Class Of Drugs Research Articles

Structural basis for antibiotic transport and inhibition in PepT2

The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the proton-coupled peptide transporter, PepT2 from Rattus norvegicus, in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of beta-lactam antibiotic recognition and the important role of protonation in drug binding and transport.

Association of Neuromelanin-Sensitive MRI Signal With Lifetime Substance Use in Young Women.

Midbrain dopamine function plays a key role in translational models of substance use disorders. Whether midbrain dopamine function is associated with substance use frequency and severity or reward function in 20-24 year-olds remains a critical gap in knowledge. The authors collected neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a validated index of lifetime dopamine function in the substantia nigra/ventral tegmentum area (SN-VTA) complex, to characterize altered dopamine function. Midbrain NM-MRI contrast-to-noise ratio (CNR) was acquired in 135 20-24 year-olds (105 women and 30 men). A composite measure of cumulative substance use was derived from factor analysis of lifetime alcohol intoxications, lifetime cannabis use, use of nicotine in heaviest month, number of classes of drugs used, and ever meeting DSM-5 criteria for a SUD. Trait reward function was assessed by self-report. Cumulative substance use was significantly positively associated with NM-MRI CNR in a large area of the bilateral SN-VTA complex, an effect which was driven by women (who comprised most of the sample) and by voxels with greater NM-MRI CNR, including the ventral tegmentum area. NM-MRI CNR was not associated with individual differences in trait reward function. History of substance use is associated with greater NM signal in NM-rich areas of the midbrain, especially in women. Future longitudinal studies with repeated NM-MRI assessments, especially in younger cohorts and while including more men, are warranted to evaluate whether aberrant dopamine function predates, follows, or is modulated by substance use.

A Comprehensive Survey of Studies on Predicting Anatomical Therapeutic Chemical Classes of Drugs

Drug classification plays a crucial role in contemporary drug discovery, design, and development. Determining the Anatomical Therapeutic Chemical (ATC) classes for new drugs is a laborious, costly, and intricate process, often requiring multiple clinical trial phases. Computational models offer significant benefits by accelerating drug evaluation, reducing complexity, and lowering costs; however, challenges persist in the drug classification system. To address this, a literature survey of computational models used for predicting ATC classes was conducted, covering research from 2008 to 2024. This study reviews numerous research articles on drug classification, focusing on drug descriptors, data sources, tasks, computational methods, model performance, and challenges in predicting ATC classes. It also examines the evolution of computational techniques and their application in identifying ATC classes. Finally, the study highlights open problems and research gaps, suggesting areas for further investigation in ATC class prediction. CCS Concepts: Applied computing → Life and medical sciences → Bioinformatics

The role of adjuvants in regional anesthesia: the postoperative analgesic effectiveness of dexamethasone vs. tramadol given as adjuvants to bupivacaine for ultrasound-guided supraclavicular block for upper extremity surgery—a prospective cohort study

BackgroundBrachial plexus block is used as a surgical anesthesia and analgesia for postoperative pain. Recently, the use of local anesthetics for regional nerve block has been enhanced by mixing them with a different class of drugs as adjuvants. These adjuvants of local anesthetics improved the quality and duration of nerve block and reduced the dose-dependent side effects of local anesthetics. However, the effectiveness of these adjuvants varies depending on the nature of the nerve block and the type of local anesthetics used. Therefore, we aimed to compare the postoperative analgesic effectiveness of dexamethasone vs. tramadol when used as adjuvants to bupivacaine for ultrasound-guided supraclavicular block in upper extremity surgery.MethodsUtilizing a prospective cohort study design, 126 consecutive patients who were undergoing upper extremity surgery with ultrasound-guided supraclavicular block were included. Patients were divided into three groups based on the preference of the responsible anesthetist to use adjuvants with bupivacaine for the block. The dexamethasone group (n = 42) were given 30 ml of 0.25% bupivacaine with 8 mg dexamethasone, the tramadol group (n = 42) were given 30 ml of 0.25% bupivacaine with 100 mg tramadol, and the non-adjuvant group (n = 42) were given 30 ml of 0.25% bupivacaine alone. The primary outcomes evaluated were postoperative pain severity using the numerical pain rating scale (NRS), the duration of analgesia, and the total postoperative analgesic consumption. Secondary outcomes included the incidence of postoperative complications.ResultA total of 126 patients were recruited and analyzed. There was no statistical difference in the demographic data among the groups. The postoperative NRS score was significantly reduced in the dexamethasone and tramadol group compared with the non-adjuvant group (p < 0.001). The NRS score in the dexamethasone group at 18 and 24 h was statistically much lower than in the tramadol and non-adjuvant group. The postoperative duration of analgesia was significantly prolonged in the dexamethasone (1,069 ± 316.99 min) group compared with the tramadol (617.02 ± 214.05 min) and non-adjuvant (434.17 ± 111.23 min) groups (p < 0.001). Patients in the non-adjuvant group had a significantly higher total analgesic consumption over 24 h. The dexamethasone group experienced significantly fewer incidences of nausea, with no differences in other complications among the groups.ConclusionThe addition of dexamethasone as an adjuvant to bupivacaine for ultrasound-guided supraclavicular block improves postoperative analgesia. We recommend the integration of dexamethasone as an adjuvant to local anesthetics during nerve blocks to enhance postoperative pain management after surgery.

ALTERNATIVAS NÃO INVASIVAS NO MANEJO DO GRANULOMA CENTRAL DE CÉLULAS GIGANTES DOS MAXILARES: UMA REVISÃO NARRATIVA DA LITERATURA

Introduction: The Central Giant Cell Granuloma of the jaws is described as an uncommon intraosseous lesion that can exhibit different clinical and imaging characteristics. It can present in an aggressive or non-aggressive manner. When aggressive, the lesion is typically expansive, painful, and associated with bone tissue destruction. The standard treatment is surgical removal, but the choice of the ideal therapeutic approach depends on factors such as the patient’s age, lesion behavior, and its extent. Objective: To explore the main conservative treatment options for the management of Central Giant Cell Granuloma of the jaws. Methods: This is a narrative literature review based on research in databases such as PubMed and Google Scholar, conducted between July and August 2024, using DeCS/MeSH descriptors in English, “calcitonin” OR “interferon” OR “denosumab” AND “central granuloma of giant cells in jaws” AND “central giant-cell lesion” OR “corticosteroids injections” AND “intralesional triamcinolone.” Literature Review: The drug class used for the treatment of Central Giant Cell Granuloma is corticosteroids, which show high rates of therapeutic success, followed by calcitonin, denosumab, and interferon. However, despite promising results, additional clinical trials are necessary to establish the true efficacy of these treatments. Conclusion: All non-invasive treatment modalities have been shown to be effective in reducing or achieving complete regression of Central Giant Cell Granuloma of the jaws, either alone or in combination. However, there are limitations, such as the risk of adverse effects and the limited number of published studies to date.

Adverse perinatal outcomes associated with different classes of antiretroviral drugs in pregnant women living with HIV: a systematic review and meta-analysis

Objective: Women living with HIV (WLHIV) are at increased risk of adverse perinatal outcomes compared to HIV-negative women, despite antiretroviral therapy (ART). There is evidence that the risk of adverse perinatal outcomes may differ according to ART regimen. We aimed to assess the risk of adverse perinatal outcomes among WLHIV receiving different classes of ART, compared to HIV-negative women. Design: Systematic review and meta-analysis Methods: We searched Medline, CINAHL, Global Health and EMBASE for studies published between 1 January 1980 and 14 July 2023. We included studies which assessed the risk of 11 predefined adverse perinatal outcomes among WLHIV receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, protease inhibitor (PI)-based ART or integrase strand transfer inhibitor (INSTI)-based ART, compared to HIV-negative women. The perinatal outcomes assessed were preterm birth (PTB), very PTB (VPTB), spontaneous PTB (sPTB), low birthweight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth and neonatal death (NND). Random effects meta-analyses examined the risk of each adverse outcome in WLHIV receiving either NNRTI-based, PI-based or INSTI-based ART, compared with HIV-negative women. Subgroup and sensitivity analyses were conducted based on country income status, study quality, and timing of ART initiation. The protocol is registered with PROSPERO, CRD42021248987. Results: Of 108,720 identified citations, 22 cohort studies including 191,857 women were eligible for analysis. We found that WLHIV receiving NNRTI-based ART (mainly efavirenz or nevirapine) are at increased risk of PTB (risk ratio (RR) 1.40, 95% confidence interval 1.27–1.56), VPTB (1.94, 1.25–3.01), LBW (1.63, 1.30–2.04), SGA (1.53, 1.17–1.99) and VSGA (1.48, 1.16–1.87), compared with HIV-negative women. WLHIV receiving PI-based ART (mainly lopinavir/ritonavir or unspecified) are at increased risk of PTB (1.88, 1.55–2.28), VPTB (2.06, 1.01–4.18), sPTB (16.96, 1.01–284.08), LBW (2.90, 2.41–3.50), VLBW (4.35, 2.67–7.09) and VSGA (2.37, 1.84–3.05), compared with HIV-negative women. WLHIV receiving INSTI-based ART (mainly dolutegravir) are at increased risk of PTB (1.17, 1.06–1.30) and SGA (1.20, 1.08–1.33), compared with HIV-negative women. Conclusions: The risks of adverse perinatal outcomes are higher among WLHIV receiving ART compared with HIV-negative women, irrespective of the class of ART drugs. This underlines the need to further optimise ART in pregnancy and improve perinatal outcomes of WLHIV.

Drug treatments to prevent first decompensation in cirrhosis.

Cirrhosis is a prevalent condition affecting more than 100 million people globally and carrying significant morbidity and mortality related to the development of portal hypertension and hepatic decompensation. Current treatment is primarily targeted at identifying chronic liver disease early and preventing the progression of fibrosis by treating the underlying etiology of liver disease. Treatment options for patients with advanced fibrosis are limited, and the only drug class approved for the prevention of hepatic decompensation remains non-selective beta blockers. There are several pharmacological therapies being developed in both preclinical and clinical trials to explore their efficacy in preventing first hepatic decompensation. Most studies evaluate primary endpoints reflective of disease severity and portal hypertension, such as change in hepatic venous pressure gradient or fibrosis stage based on histology or imaging. While many drugs are being investigated, much work is still needed to identify treatment targets with effective outcomes in order to move the needle in the field of cirrhosis management. This narrative review will address the current state of cirrhosis therapies including potential new therapeutic targets as well as provide direction on future advancements that will improve our current treatment paradigm and lead to better outcomes for those burdened with cirrhosis.

Rates of Viral Non-Suppression and Acquired HIV-1 Drug Resistance Emergence among Children during the Sociopolitical Crisis in the Northwest Region of Cameroon: A Call for Improved Monitoring Strategies.

Virological failure (VF) among children remains concerning, with high risks of HIV drug resistance (HIVDR) emergence and increased disease progression. Therefore, monitoring of viral non-suppression and emerging HIVDR is crucial, especially in the frame of sociopolitical unrest. The study sought to determine the prevalence of VF and evaluate the acquired HIVDR and viral genetic diversity among children in the northwest region of Cameroon during the ongoing sociopolitical crisis. A cross-sectional facility-based study was conducted among HIV-infected children aged ≤18 years, receiving antiretroviral therapy (ART) in urban and rural settings of Northwest Cameroon, from November 2017 through May 2018. Viral load (VL) was done using the Abbott m2000RealTime. Unsuppressed VL was defined as viral load ≥1,000 copies/ml. HIVDR testing was performed by sequencing of HIV-1 protease-reverse transcriptase at the Chantal Biya International Reference Center (CIRCB) using an in-house protocol. Drug resistance mutations (DRM) were interpreted using Stanford HIVdbv8.5 and phylogeny using MEGAv.6. Data were compared between urban and rural areas with p<0.05 considered statistically significant. A total of 363 children were recruited, average age of 12 years (urban) and 8 years (rural). VL coverage was 100% in the urban setting and 77% in the rural setting. Overall, VF was 40.5% (39% [130/332] in the urban setting and 41% (13/31) in the rural setting; p=0.45). Overall, viral undetectability (defined as VL<40 copies/ml) was 45.5% (46% (urban) and 45% (rural); p=0.47). Among those experiencing confirmed virological failure and who were successfully sequenced (n=35), the overall rate of HIVDR was 100% (35/35). By drug class, HIVDR rates were 97.1% (34/35) for non-nucleoside reverse transcriptase inhibitors (NNRTIs), 97.1% (34/35) for NRTIs and 17.1% (6/35) for protease inhibitors (22.7% (5/22) in the urban setting and 7.7% [1/13] in the rural setting). CRF02_AG was the most prevalent viral clade (75%), followed by other recombinants (09_cpx, 11_cpx, 13_cpx, 22_01A1, 37_cpx) and pure subtypes (A1, F2, G, H). In this population of children and adolescents living with HIV in a context of socio-political instability in the North-West region of Cameroon, rates of viral non-suppression are high, and accompanied by HIVDR selection. Our suggests the need for a more differentiated care of these CAHIV, especially those in these regions faced with significant socio-economic and health impacts due to the ongoing crisis.

Assessment and Monitoring of Adverse Drug Reactions at a Tertiary Care Hospital

Background: Incidences of adverse drug reactions were reported through spontane-ous reporting at an ADR monitoring unit in a tertiary care hospital. Aims: This study was conducted to describe the distribution pattern of adverse drug reaction (ADR). Objective: The objective of this study was to monitor and report the adverse drug reactions (ADRs) occurring in a tertiary care hospital and to evaluate the incidence, causality, severity, and preventability of adverse drug reactions. Methods: A prospective, observational study was conducted at a tertiary care hospital in Punjab for 6 months. All patients admitted to the hospital above 18 years of age were included in the study. Results: A total of 103 ADRs were observed over the study period of 6 months. The majority of them were females (60), comprising of 58.25%. The therapeutic class of drug associated with most of the ADRs was antibiotics 18 (17.5%). Maximum number of ADRs occurred in the gen-eral medicine ward with frequency of 27 (26.2%) and were of type b 58 (56.3%). Causality was assessed using the Naranjo scale, and most of the ADRs came out to be probable 64 (62.1%) in nature. Severity was assessed using Hartwig’s severity assessment scale, and most of the cases, 66 (64.1%), were moderate in intensity. ADR preventability was assessed using the Schumock and Thornton preventability scale, and it was observed that most of the cases, 82 (79.6%), were not preventable. Conclusion: This study seeks to strengthen the ADR database through analysis of spontaneous reporting patterns of ADRs from various clinical departments of a tertiary care teaching hospital, thereby increasing awareness and improving the reporting culture among health care practition-ers. It can be concluded that continuous medication monitoring and a well-organized and com-mitted pharmacovigilance system led by a clinical pharmacist in a hospital setting would un-doubtedly lower the incidence of adverse drug reactions.

The effects of sodium-glucose cotransporter 2 inhibitors on the 'forgotten' right ventricle.

With the progress in diagnosis, treatment and imaging techniques, there is a growing recognition that impaired right ventricular (RV) function profoundly affects the prognosis of patients with heart failure (HF), irrespective of their left ventricular ejection fraction (LVEF). In addition, right HF (RHF) is a common complication associated with various diseases, including congenital heart disease, myocardial infarction (MI), pulmonary arterial hypertension (PAH) and dilated cardiomyopathy (DCM), and it can manifest at any time after left ventricular assist devices (LVADs). The sodium-glucose cotransporter 2 (SGLT2) inhibition by gliflozins has emerged as a cornerstone medicine for managing type 2 diabetes mellitus (T2DM) and HF, with an increasing focus on its potential to enhance RV function. In this review, we aim to present an updated perspective on the pleiotropic effects of gliflozins on the right ventricle and offer insights into the underlying mechanisms. We can ascertain their advantageous impact on the right ventricle by discussing the evidence obtained in animal models and monumental clinical trials. In light of the pathophysiological changes in RHF, we attempt to elucidate crucial mechanisms regarding their beneficial effects, including alleviation of RV overload, reduction of hyperinsulinaemia and inflammatory responses, regulation of nutrient signalling pathways and cellular energy metabolism, inhibition of oxidative stress and myocardial fibrosis, and maintenance of ion balance. Finally, this drug class's potential application and benefits in various clinical settings are described, along with a prospective outlook on future clinical practice and research directions.

Les cellules CAR-T anti-CD19 : prototypes du médicament vivant

Chimeric antigen receptors (CARs) are synthetic receptors that determine the specificity and functions of transduced T cells. They bind cell surface antigens through their extracellular domain and initiate via their intracellular domain cytolytic functions, cytokine secretion and proliferation. The CAR thus specifies the properties of a living drug that is programmed to exert anti-tumor and immunoregulatory effects.After establishing a method to stably integrate foreign genes in primary T lymphocytes in the early 1990s, we identified combinatorial signaling modules that could sustain a prolonged T cell function [17], which underpins an essential feature of a living drug. We further identified CD19 as a promising molecular target, which, based on encouraging preclinical results in mice [30], paved the way for clinical trials.The first clinical studies in patients with relapsed, refractory leukemias and lymphomas, which all made use of CAR T cells produced in the academic setting, yielded remarkable clinical response that were soon confirmed at several centers [2]. CAR T cells targeting CD19 were the first living drugs to be approved by the US Food and Drug Administration in 2017 and the European Medicines Agency in 2018.CD19 CARs have thus spawned a new class of drugs and inspired new applications to treat cancer and autoimmune diseases with engineered immune cells, warranting sustained efforts to lower their cost and increase their availability in equitable fashion.

Oleanolic acid derivatives against drug-resistant bacteria and fungi by multi-targets to avoid drug resistance

Mixed infections caused by drug-resistant bacteria and fungi pose a severe threat to human health, and multi-target drugs may provide an effective approach to combat drug-resistant pathogens. Therefore, this study aimed to investigate the efficacies of some oleanolic acid (OA) derivatives against multidrug-resistant (MDR) bacteria and fungi using in vitro and in vivo experiments. Novel amphiphilic OA derivatives were designed and optimised, in which compounds G1 and J1 exhibited effective antimicrobial activity (MICs = 1–2 μg/mL), high selectivity against MDR strains, rapid bactericidal activity, and good predictive pharmacokinetics. Mechanistically, both compounds prevented drug resistance by disrupting the bacterial cell membrane, inserting into the DNA, and binding to DNA gyrase. Additionally, J1 reduced microbial count in a mouse MRSA skin infection model and accelerated wound healing much better than vancomycin. Conclusively, this study presents a new class of potential drugs for resistant bacteria and fungi.

8243 Euglycemic Diabetic Ketoacidosis Unveiled: Delayed Presentation and Complications of SGLT-2 Inhibitor Therapy in a Multimorbid Patient - A Case Report

Abstract Disclosure: T. Amin: None. A.K. Bala: None. M.A. Jones: None. M.S. Akula: None. K. Chalasani: None. M. Patel: None. J. Cheng: None. Introduction: Normal serum glucose levels (&amp;lt;200 mg/dL) in euglycemic diabetic ketoacidosis (EDKA) can complicate the typical clinical presentation of diabetic ketoacidosis (DKA), posing a diagnostic challenge. SGLT-2 inhibitors, a class of antihyperglycemic drugs, have been rarely but significantly associated with EDKA. These inhibitors enhance renal glucose clearance by preventing glucose reabsorption via sodium-glucose cotransport. The increased renal clearance may contribute to the euglycemic picture, potentially leading to an underestimation of required insulin dosage, thereby precipitating ketoacidosis in EDKA. Although the mechanisms of EDKA are not fully understood, the association with SGLT-2 inhibitors is becoming increasingly evident. Case A 53-year-old male with a medical history of type 2 Diabetes Mellitus, coronary artery disease, chronic kidney disease, hyperlipidemia, was admitted to the trauma bay after a fall. Medications included empagliflozin, metformin, aspirin, amlodipine, spironolactone, and carvedilol. Upon presentation, he had a brief loss of consciousness, complained of headache and chest pain, and was found to have an epidural hematoma with regional brain compression on the CT head. Admission labs showed a blood glucose level of 172, an unremarkable anion gap, and normal renal and liver function tests. Due to traumatic brain injury, he was admitted to the ICU for neurological monitoring. Despite remaining neurologically stable, he developed hypoxia, necessitating intubation. After successful extubation, he exhibited worsening metabolic acidosis on the fourth day, with an elevated anion gap of 22 and a blood glucose level of 174. Arterial blood gas analysis revealed a pH of 7.3 (and elevated beta-hydroxybutyrate (&amp;gt;4), while lactic acid levels remained normal. Urine analysis showed elevated blood glucose (&amp;gt;1000) and ketones (&amp;gt;40). Home medications, metformin, and empagliflozin were appropriately withheld, but euglycemic DKA attributed to empagliflozin was diagnosed. Treatment included intravenous fluid resuscitation and insulin infusion, leading to resolution of acidosis and improved mentation within 24 hours. Conclusion: EDKA is a diagnosis of exclusion often overlooked in ICU patients due to diverse causes of high-anion gap metabolic acidosis. Typical cases occur while the patient is using the drug, often associated with triggers like illness, alcohol use, surgery, or starvation. SGLT2 inhibitors, such as empagliflozin, with a half-life of 12.4 hours, are expected to clear the bloodstream in about 48 hours, yet this case suggests an association with EDKA both during use and after drug cessation. This delayed presentation highlights additional risk considerations associated with SGLT2 inhibitors, guiding future clinical diagnoses of EDKA even several days post discontinuation. Presentation: 6/3/2024

6527 Genetic variants may influence the glycemic response to sodium-glucose cotransporter-2 inhibitors in the Mass General Brigham Biobank

Abstract Disclosure: J.H. Li: None. A. Barry: None. A. Huerta-Chagoya: None. L. Szczerbinski: None. J.M. Mercader: None. J.C. Florez: Consulting Fee; Self; AstraZeneca. Grant Recipient; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Merck. A. Leong: None. Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are increasingly prescribed for the treatment of type 2 diabetes, but there is interindividual variability in glycemic response. We investigated whether two genetic variants, rs33954001, a missense variant (p.His615Gln) in SLC5A1 encoding SGLT1, and rs8050500 near SLC5A2 encoding SGLT2, previously associated with glycemic traits in genome-wide association studies, had any influence on short-term glycated hemoglobin (HbA1c) lowering in patients on SGLT2i treatment. Methods: We identified 1,961 ancestrally diverse, genotyped individuals with documented exposure to a SGLT2i in the Mass General Brigham Biobank, a hospital-based biobank linked with patient medical records. Of these, 736 individuals had a baseline HbA1c ≥ 6% within 6 months of the index appearance of an SGLT2i and a follow-up HbA1c measured 6-12 months after. Genotyping was performed on the Illumina Multi-Ethnic Genotyping Array and the Illumina Global Screening Array. Variants were imputed with the TOPMed reference panel. Using linear regression models, we evaluated the additive effect of the genetic variants on HbA1c reduction, defined as baseline HbA1c minus follow-up HbA1c, adjusted for age, sex, 10 genetic ancestry principal components to account for population stratification, the number of concomitant glucose-lowering drug classes, and three covariates accounting for potential genotyping batch effects. To determine whether genetic effects varied by pretreatment glycemic control, we tested for a genotype × baseline HbA1c interaction and performed stratified analysis by baseline HbA1c (≥ 8% vs. &amp;lt; 8%). Results: The mean age of participants was 63.7 years and 41% were female. The baseline HbA1c was 8.0 ± 1.9%. The mean HbA1c reduction was 0.6% over a mean follow-up time of 8.7 ± 1.6 months. None of the variants were associated with HbA1c reduction (p &amp;gt; 0.05) in the whole dataset. However, in stratified analyses, among those with baseline HbA1c ≥ 8% (n = 382), we observed that carriers of the G allele at rs33954001 had a 0.5% greater HbA1c reduction (p = 0.048) compared to those with CC genotype. Further adjustment for baseline renal function did not modify results. In the Genotype-Tissue Expression (GTEx) portal, the G allele was associated with higher SLC5A1 expression in nerve (p = 1 × 10-8), esophageal mucosa (p = 4 × 10-5) and stomach (p = 9 × 10-5), but not kidney. In the Translational human pancreatic Islet Genotype tissue-Expression Resource (TIGER), the G allele was associated with SLC5A1 expression in pancreatic islets (p = 2 × 10-6). Conclusion: Genetic variation in SLC5A1 may partly explain heterogeneity in SGLT2i treatment effects among people with sub-optimally controlled diabetes, possibly due to differences in SLC5A1 tissue-specific expression. These findings require validation in large hospital-based biobanks or dedicated clinical trials. Presentation: 6/2/2024

Prescription of quadruple therapy in heart failure with reduced ejection fraction during hospitalization

BackgroundHospitalization of patients with heart failure makes it possible to optimize drug therapy, considerably improving the prognosis of this serious condition.MethodsWe conducted a retrospective descriptive study of patients with reduced left ventricular ejection fraction (≤ 40%) in the Cardiology Department of a community hospital center in France to measure the prescription rate of heart failure medications in hospitalized patients with reduced ejection fraction heart failure and identify their limiting factors. The primary endpoint was the prescription on the discharge prescription of the following four drug classes: beta-blockers, renin–angiotensin–aldosterone system blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter inhibitors.ResultsFrom September 1, 2022, to March 31, 2023, 73 patients were included in the study. About one-third of patients were discharged with the recommended four drug classes. Those discharged with all 4 drug classes were younger and had preserved renal function.ConclusionsThe low rate of prescription of heart failure medications after hospitalization is a reminder of the need to develop a specialized follow-up structure to optimize the drug treatment of reduced ejection fraction heart failure, even in the most fragile patients.

Autoimmune complications of tyrosine kinase inhibitors in cancer therapy: Clinical insights, mechanisms, and future perspectives

The tyrosine kinase inhibitors (TKIs) have emerged as a promising class of novel anticancer drugs, achieving significant success in clinical applications. However, the risk of autoimmune diseases associated with these drugs has raised widespread concerns. In this review, TKI-induced autoimmune diseases are reviewed in order to understand this complex phenomenon through clinical research and molecular mechanism exploration. Despite the relatively low incidence of autoimmune diseases, their potential severity demands heightened attention. The potential mechanisms underlying TKI-induced autoimmune diseases may involve immune system dysregulation, alterations in immune cell function, activation of inflammatory responses, and attacks on self-antigens. Various preventive strategies, including clinical monitoring, personalized treatment, optimization of therapeutic approaches, and patient education and communication, can be employed to effectively address these potential risks. Future research directions should delve into the molecular mechanisms of TKI-induced autoimmune diseases, integrate studies on genetics and immunogenetics, advance the development of novel TKIs, explore the possibilities of combining immunotherapy with TKI treatment, and propel large-scale clinical trials.

Enhanced Synergistic Efficacy Against Breast Cancer Cells Promoted by Co-Encapsulation of Piplartine and Paclitaxel in Acetalated Dextran Nanoparticles.

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment. Adverse effects, poor water solubility, and inevitable susceptibility to drug resistance seriously limit its therapeutic efficacy in the clinic. Piplartine (PPT), an alkaloid extracted from Piper longum L., has been shown to inhibit cancer cell proliferation in several cell lines due to its pro-oxidant activity. However, PPT has low water solubility and bioavailability in vivo, and new strategies should be developed to optimize its use as a chemotherapeutic agent. In this context, the present study aimed to synthesize a series of acetalated dextran nanoparticles (Ac-Dex NPs) encapsulating PPT and PTX to overcome the limitations of PPT and PTX, maximizing their therapeutic efficacy and achieving prolonged and targeted codelivery of these anticancer compounds into BC cells. Biodegradable, pH-responsive, and biocompatible Ac-Dex NPs with diameters of 100-200 nm and spherical morphologies were formulated using a single emulsion method. Selected Ac-Dex NPs containing only PPT or PTX as well as those coloaded with PPT and PTX achieved excellent drug-loading capabilities (PPT, ca. 11-33%; PTX, ca. 2-14%) and high encapsulation efficiencies (PPT, ∼57-98%; PTX, ∼80-97%). Under physiological conditions (pH 7.4), these NPs exhibited excellent colloidal stability and were capable of protecting drug release, while under acidic conditions (pH 5.5) they showed structural collapse, releasing the therapeutics in an extended manner. Cytotoxicity results demonstrated that the encapsulation in Ac-Dex NPs had a positive effect on the activities of both PPT and PTX against the MCF-7 human breast cancer cell line after 48 h of treatment, as well as toward MDA-MB-231 triple-negative BC cells. PPT/PTX@Ac-Dex NPs were significantly more cytotoxic (IC50/PPT = 0.25-1.77 μM and IC50/PTX = 0.07-0.75 μM) and selective (SI = 2.9-6.7) against MCF-7 cells than all the control therapeutic agents: free PPT (IC50 = 4.57 μM; SI = 1.2), free PTX (IC50 = 0.97 μM; SI = 1.0), the single-drug-loaded Ac-Dex NPs, and the physical mixture of both free drugs. All combinations of PPT and PTX resulted in pronounced synergistic antiproliferative effects in MCF-7 cells, with an optimal molar ratio of PPT to PTX of 2.3:1. PPT/PTX-2@Ac-Dex NPs notably promoted apoptosis, cell cycle arrest at the G2/M, accumulation of intracellular reactive oxygen species (ROS), and combined effects from both PPT and PTX on the microtubule network of MCF-7 cells. Overall, the combination of PTX and PPT in pH-responsive Ac-Dex NPs may offer great potential to improve the therapeutic efficacy, overcome the limitations, and provide effective simultaneous delivery of these therapeutics for BC treatment.

Assessment of pharmacokinetic and pharmacodynamic interactions between zavegepant and sumatriptan: A phase 1, randomized, placebo-controlled study in healthy adults.

To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults. Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug-drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings. This was a Phase 1, single-center, partially blind, randomized, placebo-controlled, single-arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre-specified time points. Forty-two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty-one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time-weighted average (TWA) of mean arterial pressure (MAP [sumatriptan+ zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: -0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: -0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: -0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC0-inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC0-24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. Overall, 90% (38/42) of participants experienced ≥ 1 treatment-emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated. Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults.

Association of polypharmacy with clinical outcomes and healthcare utilization in older adults with cardiometabolic diseases: a retrospective cohort study.

Limited knowledge exists on the association between polypharmacy among older patients diagnosed with cardiometabolic diseases and the risk of clinical outcomes and healthcare utilization. This study aimed to estimate the impact of polypharmacy on clinical outcomes and healthcare utilization in older adults with cardiometabolic diseases. A retrospective cohort analysis was performed using data from the Beijing Municipal Medical Insurance Database. The study focused on polypharmacy prescribing patterns in community-dwelling adults 65years and older with cardiometabolic diseases. Polypharmacy was defined as the use of five or more medications on the index date. The primary outcome included clinical outcomes, including hospitalizations and emergency department visits. The secondary outcome focuses on hospital utilization, specifically medication costs and length of stay. The study included a cohort of 405,608 patients. Among these, the most frequently used drug classes in the polypharmacy and non-polypharmacy groups were HMG-CoA reductase inhibitors and dihydropyridines, respectively. After adjustment for covariates, polypharmacy was not associated with an increased risk of hospitalization (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.95-1.26, p = 0.23) or ED visits (OR 1.28, 95% CI 0.97-1.68, p = 0.08). Similarly, no significant association was found with an increase in inpatient medication costs ($2,620.5, 95% CI $2387.3-$2894.3, p = 0.97) or length of stay (3.98days, 95% CI 3.68-4.30days, p = 0.79). However, polypharmacy was associated with higher medication costs in outpatient settings ($73.07, 95% CI $72-$74, p < 0.05) and ED visits ($51.2, 95% CI $44.5-$59.1, p < 0.05). Although polypharmacy is associated with increased healthcare costs in outpatient settings and ED visits, it does not significantly increase the risk of hospitalization or ED visits when properly managed.

Association between risk of Alzheimer’s disease and related dementias and angiotensin receptor Ⅱ blockers treatment for individuals with hypertension in high-volume claims data

Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive. Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses. From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P<0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P<0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P<0.0001). This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings. This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604).