Specific Drug Classes Research Articles

The pattern of reported adverse drug reactions with reference to specific drug class and organ system

Background: Adverse drug reactions (ADRs) represent a major public health problem. The overall ADR rate is estimated to be 6.5 and 28% of these are preventable.ADR incidence in Indian population ranges between 1.8-25% with 8% resulting in hospitalization. Hence, the present study was undertaken to study the pattern of reported adverse drug reactions with reference to specific drug class and organ system in a tertiary care hospital.Methods: A cross-sectional retrospective study was carried to analyse the ADRs reported over a period of one year (January-December 2019). Individual case safety reports (ICSRs) of all patients of suspected adverse drug reactions seen in various out-patient departments and admitted in the wards of the hospital were included in the study. The ICSRs were analysed for patient demography, causality, severity and with reference to specific drug class and organ system.Results: Among 382 reported ADRs, 27.2% of the ADRs were reported as serious. The most common therapeutic class of drugs causing ADRs where Antimicrobial agents (36.07%). The skin is the most common affected organ system (25.39%).Conclusions: A coordinated system of identifying the ADRs early in the course of treatment and recognizing the preventable ADRs is required by the health care system. The coordination of prescribing physicians and pharmacovigilance personnel can produce better trend of reporting the ADRs.

Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease

Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child. Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest. Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n= 242), biologics (n= 642), or both (n= 227) vs unexposed (n= 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51). Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.

Poly-prescription drug misuse across the life course: Prevalence and correlates across different adult age cohorts in the U.S.

Most research on prescription drug misuse (PDM) focuses on the misuse of specific classes of psychoactive prescription drugs among adolescents or young adults. The current research addressed important gaps in the literature by assessing poly-prescription drug misuse (poly-PDM), the misuse of more than one class of psychoactive prescription drug, across different adult age cohorts. We used the 2015-2018 National Survey on Drug Use and Health to examine the prevalence of past-year poly-PDM and specific combinations of PDM. Multinomial logistic regression was used to identify demographic, health-related factors, and substance use behaviors that were significantly associated with poly-PDM. The prevalence of poly-PDM decreases with age and is common among individuals who engage in PDM. Slightly more than one in four respondents in age cohorts 18-25 (31.66%, 95% CI=30.35, 33.00) and 26-34 (29.92%, 95% CI=25.82, 30.12) who engage in PDM, misused more than one class of prescription drug. Additionally, poly-PDM was identified as a high-risk type of PDM as roughly 60% of adults younger than 65 who endorse poly-PDM reported having a substance use disorder (SUD). While certain characteristics (i.e., race/ethnicity, marital status, depression, suicidal ideation, illegal drug use, and SUD) were consistently associated with poly-PDM across age cohorts, other characteristics (i.e., sexual identity, income, and justice involvement) varied across age cohorts. Finally, a comparison of poly-PDM to single PDM showed, in all age cohorts, that having an SUD was associated with an increased likelihood of poly-PDM, while Black adults were less likely than whites to report poly-PDM. By identifying prevalence and correlates of poly-PDM across adult age cohorts, the current research has significant implications. Understanding stability and heterogeneity in the characteristics associated with poly-PDM should inform interventions, identify at-risk groups, and shape public health approaches to dealing with high-risk substance use behavior.

Correlating Clinical and Genomic Features with Ex Vivo Drug Sensitivity in Patients with Myelodysplastic Syndromes and Related Myeloid Neoplasms

Background Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms characterized by ineffective hematopoiesis, dysplasia, cytopenias, and a variable risk of progression to acute myeloid leukemia (AML). The biologic heterogeneity of MDS and related myeloid neoplasms relates to the genomic complexity of these disorders with different combinations of cytogenetic abnormalities and mutations associated with distinct clinical phenotypes. Ex vivo drug sensitivity screening (DSS) is a promising tool that may inform personalized therapy in MDS, particularly in patients refractory to standard therapies such as hypomethylating agents (HMAs). We report our updated experience using a fully automated ex vivo DSS platform in 64 patients with MDS and related myeloid neoplasms and identify correlations between clinical and genomic features and ex vivo drug sensitivity. Methods Patients: Patients were evaluated at the Stanford MDS Center between September 2016 and May 2020 and had a diagnosis of MDS, MDS/MPN, or secondary AML. Bone marrow (BM) aspirate and peripheral blood (PB) samples were procured for mutation testing (164-gene panel) and ex vivo DSS (Notable Labs, Foster City, CA). Ex vivo DSS: Fresh BM aspirate and PB specimens were RBC-lysed and resuspended in serum-free media with cytokines as previously described (Spinner et al, Blood Adv 2020;4(12):2768-78). Samples were plated in 384-well microtiter plates and screened against a collection of up to 74 drugs and 36 drug combinations in triplicate. Specimens were treated for 72 hours and assayed using high-throughput, multi-parametic flow cytometry, gating on the blast population (expressing CD34, CD33, and/or HLA-DR) to assess for blast viability. Patient clustering & statistical analysis: The Euclidean distance metric and Ward minimum variance method were used to identify patient clusters with distinct ex vivo drug sensitivity patterns. A 1-way repeated measures ANOVA was used to identify drug classes with variable sensitivity across clusters and to identify associations between clusters and clinical variables, including blast count, mutations and cytogenetic groups, IPSS-R risk group, and prior HMA exposure. A generalized estimation equation model was used to identify associations between mutations and ex vivo drug sensitivity. Results Ex vivo DSS was performed in 64 patients with myeloid neoplasms including 43 with MDS (67%), 11 with MDS/MPNs (17%), and 10 with secondary AML (16%). The median age was 75 years (range 23-90) and 78% were male. The majority of patients had higher risk disease with IPSS-R >3.5 (66%), excess blasts (58%), and adverse cytogenetics or mutations (53%) by IPSS-R or the ELN classification. Patients had a median of 2 pathogenic mutations (range 0-7), with the most frequent including TET2, ASXL1, DNMT3A, SF3B1, RUNX1, STAG2, SRSF2, NRAS, KRAS, BCOR, TP53, and EZH2. The majority of patients (64%) had prior HMA exposure. Ex vivo DSS defined three distinct patient clusters with differential sensitivity to numerous drug classes (Figure 1). Cluster 1 (N=13) demonstrated the greatest ex vivo sensitivity to HMAs, HMA/venetoclax combinations, cytotoxic agents, kinase inhibitors, mTOR inhibitors, HDAC inhibitors, and PARP inhibitors, while cluster 3 (N=19) demonstrated the greatest ex vivo resistance (p<0.0001 for all comparisons). Correlating clinical variables with drug sensitivity clusters, only IPSS-R score differed significantly among clusters, with fewer higher risk patients in cluster 3 (p=0.02). Correlating specific mutations with ex vivo drug sensitivity, STAG2 mutations were associated with greater ex vivo sensitivity to HMAs (p=0.002), HMA/venetoclax combinations (p=0.003), kinase inhibitors (p=0.002), and PARP inhibitors (p=0.003). TP53 mutations were associated with greater ex vivo sensitivity to proteasome inhibitors (p=0.0002). Conclusions Ex vivo DSS defined distinct patient clusters with differential sensitivity to numerous drug classes. Specific mutations, such as STAG2 and TP53, were associated with greater ex vivo sensitivity to specific drug classes. A larger sample size is needed to evaluate combinations of mutations and better define associations between genotype and drug sensitivity phenotype. Ultimately, combining both genomics and functional screening may further refine personalized therapy selection for patients with MDS and related myeloid neoplasms. Figure Disclosures Spinner: Notable Labs: Honoraria. Schaffert:Notable Labs: Current Employment. Aleshin:Notable Labs: Consultancy. Santaguida:Notable Labs: Current Employment. Tada:Notable Labs: Current Employment, Current equity holder in private company. Greenberg:BMS: Research Funding; Aprea: Research Funding; H3 Biotech: Research Funding; Notable Labs: Research Funding.

MEK is a promising target in the basal subtype of bladder cancer.

While many resources exist for the drug screening of bladder cancer cell lines in 2D culture, it is widely recognized that screening in 3D culture is more representative of in vivo response. Importantly, signaling changes between 2D and 3D culture can result in changes to drug response. To address the need for 3D drug screening of bladder cancer cell lines, we screened 17 bladder cancer cell lines using a library of 652 investigational small-molecules and 3 clinically relevant drug combinations in 3D cell culture. Our goal was to identify compounds and classes of compounds with efficacy in bladder cancer. Utilizing established genomic and transcriptomic data for these bladder cancer cell lines, we correlated the genomic molecular parameters with drug response, to identify potentially novel groups of tumors that are vulnerable to specific drugs or classes of drugs. Importantly, we demonstrate that MEK inhibitors are a promising targeted therapy for the basal subtype of bladder cancer, and our data indicate that drug screening of 3D cultures provides an important resource for hypothesis generation.

Effectiveness of personalized selection of antihypertensive therapy based on genetic polymorphism

Abstract Recent data indicate that it is important to develop the problem of genetic polymorphism in patients with arterial hypertension (AH) for the long-term possibility of using it as a justification for choosing the optimal treatment strategy. Currently, despite the availability of effective antihypertensive agents, the percentage of patients who have reached the target blood pressure level remains still not enough. A rational basis for choosing a particular class of drugs and / or their combinations in a concrete patient with AH can be the detection of genetic markers that determine the degree of sensitivity to therapy, since the relationship of its effectiveness with the genetic features is not in doubt today. Material and methods The work is based on the results of a clinical, instrumental, laboratory and genetic examination of 41 patients with AH with insufficient effectiveness of previous antihypertensive therapy. The median age and duration of the disease were 54 (32; 70) years and 7 (1; 20) years, respectively. Taking into account the identified gene polymorphism, a fixed combination of an ACE inhibitor (perindopril 10 mg) and a thiazide-like diuretic (indapamide 2.5 mg) was assigned. The comparative dynamics of blood pressure daily monitoring, left ventricle echocardiographic parameters, as well as indicators of vascular wall stiffness were analyzed before therapy and 3 months later. Results The study established a relationship between the clinical and morpho-functional features of AH in the examined patients with polymorphism of the AGT, AGTR2, CYP11B2, GNB3, NOS3 genes:-786 of their heterozygotes and “mutant” homozygotes, of which 3 polymorphic genes (AGT, AGTR2, CYP11B2) encode the activity of ACE. The obtained results allowed to establish that positive dynamics of the studied indicators was revealed in all patients. Though patients, carriers of the mutant allele C of polymorphic marker T704C AGT gene, had statistically significant more expressed benefit changes in blood pressure daily profile, echocardiographic parameters (such as left ventricular mass index, indicators of left ventricular diastolic function) and all parameters of arterial wall stiffness compared with patients who do not carry the “mutant” allele. Conclusion Thus, the selected treatment regimen demonstrated maximum antihypertensive, cardio - and vasoprotective effectiveness in the group of AH patients with the presence of the allele 704C of the polymorphic marker T704C of the AGT gene, which indicates the perspectivity of using genetic approaches to develop personalized tactics of AH patients drug treatment. Funding Acknowledgement Type of funding source: None

Blood pressure lowering treatment for prevention of cardiovascular events in patients with atrial fibrillation: an individual-participant data meta-analysis

Abstract Background Randomised evidence showing that pharmacological blood pressure (BP) lowering can reduce cardiovascular risk of patients with atrial fibrillation (AF) is limited. Purpose This study aimed to compare the effect of BP-lowering treatment on fatal and non-fatal cardiovascular outcomes in patients with and without AF overall and by major drug classes. Methods We extracted individual participant data from all trials with over 1,000 person-years of follow-up that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs vs placebo, or to more vs less intensive BP-lowering regimens. We investigated the effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline using fixed-effect one-stage individual participant data meta-analyses based on Cox proportional hazards models stratified by trial. Findings Twenty-two trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Patients with AF had lower BP at baseline than patients without AF (143/84 mmHg, SD 21/12mmHg) versus 155/88 mmHg, SD 21/13 mmHg, respectively). Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering, both in patients with and without AF. The hazard ratio for major cardiovascular events was 0.91 in patients with AF (95% confidence interval [0.83–1.00]) and 0.91 without AF (95% confidence interval [0.88–0.93]) for each 5-mmHg reduction in systolic BP, with no difference between subgroups (p=0.91) (Figure 1). Similar patterns were observed for individual components of the composite primary outcome. In patients with AF, there was no evidence that treatment effects varied according to baseline systolic BP or use of specific drug classes. Conclusion This study demonstrated that BP-lowering treatment reduces the risk of major cardiovascular events in patients with AF to a similar extent to that of patients without AF, even when baseline BP is below recommended treatment thresholds. Owing to their higher absolute cardiovascular risk, treatment in patients with AF is likely to result in greater absolute risk reduction than in patients without AF. Guidelines should be updated to clearly recommend pharmacological BP lowering for prevention of cardiovascular events in patients with AF. Figure 1. Forest plot Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Porównanie pośrednie wyników leczenia chorych na zaawansowane/przerzutowe czerniaki za pomocą niwolumabu lub pembrolizumabu – analiza wieloośrodkowa

Introduction. The development of a new class of drug — checkpoint inhibitors has changed the prognosis of cancer patients. A particular class of drugs are antibodies against the programmed cell death type 1 receptor/ligand of the programmed cell death type 1 receptor (nivolumab and pembrolizumab). There are, however, no trials with a random selection of the patients which directly compare nivolumab and pembrolizumab. Because of the development of immunotherapy and many new drugs registered as anti-PD-1, it is important to determine whether there are differences in respect to effectiveness and safety in using nivolumab and pembrolizumab. Material and method. 499 patients with non-resectable or metastatic melanoma treated in the years 2016–2019 in five oncological reference centers in Poland (Cracow, Gliwice, Lublin, Poznań, Wrocław) were included in the analysis. The criterion for inclusion in the analysis was first-line treatment with anti-PD-1 (nivolumab or pembrolizumab). Results. Median OS and PFS in the whole analyzed group were 19.9 and 7.9 months, respectively. Estimated median OS and PFS were 20.1 and 18.1 months and 8.5 and 6.0 months for nivolumab and pembrolizumab, respectively. No statistically significant difference was observed in median OS and PFS in the group of patients receiving nivolumab and pembrolizumab (respectively P = 0.6291 [HR = 1.06; Cl 95% 0.8–1.4] and P = 0.0956 [HR = 1.20; Cl 95% 0.97–1.48]). The percentage of grade G3 or/and G4 irAEs was similar in both groups treated with nivolumab or pembrolizumab, 5.8 and 5.2%, respectively. Conclusions. No differences in the range of OS, PFS and ORR was observed between therapy with nivolumab and pembrolizumab in previously untreated patients with advanced/metastatic melanoma. No differences were found in the frequency of irAEs of grade G3 or G4. The treatment with a specific preparation should be based on the preferences of the patient and the clinician.

A Review on Drug-Induced Nephrotoxicity: Pathophysiological Mechanisms, Drug Classes, Clinical Management, and Recent Advances in Mathematical Modeling and Simulation Approaches.

A variety of marketed drugs belonging to various therapeutic classes are known to cause nephrotoxicity. Nephrotoxicity can manifest itself in several forms depending on the specific site involved as well as the underlying pathophysiological mechanisms. As they often coexist with other pathophysiological conditions, the steps that can be taken to treat them are often limited. Thus, drug-induced nephrotoxicity remains a major clinical challenge. Prior knowledge of risk factors associated with special patient populations and specific classes of drugs, combined with early diagnosis, therapeutic drug monitoring with dose adjustments, as well as timely prospective treatments are essential to prevent and manage them better. Most incident drug-induced renal toxicity is reversible only if diagnosed at an early stage and treated promptly. Hence, diagnosis at an early stage is the need of the hour to counter it. Significant recent advances in the identification of novel early biomarkers of nephrotoxicity are not beyond limitations. In such a scenario, mathematical modeling and simulation (M&S) approaches may help to better understand and predict toxicities in a clinical setting. This review summarizes pathophysiological mechanisms of drug-induced nephrotoxicity, classes of nephrotoxic drugs, management, prevention, and diagnosis in clinics. Finally, it also highlights some of the recent advancements in mathematical M&S approaches that could be used to better understand and predict drug-induced nephrotoxicity.

Economic burden and risk factors of migraine disease progression in the US: a retrospective analysis of a commercial payer database

Aims To evaluate the prevalence and risk factors of migraine progression and to assess the incremental burden of migraine progression on healthcare systems. Materials and methods Adult patients were required to have a migraine diagnosis in IQVIA’s US adjudicated claims database between 1 January 2012 and 30 June 2016, continuous enrollment ≥12 months before and after the index date (i.e. the first observed migraine diagnosis), and ≥1 additional migraine diagnosis claim during the 12-month post-index period. A previously-developed algorithm identified patients with prevention-eligible episodic migraine (EM). All-cause healthcare resource utilization (HCRU) and costs were evaluated at baseline, over the follow-up period and pre/post progression from prevention-eligible EM to chronic migraine. Cox proportional hazards models were used to evaluate risk factors associated with progression. Results, limitations, and conclusions Of the 125,436 patients with prevention-eligible EM that were initially identified, 5,790 (4.6%) were further identified as progressed. Patients who progressed had higher healthcare costs and higher medication use at baseline compared to patients that did not progress. Mean (SD) all-cause total costs per patient per month were $1,790 ($3,788), significantly higher in the post-progression period compared to $1,414 ($2,456) in the pre-progression period in patients who progressed (p < .0001). Younger age, female sex, initial diagnosis by a neurologist, chronic pain, and use of triptans and/or non-specific acute medications were all significant progression risk factors. Results are limited by the use of a heterogeneous population (incident, prevalent, treated, and untreated patients), coding biases, and lack of information on non-prescription drug utilization and plan limits. Limitations aside, there are substantial HCRU and cost burden associated with migraine progression. Younger age, female sex, and the use of specific drug classes are likely to increase migraine disease progression risk.

Abstract 1847: Phenotypic evaluation and discrimination of clinical JAK inhibitors for myeloproliferative disorders

Abstract Small molecule inhibitors of Janus kinases (Jakinibs) represent a promising treatment for myeloproliferative disorders including polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF). Currently multiple JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, baricitinib) are either approved or in clinical development for the treatment of MF. The primary target of Jakinibs, the JAK-STAT pathway, plays a critical role in multiple cellular processes relevant for myelofibrosis, including survival, differentiation, and proliferation. However, all approved Jakinibs are reportedly promiscuous in that they inhibit kinases beyond the JAK family. Their overall clinical impact, therefore, reflects the sum of these target activities, as well as downstream secondary pharmacology relevant to both efficacy and safety. We evaluated these four Jakinibs using phenotypic profiling with the BioMAP® Diversity PLUS Panel to identify common versus differential activities. The BioMAP platform consists of human primary cell-based assay or systems designed to recapitulate key aspects of tissue and disease states. Distinct activity profiles were generated for each of the tested Jakinibs based on their impacts on 148 different biomarkers in 12 different model systems. Comparison of these profiles at concentrations relevant for clinical exposure levels revealed common activities including inhibition of T and B cell proliferation and decreased levels of inflammation and immune activation biomarkers. Together these activities represent a phenotypic signature related to shared primary JAK targets. In contrast, multiple differentiating activities were observed between the four drug profiles: baricitinib increased TNFα levels whereas momelotinib decreased TNFα in the LPS system modeling monocyte activation; fedratinib and momelotinib, but not ruxolitinib or baricitinib, inhibited endothelial cell proliferation; only momelotinib inhibited macrophage responses and decreased PGE2 levels. These data indicate that even within the specific JAK2 inhibitor drug class, individual entities have distinct modes of action relevant for clinical outcomes. Citation Format: Sharlene Velichko, Sheryl P. Denker, Alison O'Mahony. Phenotypic evaluation and discrimination of clinical JAK inhibitors for myeloproliferative disorders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1847.

Influence of Solid Lipid Nanoparticles on Pharmaco-dynamic Activity of Poorly Oral Bioavailable Drugs

In the recent scenario, lipid nanoparticles gain much attention on the oral absorption of drugs to enhance therapeutic effectiveness after oral administration. Pharmacodynamic activity of drug mainly describes the pharmacological and therapeutic activity of drug to the biological system. Lipid nanoparticles especially solid lipid nanoparticles are made of physiological inert lipid molecules and promotes the lymphatic transport. Abundant literature is available on the effect of lipid nanoparticles and other colloidal carrier systems on the pharmacokinetic parameters of poorly bioavailable drugs, to improve their oral absorption and also respective mechanisms for the improved oral bioavailability. However, little literature is reported on the pharmacodynamic activity and the effect of dose on the pharmacodynamic activity. It is of paramount importance to assess the influence of lipid nanoparticles on pharmacotherapeutic actions of specific drug classes. Therefore, current review is mainly focused on the role of solid lipid nanoparticles on the pharmacodynamic action and advantages of the developed delivery systems with respect to pharmacodynamic activity.

Ex vivo modelling of drug efficacy in a rare metastatic urachal carcinoma

BackgroundEx vivo drug screening refers to the out-of-body assessment of drug efficacy in patient derived vital tumor cells. The purpose of these methods is to enable functional testing of patient specific efficacy of anti-cancer therapeutics and personalized treatment strategies. Such approaches could prove powerful especially in context of rare cancers for which demonstration of novel therapies is difficult due to the low numbers of patients. Here, we report comparison of different ex vivo drug screening methods in a metastatic urachal adenocarcinoma, a rare and aggressive non-urothelial bladder malignancy that arises from the remnant embryologic urachus in adults.MethodsTo compare the feasibility and results obtained with alternative ex vivo drug screening techniques, we used three different approaches; enzymatic cell viability assay of 2D cell cultures and image-based cytometry of 2D and 3D cell cultures in parallel. Vital tumor cells isolated from a biopsy obtained in context of a surgical debulking procedure were used for screening of 1160 drugs with the aim to evaluate patterns of efficacy in the urachal cancer cells.ResultsDose response data from the enzymatic cell viability assay and the image-based assay of 2D cell cultures showed the best consistency. With 3D cell culture conditions, the proliferation rate of the tumor cells was slower and potency of several drugs was reduced even following growth rate normalization of the responses. MEK, mTOR, and MET inhibitors were identified as the most cytotoxic targeted drugs. Secondary validation analyses confirmed the efficacy of these drugs also with the new human urachal adenocarcinoma cell line (MISB18) established from the patient’s tumor.ConclusionsAll the tested ex vivo drug screening methods captured the patient’s tumor cells’ sensitivity to drugs that could be associated with the oncogenic KRASG12V mutation found in the patient’s tumor cells. Specific drug classes however resulted in differential dose response profiles dependent on the used cell culture method indicating that the choice of assay could bias results from ex vivo drug screening assays for selected drug classes.

Antiretroviral therapy in older people with HIV.

The age of people with HIV) continues to rise, and yet older people have tended to be under-represented or excluded from premarketing studies of antiretroviral therapy (ART). In this review, we highlight special considerations for the use of ART in older people with HIV, with a focus on toxicities associated with specific antiretroviral agents or drug classes as well as key research questions moving forward. Like all people with HIV, older people with HIV should be started on ART as soon as possible, regardless of CD4 count, and with a regimen that includes an integrase strand transfer inhibitor (INSTI) and two nucleoside reverse transcriptase inhibitors. Important toxicities to consider when choosing an ART regimen include bone and renal effects related to tenofovir, weight gain related to INSTIs and tenofovir alafenamide, neurocognitive and neuropsychiatric toxicities related to efavirenz, and increased cardiovascular risk associated with abacavir and boosted protease inhibitors. With the ongoing importance of INSTIs as a component of preferred ART regimens, further characterization of INSTI-related weight gain is a critical current research priority in understanding ART toxicity. There are multiple potential toxicities of ART to consider when selecting a regimen for older people. Specific agents or drug classes have been implicated in adverse bone or renal effects, weight gain, neuropsychiatric and neurocognitive effects, and cardiovascular risk.

Is drug consumption correlated with benign paroxysmal positional vertigo (BPPV) recurrence?

Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vertigo and its recurrence is fairly common. Several studies correlated the pathophysiological role of different comorbidities-such as diabetes, osteoporosis, vascular, psychiatric and autoimmune diseases-in the development and recurrence of BPPV. The aim of this study is to analyse the pharmacological history of patients with idiopathic BPPV in relation to the risk of developing recurrence. Data regarding 715 patients aged 12 to 87years (62.7 ± 14) with non-traumatic BPPV were retrospectively evaluated. These refer to the Vestibular Service, day clinic, and were collected over a 4-year period, between 2014 and 2018. Recurrence of BPPV was observed in 220/715 patients (30.76%). A statistically significant correlation (p < 0.006) between recurrence and drug consumption was observed for SNC agents (p = 0.0001), vitamin D (p = 0.0005), PPI (p = 0.0007), thyroid hormones (p = 0.0011), and antihypertensives in single use (p = 0.0031). On the contrary, cholesterol-lowering statin drugs, hypoglycaemic agents, antiplatelet medication, estroprogestins and combination of two or more antihypertensives did not show significant correlation. Specific classes of drugs are significantly associated with recurrence: antihypertensive therapy with a singular agent, central nervous system agents, PPIs, vitamin D and thyroid hormones. On the other hand, the lack of correlation between some drugs and recurrence could be linked to the effectiveness of therapy in controlling hypertension, dyslipidaemia and diabetes. Pharmacological history is an essential tool to identify patients at risk of BPPV recurrence.

The use of antipsychotic agents during pregnancy and the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

Previous studies have found contradicting results with regard to the use of antipsychotics during pregnancy and the risk of gestational diabetes mellitus (GDM). We aimed to evaluate the association between antipsychotic use in pregnancy and GDM. A systematic literature search was conducted in PubMed, EMBASE, PsycINFO and Cochrane Library databases up to March 2019, for data from observational studies assessing the association between gestational antipsychotic use and GDM. Non-English studies, animal studies, case reports, conference abstracts, book chapters, reviews and summaries were excluded. The primary outcome was GDM. Estimates were pooled using a random effect model, with the I2 statistic used to estimate heterogeneity of results. Our study protocol was registered with PROSPERO number: CRD42018095014. In total 10 cohort studies met the inclusion criteria in our systematic review with 6642 exposed and 1 860 290 unexposed pregnancies. Six studies were included in the meta-analysis with a pooled adjusted relative risk of 1.24 overall [95% confidence interval (CI) 1.09-1.42]. The I2 result suggested low heterogeneity between studies (I2 = 6.7%, p = 0.373). We found that the use of antipsychotic medications during pregnancy is associated with an increased risk of GDM in mothers. However, the evidence is still insufficient, especially for specific drug classes. We recommend more studies to investigate this association for specific drug classes, dosages and comorbidities to help clinicians to manage the risk of GDM if initiation or continuation of antipsychotic prescriptions during pregnancy is needed.

Gastric acid inhibitor aggravates indomethacin-induced small intestinal injury via reducing Lactobacillus johnsonii

Proton pump inhibitors (PPIs) alter the composition of the intestinal microbiome, exacerbating indomethacin (IND)-induced small intestinal damage. Vonoprazan fumarate inhibits gastric acid secretion using a different mechanism from PPIs. We investigated the effects of both drugs on the intestinal microbiome and IND-induced small intestinal damage. We sought to clarify whether PPI-induced dysbiosis and worsening of the damage were due to a specific drug class effect of PPIs. Rabeprazole administration increased operational taxonomic unit numbers in the small intestines of C57BL/6 J mice, whereas the difference was not significant in the vonoprazan-treated group but exhibited a trend. Permutational multivariate analysis of variance of the unweighted UniFrac distances showed significant differences between vehicle- and vonoprazan- or rabeprazole-treated groups. L. johnsonii was the predominant microbial species, and the population ratio decreased after vonoprazan and rabeprazole administration. The vonoprazan- and rabeprazole-treated groups showed increased IND-induced damage. This high sensitivity to IND-induced damage was evaluated by transplantation with contents from the small intestine of mice treated with either vonoprazan or rabeprazole. Supplementation of L. johnsonii orally in mice treated with rabeprazole and vonoprazan prevented the increase in IND-induced small intestinal damage. In conclusion, both rabeprazole and vonoprazan aggravated NSAID-induced small intestinal injury by reducing the population of L. johnsonii in the small intestine via suppressing gastric acid secretion.

Multi-parametric analysis of ciprofloxacin toxicity at ecologically relevant levels: Short- and long-term effects on Daphnia magna

The increased presence of emergent compounds, such as pharmaceuticals drugs, in the aquatic compartment has been acknowledged as an evolving environmental issue whose consequences are not yet fully characterized. Specific classes of pharmaceutical drugs, such as fluoroquinolone antibiotics, can exert toxic effects to non-target species with ecological significance, since these compounds are environmentally stable and persistent, and may interact with some of the key physiologic processes of organisms. Despite such characteristics, knowledge about the effects of these drugs is still scarce, especially to non-target organisms. The present study aimed to evaluate the effects of chronic and acute exposures of the cladoceran Daphnia magna to the fluoroquinolone antibiotic ciprofloxacin. Putative toxic effects were assessed, following acute and chronic exposures to ecologically relevant concentrations of ciprofloxacin, through enzymatic (cholinesterase – ChEs, catalase – CAT, glutathione S-transferases – GSTs) and non-enzymatic (thiobarbituric acid reactive substances – TBARS, glycogen – Gly) biomarkers. In addition, we also determined behavioural (swimming distance – SD) and morphological (body length of the first brood – BL1B) endpoints in animals exposed to this drug. Ciprofloxacin acute exposure resulted in increased CAT and ChEs activities, and inhibited GSTs activity. After chronic exposure, ChEs activity was significantly inhibited, while GSTs activity was significantly enhanced. TBARS levels were only increased at higher concentrations of ciprofloxacin. CAT activity and Gly content did not evidence a clear and significant pattern of variation. SD was slightly inhibited during dark cycles. BL1B presented a significant decrease for animals subjected to an intermediate concentration. Results showed that even ecologically relevant concentrations of ciprofloxacin may cause oxidative stress in individuals of D. magna. The present study showed important data that corroborate the occurrence of significant biochemical alterations in key features of an aquatic organism when exposed to relevant levels of a widely used antibiotic, establishing essential links between environmental exposure to this specific drug and putative toxic challenges that may result in irreversible changes and damages, especially at the individual level. However, changes in the size of neonates suggest that population alterations are likely to occur under real scenarios of chronic contamination by this drug.

Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies

Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia. We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses. Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease. Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia. The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.

1729. Profiling Human Neutrophil Functional Responses From Solid-Organ and Stem Cell Transplant Recipients to Candida albicans

BackgroundSolid-organ (SOT) and stem cell transplant (SCT) recipients are at increased risk of invasive fungal disease despite normal neutrophil counts in peripheral blood. However, the neutrophils function against fungi has not been completely defined. In this study, we measure human neutrophil anti-candida activity in SOT and SCT recipients.MethodsSOT and SCT patients were identified and consented from September 2018 until April 2019. Healthy control patients (HC) were identified at primary care clinics. EDTA-anticoagulated peripheral blood was obtained from healthy and transplant patients 2–4 months post-transplant. Neutrophils were isolated by negative selection. C. albicans was incubated for 2 hours with and without human neutrophils at multiplicity of infection (MOI) of 10, 5 and 1. Following neutrophil cell lysis, percent remaining live Candida was measured using a viability dye. In addition, growth inhibition of C. albicans by neutrophil swarming to C. albicans spotted onto glass slide arrays was also assessed by live cell imaging.Results22 SOT (15 kidneys, 7 livers), 20 SCT (allograft) and 22 HC were enrolled. Neutrophils from SCT and SOT had lower C. albicans killing percentages compared with HC at MOI 10 (HC: 47%, SOT: 29%, SCT 24% P = 0.0041); MOI 5 (HC: 72%, SOT: 35%, SCT 38% P < 0.0001) and MOI 1 (HC: 91%, SOT: 48%, SCT: 45% P < 0.0001). Neutrophil swarming and fungal control of C. albicans spots was significantly inhibited by neutrophils from SCT when compared with SOT and controls (P <0.0001). Analysis of medications, including tyrosine kinase inhibitor (TKI) use, did not demonstrate significant differences of a specific drug class when patient groups are compared (SCT vs. SOT).ConclusionOur study indicates that despite normal circulating numbers, neutrophils from SOT and SCT recipients are dysfunctional and show profoundly impaired anti-Candida activity. There were no medications or laboratory values that predicted functional neutrophil outcome. These data strongly support the use of functional neutrophil profiling to risk stratify those individuals at higher risk for invasive fungal infections.Disclosures All authors: No reported disclosures.