Reactive oxygen species-dependent upregulation of death receptor, tumor necrosis factor receptor 1, is responsible for theophylline-mediated cytotoxicity in MDA-MB-231 breast cancer cells.

Theophylline, a methylxanthine drug, has been used as a therapy for respiratory diseases. Recently, it has also been shown to have a potential in treating different cancers. Also, it has shown promising results in clinical trials for AML in combination therapy. Subsequently, studies have shown theophylline to kill breast cancer cells but not normal breast cells. Therefore, in this study, we have explored the molecular mechanism underlying the cytotoxic effect of theophylline on breast cancer cells. Theophylline-treated cancer cells were analyzed for the transcript and protein expression of candidate apoptotic genes such as TNFR1, caspase-8, -9, -3 using qPCR and immunoblotting, respectively. Cell viability and apoptosis was measured in the presence or absence of TNFR1 inhibitor, R7050, using AO/EtBr staining and MTT assay, respectively. Similarly, oxidative stress was studied by analyzing ROS in the presence or absence of ROS inhibitor, NAC, using DCFDA assay. Theophylline caused reduced cell viability in cancer but not normal cells. Theophylline-treated breast cancer cells showed increased expression of death receptor, TNFR1, along with elevated levels of active caspase-8, -9 and -3. Inhibition of TNFR1 reduced caspase-dependent apoptosis even in the presence of theophylline. Theophylline further caused increased ROS generation, inhibition of which resulted in reduced TNFR1-mediated apoptosis. Theophylline also increased cathepsin activity, which was reduced on exposure of cells to TNFR1 inhibitor, R7050. We conclude that ROS-mediated activation of TNFR1 is responsible for caspase-3 and cathepsin-dependent cell death in breast cancer cells on exposure to theophylline.

Calmodulin7: recent insights into emerging roles in plant development and stress.

KEY MESSAGE: Analyses of the function of Arabidopsis Calmodulin7 (CAM7) in concert with multiple regulatory proteins involved in various signal transduction processes. Calmodulin (CaM) plays various regulatory roles in multiple signaling pathways in eukaryotes. Arabidopsis CALMODULIN 7 (CAM7) is a unique member of the CAM family that works as a transcription factor in light signaling pathways. CAM7 works in concert with CONSTITUTIVE PHOTOMORPHOGENIC 1 and ELONGATED HYPOCOTYL 5, and plays an important role in seedling development. Further, it is involved in the regulation of the activity of various Ca2+-gated channels such as cyclic nucleotide gated channel 6 (CNGC6), CNGC14 and auto-inhibited Ca2+ ATPase 8. Recent studies further indicate that CAM7 is also an integral part of multiple signaling pathways including hormone, immunity and stress. Here, we review the recent advances in understanding the multifaceted role of CAM7. We highlight the open-ended questions, and also discuss the diverse aspects of CAM7 characterization that need to be addressed for comprehensive understanding of its cellular functions.

Adverse Events Reported From COVID-19 Vaccine Trials: A Systematic Review.

COVID-19 infection originated in Wuhan, China in December 2019 and crippled human health globally in no time. The public health emergency required urgent efforts to develop and test the efficacy and safety of vaccines to combat the COVID-19 pandemic. The emergency use approval has been granted to COVID-19 vaccines before the completion of conventional phases of clinical trials. However, there is no comprehensive review of safety data reported from the vaccine trials, which is critical information to inform the policies in order to improve uptake of COVID-19 vaccines and mitigate the risk aversion perceived due to the COVID-vaccine side effects. This study aims to systematically review and synthesize the evidence on the safety data from the published COVID-19 vaccine trials. This study followed PRISMA guidelines. We searched three major electronic databases (PubMed, Embase, and Google Scholar) for published studies between Dec 2019 and 2020. Eligible study designs were randomized trials and pre-and post-intervention evaluations. Descriptive findings of included studies were reported stratified by target population, setting, outcomes, and overall results. From PubMed, Embase, WHO database, and Google Scholar screened titles and abstracts, 11 studies were identified in this review. Most of the reactions reported were mild to moderate whereas a few with severe intensity. All reactions resolved within 3-4 days. The commonly reported local adverse events were pain at the site of injection, swelling, and redness. The systemic reactions included fever, fatigue, myalgia, and headache. Some trials also reported laboratory derangements  like decreased hemoglobin, increased bilirubin, altered SGOT and SGPT. None of these alterations were clinically manifested and were self-limiting. Few clinical trials reported serious adverse events, but they were unrelated to vaccination. This systematic review indicates that COVID-19 vaccines can be safe with no serious adverse events. However, long-term post-marketing surveillance data, particularly in high-risk vulnerable populations (elderly and those with co-morbidities, pregnant women, and children) is warranted to ensure the safety of COVID-19 vaccines.

Use of Complementary and Alternative Medicine (CAM) and Home Remedies by COVID-19 Patients: A Telephonic Survey.

COVID-19 is caused by a novel coronavirus which was first reported in Wuhan city, China. The pandemic has led to considerable mortality globally. India, at present has the second largest burden of COVID-19 cases globally. Clinical trials with new interventions, including new vaccine candidates are being explored in the scientific world. Countries like China and India, with a rich history of traditional medicine, are exploring the effectiveness of traditional medicines to treat COVID-19. This study included 725 patients from an Isolation center, of which 230 (31.7%) were excluded due to reasons like incorrect phone numbers, no response on phone, or denying consent to participate. Finally, 495 participants had responded, of which 367 (74.1%) had not used any Complementary and Alternative Medicine (CAM) product or home remedies while 128 (25.8%) people used 161 CAM products and home remedies during the treatment and even afterward. More than half of the participants (59.6%) among them had consumed Ayurvedic Kadha. Many respondents consumed more than one CAM products or home remedies but there were no reported acute or severe adverse effects with these products. However, it is essential to ensure the safety of these interventions on long-term use because patients with other comorbidities can have a detrimental effect due to these products or due to drug herb interaction with their ongoing medications. Hence, long-term follow-up studies of recovered patients are crucial in determining the effects of medications or CAM products on organ functions due to disease or interventions.

Functional interrelation of MYC2 and HY5 plays an important role in Arabidopsis seedling development.

Arabidopsis MYC2 bHLH transcription factor plays a negative regulatory role in blue light (BL)-mediated seedling development. HY5 bZIP protein works as a positive regulator of multiple wavelengths of light and promotes photomorphogenesis. Both MYC2 and HY5, belonging to two different classes of transcription factors, are the integrators of multiple signaling pathways. However, the functional interrelations of these two transcription factors in seedling development remain unknown. Additionally, whereas HY5-mediated regulation of gene expression has been investigated in detail, the transcriptional regulation of HY5 itself is yet to be understood. Here, we show that HY5 and MYC2 work in an antagonistic manner in Arabidopsis seedling development. Our results reveal that HY5 expression is negatively regulated by MYC2 predominantly in BL, and at various stages of development. On the other hand, HY5 negatively regulates the expression of MYC2 at various wavelengths of light. In vitro and in vivo DNA-protein interaction studies suggest that MYC2 binds to the E-box cis-acting element of HY5 promoter. Collectively, this study demonstrates a coordinated regulation of MYC2 and HY5 in blue-light-mediated Arabidopsis seedling development.

Changing clinico-epidemiology of post-kala-azar dermal leishmaniasis (PKDL) in India: Results of a survey in four endemic states.

BACKGROUND & OBJECTIVES: Detection and treatment of post-kala-azar dermal leishmaniasis (PKDL) cases is considered important for kala-azar elimination. The objective of our study was to find out the proportion of different forms of lesions, interruption of treatment and rate of treatment completion, cure rates of PKDL, risk factors for developing severe forms of PKDL and utilization of services offered by the kala-azar elimination program. METHODS: A cross-sectional survey of PKDL patients registered for treatment at all levels of care during 2015 and 2016 was done. RESULTS: 576 PKDL patients who had started treatment in 2015 and 2016 were studied. Three-fourths of all patients were found to be clinically cured after a year of follow-up. Around 90% lesions were of macular type. Interruption of treatment was observed in one-fourth of PKDL patients. Median duration between kala-azar treatment and development of PKDL was 4.5 years. Around 79% patients had past history of kala-azar treatment. Discontinuation of treatment during earlier kala-azar episode was significantly associated with the development of papular and nodular forms of lesion. 43% of patients had received the incentive of INR 2000 after completion of treatment. Around three-fourths women in the reproductive age group were found not to use any contraceptive method during PKDL treatment. INTERPRETATION & CONCLUSION: PKDL treatment interruption should be reduced through ensuring drug supply and timely retrieval of patients. Directly observed treatment should be implemented and combination regimen should be explored to improve final cure rate. Delivery of financial incentive to PKDL patients and counselling and contraception to women of reproductive age group should be improved.

Variations in chloroplast movement and chlorophyll fluorescence among chloroplast division mutants under light stress.

Chloroplasts divide to maintain consistent size, shape, and number in leaf mesophyll cells. Altered expression of chloroplast division proteins in Arabidopsis results in abnormal chloroplast morphology. To better understand the influence of chloroplast morphology on chloroplast movement and photosynthesis, we compared the chloroplast photorelocation and photosynthetic responses of a series of Arabidopsis chloroplast division mutants with a wide variety of chloroplast phenotypes. Chloroplast movement was monitored by red light reflectance imaging of whole plants under increasing intensities of white light. The accumulation and avoidance responses were differentially affected in different mutants and depended on both chloroplast number and morphological heterogeneity. Chlorophyll fluorescence measurements during 5 d light experiments demonstrated that mutants with large-chloroplast phenotypes generally exhibited greater PSII photodamage than those with intermediate phenotypes. No abnormalities in photorelocation efficiency or photosynthetic capacity were observed in plants with small-chloroplast phenotypes. Simultaneous measurement of chloroplast movement and chlorophyll fluorescence indicated that the energy-dependent (qE) and long-lived components of non-photochemical quenching that reflect photoinhibition are affected differentially in different division mutants exposed to high or fluctuating light intensities. We conclude that chloroplast division mutants with abnormal chloroplast morphologies differ markedly from the wild type in their light adaptation capabilities, which may decrease their relative fitness in nature.

Non-invasive, whole-plant imaging of chloroplast movement and chlorophyll fluorescence reveals photosynthetic phenotypes independent of chloroplast photorelocation defects in chloroplast division mutants.

Leaf chloroplast movement is thought to optimize light capture and to minimize photodamage. To better understand the impact of chloroplast movement on photosynthesis, we developed a technique based on the imaging of reflectance from leaf surfaces that enables continuous, high-sensitivity, non-invasive measurements of chloroplast movement in multiple intact plants under white actinic light. We validated the method by measuring photorelocation responses in Arabidopsis chloroplast division mutants with drastically enlarged chloroplasts, and in phototropin mutants with impaired photorelocation but normal chloroplast morphology, under different light regimes. Additionally, we expanded our platform to permit simultaneous image-based measurements of chlorophyll fluorescence and chloroplast movement. We show that chloroplast division mutants with enlarged, less-mobile chloroplasts exhibit greater photosystem II photodamage than is observed in the wild type, particularly under fluctuating high levels of light. Comparison between division mutants and the severe photorelocation mutant phot1-5 phot2-1 showed that these effects are not entirely attributable to diminished photorelocation responses, as previously hypothesized, implying that altered chloroplast morphology affects other photosynthetic processes. Our dual-imaging platform also allowed us to develop a straightforward approach to correct non-photochemical quenching (NPQ) calculations for interference from chloroplast movement. This correction method should be generally useful when fluorescence and reflectance are measured in the same experiments. The corrected data indicate that the energy-dependent (qE) and photoinhibitory (qI) components of NPQ contribute differentially to the NPQ phenotypes of the chloroplast division and photorelocation mutants. This imaging technology thus provides a platform for analyzing the contributions of chloroplast movement, chloroplast morphology and other phenotypic attributes to the overall photosynthetic performance of higher plants.

A Systematic Analysis of COVID-19 Clinical Trials Registered in the Clinical Trials Registry of India.

BACKGROUND: The Clinical Trials Registry - India (CTRI) database is a registry of various trials conducted in India and this study scrutinized the studies registered for COVID-19 from the database to detect patterns in trial design, appraising the target regions of therapies and comprehending the terrain of research endeavors. METHOD: This was a cross-sectional study that analyzed the registered trials for COVID-19 between March 2020 and September 2023. A trial search was conducted on the CTRI database to include all types of studies registered for COVID-19 with keywords like "COVID" and "coronavirus" and studies conducted on conditions other than COVID-19 were excluded. The data regarding study characteristics were noted under various sections in a preformed proforma. RESULTS: A total of 807 trials were taken for final analysis and there were about 344 prospective and 260 retrospective interventional trials, 35 prospective and 165 retrospective observational studies, and two prospective and one retrospective post-marketing surveillance study. The majority of the studies had duration under 12 months (91%). The maximum number of studies were registered from AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy) and allied therapies (n = 283), with about 104 types of interventions, followed by the drug category having 119 trials registered and about 57 types of interventions. Kabasura Kudineer and yoga in the AYUSH category, molnupiravir, colchicine, and favipiravir in the drug category, and tocilizumab and convalescent plasma among biologics were some common interventions used. The majority of trials did not mention the trial phase and declared it as not applicable (54%), whereas 15% were registered as phase 2 and 13% as phase 3. About 54% of the studies were randomized and randomized parallel-group design (20%) was the most common study design. Only 6% of the trials were post-graduate thesis and the majority of the trials (n = 535) denied sharing their individual participant data. Only 0.86% and 0.61% of the trials were terminated and suspended, respectively, denoting proper design and conduct of the trials. CONCLUSION: In the CTRI database, the majority of trials were prospective interventional studies, with a predominance of AYUSH therapies and drug interventions. Common interventions included Kabasura Kudineer and yoga in AYUSH, and molnupiravir, colchicine, and favipiravir in drugs. Most studies had durations under 12 months and randomized parallel-group design was the most common study design. The intention to use and promote an indigenous system of medicine looks promising in the absence of any definite therapy. A minute number of registered suspended and terminated trials might be a positive picture of meticulously designed and executed trials even during a pandemic situation in India.

A systematic review and meta-analysis of tolerability, cardiac safety and efficacy of inclisiran for the therapy of hyperlipidemic patients.

BACKGROUND: Dyslipidaemia is a crucial risk factor for cardiovascular morbidity and mortality. A short interfering RNA called inclisiran diminishes circulating levels of PCSK9 and LDL-C by hindering PCSK9 translation in the liver. METHODS: RCTs were electronically searched on PubMed, Cochrane Central, and Clinicaltrials.gov to assess the safety and efficacy of inclisiran. Cochrane Review Manager 5 was used to conduct the pooled analysis. Risk of bias was assessed and GRADE pro-GDT was utilized, respectively, to estimate the methodological quality and overall quality of evidence. RESULTS: Of 218 records screened, four studies were included with 2203 participants in inclisiran and 1949 participants in the placebo group. Inclisiran was related to non-significant elevated risk of total adverse events[RR = 1.05(0.98,1.12), p = 0.16; I2 = 53%], non-serious adverse events[RR = 1.09(0.97,1.22),p = 0.15;I2 = 61%] and all-cause mortality[RR = 1.01(0.60,1.70),p = 0.97;I2 = 0%] whereas a lower risk of serious adverse events[RR = 0.94(0.70,1.25),p = 0.67;I2 = 73%], cardiac disorders [RR = 0.87(0.66,1.15),p = 0.33;I2 = 42%] and Major adverse cardiovascular events(MACE)[RR = 0.79(0.62,1.00),p = 0.05; I2 = 0%] as compared to placebo. Inclisiran was also linked to a substantial decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B. CONCLUSION: The pooled analysis of the existing evidence shows that inclisiran showed reduced risk of MACE along with excellent efficacy in managing dyslipidemia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT03399370, NCT03397121, NCT03400800, and NCT02597127.

Elevated cholesterol levels have been found to be associated with a high risk of heart disease and associated deaths. There are various classes of drugs used to control high low-density lipoprotein cholesterol (LDL-C) levels in blood yet appropriate control and patient compliance, to regular cholesterol-lowering drugs have been an issue. Inclisiran, a novel drug for reducing the LDL-C levels in serum can be given every six months as an effective therapy to minimize the levels of LDL-C in serum. This study was designed to assess the safety and effectiveness of inclisiran in patients with hyperlipidemia. Inclisiran was found to have a non-significant elevated risk of total adverse events, non-serious adverse events, and all-cause mortality. The majority of the adverse events seem to be non-serious and tolerable. There was an observed non-significant lower risk of serious adverse events, cardiac disorders, and significantly reduced risk of major adverse cardiovascular events when compared to placebo. Inclisiran was also linked to a significant decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B in patients with hyperlipidemia. With the evidence available at present, inclisiran seems an efficacious and well-tolerated therapeutic strategy to manage elevated cholesterol and LDL-C levels. However, long-term, large cardiovascular outcome trials are required to conclude on the drug's cardiovascular and overall safety.

Impact of positive airway pressure therapy on intraocular pressure in obstructive sleep apnea: A systematic review.

BACKGROUND: Positive airway pressure (PAP) therapy has been reported to have variable effect on intraocular pressure (IOP) in patients with obstructive sleep apnea (OSA) . The objective of this review is to present a qualitative assessment of available literature on impact of PAP on IOP in patients of OSA.Method: Online databases were searched for relevant articles up to September 2023. It included randomized control trial (RCT), prospective observational study, case control study, cross-sectional study, published abstract having relevant information. The comparator group consisted of OSA patients not receiving the PAP therapy or the pre-PAP IOP. Studies reporting change in IOP immediately after PAP use, at 1 month and at 1 year of PAP use were included. For quality assessment Cochrane Risk of Bias tool version 2 and NIH study quality assessment tool for Before-After (Pre-Post) Studies with No Control Group was used.Result: In this systematic review of ten clinical studies with 191 patients of OSA, use of continuous positive airway pressure (CPAP) therapy led to an immediate increase in IOP but it was not significantly different from non-CPAP users. One month and 1 year of CPAP use led to a significant increase in IOP from the baseline value. CONCLUSION: The available albeit limited evidence suggests that CPAP use, particularly at higher pressures, is linked to an elevation in IOP. However, high quality evidence from well-designed RCTs is needed to confirm or refute this findings.

Association Study of Transforming Growth Factor Beta 1 + 29 T/C exon 1 Polymorphism in Breast Cancer Patients from North Indian Population.

BACKGROUND: TGFB1 cytokine is involved in normal mammary epithelial development as well as in breast tumorigenesis. It has role in both breast tumor suppression and progression. TGFB1 gene has several single nucleotide polymorphisms (SNPs) many of which modulate the activity of TGFB1. Our aim in this study was to analyze TGFB1 + 29 polymorphism in breast cancer individuals from North Indian population. METHODS: TGFB1 + 29 T/C polymorphism was analyzed using Sanger sequencing in 285 breast cancer patients and age matched 363 healthy controls from North Indian population. Next, transcript expression of 13 apoptotic genes, TRAIL, DR4, DR5, DcR1, DcR2, Bcl2, cytochrome c, Casp8L, Casp8, FlipS, FlipL, Casp3s and Casp3 were carried out in 77 breast tumor tissues obtained from 77 individuals. RESULTS: TGFB1 + 29 CC genotype provided protection against the development of breast cancer (P = 0.012). This was mainly attributable to higher age group (> 45 years) women (P = 0.016). Individuals having CC protector genotype showed significantly higher expression of TGFB1 transcript compared to the TT and TC risk genotypes (P = 0.044). Furthermore, we observed that TGFB1 + 29 CC genotype showed increased TRAIL mediated apoptosis via the extrinsic pathway in breast tumor patients with age greater than 45 years (P = 0.027). CONCLUSION: TGFB1 + 29 homozygous mutant CC genotype is related to protection against breast cancer in North Indian women population greater than 45 years of age.

Chloroplast Engineering: Fundamental Insights and Its Application in Amelioration of Environmental Stress.

Chloroplasts are specialized organelle that are responsible for converting light energy to chemical energy, thereby driving the carbon dioxide fixation. Apart from photosynthesis, chloroplast is the site for essential cellular processes that determine the plant adaptation to changing environment. Owing to the presence of their own expression system, it provides an optimum platform for engineering valued traits as well as site for synthesis of bio-compounds. Advancements in technology have further enhanced the scope of using chloroplast as a multifaceted tool for the biotechnologist to develop stress-tolerant plants and ameliorate environmental stress. Focusing on chloroplast biotechnology, this review discusses the advances in chloroplast engineering and its application in enhancing plant adaptation and resistance to environmental stress and the development of new bioproducts and processes. This is accomplished through analysis of its biogenesis and physiological processes, highlighting the chloroplast engineering and recent developments in chloroplast biotechnology. In the first part of the review, the evolution and principles of structural organization and physiology of chloroplast are discussed. In the second part, the chief methods and mechanisms involved in chloroplast transformation are analyzed. The last part represents an updated analysis of the application of chloroplast engineering in crop improvement and bioproduction of industrial and health compounds.

Detection of Protein-Protein Interactions Utilizing the Split-Ubiquitin Membrane-Based Yeast Two-Hybrid System.

Identifying the interactors of a protein is a key step in understanding its possible cellular function(s). Among the various methods that can be used to study protein-protein interactions (PPIs), the yeast two-hybrid (Y2H) assay is one of the most standardized, sensitive, and cost-effective in vivo methods available. The most commonly used GAL4-based Y2H system utilizes the yeast transcription factor GAL4 to detect interactions between soluble proteins. By virtue of involving a transcription factor, the protein-protein interactions occur in the nucleus. The split-ubiquitin Y2H system offers an alternative to the traditional GAL4-based Y2H system and takes advantage of the reconstitution of split-ubiquitin in the cytosol to identify interactions between two proteins. Moreover, new membranous and soluble interacting partner(s) can be identified by screening a target protein against proteins produced from a cDNA library using this system.

Clinical efficacy and safety of dasiglucagon in severe hypoglycemia associated with patients of type 1 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND AND AIMS: This study was carried out to analyze the clinical safety and efficacy of dasiglucagon for the treatment of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM). METHODS: We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for randomized controlled trials (RCTs) investigating the safety and efficacy of dasiglucagon in the treatment of hypoglycemia in patients with T1DM. Furthermore, time required for the recovery of blood glucose or to elevate blood glucose levels ≥20.0 mg/dL from baseline was analyzed. The data was analyzed in version 5.4 of review manager 5 (RevMan). RESULTS: We included five published RCTs with a total of 347 patients . Dasiglucagon was significantly better at reducing the recovery time of blood glucose or increasing blood glucose levels 20.0 mg/dL from baseline compared to glucagon [pooled mean difference (PMD): 1.08%, 95% confidence interval (CI): 1.96 to 0.21, p = 0.02] and placebo (PMD: - 23.30%, 95% CI: 23.97 to 22.63, p < 0.00001). Overall, the safety outcome results of dasiglucagon were comparable with the native glucagon. CONCLUSIONS: Dasiglucagon appears to be a promising human glucagon analog peptide for the safe and effective treatment of severe hypoglycemia in T1DM.

Indian Essential Medicine List for Children: Time to Revisit.

BACKGROUND: The majority of the under five mortality rate (U5MR) in India were due to treatable causes and could have been prevented by providing quality medicines. Availability and affordability of medicine can be improved by the introduction of essential medicine concepts. PURPOSE: The current study was carried out to compare the latest edition of the WHO essential medicine list for children (EMLc) with that of Indian EMLc to determine the need to update the Indian EMLc. METHODS: A descriptive observational study was carried out in the Department of Pharmacology of a tertiary care hospital. The latest edition of WHO EMLc (8th) was compared with the latest edition of Indian EMLc (1st) in terms of inclusion of categories or subcategories, the number of medicines in each category or subcategories, medicines which are present in WHO EMLc but missing in Indian EMLc and vice versa. RESULTS: In total 134 medicines are present in Indian EMLc as compared to 350 medicines in WHO EMLc. The important categories which are completely missing in Indian EMLc are medicines for reproductive health and perinatal care, peritoneal dialysis solution, medicines for mental and behavioral disorders, and medicines for diseases of joints. The important medicines which are not included in Indian EMLc are bedaquilline, delaminid, cefixime, piperacillin+tazobactum, vancomycin, acyclovir, azathioprine, cisplatin, and filgrastim. Important vaccines including rotavirus, cholera, hepatitis, and typhoid vaccine are not mentioned in Indian EMLc. CONCLUSION: There is an urgent need to update the Indian EMLc in order to promote access to pediatric medicine and facilitate the rational use of medicines.

Are we providing complete drug information to its users? Status of information adequacy of package insert in India.

Background: Package inserts (PIs) serve detailed information on drug products to the users and primary care physicians, so information should be accurate, reliable, and as per the regulatory guidelines. The study aims to analyze the information adequacy of the PIs available in the Indian market as per Drug and Cosmetic Rule 1945 and US Food and Drug Administration criteria. Materials and Methods: A cross-sectional study was conducted on PIs collected from accessible pharmacy stores. Information provided was recorded as per criteria, and total information adequacy score (IAS) and information deficiency (IDS) score were calculated. The association of factors like single-drug/FDCs, a company of origin Indian/multinational, and route of administration (ROA) with IDS was statistically analyzed. Results: Of 120 PIs, 60%, 86.66%, and 73% were single-drug, prescription-drug, and drugs by Indian manufacturers, respectively. Most PIs provided generic names, ROA, and indications for use. 85%, 12%, 29.16%, and 3.33% provided information on PIs on the ability to drive, drug-food interactions, drug-drug interactions, and addiction potential, respectively. Lacking area was information on use in pediatrics-geriatrics (30%), excipients (28.3%), preclinical (15.83%), post-surveillance data (18.33%), and approval date (2.5%). There was a statistically significant difference between pharmaceutical score (3.22 vs 4.12), therapeutic score (11.5 vs 13.18), and total IAS (14.78 ± 3.39 vs 17.31 ± 2.33) of Indian and multinational companies. IDS was statistically significantly different in both pharmaceutical and therapeutic categories for single-drug vs FDCs (P = 0.00001), OTC vs prescription drugs (P < 0.05), and Indian vs multinational companies' PIs (P = 0.00001). Conclusion: Numerous facets of information are lacking in PIs, and they do not impart whole information, especially of Indian origin, as per objective IDS.

Daridorexant as a novel pharmacotherapeutic approach in insomnia: a systematic review and meta-analysis.

BACKGROUND: Insomnia is a multi-factorial disorder with conventional treatment options that are not satisfactory for many patients. This metaanalysis analyzed the safety and efficacy of daridorexant. METHODS: An electronic database search for RCTs was conducted on Medline via PubMed, Cochrane, and Clinicaltrials.gov using the terms 'Daridorexant,' 'RCT,' 'Insomnia' trials evaluating the efficacy and/or safety of daridorexant for insomnia were included. The data were synthesized using Cochrane review manager version 5.4.1. Cochrane risk of bias 2.0 tool and GRADEpro-GDT were used to assess the methodological and evidence quality, respectively. RESULTS: Of 109 searched studies, four trials were included. The risk of treatment-emergent adverse events with 25 mg daridorexant [risk ratio (RR) = 1.12 (0.88, 1.43), p = 0.36; I2 = 0%] and 50 mg daridorexant [RR = 1.25 (0.88, 1.79), p = 0.22; I2 = 28%] and serious adverse events with 25 mg [RR = 0.86 (0.23, 3.19), p = 0.82, I2 = 56%] and 50 mg [RR = 1.32 (0.29, 6.08), p = 0.72, I2 = 52%] was comparable to placebo [Moderate quality evidence]. Risk of nasopharyngitis was also comparable to placebo. The efficacy parameters like wake after sleep onset, latency to persistent sleep, and subjective total sleep time showed significant improvement with daridorexant. The risk of bias is low for three studies and some concern for one. CONCLUSION: Daridorexant is a safer and efficacious agent for induction and maintenance of sleep for chronic insomnia. PROSPERO: The registration number is CRD42022335233. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT03575104, NCT03545191, NCT03679884, and NCT02839200).

Bexagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, for improvement of glycemia in type 2 diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVES: This study assessed the clinical safety and efficacy of bexagliflozin, a sodium-glucose cotransporter 2(SGLT2) inhibitor, in managing glycemia among patients with type 2 diabetes mellitus (T2DM). AREAS COVERED: We examined RCTs with T2DM comparing the clinical effectiveness and safety of 20 mg once daily oral dose of bexagliflozin with placebo for managing glycemia till 28 May 2023, published on databases like ClinicalTrials.gov, PubMed, Embase, and Cochrane Library. Furthermore, reduction of body weight, fasting plasma sugarr(FPG), systolic blood pressure (SBP) and the percentage of individuals who achieved glycated hemoglobin (HbA1c) of < 7% from baseline were also evaluated. The Review Manager 5 was utilized to investigate the retrieved data. EXPERT OPINION: We involved eight RCTs. Bexagliflozin was significantly superior in reducing HbA1c[least squares mean difference(LSMD) = -0.45,95% confidence interval (CI =-0.55 to -0.34,p < 0.00001], FPG [LSMD= -1.37, 95%CI =-1.73 to -1.00, p < 0.00001], body weight (LSMD= -1.77, 95%CI =-2.44 to-1.10, p < 0.00001), and SBP(LSMD= -4.11,95%CI = -6.18 to -2.03,p = 0.0001) in comparison to placebo. The safety outcomes of bexagliflozin were consistent with the placebo arm. This study concluded that bexagliflozin seems to be a promising oral anti-diabetic drug for enhancing glycemic management in adult patients with T2DM.

Bexagliflozin, a novel hypoglycemic agent, is an extremely effective SGLT2 inhibitor developed by TheracosBio to manage glycemia in T2DM. The United States Food and Drug Administration (USFDA) granted first approval of bexagliflozin on 20 January 2023, for usage as an adjunctive therapy agent alongside lifestyle changes and exercise in T2DM. All included RCTs have investigated the therapeutic efficacy and safety of bexagliflozin 20 mg concerning glycemic and extra-glycemic effects in T2DM. Bexagliflozin 20 mg significantly reduces HbA1c, FPG (glycemic effect), body weight, and SBP (extra-glycemic effect) compared to the placebo arm in T2DM. Safety data show that bexagliflozin was comparable to placebo arm and polyuria, urinary tract infection (UTI), nasopharyngitis or upper respiratory tract infection (URTI), hypoglycemia, nausea, and diarrhea were the most common non-serious adverse effects. Bexagliflozin 20 mg seems to be an effective SGLT2 inhibitor compared to the placebo arm to manage glycemia in patients with T2DM along with favorable extra-glycemic effects.

Multidrug-Resistant TB (MDR-TB) and Extensively Drug-Resistant TB (XDR-TB) Among Children: Where We Stand Now.

Drug-resistant tuberculosis (DR-TB) has continued to be a global health cataclysm. It is an arduous condition to tackle but is curable with the proper choice of drug and adherence to the drug therapy. WHO has introduced newer drugs with all-oral shorter regimens, but the COVID-19 pandemic has disrupted the achievements and raised the severity. The COVID-19 controlling mechanism is based on social distancing, using face masks, personal protective equipment, medical glove, head shoe cover, face shield, goggles, hand hygiene, and many more. Around the globe, national and international health authorities impose lockdown and movement control orders to ensure social distancing and prevent transmission of COVID-19 infection. Therefore, WHO proposed a TB control program impaired during a pandemic. Children, the most vulnerable group, suffer more from the drug-resistant form and act as the storehouse of future fatal cases. It has dire effects on physical health and hampers their mental health and academic career. Treatment of drug-resistant cases has more success stories in children than adults, but enrollment for treatment has been persistently low in this age group. Despite that, drug-resistant childhood tuberculosis has been neglected, and proper surveillance has not yet been achieved. Insufficient reporting, lack of appropriate screening tools for children, less accessibility to the treatment facility, inadequate awareness, and reduced funding for TB have worsened the situation. All these have resulted in jeopardizing our dream to terminate this deadly condition. So, it is high time to focus on this issue to achieve our Sustainable Development Goals (SDGs), the goal of ending TB by 2030, as planned by WHO. This review explores childhood TB's current position and areas to improve. This review utilized electronic-based data searched through PubMed, Google Scholar, Google Search Engine, Science Direct, and Embase.