Class Of Drugs Research Articles

Avatrombopag (Doptelet)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses avatrombopag (Doptelet), 20 mg, tablets, oral. Indication: Proposed: the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.

Translating the 2021 ESC heart failure guideline recommendations in daily practice: Results from a heart failure survey. A scientific statement of the ESC Council for Cardiology Practice and the Heart Failure Association of the ESC.

Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines. A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach. Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care.

Competing endogenous RNAs (ceRNAs) and drug resistance to cancer therapy

Competing endogenous RNAs (ceRNAs) are transcripts that possess highly similar microRNA response elements (MREs). microRNAs (miRNAs) are short, endogenous, single-stranded non-coding RNAs (ncRNAs) that can repress gene expression by binding to MREs on the 3’ untranslated regions (UTRs) of the target mRNA transcripts to suppress gene expression by promoting mRNA degradation and/or inhibiting protein translation. mRNA transcripts, circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and transcribed pseudogenes could share similar MREs, and they can compete for the same pool of miRNAs. These ceRNAs may affect the level of one another by competing for their shared miRNAs. This interplay between different RNAs constitutes a ceRNA network, which regulates many important biological processes. Cancer drug resistance is a major factor leading to treatment failure in patients receiving chemotherapy. It can be acquired through genetic, epigenetic, and various tumor microenvironment mechanisms. The involvement of ceRNA crosstalk and its disruption in chemotherapy resistance is attracting attention in the cancer research community. This review presents an updated summary of the latest research on ceRNA dysregulation causing drug resistance across different cancer types and chemotherapeutic drug classes. Interestingly, accumulating evidence suggests that ceRNAs may be used as prognostic biomarkers to predict clinical response to cancer chemotherapy. Nevertheless, detailed experimental investigations of the putative ceRNA networks generated by computational algorithms are needed to support their translation for therapeutic and prognostic applications.

Prescribing practices for Proton pump inhibitors among primary care physicians in England.

Proton pump inhibitors (PPIs) the most frequently prescribed drug class globally, are often overused. To assess PPI prescribing practice in England. Electronic medical record (EMR) evaluation from 62 primary care GP practices. Adult patients on continuous PPI treatment (repeat prescription or≥4 acute prescriptions 6 months before data extraction) were included (August 2021-June 2022) to compare PPI prescribing practices vs National Institute for Health and Care Excellence (GORD and dyspepsia management) and Medicines and Healthcare products Regulatory Agency (clopidogrel-PPI interaction) guidelines. We identified 77,356 patients on continuous PPI treatment. The most common (68%) diagnosis recorded in patients' EMRs and indicated for PPI use was gastroprotection, although 62% had no recorded indication. Of these 62% patients, 40% had no medication review in the preceding year. Among those with diagnoses indicated for≤3 months of PPI therapy (34%), 99% received their first PPI prescription≥3 months previously. Of patients with diagnoses indicated for long-term treatment (4%), 41% had no medication review in the preceding year. Furthermore, 18% of patients using omeprazole or esomeprazole were also prescribed clopidogrel, and 19% of those prescribed treatments associated with gastrointestinal risk (N=14,826) were not prescribed PPIs. This study shows that PPI prescribing in England is not in alignment with existing clinical guidelines and highlights the need for appropriate measures to increase awareness of overuse and support deprescribing where appropriate.

Equine metabolic investigation of the phosphodiesterase-4 inhibitor ibudilast as a potential performance enhancer.

Phosphodiesterase 4 (PDE4) inhibitors are a newer class of drugs that induce bronchodilation and have anti-inflammatory effects, making them susceptible to misuse as performance enhancers in competitive sports. This study explores the metabolic conversion of PDE4 inhibitor ibudilast in thoroughbred horses after oral administration and in vitro using equine liver microsomes and Cunninghamella elegans. A liquid chromatography-high resolution mass spectrometry method was used to postulate the plausible structures of the detected metabolites. A total of 20 in vivo metabolites were identified under experimental conditions, including 12 Phase I and 8 Phase II conjugated metabolites. Phase I metabolites were predominantly formed through hydroxylation (mono-, di-, and tri-hydroxylation). Demethylated metabolites were also identified during this investigation. Additionally, the research detected Phase II metabolites conjugated with glucuronic and sulfonic acids. The data presented here can assist in detecting the PDE4 inhibitor ibudilast and uncover its illicit use in competitive sports.

Abstract C128: Influence of hypertension management on all-cause mortality in a multiethnic cohort of women with metastatic breast cancer

Abstract Purpose: Breast cancer (BC) mortality rates have been declining over time; however, the decline is not consistent across racial/ethnic groups. Prior studies suggest that comorbidities, including hypertension, are associated with treatment delays, increased hospitalizations, and higher mortality in BC patients, but these studies have been limited to women with non-metastatic BC. The influence of common comorbidities on BC mortality, and their contribution to survival disparities in patients with metastatic BC (mBC), remains unknown. We examined the influence of hypertension on all-cause mortality, and if this disparity can be mitigated by better pharmacologic management of hypertension in a diverse cohort. Methods: This longitudinal cohort included 1,332 women diagnosed with de novo mBC between 2008-2020 at Kaiser Permanente Southern California (KPSC). We extracted data on cancer-related variables, sociodemographic, and clinical variables from KPSC’s cancer registry, pharmacy dispensings, and electronic health records. Deaths were identified from in-patient and national death databases. We followed patients electronically from mBC diagnosis until patients died or reached study’s end (12/31/2021), whichever occurred first. We computed person-year rates of all-cause mortality by use of antihypertensive medication (monotherapy [one drug class] or polytherapy [multiple drug classes]). Multivariable Cox regression with time-varying antihypertensive drug use status was used to estimate the association [HR, 95% CI] between overall mortality and use of antihypertensives. Results: The cohort consisted of 46.1% women of color. Overall, 48.4% patients had hypertension at mBC diagnosis, with Black patients (64.5%) having the highest prevalence, followed by White (46.3%), Hispanic (46.1%), and Asian/Pacific Islander (API) patients (42.7%). During follow-up, 52.8% were treated with antihypertensive medications (20.3% received monotherapy; 32.5% polytherapy). Overall mortality rates were lower in those treated with antihypertensive polytherapy (21.3/100 PY) vs. monotherapy (28.50/100 PY). Compared to monotherapy, the percent mortality rate reduction was greater in those treated with polytherapy, particularly in Black patients (35.7% reduction), followed by White (28.7%), Hispanic (15.9%) and API patients (7.60%) (P&amp;lt;0.05). After adjusting for age, SES, cancer treatments, other comorbidities and covariate medications, mortality risk was 44% lower (HR=0.56; 95%CI: 0.43-0.75) among those treated with polytherapy vs. monotherapy; this protection was even greater in Black women (HR=0.43; 0.19-0.97) and Hispanic women (HR=0.47; 0.24-0.95). Conclusion: In women with de novo mBC, hypertension was the most common comorbidity, and highest in Black women. All-cause mortality risk was lower among those treated with polytherapy vs. monotherapy for hypertension, with the greatest attenuation seen amongst Black and Hispanic women. Pharmacologic management of hypertension in women with mBC may potentially help extend life and mitigate mortality disparities. Citation Format: Reina Haque, Amrita Mukherjee, Lie Hong Chen, Tiffany Hogan, Moira Brady-Rogers, Zheng Gu, Ariel Silverman, Lauren P. Wallner. Influence of hypertension management on all-cause mortality in a multiethnic cohort of women with metastatic breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C128.

Abstract C054: Current anticancer drugs differentially impact Black and White prostate cancer cell lines

Abstract Introduction/Background: In pre-clinical models of prostate cancer (PCa) such as the utilization of cell lines, it is important to address the limited diversity present. This acknowledgment is vital to facilitate equitable assessment of the efficacy and safety of drug development across various races and ethnicities. Of all commercially available PCa cell lines, 98% of them are of European origin. The genetic and biological disparities between PCa cell lines derived from men of European ancestry (MEA) and men of African ancestry (MAA) may underlie the observed enhanced responsiveness of tumours to existing anticancer agents in MEA compared to MAA. This difference is notable given that MAA are 2.5 times more likely to succumb to PCa. This study compared the cytotoxic effects of five anticancer drugs (Docetaxel, Cabazitaxel, Abiraterone, Olaparib, Enzalutamide) and the natural product betaine on MAA (ACRJ-PC28, MDA-PCA-2b) and MEA (DU-145, PC-3) PCa cell lines. Method: After a 72-hour treatment with the anti-cancer drugs and the natural product, the inhibitory effects of these anti-cancer agents on the four cell lines were investigated using three different assays. CellTiter Aqueous, Neutral Red, and Crystal Violet assays were utilized due to distinct growth patterns observed in the various cell lines. By comparing the optical density (OD) readings and examining the cellular morphology through microscopic visualization, we aimed to determine which assay(s) yielded the most reliable results in determining accurate IC50 values. Results: Drug selectivity was observed for Abiraterone and Olaparib that were most effective in ACRJ-PC28 (IC50 = 1.10 μM) and PC-3 (IC50 = 0.28 μM) cells compared to the other PCa cell lines. Enzalutamide differentially impacted MAA, (IC50= 206 μM for ACRJ-PC28 and 104 μM for MDA-PCA-2b) and MEA (IC50 = 37 μM for PC-3 and 48 μM for DU-145) PCa cell lines. However, no distinct impact was observed for Docetaxel (IC50s = 0.05 nM for ACRJ-PC28; 0.08 nM for MDA-PCA-2b, 0.07 nM for PC-3 and 0.08 nM for DU-145) and Cabazitaxel ((IC50s = 0.56 nM for ACRJ-PC28; 0.45 nM for MDA-PCA-2b, 0.43 nM for PC-3 and 0.38 nM for DU-145) as both drugs impacted the cell lines very potently in the nM range. Conclusion: Due to the heterogenous nature of cancers, especially in PCa, a single drug or drug class may not be the best course of treatment. Instead, a combination of drugs with different mechanisms may be more suitable for addressing the diversity in cancer types. This points to the evolving understanding of personalized cancer treatment, where a strategic integration of first, second, and third-line therapies can effectively address the genetic and epigenetic factors that are unique to individuals in cancer management. Citation Format: Simone Badal, Bor-Jang Hwang, Ashlianne Nelson, Kristoff Frank, Rory Thompson, Belinda Morison, Valerie Marah, Camille Ragin. Current anticancer drugs differentially impact Black and White prostate cancer cell lines [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C054.

Abstract A075: Racial and ethnic inequities in receipt of degarelix among patients diagnosed with advanced prostate cancer in United States

Abstract Background: Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer among men in the United States (US). Limited data currently exists regarding inequities in access to androgen deprivation therapy (ADT) which is the backbone of systemic treatment in management of advanced CaP. Gonadotropin-releasing hormone (GnRH) antagonists, first approved in 2008, represent a novel class of ADT drugs with faster onset of action and without initial testosterone surge or symptom flare when compared to GnRH agonists. There is also some evidence that GnRH antagonists, compared to GnRH agonists, may be associated with lower cardiovascular complications. Thus, in this study, we assessed inequities in access to GnRH antagonist (degarelix) by examining the associations of race and ethnicity with initiation of this drug among patients diagnosed with distant CaP. Methods: Using the Surveillance, Epidemiology and End Results (SEER) data linked to Medicare fee-for-service (Parts A, B, and D), we identified a cohort of patients, at least 66 years of age, who were diagnosed with distant CaP between 2008 and 2019 with follow-up through 2020. We defined treatment initiation with a GnRH antagonist (degarelix) or GnRH agonists (leuprolide, goserelin, histrelin, or triptorelin) as starting treatment with the study drug within one year after diagnosis. Poisson regression models were used to estimate adjusted rate ratios (aRR) and 95% confidence intervals (CI) for the association between race and ethnicity and degarelix treatment initiation (vs GnRH agonists, no treatment). All models were adjusted for age and Gleason score and compared Non-Hispanic Black (NHB), Hispanic, Non-Hispanic Asian American and Pacific Islander (NHAAPI), and Non-Hispanic American Indian and Alaska Native (NHAIAN) with Non-Hispanic White (NHW) patients. Results: There were 25,277 patients diagnosed with CaP in our analytic cohort, 3,033 (12.0%) initiated degarelix, and 14,045 (55.6%) initiated GnRH agonists over the study period. Mean (SD) age in the study population was 77.8 (7.8). Among all patients, 19,231 (76.1%) were NHW, 3,013 (11.9%) were NHB, 2,075 (8.2%) were Hispanic, 770 (3.0%) were NHAAPI, and 119 (0.5%) were NHAIAN. In the primary analysis, NHB (aRR: 0.58, 95% CI: 0.51-0.66), Hispanic (aRR: 0.59, 95% CI: 0.51-0.69), NHAIAN (aRR: 0.85, 95% CI: 0.49-1.47), and NHAAPI (aRR: 0.75, 95% CI: 0.59-0.94) were less likely to initiate degarelix compared with NHW patients. Discussion: In this US population-based study of patients diagnosed with distant CaP, we observed lower rates of treatment initiation with degarelix among patients of all other racial and ethnic groups compared to NHW patients, which may suggest lower access to these new class of ADT in these groups. Additional research is needed to elucidate health systems, provider, and patient access barriers that contribute to these inequities. Citation Format: Farzin Khosrow-Khavar, Mingchao He, Elizabeth Handorf, Tina Mayer, Thomas Jang, Saum Ghodoussipour, David Golombos, Biren Saraiya, Elisa V. Bandera, Hari S. Iyer. Racial and ethnic inequities in receipt of degarelix among patients diagnosed with advanced prostate cancer in United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A075.

Evaluation of the pharmacokinetics of an experimental combined form of IFNα and IFNγ for intranasal use

Polypous rhinosinusitis is a chronic inflammatory disease of the nasal mucosa and paranasal sinuses. Recombinant interferon has antiproliferative activity and corrects the deficiency of endogenous regulatory molecules, which allows us to consider this class of immunotropic drugs as a promising component of conservative immunotherapy for polyposis rhinosinusitis. Purpose of the study: To select the optimal composition of the experimental composition of interferons and evaluate their pharmacokinetic parameters in laboratory animals.For laboratory evaluation of the effectiveness of the auxiliary components of the proposed composition in creating a local effect, Wistar rats in the amount of 30 animals were selected, to which the proposed form of the drug (IFN1) was administered once intranasally. The control group included 30 animals that were alternately administered intranasally with a similar dose of IFNα2b and IFNγ dissolved in water for injection (IFN2). Quantitative determination of interferon concentration in blood samples was carried out using the enzyme immunoassay method. To assess the dependence of changes in concentrations in the blood of animals on the time elapsed after their administration, standard pharmacokinetic models were used. Next, the integral from the initial moment of time to infinity was determined, which corresponded to the area under the pharmacokinetic curve and made it possible to calculate a number of pharmacokinetic characteristics.The following indicators were obtained: 1) Area under the pharmacokinetic curve (AUCt) ng/ml/min – IFN1 = 683.0; IFN2 = 1707.7. 2) Absorption constant (Kp) – IFN1 = 0.13096; IFN2 = 0.03836. 3) Suction constant (Kel) – IFN1 = 0.00177; IFN2 = 0.00317. 4) Clearance (Cl) ml/min – IFN1 = 129.35; IFN2 = 51.73.Based on the differences in the values of pharmacokinetic parameters (AUCt) for the IFN1 and IFN2 preparations, it can be concluded that the use of a composition based on chitosan, succinic acid and DMSO leads to a pronounced retention of interferon in the nasal mucosa, which provides a pronounced local therapeutic effect and allows for fewer systemic adverse reactions. This composition is suitable for further clinical studies of the effectiveness of immunotherapy for polyposis rhinosinusitis.

Isolation and antimicrobial susceptibility profile of Salmonella species from slaughtered cattle carcasses and abattoir personnel at Dessie, municipality Abattoir, Northeast Ethiopia

BackgroundAntibiotic-resistant Salmonella is one of the main public health concerns in the world. Isolation of Salmonella in abattoirs has been considered the core source of infection in the community from meat. Still, there is limited information on the contamination rate of cattle carcasses.ObjectiveThis study aimed to document the occurrence and antimicrobial susceptibility profile of Salmonella species recovered from cattle carcass and abattoir personnel at Dessie, municipality abattoir, Northeast Ethiopia:MethodsA total of 336 carcass swabs of abdomen, neck, and hind limb from cattle carcasses and 24 stool samples were collected from abattoir personnel using a systematic sampling method from February to April 2019. The collected samples were transported using Cary-Blair transport media and cultivated on Selenite cysteine F-broth, Brilliant green agar, and Xylose-lysine deoxycholate agar plates to isolate Salmonella species. Gram stain, colony morphology, and biochemical tests were performed to identify the isolated bacteria. An antimicrobial susceptibility test for Salmonella was performed using the Kirby-Bauer Disc Diffusion method. Descriptive statistics; both bivariable and multivariable logistic regression analysis was performed using SPSS version 25 software. P-value < 0.05 at 95% CI was considered statistically significant.ResultsThe prevalence of salmonella species was 8%(27/336) from all samples.‘The prevalence of Salmonella isolates in cattle carcass and abattoir personnel was 8%(25/312) and 8.3%(2/24) respectively. The antimicrobial test showed that Salmonella species were 100% resistant to ampicillin, 59.3% to trimethoprim-sulfamethoxazole, 59.3% to tetracycline, and 55.6% to amoxicillin/clavulanate. From the total antimicrobial tested bacteria, 81.5%(22/27) were resistant to three and above classes of antibiotics (drug classes). Unwashed knives, carcasses, and hands of butchers during slaughtering were significantly associated (p < 0.05) with Salmonella found in carcasses.ConclusionsSalmonella isolation rates from cattle carcasses were high, with the bacteria showing notable resistance to most tested antibiotics. Poor hygiene practices, unsanitized equipment, and unhygienic beef processing were contributing factors.

Daily defined dose-costs have a stronger influence on antibacterial drug prescriptions in Germany than bacterial resistance: economic factors are more important than scientific evidence

AbstractPrevious research from our group revealed a strong association between daily defined dose (DDD)-costs and -prescriptions of antibacterial drugs in Germany (https://pubmed.ncbi.nlm.nih.gov/38842562/; https://pubmed.ncbi.nlm.nih.gov/39042156/). These data indicate that low costs are major driver of high prescription numbers. This study examines the relationship between bacterial resistance and DDD-prescriptions of antibacterial drugs using data from the Arzneiverordnungsreport (AVR) from 2008 to 2022 and the Antibiotic Resistance Surveillance (ARS) statistics provided by the Robert Koch Institute (RKI). We hypothesized that semi-rational or irrational prescribing behavior of antibacterial drugs is evident in Germany, i.e., prescriptions are driven to a greater extents by low DDD-costs than bacterial resistance. A bivariate correlation analysis was performed to test these models. Our data point to irrational prescribing behavior for amoxicillin, cefuroxime axetil, doxycycline, nitrofurantoin, ciprofloxacin, and clarithromycin. For amoxicillin clavulanic acid and sulfamethoxazole-trimethoprim, data point to semi-rational prescribing. For no antibacterial drug, a model pointing to rational drug prescribing was found. In conclusion, our study shows that DDD-costs exert a more significant influence on DDD-prescriptions than bacterial resistance, indicating that economic factors, rather than scientific evidence, primarily drive antibacterial drug prescriptions in outpatient settings in Germany. It will be important to conduct similar studies on the prescription of antibacterial drugs in other countries. It will also be important to study the relation between DDD-costs and -prescriptions for other drug classes and assess the scientific basis for these relations.

Unintentional poisoning in older Australians: a retrospective audit of New South Wales Poisons Information Centre data

Introduction Poisons information centres provide phone-based risk assessment and management advice on poisonings. Unintentional poisonings are a common reason for consulting a poisons information centre, and older adults are at increased risk of unintentional poisoning and adverse outcomes. We describe patterns of unintentional poisoning in older adults reported to a regional poisons information centre. Methods We conducted a retrospective audit of poisons information centre call records and identified unintentional poisonings involving older adults (≥75 years) over a 12-month period to determine patient demographics and poisoning circumstances (substances, contributing factors, and disposition recommendation). Univariate analyses identified variables associated with hospital referral and multivariate models to identify independent risk factors in home-dwelling older adults. Results We identified 2,757 calls. More exposures occurred in women (62%) and involved therapeutic errors (70.8%). Paracetamol was the most common drug involved (11%), and cardiovascular drugs were the most common drug class (36%). Only 14.3% of the study population was referred to hospital. Independent risk factors for hospital referral in home-dwelling older adults were exposure to cardiovascular, centrally acting and antihyperglycaemics, non-oral route of administration and symptoms at the time of the call. Discussion Unintentional poisoning is not uncommon, and our findings are similar to those in other countries over recent decades. These findings suggest that unintentional poisoning in older adults is inadequately addressed by current medication safety strategies. Our findings indicate the value of timely advice by poisons information centres for preventing potentially unnecessary hospitalizations. Conclusion Further research is needed to identify more effective approaches to medication safety strategies for older adults. Poisons information centre data contribute to pharmacovigilance activities and could inform patient care.

Macrolide resistance outcomes after the Covid-19 pandemic: A one health approach investigation

During the Covid-19 pandemic period, the indiscriminate use of macrolide-class antibiotics was frequent among the Brazilian population due to the lack of knowledge and information with a scientific basis. Thus, the class of drugs that includes azithromycin, clarithromycin, and erythromycin, which alter metabolic reactions in the body and act on the immune system, was widely used without medical prescription. Samples of bacterial strains from hospital environments were obtained during the most extensive spread of Covid-19 and studied in the present article, emphasizing the investigation for macrolide resistance genes (erm and msr) bacteria of the genus Staphylococcus isolated from urinary tract infections. In addition, the physiological, genetic, immunological, and socio-epidemiological aspects were highlighted with a focus on the One Health approach and implications on the gut-brain axis in this integrative research, revealing that the inappropriate use of antibiotics directly affects entire communities, representing a significant concern for public and environmental health.

Mathematical model of the relationship between pH holding time and erosive esophagitis healing rates.

Effective suppression of gastric acid secretion promotes healing of erosive esophagitis. Treatment guidelines recommend proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs). Emerging evidence also supports potassium-competitive acid blockers (P-CABs). The aim was to construct a mathematical model to examine the relationship between pH holding time ratios (HTRs) and erosive esophagitis healing rates with H2RAs, PPIs and P-CABs. By literature search, we identified studies of H2RAs, PPIs or P-CABs that reported mean pH >4 HTRs at steady state (days 5-8) and erosive esophagitis healing rates after 4 and/or 8 weeks. We aggregated treatments by drug class and developed a non-linear, mixed-effects model to explore the relationship between pH >4 HTRs and healing rates. The pH dataset included 82 studies (4297 participants; 201 dosage arms); healing rate data came from 103 studies (43,417 patients; 196 treatment arms). P-CABs achieved the longest periods with intragastric pH >4, and the highest healing rates after 4 and 8 weeks. The predicted probabilities of achieving ≥90% healing rates at 8 weeks were 74.1% for P-CABs, 17.3% for PPIs and 0% for H2RAs. P-CABs provide the longest duration with intragastric pH >4 and, accordingly, the highest healing rates of erosive esophagitis.

A Phase Ib Study of Linperlisib in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-cell Lymphoma

Abstract Purpose: Relapsed and/or refractory peripheral T-cell lymphoma (r/r PTCL) is an aggressive and heterogeneous hematologic malignancy with high unmet need. Previously, PI3K inhibitors were shown to be efficacious in B- and T-cell lymphomas, but as a drug class, these agents have frequently been observed to have tolerability limitations. Next-generation agents that improve the tolerability while maintaining efficacy are desirable. Patients and Methods: A phase Ib clinical study was conducted with the oral PI3K-delta isoform-selective small-molecule inhibitor, linperlisib, in patients with r/r PTCL, and the clinical benefit was explored by the evaluation of safety and efficacy. Results: In this clinical study, 43 patients with r/r PTCL in China were treated with continuous dosing of 80-mg linperlisib once a day. Treatment-related adverse events (AE) were manageable. The most frequently reported grade 3 AE were neutropenia (21%), pneumonia (11.6%), and hypertriglyceridemia (7%). All other AE were either absent or reported in &amp;lt;5% of the patients. Linperlisib treatment for these patients with r/r PTCL, consisting of the major PTCL subtypes, was observed to have a 60.5% overall response rate with 35% complete responses and led to a median duration of response of 11.1 months, median progression-free survival of 11.8 months, and a median overall survival of &amp;gt;38 months (not reached). Conclusions: With the very promising clinical activity against r/r PTCL, the results of this study support the further investigation of linperlisib for the treatment of r/r PTCL.

High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma

Low grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.

What makes Candida auris pan-drug resistant? Integrative insights from genomic, transcriptomic, and phenomic analysis of clinical strains resistant to all four major classes of antifungal drugs.

The global epidemic of drug-resistant Candida auris continues unabated. The initial report on pan-drug resistant (PDR) C. auris strains in a hospitalized patient in New York was unprecedented. PDR C. auris showed both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine. However, the factors that allow C. auris to acquire pan-drug resistance are not known. Therefore, we conducted a genomic, transcriptomic, and phenomic analysis to better understand PDR C. auris. Among 1,570 genetic variants in drug-resistant C. auris, 299 were unique to PDR strains. The whole-genome sequencing results suggested perturbations in genes associated with nucleotide biosynthesis, mRNA processing, and nuclear export of mRNA. Whole transcriptome sequencing of PDR C. auris revealed two genes to be significantly differentially expressed-a DNA repair protein and DNA replication-dependent chromatin assembly factor 1. Of 59 novel transcripts, 12 transcripts had no known homology. We observed no fitness defects among multi-drug resistant (MDR) and PDR C. auris strains grown in nutrient-deficient or -enriched media at different temperatures. Phenotypic profiling revealed wider adaptability to nitrogenous nutrients and increased utilization of substrates critical in upper glycolysis and tricarboxylic acid cycle. Structural modeling of a 33-amino acid deletion in the gene for uracil phosphoribosyl transferase suggested an alternate route in C. auris to generate uracil monophosphate that does not accommodate 5-fluorouracil as a substrate. Overall, we find evidence of metabolic adaptations in MDR and PDR C. auris in response to antifungal drug lethality without deleterious fitness costs.

Sintilimab plus GemOx is an effective salvage therapy in patients with refractory/relapsing nodal peripheral T cell lymphomas

PurposeThe retrospective study was to explore the effectiveness and safety of GemOx (gemcitabine, oxaliplatin) plus sintilimab (belongs to the class of drugs known as immune checkpoint inhibitors, particularly targeting the PD-1 receptor) in relapse or refractory nodal PTCLs.MethodsPatients with nodal PTCL who initiated salvage therapy with sintilimab and GemOx between January 2020 to September 2021 were identified from the database of the hematology department of the Second Affiliated Hospital of Zhejiang University School of Medicine. All patients received 2–4 cycles (3 weeks/cycle) of treatment of sintilimab (200 mg, I.V, D1) in combination with GemOx. Treatment response was assessed every six weeks during the salvage treatment phase. Eligible patients received maintenance therapy according to the investigator’s decision. Follow-ups were routinely conducted every three months.Results31 patients with r/r nodal PTCLs were enrolled, including 23 PTCL-NOS, 4 AITL, and 4 ALCL. 21 (67.7%) patients received at least two lines of therapy. 71.0% (95% CI, 53.4%-83.9%) of patients documented objective response of 2–4 cycles of sintilimab plus GemOx therapy, including 9 complete response and 13 partial response. 21 (67.7%) patients received consolidation therapy, including 5 autologous stem-cell transplantation and 12 histone deacetylase inhibitors. After a median 25.6 months follow-up, the median PFS was 22.0 (95% CI,11.8–24.7) months, and the median OS was 26.2 (95% CI, 24.4 –NA) months. 29 (93.5%) patients experienced at least one adverse event, and 26 (83.9% patients only had mild (grade 1–2) AEs.Univariable Cox regression showed the progression risk of AITL is 22.7 (3.9- 131.0, p < 0.01) times of PTCL-NOS, while the HR of ALCL was 1.14 (0.33–3.96,p = 0.833).ConclusionSintilimab plus GemOx showed encouraging activity and manageable toxicity for patients with r/r PTCL.

Investigating drug-induced urinary retention: a pharmacovigilance analysis of FDA adverse event reports from 2004 to 2024

ABSTRACT Background Drug-induced urinary retention (DIUR) can severely impact patient quality of life and complicate treatment. This study investigates the incidence and characteristics of DIUR using data from the FDA Adverse Event Reporting System (FAERS) over 20 years. Methods FAERS reports related to urinary retention (UR) from Q1 2004 to Q1 2024 were analyzed. Potential causative drugs were identified, and the top 30 drugs with the most UR reports were ranked. Statistical disproportionality analyses, including Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were conducted to detect significant safety signals. Results Out of 17,703,515 reports in the FAERS database 28,423 cases of UR were identified. Anticholinergics, antidepressants, and opioids were the most frequently implicated drug classes. The highest ROR and PRR values were observed for drugs like ezogabine. Additionally, less commonly associated drugs, such as adalimumab and others, were implicated, suggesting potential under-recognition of this adverse effect. However, these associations should be interpreted with caution, as they do not confirm a direct causal relationship. Conclusion This study underscores the importance of pharmacovigilance in identifying and understanding DIUR. Further research is needed to confirm these findings and develop strategies to manage and reduce the risk, improving patient outcomes.

Update on Sodium Glucose Cotransporter Type 2 Inhibitors Use in Kidney Transplant Patients

Sodium glucose cotransporter type 2 inhibitors are a new class of drugs that act on the cardiovascular system, kidneys and metabolism in a multiple ways. Indeed, even though their principal action involves the transport of sodium and glucose in the convoluted distal tubule, they have multiple actions, such as antifibrotic and endothelial protective effects. Their principal mechanism consists of the loss of sodium and glucose. Therefore, they affect blood pressure and glucose metabolism. Their first use was in the diabetic general population; later, some studies documented their activity in the nondiabetic general population and in heart failure in chronic kidney disease patients. Only in recent years have several small studies documented the efficacy of these drugs in diabetic and nondiabetic kidney transplant patients; relatively large studies are rare, very recent, and open new routes for the development of these drugs.