Efficacy of oral sodium chloride in reducing the incidence of hyponatremia in children with epilepsy receiving oxcarbazepine monotherapy: A randomized controlled trial (SCHO Trial).

INTRODUCTION: Hyponatremia is a well-documented adverse effect of oxcarbazepine treatment, but no clinical trial has yet been conducted to explore any intervention for reducing the incidence of hyponatremia. MATERIALS AND METHODS: This open-label trial evaluated the efficacy of add-on daily oral sodium chloride supplementation of 1-2 g/day for 12 weeks in reducing the incidence of hyponatremia in children receiving oxcarbazepine monotherapy aged 1-18 years. Apart from comparing the incidence of symptomatic and severe hyponatremia, serum and urine sodium levels, serum and urine osmolality, changes in behavior and cognition, and the number of participants with recurrence of seizures and requiring additional antiseizure medication (ASM) were also compared. RESULTS: A total of 120 children (60 in each group) were enrolled. The serum sodium level at 12 weeks in the intervention group was higher than that of the control group (136.5 ± 2.6 vs 135.4 ± 2.5 mEq/L, p = 0.01). The number of patients with hyponatremia was significantly lower in the intervention group (4/60vs14/60, p = 0.01). However, the incidence of symptomatic and severe hyponatremia (0/60vs1/60, p = 0.67 for both), changes in social quotient and child behavior checklist total score (0.6 ± 0.8 vs 0.7 ± 0.5, p = 0.41 and 0.9 ± 1.2 vs 1.1 ± 0.9, p = 0.30 respectively), the number of patients with breakthrough seizures (9/60vs10/60, p = 0.89), and the number of patients requiring additional ASMs (8/60vs10/60, p = 0.79) were comparable in both groups. CONCLUSIONS: Daily oral sodium chloride supplementation is safe and efficacious in reducing the incidence of hyponatremia in children with epilepsy receiving oxcarbazepine monotherapy. However, sodium chloride supplementation does not significantly reduce more clinically meaningful outcome measures like symptomatic and severe hyponatremia. Trial registry No. CTRI/2021/12/038388.

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.

Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2.

The scientific community is continuously working to discover drug candidates against potential targets of SARS-CoV-2, but effective treatment has not been discovered yet. The virus enters the host cell through molecular interaction with its enzymatic receptors i.e., ACE2 and TMPRSS2, which, if, synergistically blocked can lead to the development of novel drug candidates. In this study, 1503 natural bioactive compounds were screened by HTVS, followed by SP and XP docking using Schrodinger Maestro software. Bio-0357 (protozide) and Bio-597 (chrysin) were selected for dynamics simulation based on synergistic binding affinity on S1 (docking score -9.642 and -8.78 kcal/mol) and S2 domains (-5.83 and -5.3 kcal/mol), and the RMSD, RMSF and Rg analyses showed stable interaction. The DFT analysis showed that the adsorption of protozide/chrysin, the band gap of protozide/chrysin-F/G reduced significantly. From SERS, results, it can be concluded that QDs nanocluster will act as a sensor for the detection of drugs. The docking study showed Bio-0357 and Bio-0597 bind to both S1 and S2 domains through stable molecular interactions, which can lead to the discovery of new drug candidates to prevent the entry of SARS-CoV-2. This in-silico study may be helpful to researchers for further in vitro experimental validation and development of new therapy for COVID-19.

Impact of regulatory spin of pioglitazone on prescription of antidiabetic drugs among physicians in India: A multicentre questionnaire-based observational study.

Background & objectives: Pioglitazone was suspended for manufacture and sale by the Indian drug regulator in June 2013 due to its association with urinary bladder carcinoma, which was revoked within a short period (July 2013). The present questionnaire-based nationwide study was conducted to assess its impact on prescribing behaviour of physicians in India. Methods: Between December 2013 and March 2014, a validated questionnaire was administered to physicians practicing diabetes across 25 centres in India. Seven hundred and forty questionnaires fulfilling the minimum quality criteria were included in the final analysis. Results: Four hundred and sixteen (56.2%) physicians prescribed pioglitazone. Of these, 281 used it in less than the recommended dose of 15 mg/day. Most physicians (94.3%) were aware of recent regulatory events. However, only 333 (44.8%) changed their prescribing pattern. Seventeen of the 416 (4.1%) physicians who prescribed pioglitazone admitted having come across at least one type 2 diabetes mellitus patient (T2DM) who had urinary bladder carcinoma, and of these 13 said that it was in patients who took pioglitazone for a duration of more than two years. Only 7.8 per cent of physicians (n=58) categorically advocated banning pioglitazone, and the rest opined for its continuation or generating more evidence before decision could be taken regarding its use in T2DM. Interpretation & conclusions: Majority of the physicians though were aware of the regulatory changes with regard to pioglitazone, but their prescribing patterns were not changed for this drug. However, it was being used at lower than the recommended dose. There is a need for generating more evidence through improved pharmacovigilance activities and large-scale population-based prospective studies regarding the safety issues of pioglitazone, so as to make effectual risk-benefit analysis for its continual use in T2DM.

Indian College of Physicians (ICP) Position Statement on Pharmacovigilance.

Pharmacovigilance is the art and science of detection, understanding and prevention of adverse drug reactions and not merely a critical analysis of prescriptions and errors. This field starts with reporting by clinicians of a suspected adverse drug reaction (ADR) to the pharmacologist followed by joint causality analysis and ends at the application of new information by a clinician for benefit of patients. There are a number of ways, which can be utilised for reporting adverse effects using pen and paper format to software applications for smart phones. Varied types of activities spreading from systematic reviews to the mechanistic evaluation of ADR can be performed under the umbrella of pharmacovigilance. It is of utmost importance for clinicians to understand how to identify, communicate and understand adverse effects of drugs with an aim to prevent harm to patients.

Indian College of Physicians Position Statement: Addictive Disorders Among Persons with Diabetes Mellitus.

OBJECTIVES: Migraine, a common primary headache disorder which can be severely disabling, associated with poor health-related quality of life (HRQoL) amongst affected patients. The present study was performed to provide adequate clinical data on migraine and the management practices in India. MATERIAL AND METHODS: A cross-sectional study was designed to assess disease burden, HRQoL, symptom profile, management trends and comorbidities associated with migraine patients across ten centres in India. This study assessed HRQoL using Migraine Specific Quality of life (MSQ) and Migraine Disability Assessment Scores (MIDAS) questionnaire. Categorical variables were summarized as frequency, and percentage and continuous variables as mean and standard deviation respectively. RESULTS: A total of 705 patients were enrolled with a mean age of 35.2 years. Hypertension (7.0%) was the highest co-morbid illness associated with migraine. A higher MSQ score was observed in females as compared to males (39.3±12.4 and 37.4±11.6) while MIDAS showed a comparable score (27.7±47.6 and 27.2±35.4). Majority of migraine patients were unemployed (61.6%) and in profession, females had poor HRQoL than males by MIDAS and MSQ. Majority of patients had pulsating, bilateral attacks for the duration of 4h to 72 h. Paracetamol (47.1%) and propranolol (50.9%) was most commonly prescribed drugs for acute attack and prophylaxis, respectively. CONCLUSION: The quality of life was superior in males as compared to females amongst migraine patients in India. Hypertension was the commonest comorbidity associated with migraine. KEY MESSAGES: Migraine is associated with substantial disability with higher prevalence in females and older people (age >40 years). NSAIDs and propanol was widely prescribed drug in acute attacks and prophylaxis of migraine respectively. Cardiovascular diseases, diabetes mellitus and anxiety were common comorbidities associated with migraine.

Association of Physicians of India: Position Statement on Role of Chirally Pure Molecules in Clinical Practice.

Chirally pure molecules or enantiomers are non-superimposable mirror images of each other with a chiral center (such as carbon, sulphur, nitrogen or phosphorous atom). An equimolar mixture of enantiomers forms a racemate. Chirally pure molecules (single enantiomers) are important in the field of drug discovery as the drug targets such as enzymes and receptors are enantioselective in nature. Clinical studies have demonstrated that chirally pure drugs exhibit different pharmacokinetic and metabolic profiles, reduced adverse events, improved safety profiles and similar therapeutic activity at lowered drug dosage as compared with the racemate in many therapeutic areas. However, since there is a low level of awareness on the advantages of chirally pure molecules among clinicians, pharmacists and patients in India, the Association of Physicians of India (API) developed this position statement to increase awareness on the concept of chirality and the associated advantages of using chirally pure drugs in certain therapeutic areas to maximize patient outcomes. This includes the clinical evidence associated with single enantiomers such as S-metoprolol, S-amlodipine, esomeprazole, escitalopram, levobupivacaine, cisatracurium, S-etodolac, dexketoprofen, levofloxacin in terms of efficacy and safety as compared with their racemates. In addition, the API also provides some tactical recommendations for clinicians, pharmacists, patients, regulatory body and pharmaceutical companies to increase awareness on chirally pure drugs and puts forth the need for expedited availability of chirally pure drugs in the Indian market.

Navigating the Antiretroviral Therapy Switch Conundrum: Unveiling the Dilemma of Drug Resistance and Disease Progression in HIV/AIDS.

There is a need to establish consensus for harmonization in antiretroviral (ARV) therapy (ART) switch treatment strategy and address the dilemma that exists in terms of subpar immune response to therapy or an immunologic deterioration while on therapy. The purpose of this review is to identify the factors that contribute to ARV treatment failure, such as insufficient dosage, drug interactions, poor adherence, drug resistance, and poor medication absorption. It is crucial to adopt a more efficient strategy to address this challenging dilemma. After ARV treatment failure, the aim of therapy is virologic suppression, which targets plasma viral load below the limits of detection as assessed by very sensitive tests with lower limits of quantification of 20 to 75 RNA copies/ml. The therapeutic objectives when complete virologic suppression is not possible, should be to maintain or restore immunologic function, stop the progression of the clinical illness, and minimize the emergence of new drug resistance that could further restrict the options for ARV drugs. Treatment history and drug-resistance testing, including the findings of previous and ongoing resistance tests, should be considered while selecting ARV regimens. Hence, the treatment approach post-ARV failure can be personalized based on clinical, immunologic, virologic, or as a mix of the three domains on a case-to-case basis. The evaluation of projected ARV activity should be based on treatment history and previous resistance test findings.

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.

Computational Analysis of Lenalidomide and Pomalidomide Enantiomers' Binding Interactions With Prostaglandin (PG)-Protein: Implications for Inflammatory Activity in Cancer.

BACKGROUND: Lenalidomide and Pomalidomide are chiral immunomodulatory drugs (IMiDs) and have antiangiogenic and anti-immunomodulatory activity. Each enantiomer may have distinct binding and biological activity. This study aimed to explore the in-silico binding of both enantiomers of Lenalidomide and Pomalidomide with Prostaglandin and its potential impact on persisting inflammatory activity in cancer. This can further provide insight into the transport of pro-inflammatory mediators and their potential implications for the inflammatory microenvironment within tumors. MATERIALS AND METHODS: Molecular docking studies were performed to explore the binding potential of both enantiomers of Lenalidomide and Pomalidomide with Pg protein. The crystal structure of Pg-protein (PDB ID: 1IW7) was obtained from the Protein Data Bank. RESULTS: The binding energies for (-)-Lenalidomide and (+)-Lenalidomide were -6.7 and -7.2 kcal/mol, respectively, while the binding energies for (-)-Pomalidomide and (+)-Pomalidomide were -7.8 and -8.1 kcal/mol, respectively. The binding mode analysis revealed that all four compounds formed hydrogen bonds with key amino acid residues of Pg-protein. The hydrogen bond distances for (-)-Lenalidomide, (+)-Lenalidomide, (-)-Pomalidomide, and (+)-Pomalidomide were 2.1 Å, 2.0 Å, 2.2 Å, and 2.1 Å, respectively. CONCLUSIONS: The present study suggests that both enantiomers of Lenalidomide and Pomalidomide have a high affinity for Pg-protein and can effectively target the Pg-protein pathway to persist inflammatory activity in cancer. By targeting inflammation-mediated processes, these drugs may offer a novel strategy to combat tumor progression.

Early versus late switch over of antiseizure medications from intravenous to the oral route in children with seizures: Single-blinded, randomized controlled trial (ELAIO trial).

INTRODUCTION: Early switch-over of anti-seizure medications (ASMs) from intravenous to oral route may reduce the duration of hospitalization, drug acquisition costs, and behavioral upset in hospitalized children with seizures. OBJECTIVE: The primary objective was to compare short-term seizure recurrence within 1 week in hospitalized children aged 1 month to 18 years with new-onset/breakthrough seizures after an early versus late switch-over from intravenous to the oral route of ASMs. Secondary objectives were to compare the incidence of status epilepticus, duration of hospital stay, drug acquisition costs, and caregiver-reported satisfaction scores in both groups. METHODS: In this single-blind randomized controlled trial, patients with seizures were categorized based on the number of ASMs required and the history of status epilepticus. Patients in each category were randomized in a 1:1 ratio into either early or late switch-over (ES or LS) groups. In the ES groups, ASMs were tapered one-by-one between 0 and 24 hours of seizure freedom, while in the LS groups, they were tapered one-by-one between 24 and 48 hours of seizure freedom. RESULTS: A total of 112 children were enrolled in the study, with 56 in each arm. Seizure recurrence at 1 week and 12 weeks was comparable in ES and LS groups (3/55 vs. 1/54 at 1 week, p=0.61; 7/49 vs. 6/49 at 12 weeks, p=0.98). Drug acquisition costs were significantly lower in the ES group (393±274 vs. 658±568 INR, p=0.002). Thrombophlebitis and dysphoria were significantly more common in the LS group (p=0.008 and 0.03, respectively). CONCLUSION: The early switch-over of ASMs from intravenous to oral route is safe without any significant increased risk of short-term seizure recurrence and also associated with a reduction in the incidence of thrombophlebitis and ASM acquisition costs. TRIAL REGISTRATION NO: CTRI/2021/03/032145.

Evaluating Yoga-Based Intervention Versus the American Diabetes Association Exercise Regimen in Conjunction With Standard Care for Autonomic Neuropathy in Diabetes Mellitus: An Exploratory Clinical Trial.

INTRODUCTION: Diabetic autonomic neuropathy (DAN) is a prevalent yet often overlooked complication of diabetes mellitus (DM), impacting multiple organs and substantially elevating the risk of morbidity and mortality. This study aimed to assess the effectiveness of yoga-based intervention (YBI) compared to the American Diabetes Association exercise regimen (ADA Ex. Regime) and standard care for treating autonomic neuropathy in type 2 DM. METHODS: This open-label exploratory clinical trial featured two parallel study arms: Group A (Intervention), which received YBI alongside standard care, and Group B, which adhered to the ADA Ex. Regime in conjunction with standard care. A total of 80 participants aged 35-60, diagnosed with type 2 DM and autonomic neuropathy, were equally allocated to both groups. Data collection included nerve conduction velocity (NCV) tests, autonomic function tests (AFTs), as well as evaluations of depression and quality of life. RESULTS: YBI demonstrated a drop in parasympathetic tone compared to the ADA Ex. Regime. Following a six-month intervention, the sympathetic activity indicator (SD2) exhibited a significantly lower value in the YBI group than in the ADA Ex. Regime group, indicating a positive effect (p < 0.05), while the ADA Ex. Regime showed more improvement in certain areas of NCV (e.g., left and right peroneal NCV, right and left peroneal F-latency), notable differences were observed in alkaline phosphatase levels, depression scores, and WHO-5 wellness, all reaching statistical significance at p < 0.05. CONCLUSIONS: The study findings observed that a 24-week YBI significantly reduced in symptoms of diabetic neuropathy and stress. Although the ADA Ex. Regime demonstrated greater improvement in specific aspects of NCV compared to YBI, YBI outperformed the ADA Ex. Regime in enhancing WHO-5 wellness and reducing depression symptoms.

Efficacy and safety of phenytoin and levetiracetam for acute symptomatic seizures in children with acute encephalitis syndrome: an open label, randomised controlled trial.

INTRODUCTION: Seizures represent a significant comorbidity in children with acute encephalitis syndrome (AES). Despite this, there is a notable absence of randomized controlled trials (RCTs) directly comparing antiseizure medications (ASMs) in children with AES. MATERIALS AND METHODS: This RCT aimed to assess the efficacy and safety of phenytoin and levetiracetam in controlling seizures among children with AES. Both ASMs were administered with a loading followed by maintenance dose. After a 12-week period, children exhibiting a normal electroencephalogram and no seizure recurrence underwent tapering and discontinuation of ASM. Clinical follow-up occurred daily for the first week, and subsequently at 4, 12, and 24 weeks, evaluating seizure recurrence, incidence of status epilepticus, cognition, behavior, functional status, ASM acquisition cost, and adverse effects. RESULTS: A total of 100 children (50 in each group) were enrolled. Within the first week, 5 and 3 children in the phenytoin and levetiracetam groups expired. Up to 1 week or death (whichever occurred earliest), 46 (92 %) and 44 (88 %) children remained seizure-free. Intention-to-treat analysis for both best and worst-case scenarios showed insignificant differences (p=0.52 and 1.0). No children experienced seizure recurrence after 1 week in either group. The number of patients with breakthrough status epilepticus, need for mechanical ventilation, duration of hospital stay, presence of epileptiform abnormalities in repeat electroencephalogram at 12 weeks, functional outcomes at 1, 12, and 24 weeks, as well as cognition and behavioral profiles at 24 weeks, were comparable in both groups (p>0.05 for all). However, the incidence of treatment-emergent adverse events (TEAEs) causally related to study medications was significantly higher in the phenytoin group (p=0.04). CONCLUSION: Levetiracetam and phenytoin are comparable in efficacy in terms of achieving clinical seizure control in children with acute encephalitis syndrome, although levetiracetam group demonstrated fewer adverse effects.

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.

A Randomized, Open Label, Exploratory Trial Comparing Efficacy of Amantadine and Ropinirole in Restless Legs Syndrome.

Objective Amantadine has both anti-glutamatergic and dopaminergic action and may improve restless legs syndrome (RLS). We compared the efficacy and adverse-effect profile of amantadine and ropinirole in RLS. Methods In this randomized, open-label, 12-week flexible-dose exploratory study, RLS patients with international RLS study group severity scale score (IRLSS) > 10 were randomized to receive either amantadine(100-300mg/day) or ropinirole (0.5-2mg/day). Drug dose was increased until week-6 if IRLSS failed to improve by ≥10% of previous visit score. IRLSS change from baseline at week-12 was the primary outcome. Secondary outcomes included change in RLS-related quality of life (RLS-QOL) and insomnia severity index (ISI), along with clinical-global-impression of change/improvement (CGI-I), and proportion of patients with adverse-effects and resulting discontinuation. Results Twenty-four patients received amantadine and 22 received ropinirole. Both groups had a significant effect for visit*treatment arm (F (2.19,68.15) =4.35;P = 0.01). With a similar baseline IRLSS, both intention-to-treat (ITT) and per-protocol analyses revealed comparable IRLSS until week-8, with ropinirole appearing superior from week-10 to week-12 (week-12 IRLSS, amantadine vs ropinirole:17.0 ± 5.7 vs 9.0 ± 4.4;P < 0.001). ITT analysis at week-12 showed comparable proportion of responders (≥10% IRLSS reduction) in both groups (P = 0.10). Both drugs improved sleep and QOL, but week-12 scores favoured ropinirole [(ISI:14.4 ± 5.7 vs 9.4 ± 4.5; P = 0.001) ;(RLS-QOL:70.4 ± 17.9 vs 86.5 ± 9.8; P = 0.005)]. CGI-I at week-12 favoured ropinirole (Mann-Whitney U = 35.50, S. E = 23.05;P = 0.01). Four patients in amantadine and two in ropinirole group developed adverse effects, with resulting discontinuation in two patients on amantadine. Conclusions The present study reports equivalent reduction in RLS symptoms with both amantadine and ropinirole until week-8, with the latter being superior from week-10 onwards. Ropinirole was better tolerated.

Clinical outcome of testosterone supplementation assessed by andropausal male symptom scores in type 2 diabetes testosterone-deficient patients receiving testosterone compared to those not receiving testosterone: A nested case-control study.

BACKGROUND AND AIMS: This study aimed to explore the proportion of andropause in male patients with type 2 diabetes using an aging male symptoms scale and assess the clinical outcome of testosterone supplementation in patients with deficient testosterone levels at a tertiary care hospital. METHODS: Male patients with diabetes and total serum testosterone levels (≤12 nmol/L) were included in the study. Patients with testosterone supplementation, the standard of care among testosterone-deficient male patients, were included in the study (n = 35). Those not exposed to testosterone supplementation were considered controls (n = 35) and reassessed over 14 weeks for aging male symptom scores (AMS). RESULTS: The prevalence of andropause among the participants was 11% (117/1057). Data was analyzed as per protocol analysis. Exposure group had a frequency of 25.80%, and 19.35% in moderate and severe symptoms of AMS scores. Non-exposure group had frequency of 26.66% and 23.34% in moderate and severe symptoms of AMS scores. A significant mean difference (t = -2.93, P-value <0.05) was noted between exposure and non-exposure to testosterone supplementation. CONCLUSION: Results concluded that andropause is prevalent in patients with type 2 diabetes and low testosterone levels. Testosterone therapy affects aging andropausal symptoms such as the feeling of general well-being, joint pain and muscular ache, sleep problems, anxiety, and libido among patients with type 2 diabetes.

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.

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.