S1P Signaling Genes as Prominent Drivers of BCR-ABL1-Independent Imatinib Resistance and Six Herbal Compounds as Potential Drugs for Chronic Myeloid Leukemia.

Imatinib (IM), a breakthrough in chronic myeloid leukemia (CML) treatment, is accompanied by discontinuation challenges owing to drug intolerance. Although BCR-ABL1 mutation is a key cause of CML resistance, understanding mechanisms independent of BCR-ABL1 is also important. This study investigated the sphingosine-1-phosphate (S1P) signaling-associated genes (SphK1 and S1PRs) and their role in BCR-ABL1-independent resistant CML, an area currently lacking investigation. Through comprehensive transcriptomic analysis of IM-sensitive and IM-resistant CML groups, we identified the differentially expressed genes and found a notable upregulation of SphK1, S1PR2, and S1PR5 in IM-resistant CML. Functional annotation revealed their roles in critical cellular processes such as proliferation and GPCR activity. Their network analysis uncovered significant clusters, emphasizing the interconnectedness of the S1P signaling genes. Further, we identified interactors such as BIRC3, TRAF6, and SRC genes, with potential implications for IM resistance. Additionally, receiver operator characteristic curve analysis suggested these genes' potential as biomarkers for predicting IM resistance. Network pharmacology analysis identified six herbal compounds-ampelopsin, ellagic acid, colchicine, epigallocatechin-3-gallate, cucurbitacin B, and evodin-as potential drug candidates targeting the S1P signaling genes. In summary, this study contributes to efforts to better understand the molecular mechanisms underlying BCR-ABL1-independent CML resistance. Moreover, the S1P signaling genes are promising therapeutic targets and plausible new innovation avenues to combat IM resistance in cancer clinical care in the future.

A Multi-epitope Subunit Vaccine Identification and Development Against Scrub Typhus (Orientia tsutsugamushi) Using Immunoinformatics Approaches.

Background The pathogen Orientia tsutsugamushi, which causes scrub typhus, is rapidly spreading throughout the tropics. As a measure to improve public health, the development of a vaccine for human use is essential. Scrub typhus is listed as one of the underdiagnosed and underreported febrile infections. This vector-borne zoonotic infection appears as eschar on the patient's skin. Methods Immunoinformatics was employed to predict the multi-epitope subunit vaccine that will activate both B and T cells. The final vaccine includes lipoprotein LprA as an adjuvant at the N-terminus along with B-cell, helper T lymphocyte (HTL), and cytotoxic T lymphocyte (CTL)-binding epitopes to boost immunogenicity. Assessing the vaccine's physiochemistry demonstrates that it is both antigenic and non-allergic. The vaccine structure was developed, enhanced, confirmed, and disulfide-engineered to provide the best possible model. Using molecular docking, the interaction of the produced vaccine with toll-like receptor 2 (TLR2) was analyzed, and the vaccine-receptor complex was stabilized by molecular dynamics (MD) simulation. According to in silico cloning, Escherichia coli can efficiently produce the recommended vaccine. Additionally, the efficacy of the in silico-developed vaccine must be evaluated in an in vitro and in vivo experiment. Results The developed vaccine successfully stimulates cellular and humoral immune responses. The vaccine, which has three B-cell epitopes, three HCL epitopes, and nine CTL epitopes, can bind firmly to immunological receptors. Dynamic investigations of the vaccine-receptor complex show a strong interaction and stable conformation. Conclusion In this study, the vaccine candidate demonstrated strong antigenicity, stability, and solubility while also being non-allergenic to host cells. The vaccine candidate's stability with the TLR2 immune receptor is established by binding studies, and in silico cloning verifies efficient and stable expression in the bacterial system.

A Validated Chiral Chromatography Method for Enantiomeric Separation of Pomalidomide in Human Plasma.

In the present work, new chiral stationary phase high-performance liquid chromatography (CSP-HPLC) method was established and validated for the quantification of pomalidomide (PMD) enantiomers in human plasma. The chromatographic enantiomeric separation was achieved on a Daicel-CSP, Chiralpack IA 4.6 × 250 mm, 5 µm; because of its advantages of high degree of retention, high resolution capacity, better reproducibility, ability to produce lower back pressure and low degree of tailing. The mobile phase was maintained as methanol: glacial acetic acid (499.50 ml:50 µL). Ultraviolet wavelength for detection was 220 nm. PMD enantiomer-I and enantiomer-II were separated at 8.83 and 15.34 min, respectively. Limit of detection and limit of quantification for each enantiomer and the calibration curve of standard PMD was linear in range between 10-5,000 ng mL-1. The method was validated according to The International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH(Q2R1)) specific guidelines. We found no interference peak with PMD chromatogram obtained. This is a simple, reliable and specific method for detection and quantification of enantiomer of PMD in human plasma sample.

An observational study of root-cause analysis of medication errors in elderly with methotrexate toxicity.

INTRODUCTION: Medication errors are inherent in a healthcare system. This results in both time and cost burdens for both the patient and the health system. The aim of this study was to conduct a root-cause analysis of medication errors in elderly patients with methotrexate toxicity, analyze associated factors, and propose solutions. METHODS: This single-center prospective study was designed to identify medication errors in cases of methotrexate toxicity between November 2022 to May 2023. Categorical data and free-text data are used to describe incidents. Harm assessment, factors related to medication errors, and preventability were evaluated for each case. Possible strategies to prevent similar occurrences are discussed. RESULTS: Out of a total of 15 patients who presented during the study period, nine suffered from methotrexate toxicity due to medication errors. Most medication errors occurred during prescribing or dispensing (seven cases). Inadequate knowledge about medication and dosage, inadequate communication was identified as a contributing factor for all medication errors. Patients on long-term methotrexate treatment are at high risk of methotrexate toxicity. CONCLUSION: This study highlights the challenges of health literacy and lacking communication between healthcare providers and patients that can be met through community pharmacy programs for the elderly in lower-middle-income countries.

Safety and efficacy of Vitamin D3 supplementation with Imatinib in Chronic Phase- Chronic Myeloid Leukaemia: an Exploratory Randomized Controlled Trial.

OBJECTIVES: The study aimed to compare early molecular response (EMR) rates at 3 months of imatinib therapy with and without vitamin D3 supplementation in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP). The secondary objective was to assess the effects of vitamin D3 on complete haematological response (CHR) and its safety. DESIGN: Double-blind, placebo-controlled, exploratory randomised trial. SETTING: Tertiary care hospital in northern India. PARTICIPANTS: Treatment-naive patients with chronic phase chronic myeloid leukaemia (n=62) aged >12 years were recruited from January 2020 to January 2021. Patients with progressive disease, pregnancy and hypercalcaemia were excluded. INTERVENTION: Oral vitamin D3 supplementation (60 000 IU) or matched placebo was given once weekly for an initial 8 weeks along with imatinib after randomisation with 1:1 allocation ratio. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to compare EMR (defined as BCR-ABL1 transcript level ≤10%, international scale) at 3 months. The secondary outcomes were to compare effect of the intervention on CHR, correlation of 25(OH)2D3 levels with treatment response and safety according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS: At baseline, 14.5% of the patients had normal vitamin D3 levels. EMR at 3 months was attained in 24 patients (82.7%) of the vitamin D3 group and 21 (75%) of the placebo group (OR 1.6, 95% CI 0.37 to 7.37, p=0.4). A significant difference in vitamin D3 levels from baseline to the end of study was observed. Patients with vitamin D3 supplementation did not achieve higher CHR in comparison with placebo (OR 1.3, 95% CI 0.25 to 7.23, p=1.0). Vitamin D3 levels were not significantly correlated with BCR-ABL1 levels. No dose-limiting toxicities were observed. CONCLUSION: Vitamin D3 levels were low among patients with CML-CP in this study. Vitamin D3 supplementation with imatinib therapy did not have significant effect on EMR or CHR. Further clinical trials could be undertaken to assess the effective dosage and duration of vitamin D3 supplementation in these patients. TRIAL REGISTRATION NUMBER: CTRI/2019/09/021164.

Association of depression with disease duration, quality of life and adherence in Parkinson's disease: A cross sectional study.

Background: Parkinson's disease (PD) is a progressive motor disorder often accompanied by non-motor symptoms such as depression. Objectives: The objective was to estimate the prevalence of depression in PD patients, and assess its association with disease duration, quality of life and adherence to treatment. Materials and Methods: This cross-sectional study was conducted in a tertiary care centre for patients diagnosed with PD. Depression was diagnosed using Hamilton Depression Rating Scale. The Chi-square test was used to assess the difference in proportions of depression in various types and severity of PD. Depression was also correlated with disease duration, quality of life (QOL) and adherence to treatment using the Pearson correlation test. A P value of <0.05 was considered statistically significant. Results: Among 51 patients, 20 (39.22%) patients were found to have depression. The mean duration of disease in depressed patients was significantly longer compared to that in non-depressed patients (7.99 ± 4.53 vs. 3.62 ± 2.23, P < 0.001), respectively. The non-depressed patients were better adherent to treatment (1.71 ± 1.5 vs. 0.56 ± 0.91). The quality of life of patients was significantly low for depressed patients (21.90 ± 6.91 vs. 13.16 ± 6.93, P < 0.001). Depression in Parkinson's patients was positively correlated with the duration of the disease (P-value <0.001); disease staging (P-value <0.001). Quality of life (QOL) had a strong correlation with depression (P-value <0.001) and Hoehn and Yahr (HY) staging (P-value <0.05). Conclusion: Depression was found in 39.22% of PD patients and was more significantly associated with disease duration, non-adherence to treatment and decreased quality of life.

The Cost-Effectiveness of and Adherence to Disease-Modifying Antirheumatic Drug (DMARD) Therapy in Rheumatoid Arthritis Patients in a Tertiary Care Teaching Hospital in Uttarakhand, India.

Objective This study was conducted with the aim of evaluating the cost-effectiveness of and adherence to treatment in patients on disease-modifying antirheumatic drug (DMARD) therapy for rheumatoid arthritis (RA) in a tertiary care teaching hospital in Uttarakhand, India. Methodology This prospective observational study was conducted on 150 rheumatoid arthritis patients presenting to the Rheumatology Outpatient Department (OPD) receiving DMARD therapy (approval number AIIMS/IEC/18/160). The patients were followed up for an average of 10.7 weeks and received drugs in four regimens with methotrexate (MTX) (Regimen 1) having the least contribution with a mean of 46.05 Rs, methotrexate + hydroxychloroquine (MTX + HCQ) (Regimen 2) with 174.15 Rs, methotrexate + hydroxychloroquine + leflunomide (MTX + HCQ + Lef) (Regimen 3) with Rs 371.70, and methotrexate + hydroxychloroquine + leflunomide + biological DMARD adalimumab (MTX + HCQ + Lef + bDMARD adalimumab) (Regimen 4) with 17,349.4 Rs. The cost of drug therapy was assessed by calculating the cost of therapy per month for each patient, and adherence was assessed using the Morisky-Green-Levine Scale (MGLS) at the follow-up visit. Results The overall mean cost of DMARD treatment was 205.81 Rs. The overall DMARD therapy cost-effectiveness was Rs 878.14 for a unit change of Disease Activity Score (DAS28). The most cost-effective treatment came out to be Regimen 1 with the least cost of 290.9 Rs for a unit change of DAS28, and the least cost-effective was Regimen 4 with 65,661.8 Rs for a unit change of DAS28. At follow-up, among all subjects of the study, 49 (32.7%) subjects showed high adherence, 71 (47.3%) subjects showed medium adherence, and 30 (20%) subjects showed low adherence. Accordingly, the maximum number of participants fell in the category of medium adherence, i.e., 71 (47.4%). Conclusion Our study concluded that the cost burden varied according to the number of DMARDs being given to the patient. The double-drug therapy of methotrexate + hydroxychloroquine had a maximum "high adherence." On a whole, the majority of patients had "medium adherence" to therapy.

Development and validation of a novel chiral chromatographic method for separation of lenalidomide enantiomers in human plasma.

Lenalidomide (LND) is an analogue of thalidomide that is second generation immunomodulatory drugs (IMiDs). LND contains asymmetric carbon atom and exist R and S enantiomer. S (-) form of enantiomer are considered to be more potent and biologically active in tumor cell. It is available in racemic form for clinical use. The study aims to develop and validate enantiomer separation of LND in human plasma. The chromatographic enantiomeric separation was achieved on a Daicel-CSP, Chiralpack IA 4.6 × 250 mm_5 µm. The mobile phase was constituted in combination of methanol:glacial acetic acid at a concentration of 499.50 ml: 50 µl. UV wavelength detection was 220 nm. The RSD% for all validation parameters was found to be within the acceptable limit. The chiral chromatographic (chiral stationary phase-high-performance liquid chromatography [CSP-HPLC]) method developed and validated for the quantitative estimation of LND enantiomers S (-) and R (+) in human plasma sample is accurate, precise, robust, stable and selective.

Identification and in-vitro analysis of potential proteasome inhibitors targeting PSMß5 for multiple myeloma.

The proteasome subunit ß5 (PSMß5) is a chief target of proteasome inhibitors (PIs) for treatment of multiple myeloma (MM). The relevance of PSMß5 mutations and their functional impact on the development of resistance to PIs have been demonstrated recently. Therefore, this present study deals with an in-depth E-pharmacophore based screening and repurposing of FDA-approved drugs that could target PSMß5 for MM. Our molecular docking-based investigation revealed risedronate and zoledronate as potential alternative therapeutic molecules for targeting the PSMß5 gene. Risedronate and zoledronate displayed high binding affinity (-9.51 and -8.56 kcal/mol respectively) to PSMß5. Moreover, 100 ns molecular dynamics simulation analysis of docking complexes revealed risedronate and zoledronate with a superior binding free energies and stable interactions with PSMß5. The RMSD plot shows that the risedronate-PSMß5 (mean: 0.24 nm) and zoledronate-PSMß5 (mean: 0.25 nm) complexes are identical and stays stable until 100 ns. We further validated the activity of zoledronate in MM cell lines RPMI8226 and U266 where zoledronate showed significant anti-proliferative and apoptotic activity. Importantly, zoledronate showed an enhanced anti-proliferative activity when combined with bortezomib in MM cell lines. Thus, this study demonstrates that combining bortezomib with zoledronate could have a significant impact on reducing MM cell growth and can be an alternative strategy for treating MM.

Efficacy of Ferulic Acid in an Animal Model of Drug-Resistant Epilepsy: Beneficial or Not?

Background Lamotrigine (LTG) and subconvulsive doses of pentylenetetrazol (PTZ) as a model mimic drug-resistant epilepsy (DRE), which is a serious unmet medical condition. Previous evidence suggests an imperative role of neuroinflammation in the development of DRE. Various preclinical models of brain injury have reported potent anti-inflammatory and antioxidant properties of ferulic acid (FA). Therefore, its efficacy against intractable epilepsy is worthwhile to study. Materials and methods The present study evaluated the efficacy of FA in LTG and PTZ-induced refractory seizures in mice. On every alternate day for 38 days, LTG (5mg/kg) was injected before PTZ (30-40mg/kg) to establish a murine model of DRE. Animals were treated with two doses of FA (40, 80 mg/kg). All the animals were assessed for seizure score and the latency of seizures every alternate day till the end of the study. Histopathological score and the levels of pro-inflammatory mediators, interleukin-1ßeta (IL-Iß), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) were quantified in the brain tissue of these mice.  Results Ferulic acid (FA) neither decreases the LTG and PTZ-induced refractory seizures score nor increases the latency to develop seizures. In addition, the injury to hippocampal neurons and the levels of pro-inflammatory cytokines were comparable with two doses of FA in treated mice. Conclusion In the present study, single-dose FA treatment does not show any beneficial effect against the LTG/PTZ model of DRE. Therefore, its single-dose administration might not be beneficial against the DRE model.

Dimethyl Fumarate Ameliorates Paclitaxel-Induced Neuropathic Pain in Rats.

Background Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is nonresponsive to the currently available analgesics. Previous studies have shown the role of oxidative stress and central sensitization in the development of peripheral neuropathy. Dimethyl fumarate (DMF) acts as a nuclear factor erythroid-2-related factor 2 (Nrf2) activator with neuroprotective benefits and is approved for use in multiple sclerosis. Materials and methods In the current research, we evaluated the efficacy of DMF on paclitaxel-induced peripheral neuropathy in rats. Every alternate day for one week, paclitaxel 2 mg/kg dose was injected to establish a rat model of PIPN. Animals were treated with 25 mg/kg and 50 mg/kg of DMF. All the animals were assessed for thermal hyperalgesia, cold allodynia, and mechanical allodynia once a week. The gene expression of Nrf2 and the levels of pro-inflammatory mediators (interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and IL-1ß) were quantified in the sciatic nerves of these rats. The levels of p38 mitogen-activated protein kinase (MAPK) and brain-derived neurotrophic factor (BDNF) were quantified in the dorsal horn of the spinal cord. Results DMF significantly attenuated paclitaxel-induced thermal hyperalgesia and cold/mechanical allodynia. A significant decrease in the levels of pro-inflammatory cytokines with the levels of p38 MAPK and BDNF was observed in the DMF-treated animals. DMF treatment significantly upregulated the gene expression of Nrf2 in the sciatic nerve. Conclusion These findings suggest that DMF prevented the development of PIPN in rats through the activation of Nrf2 and the inhibition of p38 MAPK and BDNF.

Piperlongumine inhibits diethylnitrosamine induced hepatocellular carcinoma in rats.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory effects in various cancer cell lines and xenograft models, but the chemopreventive potential of PL has not been studied in experimentally induced HCC yet. RESEARCH DESIGN: Twenty-four Wistar male rats were divided into four groups of six each, Group A: untreated control; Group B: Diethylnitrosamine (DEN) control (200 mg/kg), Group C: DEN + PL 10 mg/kg; and Group D: DEN + PL 20 mg/kg. Rats from all groups were assessed for liver cancer progression or inhibition by evaluating biochemical, cytokines, tumor markers, lipid peroxidation, and histological profiles. RESULTS: The liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) levels, and lipid peroxidation were significantly decreased in Group C and Group D compared to Group B. Upregulation in the level of pro-inflammatory cytokines IL-1B, TNF-α, inflammatory mediator (NF-κB) and tumour marker alpha-fetoprotein (AFP) in Group B were brought down upon treatment with piperlongumine in a dose-dependent manner. Antitumor cytokine (IL-12) was upregulated in PL-treated rats compared to DEN control rats. DEN treated group (Group B) showed histological features of HCC, and in rats treated with PL (Groups C, D) partial to complete reversal to normal liver histoarchitecture was observed. CONCLUSIONS: The potential chemopreventive actions of piperlongumine may be due to its free radical scavenging and antiproliferative effect. Therefore, piperlongumine may serve as a novel therapeutic agent for the treatment of hepatocellular carcinoma.

Prescribing pattern of anti-diabetic drugs and adherence to the American Diabetes Association's (ADA) 2021 treatment guidelines among patients of type 2 diabetes mellitus: A cross-sectional study.

Background: Glycemic control is the major therapeutic objective in diabetes. Poor glycemic control in diabetes mellitus can be prevented by using rational use of anti-diabetic medication, which needs to be evaluated for effectiveness by prescription pattern studies. The objective of this study was to assess the prescribing pattern and adherence to the American Diabetic Association's (ADA) treatment guidelines in type 2 diabetes mellitus patients in a tertiary care teaching hospital in Uttarakhand, India. Methodology: This cross-sectional study was conducted on 206 type 2 diabetic patients who were prescribed anti-diabetic therapy. Patient's demographic details and drugs prescribed, with their dosage, were recorded to study the prescription pattern. Results: Oral anti-diabetic drugs were most commonly prescribed in 149 (72.33%) type 2 diabetic mellitus patients. Five of these patients (3.35%) were on metformin monotherapy, whereas majority of patients (81, 54.36%) were on a fixed dose combination of Glimepiride (SU) + Metformin (MET). Forty-five patients (30.20%) were on MET + Dipeptidyl peptidase 4 inhibitors (DPP4I) combination; 5 (3.35%) were on MET + SU + alpha-glucosidase inhibitors (AGI) combination; 7 (4.69%) were on MET + SU + Pioglitazone (PIO) (Thiazolidinediones) combination; 6 (4.02%) were on sodium/glucose cotransporter-2 inhibitors (SGLT2I) and 57 (27.66%) were on insulin therapy. Out of 206 patients, the prescriptions of 185 patients (89.8%) were adherent and of 21 patients (10.19%) were not adhering to ADA 2021 treatment guidelines. Conclusion: Oral anti-diabetic agents predominate the prescribing pattern practices for type 2 DM but there was a shift in trend towards the use of fixed-dose combinations (FDC) in the management of type 2 DM, and majority of prescriptions were adherent to ADA treatment guidelines.

Antiviral Combination Clinically Better Than Standard Therapy in Severe but Not in Non-Severe COVID-19.

PURPOSE: Definitive antiviral treatment is not available for COVID-19 infection, with the exception of remdesivir, which still evokes many doubts. Various monotherapy or combination therapies with antivirals or other agents have been tried. The present study aims to evaluate the therapeutic potential of hydroxychloroquine and lopinavir-ritonavir in combination with ribavirin in mild-severe COVID-19. PATIENTS AND METHODS: A single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of combination antiviral therapies. Enrolled patients in the severe category were randomized into three groups: (A) standard treatment, (B) hydroxychloroquine+ribavirin+standard treatment, or (C) lopinavir+ritonavir+ribavirin+standard treatment; while the non-severe category comprised two groups: (A) standard treatment or (B) hydroxychloroquine+ribavirin. Combination antivirals were given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report. RESULTS: In total, 111 patients were randomized: 24, 23, and 24 in severe categories A, B, and C, respectively, and 20 in each of the non-severe groups. Two patients receiving ribavirin experienced drug induced liver injury, and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups, respectively, showed symptomatic recovery, compared to 93.3% and 86.7% in A and B groups, respectively, in the non-severe category at 72 hours (P>0.05). CONCLUSION: Though the results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19 due to very small sized trial, clinically hydroxychloroquine+ribavirin therapy is showing better recovery by 7.4% than standard therapy in the former category. However, results do indicate the benefit of standard therapy in the non-severe category by 6.6%. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.

Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets.

Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus's spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.

A prospective study to evaluate antimicrobial prescribing pattern among admitted patients in hilly Himalayan region of northern India.

BACKGROUND AND AIM: Global scenario of antimicrobial (AM) utilization depicts 20-50% inappropriateness. Majority of the hospital admissions are due to unwanted effects because of non-judicial usage of these drugs. The present study focuses on utilization pattern of antimicrobials (AMs) in a tertiary care hospital in northern India. MATERIALS AND METHODS: A prospective observational study was conducted over a period of one year in seven departments of a tertiary care hospital in hilly Himalayan region. Aim of the study was to analyze the AM utilization pattern using World Health Organization (WHO) indicators and instruments. RESULTS: A total 700 prescriptions were analyzed in the present study. Injectable antibiotics (71%) followed by oral (29%) were most commonly prescribed. Beta lactams (79%) were the most frequently used antibiotic class. Most commonly prescribed AM was Ceftriaxone (30%). Majority of the time AMs were given empirically (44.8%), where most common indication was respiratory infections (42%). Culture and sensitivity tests were done for guiding curative therapy in 34.71% cases. The average duration of patient hospital stay was 8.81 days in the study population. The mean duration of prescribed antimicrobial treatment was 5.12 days. On an average 1.93 AMs were prescribed per patient. AMs were prescribed by International nonproprietary name (INN) in 62.19% of the admissions. The most common AM related adverse drug reaction was gastritis (96%) and skin rash (4%) with Amoxicillin + clavulanic acid being the most common causative agent. Total antimicrobial consumption was 148.24 DDD/100 bed days with Medicine department showing the highest consumption (36.25/100 bed days). CONCLUSION: The present study is the first and largest antimicrobial utilization study in the hilly Himalayan region of northern India. Our study found an urgent need for improvement of prescribing patterns, patient care indicators and strict adherence to standard guidelines.

Evaluation of prescription practices in rheumatoid arthritis at the rheumatology clinic in a tertiary care teaching hospital in Uttarakhand: A cross-sectional study.

OBJECTIVE: This study was aimed to analyze the prescription pattern of disease modifying anti-rheumatic drug (DMARD) therapy in patients with rheumatoid arthritis (RA) in a tertiary care teaching hospital in Uttarakhand, India. METHODOLOGY: This cross-sectional study was conducted in 150 RA patients who were given DMARD therapy. Patient's demographic details, drugs prescribed with their dosage and administration routes and the usage of complementary and alternative medicine (CAM) therapy were recorded to study the prescription pattern. RESULTS: Overall, 4 DMARDs were prescribed in all the studied patients: Methotrexate (n = 150), hydroxychloroquine (n = 35), leflunomide (n = 5), and adalimumab (n = 1). Single DMARD therapy with methotrexate was prescribed to 110 (73.3%) followed by double therapy with methotrexate + hydroxychloroquine in 35 (23.3%), triple therapy (methotrexate + hydroxychloroquine + leflunomide) in 4 (2.7%) and triple therapy with biological DMARD (methotrexate + hydroxychloroquine + leflunomide + adalimumab) in 1 (0.7%) patient. Adjuvant therapy drugs included: Prednisolone (n = 150), folic acid (n = 150), naproxen (n = 150), calcium (n = 150), vitamin D (n = 150) and indomethacin (n = 40). Of the total, 61.4% patients also took complimentary alternative medicine (CAM) therapy. CONCLUSION: Our study concludes that the most commonly prescribed DMARDs in our setting, to patients of RA, in descending order of frequency were methotrexate, followed by hydroxychloroquine, leflunomide and lastly adalimumab. A total of five adjuvant medications were commonly prescribed to all patients. There was a high prevalence of self-medicated CAM therapy in the majority of these patients.

Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19.

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10-20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5' end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

A Review on Potential Footprints of Ferulic Acid for Treatment of Neurological Disorders.

Ferulic acid is being screened in preclinical settings to combat various neurological disorders. It is a naturally occurring dietary flavonoid commonly found in grains, fruits, and vegetables such as rice, wheat, oats, tomatoes, sweet corn etc., which exhibits protective effects against a number of neurological diseases such as epilepsy, depression, ischemia-reperfusion injury, Alzheimer's disease, and Parkinson's disease. Ferulic acid prevents and treats different neurological diseases pertaining to its potent anti-oxidative and anti-inflammatory effects, beside modulating unique neuro-signaling pathways. It stays in the bloodstream for longer periods than other dietary polyphenols and antioxidants and easily crosses blood brain barrier. The use of novel drug delivery systems such as solid-lipid nanoparticles (SLNs) or its salt forms (sodium ferulate, ethyl ferulate, and isopentyl ferulate) further enhance its bioavailability and cerebral penetration. Based on reported studies, ferulic acid appears to be a promising molecule for treatment of neurological disorders; however, more preclinical (in vitro and in vivo) mechanism-based studies should be planned and conceived followed by its testing in clinical settings.