Daridorexant, a Recently Approved Dual Orexin Receptor Antagonists (DORA) in Treatment of Insomnia.

Insomnia is one of the major challenges in medical science nowadays as it leads to great socio-economic burden by impairing daytime function as well as the development of exhaustion, depression, and memory disturbance in affected individuals. Several important classes of drugs have been tried, including the BZDs and non-BZD hypnotics. Available drugs to combat this disease have the limitations of abuse potential, tolerance, and cognitive impairment. In some instances, withdrawal symptoms have been observed upon the abrupt cessation of those drugs. The Orexin system has been very recently targeted as a therapeutic option to overcome those limitations. Treatment of insomnia with Daridorexant as a Dual Orexin Receptor Antagonist (DORA) has been evaluated in several preclinical and clinical studies. Available information obtained from those studies has shown a promising future for this drug in the management of insomnia. Beyond its effectiveness in insomnia, it has been successfully used in patients suffering from obstructive sleep apnoea, chronic obstructed airway disease (COAD), Alzheimer's disease (AD), hypertension, and cardiovascular disorders. Larger studies need to address the safety issues as well as obtain robust pharmacovigilance information to safeguard the risk-benefit aspect of this drug in insomniac adults.

Daridorexant, a Recently Approved Dual Orexin Receptor Antagonists (DORA) in the Treatment of Insomnia.

Insomnia is one of the major challenges in medical science nowadays as it leads to the great socio-economic burden by impairing daytime function as well as the development of exhaustion, depression and memory disturbance in affected individuals. Several important classes of drugs have been tried including the BZDs and Non-BZD hypnotics. Available drugs to combat this disease have the limitations of abuse potential, tolerance and cognitive impairments. In some instances, withdrawal symptoms have been observed on abrupt cessation of those drugs. The Orexin system has been very recently targeted as a therapeutic option to overcome those limitations. Daridorexant as a Dual Orexin Receptor Antagonists (DORA) in the treatment of insomnia has been evaluated in several preclinical and clinical studies. Available information obtained from those studies has shown promising future for this drug in the management of insomnia. Beyond its effectiveness in insomnia, it has been successfully used in patients suffering from Obstructive sleep apnoea, Chronic Obstructive Airway Disease (COAD), Alzheimer's Disease (AD), hypertension and cardiovascular disorders. Larger studies need to address the safety issues as well as obtain robust pharmacovigilance information to safeguard the risk-benefit aspect of this drug in insomniac adults.

An update of antispike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies.

The use of monoclonal antibodies has expanded beyond the realm of autoimmune disease and cancer therapeutics to communicable diseases. Their antiviral activities were evaluated in some diseases such as SARS MERS (Middle East Respiratory Syndrome) and Ebola. In recent times, antispike SARS-CoV-2 monoclonal antibody cocktails (casirivimab with imdevimab and bamlanivimab with etesevimab) and single agent sotrovimab have received emergency use authorization for treatment of nonhospitalized COVID-19 patients with mild-to-moderate disease at high risk of disease progression. This review summarizes their mechanism of action, salient pharmacokinetic profile, safety and clinical trial (ongoing and completed) data. Despite evidence to support its use for the indication, the high cost of these biologics may make it unaffordable for many patients, but further clinical studies on their cost-benefit profile shall provide useful information to the scientific community and patients.

Knowledge, Attitude and Practice Survey Regarding High Alert Medication Among Resident Doctors in a Tertiary Care Teaching Hospital in Eastern India.

BACKGROUND: Medication errors are a reality in all settings where medicines are prescribed, dispensed, and used. High-alert medications (HAM) are those that bear a heightened risk of causing significant harm to the patient if used erroneously. Though mishaps with HAM may not be more common than with other drugs, the consequences of error with them can be especially serious. We conducted a survey on knowledge, attitude, and practice, among residents working in a teaching hospital to assess the ground situation regarding HAM awareness and handling. METHODS: We approached 492 residents among the approximately 600 currently working through purposive sampling. Residents in all disciplines (clinical, paraclinical, and preclinical) were targeted. A structured questionnaire with 54 questions, pilot-tested on 20 volunteer residents, was used for data collection. The questionnaire was administered to residents through face-to-face interviews by two raters while they were on duty, but not during rush hours. RESULTS: Of the total 261 responses received, 32.33% respondents correctly defined or explained the meaning of the term 'medication error'. Knowledge regarding the difference between medication error and adverse events did not get reflected in 68.38% of the participants, and only 16.86% were able to name the relevant group of medicines as HAM. Regarding attitude in dealing with HAM, the majority believed that taking the history of drug allergy and reconciling all prescription and over-the-counter (OTC) drugs already being used before prescribing or using medicine is important. In practice, most respondents followed protocols but not routinely. Several potential errors in practice were identified. CONCLUSION: The current situation requires corrective action. There is an urgent need for improving awareness regarding HAM for the sake of patient safety. The pharmacology department can take the lead in designing awareness campaigns with support from the hospital administration.

Cefiderocol: A new Antimicrobial for Complicated Urinary Tract Infection (CUTI) Caused by Carbapenem-resistant Enterobacteriaceae (CRE).

The incidence of carbapenem-resistant gram-negative (CRGNB) bacterial infections has increased globally. The wide diversity of strains, multiplicity of infections, and rapid development and spread of resistance are a matter of great concern both in community and hospital settings. Cefiderocol is a novel injectable siderophore containing cephalosporin with potent microbicidal activity against most carbapenem-resistant Enterobacteriaceae (CRE). It has recently been approved by USFDA for the treatment of complicated urinary tract infections (cUTI) caused by susceptible gram-negative microorganisms. This review focuses on the salient pharmacological profile of the drug and the clinical studies that were undertaken. Cefiderocol is first in class injectable siderophore cephalosporin showing potency against carbapenem- resistant Enterobacteriaceae. It has recently been approved by US FDA for the treatment of adult patients with complicated urinary tract infections (cUTI) caused by susceptible Gram-negative microorganisms, where there are limited or no alternative treatment options.

Hypertension Clinical Practice Guidelines (ISH, 2020): What Is New?

OBJECTIVE: In May 2020, the International Society of Hypertension (ISH) published "Practice Guidelines for the Management of Hypertension." The ISH 2020 guidelines were developed based on evidence criteria (i) to be used globally, (ii) to be fit for application in low-middle-income and high-income settings, and (iii) to be concise, simple, and easy to use by clinicians, nurses, and community health workers, as appropriate. The defined purpose was to adhere to the current evidence and develop a balanced proposal for global use in line with the ISH mission. METHODOLOGY: Multiple novel approaches have been included keeping in mind about lifestyle modification and flexibility in treatment options. RESULTS AND CONCLUSIONS: The ISH 2020 guidelines are practical and physician friendly. It also proves immensely helpful for low-resource countries without national guidelines on the management of hypertension.

Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma.

Plexiform neurofibroma (PN) is one of the most striking clinical features of neurofibromatosis 1. Growth of PN can occur at any stage of life but mostly in childhood and during hormonal changes. They arise from multiple nerve fascicles and may transform into malignant peripheral nerve sheath tumors. There was previously no approved medical therapy for tumor shrinkage or regression. Surgery is not always possible due to inaccessible location, involvement of vital tissue, optimal timing, and incomplete removal. Recently, the US Food and Drug Administration approved selumetinib for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 who have symptomatic, inoperable tumor. Neurofibromin, a 2818 amino acid long cytoplasmic protein, is the product of the NF1 gene. It inhibits the activity of Ras GTPase proteins. Lack of functional neurofibromin in patients with NF1 leads to dysregulated Ras and tumorigenesis. RAS MAPK pathway is hyper activated in NF1. Selumetinib is an inhibitor of MEK1 and MEK2 proteins, which play an important role in the MAPK signaling pathway related to tumor growth. Approval was based on one pivotal, single-arm, phase II trial. 70% of participants experienced confirmed partial response of tumor shrinkage, and 68% also had improvement of related complications, and other studies have also shown beneficial responses. The major limitation of this molecule regarding its mechanism of action is the dose-dependent effect of MEK inhibition in growth of neurofibroma. Long-term safety and efficacy studies are to be done in the future to establish selumetininb as a useful medicine.

Immunohistochemical analysis of beta-catenin expression: a probable prognostic marker and potential therapeutic target in renal cell carcinoma.

BACKGROUND AND AIMS: Renal cell carcinoma (RCC) seems to be the most aggressive type of genitourinary neoplasm. Down regulation of normal beta-catenin expression contributes to development of RCC, reflecting the role of beta-catenin/Wnt signaling pathway in pathogenesis. This study aims to evaluate the significance of beta-catenin expression and its correlation with the prognostic parameters. METHODS: A cross-sectional observational study was carried out in a tertiary care center on 58 RCC cases using variables like histological grade and type, tumor stage, necrosis. Formalin fixed, paraffin-embedded blocks were evaluated for beta-catenin expression by immunohistochemistry using scoring system. Data were analyzed by mean ± SD, χ2 test, Pearson's correlation test. RESULTS: Membranous score (MS) had a strong negative correlation with tumor stage (r=-0.407, p=0.044) and grade (r=-0.787, p=<0.001). Mean membranous score difference between low (Stage 1 and 2) vs. high stage (Stage 3 and 4) and low (Grade 1 and 2) vs. high grade (Grade 3 and 4) was statistically significant (p<0.001). Cytoplasmic score (CS) had positive correlation with tumor stage (r=0.586; p=0.002). No significant correlation was evident between cytoplasmic scores and tumor grade, however the mean cytoplasmic score difference between low grade vs. high grade was statistically significant (p < 0.001). CONCLUSION: Beta-catenin may play a crucial role in the pathogenesis of RCC and has a positive correlation with the biological behavior of this tumor. The important role of beta-catenin as a prognostic parameter and probably a critical evaluator of targeted chemotherapy cannot be overemphasized.

Newer Horizon for Treatment of Acute Attack of Migraine: Lasmiditan and Ubrogepant.

Migraine is characterized by severe, intermittent headache attacks with associated symptoms including nausea, vomiting, phonophobia, and photophobia. Still Triptans (selective 5-HT1B/D agonists) are considered as the first-line therapy in acute attack of migraine. Recently two new drugs Lasmiditan and Ubrogepant were approved by United States Food and Drug Administration in acute attack of migraine with or without aura in adults. Lasmiditan is a highly selective 5-HT1F receptor agonist which demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed phase-3 trials, SAMURAI and SPARTAN. Ubrogepant is a novel small molecule oral calcitonin gene-related peptide receptor antagonist. The approval was supported by two pivotal phase-3, randomized, double-blind, placebo-controlled trials (ACHIEVE I and ACHIEVE II) that evaluated the efficacy, safety, tolerability. Hopefully, these two drugs may soon be a new addition to the mounting armory of drugs against migraine and may fulfill a substantial unmet need.

Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times.

In the current COVID-19 pandemic, evidence to justify the use of any specific antiviral drug with proven efficacy is not yet available. Antiviral drug development always remains a challenge to the scientists. Remdesivir has emerged as a promising molecule, based on results of clinical trials and observational studies and has receieved marketing approval for COVID-19 treatment under "emergency use authorization" in countries such as United States. Remdesivir is a newer antiviral drug that acts as an RNA-dependent RNA polymerase (RdRp) inhibitor targeting the viral genome replication process. Therapeutic efficacy was first demonstrated by suppressing viral replication in Ebola-infected rhesus monkeys. It is available for parenteral use with reasonable safety and tolerability profile. Multiple clinical trials are going on in many countries to evaluate its safety, efficacy and tolerability. Positive outcome will make the drug capable of meeting the demand generated by both the current pandemic and future outbreak. HOW TO CITE THIS ARTICLE: Choudhury S, Chakraborty DS, Lahiry S, Chatterjee S. Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times. Indian J Crit Care Med 2020;24(7):570-574.

The National Guidelines for Stem Cell Research (2017): What academicians need to know?

India recently updated its guidelines on stem cell research (SCR), the National Guidelines for Stem Cell Research 2017. It was drafted under a collaborative effort from the Indian Council of Medical Research and Department of Biotechnology. The new guidelines are a part of a continuous endeavor to tackle scientific, technical, as well as perceived challenges in the field of SCR. It seeks to facilitate safe, ethical, and regulated translational and clinical SCR by engaging all stakeholders proactively.

Impact of social media on academic performance and interpersonal relation: A cross-sectional study among students at a tertiary medical center in East India.

CONTEXT: There is limited evidence on the influence of social media among medical students. AIMS: To assess the pattern of social media usage among medical students in eastern part of India and analyze self-perceived impact on academic performance and interpersonal relations. METHODS: This cross-sectional study was based on an online survey, taken by 650 medical students at a tertiary medical center in Kolkata. The survey was created using an online tool, Google Forms. It assessed social media usage patterns and students' perspective on how it affects their academic performance and interpersonal relations. STATISTICAL ANALYSIS USED: Pearson's correlation coefficient was used to quantify the association between self-rated academic performance and social and physical well-being, with different variables, assuming linear relationships. P <0.05 was considered statistically significant. RESULTS: The usable responder rate was 55.23%, with majority being undergraduates (57.3%) in the age group of 18-24 years. The proportion who confirmed using social media was 88.58% (95% confidence interval [CI]: 85.29%-91.87%), mainly for academic purposes (82.73%; 95% CI: 78.82%-86.64%). In general, social media usage was more prevalent among medical students compared to paramedical and nursing students (P = 0.009), although the extent of use for an academic purpose was comparable. Nearly two-thirds (60.87%) regarded social networking having a positive (improved) impact on academic performance. However, the perceived impact on interpersonal relations was inconclusive (i.e., was positive and negative in a nearly equal measure; 45% each). CONCLUSIONS: Social media usage for academic purposes is high among medical and paramedical students. Students benefit from social networking and are conscious of its positive as well as negative influence on interpersonal relations.

Comparative Evaluation of the Embrasure Wire versus Arch Bar Maxillomandibular Fixation in the Management of Mandibular Fractures: Are Arch Bars Replaceable?

The aim of this prospective study was to appraise the role of embrasure wiring in the treatment of mandibular fractures over the arch bar as adjunctive techniques of maxillomandibular fixation (MMF). This study was conducted on 40 patients who were surgically treated for mandibular fractures with accessory use of MMF (embrasure: group A vs. arch bars: group B). All patients were evaluated for demographic data, etiology, and location of fracture. Characteristically, the complications, including wire injury, infection, and malocclusion, were recorded. The data were analyzed using Student's t -test and chi-square test as appropriate. Statistical significance was set at p < 0.05). In this study, data from 40 patients were included. In group A (embrasure wiring), time required for placement of MMF was significantly less than (7.85 ± 0.81 minutes) that in group B, and also there was less incidence of wire prick to the operator in group A than in group B ( p < 0.05). However, in terms of wire prick and malocclusion, no statistically significant difference was noted in groups A and B ( p > 0.05). Patient treated with embrasure wiring intermaxillary fixation had better outcomes especially in terms of time of placement and less incidence of wire prick injury when compared with arch bar.

Polymyxin B-Induced Diffuse Cutaneous Hyperpigmentation.

Polymyxin B is a polypeptide-antibiotic, primarily used for resistant Gram-negative infections, first obtained from bacterium Bacillus polymyxa in the late 1940s. Antibiotic spectrum are restricted to mainly gram negative bacterias like Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, Shigella; and particularly organisms like Pseudomonas aeruginosa and Acinetobacter baumannii, which are extremely potent to acquire antibiotic resistance. Side effects include neurotoxicity and acute renal tubular necrosis. Here, we present a rare case of skin hyper-pigmentation in a 65-year-old elderly male of Indian origin, diagnosed as a case of Multi-Drug Resistant (MDR) Klebsiella pneumonia, treated with intravenous antibiotics. The manifestations were observed after 4 days of Polymyxin B therapy initiation. All other concomitant drugs, infections, or immunologic disorders that, could have caused this symptom, were carefully excluded. An objective causality assessment reveals that, the cutaneous hyperpigmentation was possibly associated with Polymyxin B therapy, though further studies may be needed to explain the underlying mechanism.