction in infarct size (measured by MRI) and effect on apoptosis (evaluated by protein expression of Bax, Bcl-2 and cleaved caspase-3 and TUNEL assay) in peri-infarct cortex. Furthermore, effects of DHM on neuronal damage and activation of astrocytes were studied by immunofluorescence. RESULTS: Poststroke DHM (100 mg/kg) administered for 3 days showed significant improvements in motor-coordination and infarct damage (TTC staining and MRI). MCAo-induced altered apoptotic proteins were normalized to a significant extent in peri-infarct cortex with DHM treatment. Data from TUNEL assay were complementary to the effects on apoptotic proteins. Additionally, DHM caused a significant reduction in the number of reactive astrocytes when compared with the MCAo group. DISCUSSION: This study demonstrated the efficacy of subacute DHM treatment in ischemia/reperfusion injury by modulating apoptosis and astrogliosis in the peri-infarct cortex. This suggests the potential of DHM in attenuating disease progression.

Preclinical Stroke Research and Translational Failure: A Bird's Eye View on Preventable Variables.

Despite achieving remarkable success in understanding the cellular, molecular and pathophysiological aspects of stroke, translation from preclinical research has always remained an area of debate. Although thousands of experimental compounds have been reported to be neuro-protective, their failures in clinical setting have left the researchers and stakeholders in doldrums. Though the failures described have been excruciating, they also give us a chance to refocus on the shortcomings. For better translational value, evidences from preclinical studies should be robust and reliable. Preclinical study design has a plethora of variables affecting the study outcome. Hence, this review focusses on the factors to be considered for a well-planned preclinical study while adhering to guidelines with emphasis on the study design, commonly used animal models, their limitations with special attention on various preventable attritions including comorbidities, aged animals, time of dosing, outcome measures and physiological variables along with the concept of multicentric preclinical randomized controlled trials. Here, we provide an overview of a panorama of practical aspects, which could be implemented, so that a well-defined preclinical study would result in a neuro-protectant with better translational value.

Post Stroke Safinamide Treatment Attenuates Neurological Damage by Modulating Autophagy and Apoptosis in Experimental Model of Stroke in Rats.

Exploring and repurposing a drug have become a lower risk alternative. Safinamide, approved for Parkinson's disease, has shown neuroprotection in various animal models of neurological disorders. The present study aimed to explore the potential of safinamide in cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley rats were used in middle cerebral artery occlusion model of stroke. The effective dose of safinamide was selected based on the results of neurobehavioral parameters and reduction in infarct size assessed 24 h post-reperfusion. For sub-acute study, the treatment with effective dose was extended for 3 days and effects on neurobehavioral parameters, infarct size (TTC staining and MRI), oxidative stress parameters (MDA, GSH, SOD, NOX-2), inflammatory cytokines (TNF-α, IL-1ß, IL-10), apoptosis (Bax, Bcl-2, cleaved caspase-3 expression, and TUNEL staining), and autophagy (pAMPK, Beclin-1, LC3-II expression) were studied. The results of dose selection study showed significant reduction (p < 0.05) in infarct size and improvement in neurobehavioral parameters with safinamide (80 mg/kg). In sub-acute study, safinamide showed significant (p < 0.05) improvement in motor coordination and infarct size reduction. Additionally, safinamide treatment significantly normalized altered redox homeostasis and inflammatory cytokine levels. However, no change was observed in expression of NOX-2 in I/R or safinamide treatment group when compared with sham. I/R induced deranged expression of apoptotic markers and increased TUNEL positive cells in cortex were significantly normalized with safinamide treatment. Further, safinamide significantly (p < 0.05) induced the expressions of autophagic proteins (Beclin-1 and LC3-II) in cortex. Overall, the results demonstrated neuroprotective potential of safinamide via anti-oxidant, anti-inflammatory, anti-apoptotic, and autophagy inducing properties. Thus, safinamide can be explored for repurposing in ischemic stroke after further exploration.

Safinamide in neurological disorders and beyond: Evidence from preclinical and clinical studies.

The discovery and development of safinamide, an alpha-aminoamide, has been a valuable addition to the existing clinical management of Parkinson's disease (PD). The journey of safinamide dates back to the year 1983, when an alpha-aminoamide called milacemide showed a weak anticonvulsant activity. Milacemide was then structurally modified to give rise to safinamide, which in turn produced robust anticonvulsant activity. The underlying mechanism behind this action of safinamide is attributed to the inhibition of voltage gated calcium and sodium channels. Moreover, owing to the importance of ion channels in maintaining neuronal circuitry and neurotransmitter release, numerous studies explored the potential of safinamide in neurological diseases including PD, stroke, multiple sclerosis and neuromuscular disorders such as Duchenne muscular dystrophy and non-dystrophic myotonias. Nevertheless, evidence from multiple preclinical studies suggested a potent, selective and reversible inhibitory activity of safinamide against monoamine oxidase (MAO)-B enzyme which is responsible for degrading dopamine, a neurotransmitter primarily implicated in the pathophysiology of PD. Therefore, clinical studies were conducted to assess safety and efficacy of safinamide in PD. Indeed, results from various Phase 3 clinical trials suggested strong evidence of safinamide as an add-on therapy in controlling the exacerbation of PD. This review presents a thorough developmental history of safinamide in PD and provides comprehensive insight into plausible mechanisms via which safinamide can be explored in other neurological and muscular diseases.

Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to infect hundred thousands of people every day worldwide. Since it is a novel virus, research continues to update the possible therapeutic targets when new evidence regarding COVID-19 are gathered. This article presents an evidence-based hypothesis that activating the heme oxygenase-1 (HO-1) pathway is a potential target for COVID-19. Interferons (IFNs) have broad-spectrum antiviral activity including against SARS-CoV-2. Induction of HO-1 and increase in the heme catabolism end-product confer antiviral activity. IFN activation results in inhibition of viral replication in various viral infections. COVID-19 induced inflammation as well as acute respiratory distress syndrome (ARDS), and coagulopathies are now known major causes of mortality. A protective role of HO-1 induction in inflammation, inflammation-induced coagulation, and ARDS has been reported. Based on an association of HO-1 promoter polymorphisms and disease severity, we propose an evaluation of the status of these polymorphisms in COVID-19 patients who become severely ill. If an association is established, it might be helpful in identifying patients at high risk. Hence, we hypothesize that HO-1 pathway activation could be a therapeutic strategy against COVID-19 and associated complications.

Influence of Qualification and Practice Settings of Dental Practitioners on Antimicrobial Prescribing in Delhi and National Capital Region, India.

BACKGROUND AND OBJECTIVES: Inappropriate antimicrobial prescribing is highly reported in dentistry. The objective of the study was to see the effect of dental qualification and practice settings on antimicrobial prescribing practices among dental practitioners in Delhi and National Capital Region (NCR) of India. MATERIALS AND METHODS: A self-designed and pretested questionnaire was given to 667 dental practitioners holding degrees of graduation, postgraduation, and those pursuing postgraduation, working in academic institutions and private clinics in NCR of India. Data were analyzed using statistical software Stata version 12.0. Chi-square and logistic regression tests were used for analysis. RESULTS: Out of total 539 responded, 66.4% of the practitioners prescribed by brand name and 27.8% by generic name. Amoxicillin + clavulanic acid (27.4%) was the first choice. Only 26% of the practitioners asked for antimicrobial susceptibility testing. Space infections (91.9%), impacted third molar extractions (89.7%), and periodontal abscess (88.1%) were the conditions where antimicrobials were most frequently prescribed. However, 60.9% and 53.3% of the practitioners also prescribed antimicrobials for acute pulpitis and dry socket, respectively. For prophylaxis in medical conditions, amoxicillin was the first choice. In case of history of allergy to penicillin, 52.3% of the practitioners prescribe erythromycin whereas 14.6% prescribe amoxicillin. The adverse drug reporting culture was negligible, and only 14.3% of the practitioners were aware of the Pharmacovigilance Program of India. Level of qualification had a significant effect on prescribing (P < 0.05). INTERPRETATION AND CONCLUSION: Frequent irrational prescribing of antimicrobials used in odontogenic conditions warrants an urgent and continued need for guidelines as well as educational intervention programs in dentistry. This will improve the quality of antimicrobial prescribing practices in dentistry.