Class Of Drugs Research Articles

Novel N,N-Dimethyl-idarubicin Analogues Are Effective Cytotoxic Agents for ABCB1-Overexpressing, Doxorubicin-Resistant Cells.

Anthracyclines comprise one of the most effective anticancer drug classes. Doxorubicin, daunorubicin, epirubicin, and idarubicin have been in clinical use for decades, but their application remains complicated by treatment-related toxicities and drug resistance. We previously demonstrated that the combination of DNA damage and histone eviction exerted by doxorubicin drives its associated adverse effects. However, whether the same properties dictate drug resistance is unclear. In the present study, we evaluate a library of 40 anthracyclines on their cytotoxicity, intracellular uptake, and subcellular localization in K562 wildtype versus ABCB1-transporter-overexpressing, doxorubicin-resistant cells. We identify several highly potent cytotoxic anthracyclines. Among these, N,N-dimethyl-idarubicin and anthracycline (composed of the idarubicin aglycon and the aclarubicin trisaccharide) stand out, due to their histone eviction-mediated cytotoxicity toward doxorubicin-resistant cells. Our findings thus uncover understudied anthracycline variants warranting further investigation in the quest for safer and more effective anticancer agents that circumvent cellular export by ABCB1.

Unveiling Resistance and Virulence Mechanisms under Darwinian Positive Selection for Novel Drug Discovery for Gardnerella vaginalis

Gardnerella vaginalis is a Gram-variable bacillus capable of causing bacterial vaginosis, a condition prevalent in reproductive-age women, this bacterium is present in almost 100% of cases and is also considered a gateway to various sexually transmitted infections. This organism exhibits high pathogenicity linked to virulence and resistance genes acquired throughout evolution, showcasing elevated resistance to a broad spectrum of drug classes. This study conducted comparative genomic analyses to identify these genes and correlate their presence with positive Darwinian selection. Additionally, new drug targets were selected through docking and molecular modeling, guided by the heightened antimicrobial resistance exhibited by this microbial species. The available genomes of G. vaginalis were analyzed, and the orthologous genes were delineated and positively selected, whereby 29 groups were found. Of these genes, one of great importance was predicted, Mef(A), which is related to resistance to the macrolide group of antibiotics, which are one of the main choices for the treatment of sexually transmitted infections. Additionally, two potential protein candidates were selected as drug targets. These proteins were linked with a natural compound each and are considered good potential drug targets. The analyses in this study contribute to analyzing the evolution of the species and how resistance genes are related to their permanence as a potential pathogen.

Chemotherapy-Induced Peripheral Neuropathy Impacts Quality of Life and Activities of Daily Living of Brazilian Multiple Myeloma Patients.

Survival in multiple myeloma (MM) has improved in the past years with the introduction of immunomodulators and proteasome inhibitors. However, chemotherapyinduced peripheral neuropathy (CIPN) is associated with both drug classes affecting Health- Related Quality of Life (HRQoL) and activities of daily living (ADL). We evaluated CIPN in MM patients to identify associated factors and impacts on HRQoL and ADL. This is a cross-sectional study with Brazilian patients from public and private health services. Patients were interviewed using validated tools to measure CIPN and HRQoL, along with sociodemographic and clinical questions. Logistic regression was used to assess the association of CIPN with sociodemographic, clinical, and HRQoL variables. In total, 217 patients were eligible for the study. The median age was 67, 50.9% were women, 51.6% had low income, 47.5% had low education, and 55.3% attended private health services. The chemotherapy regimen most used was the combination of cyclophosphamide, thalidomide, and dexamethasone (17.5%) among the 24 types of regimens found. Most patients (90.3%) had at least one CIPN symptom: 62.7% were severe, and 51.62% were extremely bothered ADL. Numbness was the most common symptom (40.6%). CIPN was independently associated with education, hospitalization, chemotherapy, side effects, disease symptoms, and global health status in HRQoL. MM patients showed a high frequency of CIPN, which affected ADL and impaired HRQoL. Early and accurate detection of CIPN and dose management in patients with thalidomide and bortezomib-based regimens should be performed to provide better treatment outcomes and avoid permanent disabilities.

Glucose Transporter and Sensor Mechanisms in Fungal Pathogens as Potential Drug Targets.

Fungal infections are emerging as major health challenges in recent years. The development of resistance against existing antifungal agents needs urgent attention and action. The limited classes of antifungal drugs available, their tendency to cause adverse effects, lack of effectiveness, etc., are the major limitations of current therapy. Thus, there is a pressing demand for new antifungal drug classes to cope with the present circumstances. Glucose is the key source of energy for all organisms, including fungi. Glucose plays a crucial role as a source of carbon and energy for processes like virulence, growth, invasion, biofilm formation, and resistance development. The glucose transport and sensing mechanisms are well developed in these organisms as an important strategy to sustain survival. Modulating these transport or sensor mechanisms may serve as an important strategy to inhibit fungal growth. Moreover, the structural difference between human and fungal glucose transporters makes them more appealing as drug targets. Limited literature is available for fungal glucose entry mechanisms. This review provides a comprehensive account of sugar transport mechanisms in common fungal pathogens.

Assessment of ∆9-THC and ∆9-THCCOOH Bias, Precision, and Ionization Suppression/Enhancement between Solid Tissue Homogenate and Supernatant by LC-MS/MS.

LC-MS-MS assays are frequently utilized for screening and confirmatory purposes in the forensic toxicology laboratory. While these techniques are excellent for the targeted identification and quantitation of a wide variety of drug classes, validation and determining fit-for-purpose is a requirement for each method. In the United States, ANSI/ASB Standard 036 currently serves as a primary resource in forensic toxicology method validation, and mandates that laboratories evaluate critical performance characteristics to help ensure the production of forensically defensible results. Due to the variability of specimen quality frequently encountered in the discipline of postmortem toxicology, the [Author Information Removed] Office of the Chief Medical Examiner Forensic Toxicology Laboratory routinely analyzes solid tissue specimens as part of the medicolegal death investigation process and evaluates liver as a representative solid tissue matrix during method validation. Authentic postmortem specimens (e.g., liver, kidney, skeletal muscle, and spleen) were used to investigate the effects of analyzing solid tissue homogenate versus solid tissue supernatant on bias, precision, and ionization suppression/enhancement of ∆9-THC and ∆9-THCCOOH. Bias was <20% for Δ9-THC and ∆9-THCCOOH in liver homogenate and supernatant with a single exception of the low QC concentration for Δ9-THC in liver homogenate (-29%). Within-run and between-run CV was <20% for Δ9-THC and ∆9-THCCOOH in liver homogenate and supernatant. Δ9-THC and Δ9-THC-d3 exhibited significant ion suppression in both liver homogenate and supernatant, while ∆9-THCCOOH and ∆9-THCCOOH-d3 showed both ion suppression and enhancement in these matrices. Noticeable quantitative differences were observed in authentic postmortem solid tissue homogenate and supernatant specimens despite evaluating from identical tissue samplings. A brief discussion of the results is presented using a validated LC-MS-MS method for the confirmation and quantitation of ∆9-THC and ∆9-THCCOOH in postmortem casework.

Impact of opioid overdoses on US life expectancy and years of life lost, by demographic group and stimulant co-involvement: a mortality data analysis from 2019 to 2022

The United States' opioid crisis is worsening, with the number of deaths reaching 81,806 in 2022 after more than tripling over the past decade. This study aimed to comprehensively characterize changes in burden of opioid overdose mortality in terms of life expectancy reduction and years of life lost between 2019 and 2022, including differential burden across demographic groups and the contribution of polysubstance use. Using life tables and counts for all-cause and opioid overdose deaths from the National Center for Health Statistics, we constructed cause-eliminated life tables to estimate mortality by age in the absence of opioid-related deaths. We calculated the loss in life expectancy at birth (LLE) and total years of life lost (YLL) due to opioid overdose deaths by state of residency, sex, racial/ethnic group, and co-involvement of cocaine and psychostimulants. Opioid-related deaths in the US led to an estimated 3.1 million years of life lost in 2022 (38 years per death), compared to 2.0 million years lost in 2019. Relative to a scenario with no opioid mortality, we estimate that opioid-related deaths reduced life expectancy nationally by 0.67 years in 2022 vs 0.52 years in 2019. This LLE worsened in all racial/ethnic groups during the study period: 0.76y-0.96y for white men, 0.36y-0.55y for white women, 0.59y-1.1y for Black men, 0.27y-0.53y for Black women, 0.31y-0.82y for Hispanic men, 0.19y-0.31y for Hispanic women, 0.62y-1.5y for American Indian/Alaska Native (AI/AN) men, 0.43y-1y for AI/AN women, 0.09y-0.2y for Asian men, and 0.08y-0.13y for Asian women. Nearly all states experienced an increase in years of life lost (YLL) per capita from 2019 to 2022, with YLL more than doubling in 16 states. Cocaine or psychostimulants with abuse potential (incl. methamphetamines) were involved in half of all deaths and years of life lost in 2022, with substantial variation in the predominant drug class by state and racial/ethnic group. The burden of opioid-related mortality increased dramatically in the US between 2019 and 2022, coinciding with the period of the COVID-19 pandemic and the associated disruptions to social, economic, and health systems. Opioid overdose deaths are an important contributor to decreasing US life expectancy, and Black, Hispanic, and Native Americans now experience mortality burdens approaching or exceeding white Americans. None.

Myocarditis Following Pembrolizumab Plus Axitinib, and Belzutifan Plus Lenvatinib for Renal Cell Carcinoma: A Case Report.

Cardiac toxicity is an adverse event of several classes of anti-cancer drugs. Herein, we present the case of a 52-year-old woman with metastatic renal cell carcinoma (RCC), previously treated with debulking surgery, pembrolizumab (immune checkpoint inhibitor) in combination with axitinib (tyrosine kinase inhibitor (TKI)), followed by lenvatinib (TKI) and belzutifan (HIF-2α inhibitor), who developed myocarditis proven by cardiac magnetic resonance and endomyocardial biopsy. The case was notable for reporting a not-yet described adverse event during treatment with belzutifan plus lenvatinib, the etiology of which was of unobvious determination given the pre-exposure to pembrolizumab, a known cause of drug-related myocarditis. We surmise that myocarditis was a delayed adverse event related to pembrolizumab (8months after treatment interruption), although we emphasize that only attentive monitoring of cardiac adverse events of patients exposed to belzutifan and lenvatinib in the context of large clinical trials may rule out any causal implication of these drugs.

Chinese medicine Linggui Zhugan formula protects against diabetic kidney disease in close association with inhibition of proteinase 3-mediated podocyte apoptosis in mice

Ethnopharmacological relevanceLinggui-Zhugan (LGZG) comprises four herbs and is a classic formula in traditional Chinese medicine. There is strong clinical evidence of its pleiotropic effects in the prevention of diabetes and its related complications. Although several classes of drugs are currently available for clinical management of diabetic kidney disease (DKD), tight glycemic and/or hypertension control may not prevent disease progression. This study evaluated the therapeutic effect of the ethnopharmacological agent LGZG on DKD. Aim of the studyThis study aimed to investigate the effects of LGZG formula with standard quality control on experimental DKD and its related metabolic disorders in animal model. Meanwhile, the present study aimed to investigate regulatory effects of LGZG on renal proteinase 3 (PR3) to reveal mechanisms underlying renoprotective benefits of LGZG. Materials and methodsLGZG decoction was fingerprinted by high-performance liquid chromatography for quality control. An experimental model of DKD was induced in C57 BL/6J mice by a combination of high-fat diet feeding, uninephrectomy, and intraperitoneal injection of streptozocin. The LGZG decoction was administrated by daily oral gavage. ResultsTreatment with LGZG formula significantly attenuated DKD-like traits (including severe albuminuria, mesangial matrix expansion, and podocyte loss) and metabolic dysfunction (disordered body composition and dyslipidemia) in mice. RNA sequencing data revealed a close association of LGZG treatment with marked modulation of signaling pathways related to podocyte injury and cell apoptosis. Mechanistically, LGZG suppressed the DKD-triggered increase in renal PR3 and podocyte apoptosis. In-vitro incubation of mouse immortalized podocytes with LGZG-medicated serum attenuated PR3-mediated apoptosis. ConclusionOur data demonstrated that the LGZG formula protected against DKD in mice and was closely associated with its inhibitory effects on PR3-mediated podocyte apoptosis.

An analysis of the trends in the usage of Pharmaceutical Benefits Scheme-subsidised cancer drugs in Australia from 2012 to 2022

PurposeCancer treatment remains a significant and escalating healthcare expense worldwide. Although annual reports on total cancer care costs are available, the potential impact of evolving treatment guidelines and the introduction of new drugs on future budgeting remains largely uncertain. The aim of this study was to examine the trends in the use of Pharmaceutical Benefits Scheme (PBS)-subsidised cancer drugs in Australia over the past decade.MethodsPBS codes for all PBS-subsidised cancer drugs that were listed in government-endorsed treatment protocols were obtained and used to retrieve usage data. Their patterns of use, represented by the number of prescriptions (services) processed by Services Australia, were analysed for the period between 2012 and 2022.ResultsThe overall prescribing of cancer drugs is outpacing Australia’s population growth, primarily due to an ageing population and the accelerated rise in cancer diagnoses observed over the past decade. From 846 eviQ protocols, 141 cancer drugs were available on the PBS, of which kinase inhibitor (39 drugs) and monoclonal antibody drugs (24 drugs) had the highest increase in use during the study period; 16% and 23% respectively. Of the 8 drug classes, hormonal agents (20 drugs) were the most prescribed.ConclusionThe utilisation of PBS-listed cancer drugs is increasing faster than population growth, especially for high-cost monoclonal antibody and kinase inhibitor drugs, indicating continued pressure on government spending.

The effect of sodium-glucose cotransporter type 2 inhibitors on left ventricular diastolic function: current status and prospects

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). Impaired left ventricular (LV) diastolic function (DF) is an important element in the pathogenesis of HFpEF. Experimental studies have found intracellular mechanisms for the so-called diastolic effects in gliflozins. Studies using laboratory models of experimental HFpEF have demonstrated a positive effect of dapagliflozin and empagliflozin on the elastic properties of cardiomyocyte myofilaments, the dynamics of myocardial fibrosis, and intracellular sodium and calcium homeostasis. The significance of anti-inflammatory, antioxidant properties of gliflozins in improving the cardiomyocyte DF has been experimentally established. The effect of SGLT2 inhibitors on LV DF in patients at high risk for cardiovascular diseases and their complications, that has been demonstrated in relatively small clinical studies, is due to primary cardiac and secondary effects. Results of individual studies confirmed the protective (in relation to myocardial relaxation) properties of gliflozins in the conditions of a diastolic stress test. The regression of LV diastolic dysfunction associated with the SGLT2 inhibitor treatment found in small observational studies is important in the context of the significant beneficial effect of empagliflozin and dapagliflozin on the prognosis of cardiovascular diseases that has been demonstrated in large randomized clinical trials in patients with HFpEF.

Metformin in COVID-19: a magical role beyond the hyperglycemia

Coronavirus disease-2019 (COVID-19) has emerged as an aggressive viral infection in the last few years. Initially reported in the Wuhan area of the People’s Republic of China, it soon emerged across the globe. Researchers confront a worrying situation to rapidly develop effective strategies to combat this novel infection and its long-term aftereffects. To date, there have been myriad reports ranging from the repurposing of the classical antimalarial drug hydroxychloroquine to several other antiviral and anti-bacterial agents like remdesivir, favipiravir, and most recently azithromycin, which has entered clinical use in many countries for combating COVID-19 infections. Several studies have highlighted the nexus between COVID-19-associated morbidity and diabetes in a wide-ranging class of subjects ranging from pediatric cases to adults and patients with other co-morbidities. Metformin is a mainstay in the treatment of type 2 diabetes (T2D). It is safe, inexpensive, and effective and does more than merely control blood sugar levels. Important metabolites that encourage blood clotting and inflammation are also suppressed by metformin. Pro-inflammatory molecules are linked to obesity and T2D. Both are major risk factors for aggravated COVID-19. These characteristics gave rise to a hypothesis that metformin may find use as an efficacious treatment for COVID-19 especially if it decreases the inflammatory molecules that fuel the COVID-19 virus-induced effects. In this review, we attempt to elucidate the role of classical anti-diabetic medicine metformin in the treatment of COVID-19 infections by highlighting the pharmacological role of this drug during elevated glucose levels and insulin resistance. We examine how COVID-19 has correlations to diabetic physiology and thereby the possibility of repurposing metformin for COVID-19 treatment.

The medication usage pattern and prevalence of polypharmacy among patients with sickle cell disease: a population-based study in southern Iran

ABSTRACT Background Due to the numerous complications associated with sickle cell disease (SCD), patients often receive a variety of medications alongside their SCD treatment. However, a notable gap exists in the current literature regarding medication use patterns among them. This study aimed to investigate medication usage patterns in patients with SCD. Research design and methods This cross-sectional study, conducted in Bushehr Province, employed a stratified random sampling method to select eligible participants with SCD. A thorough interview gathered various information, including details about the medications. The Anatomical Therapeutic Chemical classification system was utilized for drug classification. Polypharmacy was defined as the concurrent use of at least five medications. Results A total of 300 individuals with SCD were included in this study. Polypharmacy was observed in 26.3% (95% CI: 20.8%-32.8%) of the study population. The analyses revealed positive associations between the use of more concurrent medication use and higher age groups and having multimorbidity. Antianemic preparations (86.7%), antineoplastic agents (58.3%), and vitamins (41.0%) were the most frequent medication classes used by the study participants. Conclusions Our study revealed notable underutilization of hydroxyurea and a high rate of polypharmacy, associated with age and multimorbidity, among patients with SCD in southern Iran.

Green synthesis of CuO nanoparticles via Tulsi (Ocimum Sanctum) leaf extract for efficient adsorptive removal of doxycycline hydrochloride from aqueous solution

Due to significant consumption and improper disposal, the increase in emerging broad-spectrum antibacterial pharmaceutical contaminants in water bodies leds to degradation of quality of water resources and aquatic life, causes water availability issues. Doxycycline hydrochloride belongs to the tetracycline antibiotic class of drug, exhibits a significant persistence of toxicity in the aquatic environment. In the present study, eco-friendly CuO nanoparticles were biosynthesized using ocimum sanctum leaf waste extract and an investigation was carried out for the efficient adsorptive removal of doxycycline hydrochloride from pharmaceutical waste with harmful impacts on the environment. UV–visible spectra, XRD, FTIR, EDX, BET, HRTEM and FESEM analysis were used to characterize surface modification of the biosynthesized nanoparticles. Drug concentration, contact time, pH, temperature and adsorbent dosage were among the main adsorption parameters that were examined in order to optimize the most effective removal results. Maximum adsorption capacity of 8.56 mg/g was achieved at optimum process parameter; 100 mg/L, 170 min., pH 6 at 298 K. Moreover, various isotherm models were examined in order to accurately describe the adsorption equilibrium experimental results. Although, the thermodynamic data and kinetic study showed that the sorption process was spontaneous and endothermic, followed second order kinetic model. The outcomes showed that green synthesized CuO nanoadsorbent can be effectively employed for the removal of antibiotic medications from actual wastewater.

Drug-drug interactions in hospitalized urological patients: a retrospective cohort study.

Exposure to potential drug-drug interactions (pDDIs) can be a notable source of avoidable drug-related harm that requires adequate management to prevent medical errors. We aimed to evaluate pDDIs and associated factors in hospitalized urological patients on admission, during hospitalization, and on discharge. A retrospective cohort study was conducted at the Clinic of Urology of the University Clinical Centre Kragujevac, Serbia. To detect pDDIs we used Lexicomp, which categorizes pDDIs as follows: X (Avoid combination), D (Consider therapy modification), C (Monitor therapy), B (No action needed) and A (No known interaction). Multiple linear regression analysis was used to identify factors associated with the number of pDDIs. More than half of the 220 included patients had at least one pDDI on admission and discharge (57.3% and 63.6%, respectively), whereas 95.0% had at least one pDDI during hospitalization. The total number and number of X, D, C, and B categories of pDDIs were the highest during hospitalization and the lowest on admission. Duration of hospitalization, arrhythmias, dementia, renal failure, cancer, surgery during hospitalization, number of prescribed drugs, and various pharmacological drug classes were risk factors for a higher number of pDDIs, while age, ischemic heart disease, hypertension, and development of infection during hospitalization were protective factors in at least one of the stages. The impact of renal colic depended on the stage and category of pDDI. More than half of the urological patients were exposed to at least one pDDIs at all stages. Medical professionals should regularly screen for pDDIs, particularly in patients with risk factors.

Patch tests in non-immediate cutaneous adverse drug reactions: Late readings on Day 4 is more sensitive than on Day 3.

Patch tests (PTs) are recommended to identify the culprit drug in non-immediate cutaneous adverse drug reactions (NICADRs). We recently reported that, in patients with NICADRs, a unique reading of PTs at day (D)2 compared with an additional second late reading at D4 missed almost half (45.3%) of the positive PTs. To assess the change in sensitivity of the PT reading on D4 compared with the reading on D3. We performed a retrospective (July 2020-June 2023) monocentric study of patients who had PTs with two readings for a NICADR. We compared reading on D3 and the second reading on D4 for the suspected drug (primary outcome) and for the related drugs tested simultaneously (secondary outcome). During the study period, 249 patients underwent patch testing with D3 and D4 readings. Regarding the primary outcome, the first reading at D3 was positive for 13.7% of patients, and the reading at D4 for 24.9% of patients (p < 0.0001). Regarding the secondary outcome, only 9.6% of patients had all their positive PT at D3 compared with 24.9% of patients at D4 (p < 0.0001). Considering the evaluated drug classes, no statistical difference was observed. However, we highlight that D3 reading detected all positive carbamazepine PTs (n = 3) while positive clindamycin PTs (n = 4) were identified only with the help of the second reading on D4. This study showed that, an additional D4 reading compared with a single D3 reading enhanced the sensitivity of PTs to identify culprit drugs and related. Further studies should replicate these findings and evaluate the medico-economic balance and safety of a single reading of PTs on D4.

Factor XI inhibitors – Rising stars in anti-thrombotic therapy?

The “holy grail” of preventing and treating thrombosis and thromboembolism would be a drug that was highly effective (preventing clots) and at the same time had a low risk of bleeding. From a hemostasiological perspective, the inhibition of factor XI represents a promising target because a reduced level of factor XI protects against thrombosis without significantly increasing the risk of spontaneous bleeding.Currently, three different classes of drugs of factor XI-inhibition are tested. These are (1) monoclonal antibodies (mAbs), (2) so-called synthetic, small molecules and (3) antisense oligonucleotides (ASOs). This article provides a narrative overview of the current status of studies on all three classes of drugs.Tests with mAbs have been conducted primarily in DVT prevention after knee replacement surgery. One large phase 3 study is testing the mAbs Abelacimab in patients with atrial fibrillation. The synthetic, small molecules Asundexian and Milvexian are tested in several phase 3 trials, mainly in patients with non-cardioembolic ischemic stroke. Results can be expected in the coming years. Clinical testing of ASOs to inhibit factor XI are still in their infancies.

Harnessing transcriptomic signals for amyotrophic lateral sclerosis to identify novel drugs and enhance risk prediction

IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics. MethodsGenes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival. ResultsSNP-based fine-mapping, TWAS and PWAS identified 118 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified six drugs significantly enriched for interactions with ALS associated genes, though directionality could not be determined. Additionally, drug class enrichment analysis showed gene signatures linked to calcium channel blockers may reduce ALS risk, whereas antiepileptic drugs may increase ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk (R2 = 5.1 %; p-value = 3.2 × 10−27) and clinical characteristics. ConclusionsFunctionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.

Unraveling the molecular regulation of biofilm underlying effect of chronic disease medications.

A biofilm is a complex microbial structure that promotes the progression of persistent infections, particularly in nosocomial settings via indwelling medical devices. Conventional antibiotics are often ineffective treatments for biofilms; hence, it is crucial to investigate or design non-antibiotic antibiofilm compounds that can successfully reduce and eradicate biofilm-related infections. This study was an attempt to repurpose chronic disease medications of the antihypertensive and antilipidemic drug classes, including candesartan cilexetil (CC) and ursodeoxycholic acid (UDCA), respectively, to be used as antibiofilm agents against the two infectious pathogens Staphylococcus aureus and Enterococcus faecalis. Crystal violet (CV) staining assay was used to evaluate the antibiofilm activity of the drugs. Real-time polymerase chain reaction (RT-PCR) was performed to determine the transcription levels of the biofilm-related genes (icaA and icaR in S. aureus and fsrC and gelE in E. faecalis) following treatment with different concentrations of CC and UDCA. we found that a concentration of greater than 1.5 µg/ml of CC significantly (p < 0.005) inhibited the biofilm formation of both bacterial isolates, and a concentration of greater than 50 µg/ml of UDCA significantly (p < 0.005) inhibited the biofilm formation of both bacterial isolates. Interestingly, the mRNA expression levels of biofilm-related genes were decreased in the two bacterial isolates at concentrations that were lower than the human pharmaceutical daily doses.

PRESCRIPTION PROFILE OF ANTIHYPERTENSIVE DRUGS IN PREECLAMPSIA PATIENTS AT KIRANA HOSPITAL

Preeclampsia is a complication of pregnancy with symptoms of hypertension ≥ 140/90 mmHg and proteinuria ≥ 0.3 grams/24 hours or 30 mg/dl (+1 dipstick) arising after more than 20 weeks of gestation in previously normotensive pregnant women. Maternal deaths in Indonesia in 2021 related to hypertension in pregnancy reached 1077 cases (Source: Directorate General of Public Health, Ministry of Health, 2021). Pharmacological therapy intervention, antihypertensive treatment is also needed in addition to maintaining a healthy lifestyle. The purpose of the study was to determine the description of pharmacological therapy including the pharmacological class of drugs, drug names, drug doses, rules of use, and types of antihypertensive drug therapy (single / combination) in patients with preeclampsia. This type of descriptive observational research is retrospective with total sampling obtained from medical records and patient prescriptions. The results of this study were the incidence of preeclampsia aged 35 years and over by 21 patients (36%) and the most common diagnosis was mild preeclampsia by 38 samples (66%). The use of nifedipine which is included in the CCB (Calcium Channel Blocker) group was 42 respondents (72%). Meanwhile, the use of methyldopa which is included in the central sympatholytic group was 17 respondents (28%). In the single therapy type study, 59 prescriptions (100%) used nifedipine or methyldopa. Pregnant women are encouraged to routinely conduct antenatal care checks at the hospital every month.

Assessment of adverse events related to anti-interleukin-6 receptor monoclonal antibodies using the FDA adverse event reporting system: a real-world pharmacovigilance study

ABSTRACT Background Interleukin-6 (IL-6) monoclonal antibodies are commonly acknowledged for their efficacy in managing coronavirus disease 2019 (COVID-19); however, there remains a paucity of comprehensive studies on their potential adverse effects. Research design and methods This is a retrospective pharmacovigilance investigation. We employed FAERS using OpenVigil FDA to detect adverse reactions linked to the interleukin-6 antagonist tocilizumab and sarilumab. Results Completely 67,976 reports were identified as ‘primary suspected (PS)’ adverse events (AEs) for tocilizumab, and 12,560 reports for sarilumab. 109 significant disproportionality preferred terms (PTs) of tocilizumab and 158 PTs of sarilumab were retained. A higher incidence of adverse reactions occurred in females aged 45-64 years, with a higher rate of subsequent hospitalization. Both drugs exhibited adverse reactions consistent with previously reported side effects, such as leukopenia, elevated liver enzymes, and hypercholesterolemia. Additionally, there was a strong correlation with gastrointestinal issues. Unexpected significant adverse events, including diabetes, fluctuations in blood pressure, drug ineffectiveness, malignancies, and disorders of the nervous system, were also observed. Gender and age differences existed in AEs signals related to IL-6RAs. Conclusion Our study identified significant new AE signals for interleukin-6 receptor antagonists, potentially supporting clinical monitoring and risk identification for this class of drugs.