Risk Of Drug Toxicity Research Articles

EXTH-82. TUMOR ORGANOID PREDICTED THERAPEUTIC RESPONSES TO NOVEL EPIGENETIC DRUGS VIA HIGH-THROUGHPUT SCREENING

Abstract INTRODUCTION The treatment choices for pediatric brain tumors are still very limited. Epigenetic therapy emerges as a promising option recently. The lack of in vitro models that represent tumors in vivo and can be scalable for large scale drug screening is major barrier. We have developed tumor organoids from patient-derived orthotopic xenograft and performed a multi-stage high throughput screening for single or combined epigenetic agents and radiation therapy in tumor organoids. METHOD Primary xenograft tumor cells were cultured in matrix and cancer stem cell culture medium in 384-well plates. Radiation sensitivity was examined at 5 different doses. Epigen40 (40 drugs/compounds) targeting various epigenetic modifications was used alone to identify agents with the most cell killing (4 doses for up to 19 days). The drugs that showed partial activity were combined with radiation (at 5 doses) to evaluate additive or synergistic effects. The anti-tumor efficacy of selected drug was then evaluated in vivo. RESULTS The conditions of organoid growth and screen variability were optimized. 7 tumor organoids including 4 glioblastomas and 3 medulloblastomas were successfully established and characterized. The different radio-sensitivities were observed among these models. 7 compounds (JIB-04, SP2509, AS-8351, GSK J4 HCI, 3-Deazaneplanocin A HCL, Chaetocin, TC-E-5003) were shown to effectively suppress organoid growth. Chaetocin, methyltransferase SUV39H inhibitor, demonstrated broadly active and highly potent inhibition across all 7 tested organoids. In addition, bioinformatic analysis identified a subset of epigenetic inhibitors combined with radiation that produced additive anti-tumor activities in vitro. Unfortunately, in vivo treatment of Chaetocin (0.25mg/kg) didn’t convey consistent anti-tumor effects as shown in vitro whereas a high risk of drug toxicity to the mice. CONCLUSION Tumor organoids were successfully developed from primary tumors. With our optimized assay using primary tumor organoids and a multi-stage high throughput drug screening, a novel panel of epigenetic drugs that effective alone or additively with radiation was identified.

Pharmacological Potential and Electrochemical Characteristics of Typha angustifolia Pollen

Typha angustifolia L. (TA) pollen has been utilized as a traditional Chinese medicine for treating various internal and external traumas. Moreover, bioactive compounds possess diverse pharmacological activities. This study aims to evaluate the antiviral properties of TA based on its ability to generate bioenergy, capable of inhibiting viruses. TA pollens were extracted using water and ethanol solvents. These extracts were utilized to identify the phytochemical contents and correlate with the antioxidant activity via 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. HPLC analysis was conducted to identify its electron-shuttling compositions. The bioenergy-generating characteristics were determined via microbial fuel cells. The water extract (TA-W) showed higher antioxidant activity due to a higher phenolic and flavonoid content compared to the ethanol extract (TA-E). Quercetin-3-O-(2G-α-L-rhamnosyl)-rutinoside, quercetin-3-O-neohesperidoside, and quercetin are the electron shuttles (ES) identified out of the 11 compounds. TA obtained a 1.39 ± 0.10 amplification factor of power generation that indicates potential bioenergy-generating and associated antiviral characteristic properties. The findings may provide a foundation for developing antiviral medications specifically designed to target virus-related diseases, while minimizing the risk of drug toxicity and reducing the costs of drug development.

Adverse Event Profiles of the Third-Generation Aromatase Inhibitors: Analysis of Spontaneous Reports Submitted to FAERS.

The third-generation aromatase inhibitors (AIs), represented by letrozole, anastrozole, and exemestane, have been used as a standard first-line adjuvant therapy for postmenopausal breast cancer patients with positive hormone receptor. However, their safety in the real world has not been systematically analyzed. We used the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to investigate adverse event (AE) profiles of the three AIs, covering the period from Q1 2004 to Q3 2023. The time-to-event onset profiles and cumulative incidence were analyzed by Weibull shape parameter test and Kaplan-Meier method, respectively. The disproportionality analysis was utilized to assess drug toxicity risk. Based on the FAERS database, 18,035, 8242, and 7011 reports listing letrozole, anastrozole, and exemestane as primary suspected drugs were extracted, respectively. AEs associated with anastrozole displayed the latest onset (p < 0.0001); meanwhile, WSP test showed that all three AIs had early failure-type profiles. At the preferred term level, we acquired 95, 59, and 42 significant signals associated with letrozole, anastrozole, and exemestane, which involved 18, 13, and 15 system organ classes, respectively. The three AIs all reported that their strongest AE signal was trigger finger. Neutropenia was the most frequent AE for letrozole, while the highest occurrences of anastrozole and exemestane were arthralgia. We also found that interstitial lung disease, a rare but serious AE, showed strong signal intensity in all three AIs. Additionally, letrozole was also associated with lots of other rare but serious AEs in hematologic, respiratory, and hepatic systems, which were not recorded in the instructions. Our analysis of safety warning signals of the third-generation AIs from the FAERS database provided reference for clinical safe and rational drug use.

Genetic Polymorphisms in CYP2 Gene Family in Bulgarian Individuals and their Clinical Implications

Abstract The cytochrome P450 superfamily consists of hemeproteins involved in the detoxication of different xenobiotics, including drugs. The CYP2 gene family is responsible for the metabolism of 80% of the drugs in clinical use. There are considerable interindividual and interethnic variabilities in the rate of drug metabolism as a result of genetic polymorphisms. The goal of our study was to determine the frequency of 10 genetic polymorphisms in CYP2 family genes to give light on the pharmacogenetic defects of the main CYPs, involved in drug metabolism, in Bulgarian individuals. We detected high allele frequency for CYP2D6*10 (0.27), CYP2D6*4 (0.22), and CYP2B6*9 (0.24), followed by CYP2C19*2 (0.14), CYP2C9*3 (0.11) and CYP2C9*2 (0.09). The genotype frequencies were also determined for all investigated variants. In total 47.2% of the analyzed individuals carried CYP2D6 genetic polymorphisms – 5.6% carried a single variant and 41.6% were found to have two or more such variants. Homozygotes for CYP2D6 variants were established among 14% of Bulgarian individuals. Determination of the prevailing pharmacogenetic polymorphisms of the CYPs, most responsible for drug metabolism, will lead to a lower risk of drug toxicity, increased drug efficacy, and drug dose optimization.

Measurement of CYP1A2 and CYP3A4 activity by a simplified Geneva cocktail approach in a cohort of free-living individuals: a pilot study.

Introduction: The cytochrome P450 enzyme subfamilies, including CYP3A4 and CYP1A2, have a major role in metabolism of a range of drugs including several anti-cancer treatments. Many factors including environmental exposures, diet, diseaserelated systemic inflammation and certain genetic polymorphisms can impact the activity level of these enzymes. As a result, the net activity of each enzyme subfamily can vary widely between individuals and in the same individual over time. This variability has potential major implications for treatment efficacy and risk of drug toxicity, but currently no assays are available for routine use to guide clinical decision-making. Methods: To address this, a mass spectrometry-based method to measure activities of CYP3A4, CYP1A2 was adapted and tested in free-living participants. The assay results were compared with the predicted activity of each enzyme, based on a self-report tool capturing diet, medication, chronic disease state, and tobacco usage. In addition, a feasibility test was performed using a low-volume dried blood spots (DBS) on two different filter-paper supports, to determine if the same assay could be deployed without the need for repeated standard blood tests. Results: The results confirmed the methodology is safe and feasible to perform in free-living participants using midazolam and caffeine as test substrates for CYP3A4 and CYP1A2 respectively. Furthermore, though similar methods were previously shown to be compatible with the DBS format, the assay can also be performed successfully while incorporating glucuronidase treatment into the DBS approach. The measured CYP3A4 activity score varied 2.6-fold across participants and correlated with predicted activity score obtained with the self-report tool. The measured CYP1A2 activity varied 3.5-fold between participants but no correlation with predicted activity from the self-report tool was found. Discussion: The results confirm the wide variation in CYP activity between individuals and the important role of diet and other exposures in determining CYP3A4 activity. This methodology shows great potential and future cross-sectional and longitudinal studies using DBS are warranted to determine how best to use the assay results to guide drug treatments.

A change in risk assessment for treatment with statins in patients with familial hypercholesteremia and Gilbert's syndrome

Abstract Background Gilbert’s Syndrome (GS) is a heredity disease that mildly increases serum unconjugated bilirubin. GS is usually asymptomatic and considered to be benign. It is postulated to be present in 10-16% of the population but the exact incidence is unknown since it is usually an incidental finding that goes under diagnosed and under-reported. Conversely, heterozygous familial (FH) hypercholesteremia, estimated to be present in 1 in 250, is responsible for significant morbidity and mortality and never ignored. Patients with FH are especially at risk for atherosclerotic cardiovascular disease (ASCVD) due to the cumulative effect of high cholesterol starting at a young age. Recent studies report that mildly elevated serum bilirubin (especially the UGT1A1*28 allele), in patients with concurrent GS and FH, is protective against ASCVD. The deleterious effect of one liver mutation may be offset by the beneficial effect of the second mutation resulting in an inverse relationship between the two diseases. Due to that association, statins may be contraindicated in patients with concurrent FH and GH because they are more susceptible to toxicity and adverse events. Purpose Patients with coexisting FH and GS are postulated to have innate cardioprotection and therefore, treatment with statins may be unnecessary and should be avoided due to an increased risk for drug toxicity and intolerable adverse events. Methods This was a systematic review of 31 peer-reviewed publications identified by using databases: EBSCO Discovery, World Cat, PubMed, OVID, Google Scholar, Springer, Theime, Elsevier, Science Direct, and Cochrane Collaboration. Publications ranged from 2006-2021 and included subjects ages 18-80 and bench studies using Gunn rats. The quality of evidence was analyzed and evaluated. Results Recent retrospective and prospective studies indicate that mildly elevated serum bilirubin, in patients with concurrent GS and FH, is protective against ASCVD. Consequently, this population may not need statin therapy and may be more susceptible to statin toxicity and intolerable adverse events. Conclusion GS is postulated be innately cardioprotective for ASCVD. The identification of patients with concurrent FH and GS is not mainstream and is overdue. These are not uncommon diseases and their co-existence has been underestimated because GS is considered benign and underreported. The potential exists for patients with FH and silent Gilbert’s Syndrome to be overtreated or unnecessarily treated with statins. Medications that inhibit UDP-glucuronosyltranferase-enzyme activity and UG1A1 mediated glucuronidation may lead to toxicity and intolerable adverse events. Studies have shown an adverse relationship between statins and increased bilirubin. It is recommended that both FH and Gilbert’s Syndrome be routinely screened for in pediatric and adult populations, especially prior to statin prescribing.

Electrochemical analysis via microbial fuel cells reveals electron-stimulating characteristics, immunomodulation and antiviral properties of Ji Qin Yin

BackgroundDue to the Covid-19 pandemic, a newly formulated Chinese herbal medicine, Ji Qin Yin (JQY), has emerged as a potential antiviral adjuvant. JQY contains nine medicinal herbs with established pharmacological activities but unknown mechanisms. Thus, this first-attempt study aims to provide a novel electrochemical perspective to reveal the antiviral and immunomodulatory properties of JQY for antiviral drug development. MethodsThe bioenergy-stimulating characteristics and therapeutic efficacy of JQY were assessed by adopting voltammetry and Microbial Fuel Cells (MFCs) as novel bioenergy-based platforms. Phytochemical analyses correlated the total phytonutrient content with the antioxidant and electron-stimulating activities of JQY. The antiviral and immunomodulatory potential of JQY were assessed via molecular docking. Significant findingsJQY has significant bioenergy-stimulation properties with a 1.85 ± 0.19 amplification factor, implying bioenergy-steered and electron-mediated antiviral and immunomodulatory efficacy. Major flavonoids (e.g., chlorogenic acid, rosmarinic acid) identified by HPLC exhibit electron-shuttling (ES) properties due to their ortho- or para-dihydroxyl groups. These dihydroxyl groups also bound enzymes via hydrogen bonds; thus, chlorogenic acid and rosmarinic acid exhibited higher LibDock scores than the standard drugs. All test compounds passed Lipinski's rule of five with low drug toxicity risks, suggesting prospective candidates for drug development.

In silico Investigation of Identified Major Metabolites from Coffea Arabica Leaves against Parkinson’s Disease Target Proteins for Neuroprotective Drug Development

Introduction: Parkinson’s disease (PD) is a prevalent neurological disease characterized by the gradual degeneration of dopaminergic neurons leading to a dysfunctional central nervous system. Recently, major metabolites of Coffea arabica leaves were revealed to exhibit good electronshuttling potential in Microbial Fuel Cells (MFCs), similar to neurotransmitters dopamine and epinephrine. Objective: This In silico study aimed to identify the neuroprotective potentials of plant metabolites from coffee leaves and to determine their physicochemical and pharmacokinetic properties for developing viable anti-parkinsonian drug design. Methodology: Molecular docking was performed to evaluate the affinity of identified major compounds in C. arabica against PD-target proteins and compare the results with the binding activity of existing drugs and natural ligands of the identified protein targets via LibDock scores. The druglikeness and ADMET profiles of each ligand were also evaluated using bioinformatics tools. Results: C. arabica metabolites exhibited various degrees of binding activity against PD targets. LibDock scores of test compounds showed that catechin, mangiferin, and chlorogenic acid exhibited higher docking scores than dopamine and levodopa. Physicochemical and pharmacokinetics analysis of the selected molecules revealed caffeine, catechin, and chlorogenic acid as promising candidates for drug development with a low risk of drug toxicity. Conclusion: The present study indicates that Coffea arabica leaves contain promising neuroprotective active compounds against Parkinson’s disease.

An update on drug-drug interactions for care of the acutely ill in the era of COVID-19.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To provide key pharmacological concepts underlying drug-drug interactions (DDIs), a decision-making framework, and a list of DDIs that should be considered in the context of contemporary acutely ill patients with COVID-19. DDIs are frequently encountered in the acutely ill. The implications of DDIs include either increased risk of drug toxicity or decreased effectiveness, which may have severe consequences in the acutely ill due to lower physiological and neurocognitive reserves in these patients. In addition, an array of additional therapies and drug classes have been used for COVID-19 that were not typically used in the acute care setting. In this update on DDIs in the acutely ill, we provide key pharmacological concepts underlying DDIs, including a discussion of the gastric environment, the cytochrome P-450 (CYP) isozyme system, transporters, and pharmacodynamics in relation to DDIs. We also provide a decision-making framework that elucidates the identification of DDIs, risk assessment, selection of alternative therapies, and monitoring. Finally, important DDIs pertaining to contemporary acute care clinical practice related to COVID-19 are discussed. Interpreting and managing DDIs should follow a pharmacologically based approach and a systematic decision-making process to optimize patient outcomes.

An optimal extended-infusion dosing of cefepime and ceftazidime in critically ill patients with continuous renal replacement therapy.

This study aimed to determine optimal extended-infusion dosing regimens for cefepime and ceftazidime in critically ill patients receiving continuous renal replacement therapy using Monte Carlo Simulations (MCS). Pharmacokinetic models were built using published pharmacokinetic/demographic data to predict drug disposition in 5000 virtual critically ill patients receiving continuous venovenous hemofiltration (CVVH) with the standard (20-30 mL/kg/h) and a higher (40 mL/kg/h) effluent rates. MCS was performed to assess the probability of target attainment (PTA) of four cefepime and ceftazidime doses administered over 4-h with the target of ≥60% fT > 4×MIC. The lowest dose attaining PTA ≥90% during the first 48-h was considered optimal. Additionally, risk of drug toxicity was assessed at 48-h using suggested neurotoxicity thresholds. Cefepime 2 g loading dose (LD), then extended-infusion of 2 g q8hr was optimal in CVVH at 20 mL/kg/h and the same ceftazidime dose was optimal in CVVH at 20-30 mL/kg/h. Higher cefepime and ceftazidime doses were required to be optimal at higher effluent rates. This optimal dose particularly for cefepime likely increases neurotoxicity risk in most virtual patients with all CVVH settings. Cefepime and ceftazidime 2 g LD, followed by extended-infusion 2 g q8hr may be optimal in CVVH with standard effluent rates.

The Pharmacokinetics of Levetiracetam in Critically Ill Adult Patients: An Intensive Care Unit Clinical Study

The aim of this study was to investigate levetiracetam pharmacokinetics in critically ill adult intensive care patients and to identify pathophysiological factors affecting its kinetics. Fourteen critically ill patients in an intensive care unit were enrolled in the study and received intravenous levetiracetam. Blood samples were collected at specific time points to determine the levetiracetam pharmacokinetics. Patient characteristics such as renal function, demographics, disease severity, organ dysfunction, and biochemical laboratory tests were evaluated for their influence on the kinetics of levetiracetam. Estimated glomerular filtration rate (eGFR) had a statistically significant (p = 0.001) effect on levetiracetam clearance. None of the other patient characteristics had a statistically significant effect on the pharmacokinetics. Simulations of dosing regimens revealed that even typically administered doses of levetiracetam may result in significantly increased concentrations and risk of drug toxicity in patients with impaired renal function. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score differed significantly among the three groups with different epileptic activity (p = 0.034). The same groups also differed in terms of renal function (p = 0.031). Renal dysfunction should be considered when designing levetiracetam dosage. Patients with a low APACHE II score had the lowest risk of experiencing epileptic seizures.

Using informative features in machine learning based method for COVID-19 drug repurposing

Coronavirus disease 2019 (COVID-19) is caused by a novel virus named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This virus induced a large number of deaths and millions of confirmed cases worldwide, creating a serious danger to public health. However, there are no specific therapies or drugs available for COVID-19 treatment. While new drug discovery is a long process, repurposing available drugs for COVID-19 can help recognize treatments with known clinical profiles. Computational drug repurposing methods can reduce the cost, time, and risk of drug toxicity. In this work, we build a graph as a COVID-19 related biological network. This network is related to virus targets or their associated biological processes. We select essential proteins in the constructed biological network that lead to a major disruption in the network. Our method from these essential proteins chooses 93 proteins related to COVID-19 pathology. Then, we propose multiple informative features based on drug–target and protein−protein interaction information. Through these informative features, we find five appropriate clusters of drugs that contain some candidates as potential COVID-19 treatments. To evaluate our results, we provide statistical and clinical evidence for our candidate drugs. From our proposed candidate drugs, 80% of them were studied in other studies and clinical trials.

High risk of drug toxicity in social isolation stress due to liver dysfunction: Role of oxidative stress and inflammation.

Background: Previous studies have shown that social isolation stress (SIS) could associate with several systemic diseases; however, the role of SIS on liver dysfunction has yet to be established. This study aimed to investigate the effect of SIS on liver function and possible drug toxicity through liver inflammation and oxidative stress.Methods: Male Naval Medical Research Institute mice in two groups of SIS and control were treated with typical anti‐depressant and anxiolytic agents including fluoxetine, norfluoxetine, desipramine, and imipramine in both groups. Then blood concentrations (or their active metabolites) of these drugs were assessed. Liver function test, including aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, and conjugated bilirubin), oxidative activity, inflammatory cytokines, and the gene expression of cytochrome P450 enzymes were assessed.Results: We observed that the liver enzymes including AST and ALT was slightly higher in SIS animals. The blood concentrations of fluoxetine, norfluoxetine, desipramine, and imipramine were significantly higher in SIS animals. The gene expression of CYP1A2, CYP2A6, CYP2C9, CYP2C29, and CYP2D were significantly decreased in SIS animals. Our results showed that SIS animals had significantly higher level of tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6. SIS could significantly decrease the activity of antioxidant agent (Glutathione).Conclusion: We hypothesized that SIS could induce liver dysfunction and decrease the rate of drug clearance through liver inflammation and oxidative stress; therefore, the blood concentration of anti‐depressant/anxiolytic agents should closely monitor in SIS due to the high toxicity of these agents.

Undernutrition and Associated Factors Among Adult Tuberculosis Patients in Jigjiga Public Health Facilities, Somali Region, East, Ethiopia.

BackgroundTuberculosis and undernutrition are the public health concerns of people living in middle and low-income countries. When patient develops TB, undernutrition is not only a risk factor for progression of latent TB infection to active disease, but also intensifies the risk of drug toxicity, relapse and death. Nutritional supplementation in patients with TB is associated with faster sputum conversion, higher cure and treatment completion rates, and body-weight gain.ObjectiveTo find out the magnitude of undernutrition and associated factors among adult tuberculosis patients in jigjiga public health facilities.Methods and MaterialsA facility-based cross-sectional study design was applied. Data were collected using a structured questionnaire while anthropometric measurements were collected in their scale measurements. The data were entered into an Epi-data version 3.1, then were exported and analyzed using SPSS v20. Bivariate logistic regression was done to assess the association between the outcome variable and the independent variables, value <0.25 was considered as a candidate for multivariate logistic regression at 95% CI. In multivariable logistic regression analysis, the level of statistical significance was declared at a p-value less than 0.05.ResultsThe magnitude of undernutrition was 44.3% [95% CI (38.2, 49.7)]. Sex (female) [AOR=1.769, CI=1.035, 3.024], educational status [AOR=3.939, CI=2.285, 6.792] and being Bedridden [AOR=3.718, CI=1.115, 12.394) were predictors of Undernutrition among adult tuberculosis patients.ConclusionThe magnitude of undernutrition among adult patients with TB was high in the area. Overall routine appropriate nutrition assessment and support should be given to undernourished patients with TB. The level of education about nutrition should be improved by counseling on a balanced diet to all patients with TB and particularly for female patients. Appropriate nutrition support should be provided to undernourished TB patients, and more focused on those who are bedridden.

MO291RITUXIMAB IS EFFECTIVE AND SAFE IN ADULTS WITH STEROID-DEPENDENT NEPHROTIC SYNDROME: A LONG-TERM, SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Steroid-dependent nephrotic syndrome (SDNS) may require a prolonged multi-drug therapy with risk of drug toxicity and renal failure. Rituximab (RTX) treatment has been found to be helpful in reducing the steroid dosage and the need for immunosuppressants (ISs), but little data are currently available regarding very long-term outcomes in adults. We herein describe a long-term, single-center experience of RTX use in a large series of adults with SDNS. Method We studied 23 adult patients with SDNS (mean age 54.2±17.1 y; 65% male; BMI 28.5±4.7), mostly consequent to membranous (47.8%) or focal glomerulonephritis (30.2 %) who were eligible to start a RTX regimen. Before entering the RTX protocol, proteinuria and eGFR were 7.06±3.87 g/24h and 65.9±28.2 ml/min/1.73 m2, respectively; albumin and CD19/CD20 ratio were 2.9±0.9 g/L and 0.99±0.01 respectively; the mean number of ISs was 2.39±0.89 and the mean annual rate of relapses was 2.2±0.9. Results Patients were followed over a mean follow-up of 64 months (range: 12-144). After RTX (mean dose: 1202.1±372.4 mg) the rate of relapses was virtually nullified (p&amp;lt;0.001). eGFR remained roughly stable (62.1±19.8 ml/min/1.73 m2, p=NS), while proteinuria, albumin, CD19/CD20 and BMI all significantly improved (p ranging from 0.01 to 0.001). The mean number of additional ISs was also reduced (0.44±0.12; p&amp;lt;0.001) and RTX enabled discontinuation of steroids in 13/23 (56.5%) patients. No major adverse events related to therapy were recorded. Conclusion Findings from this large case-series with a remarkable very long follow-up reinforce the role of RTX as an efficient and safe weapon to improve outcomes in adult patients suffering from SDNS.

Drug-drug Interactions in Patients with HIV and Cancer in Sub-Saharan Africa.

In Sub-Saharan Africa, the cancer burden is predicted to increase by > 85% by 2030, the largest increase worldwide. This region has a large HIV-positive population. Drug-drug interactions (DDIs) from concomitant use of multiple drugs increase the risk of drug toxicities, sub-optimal therapy, and drug resistance. With the increase in polypharmacy, involving antiretroviral (ARV), and anticancer drugs, there is a greater need for an appreciation of clinically relevant DDIs. Anticancer and ARV drugs studied in this review were from The World Health Organization's Model List of Essential Medicines 2017. We reviewed; drug package inserts, www.drugbank.ca and www.UpToDate.com, to evaluate pharmacokinetic interactions with cytochrome P450 (CYP450) and ABCB1. The DDIs between drugs were assessed using the University Of Liverpool, UK HIV Drug Interactions Checker, and the LexiComp Drug Interaction tool of www.UpToDate.com. About 70% of ARVs studied interact with CYP450, all involve CYP3A4, and 55% interact with ABCB1. About 65% of anticancer drugs interact with CYP450, 44% of which do so through CYP3A4. About 75% of anticancer drugs interact with ARV drugs, with nine absolute contraindications to concomitant therapy. There exist a substantial number of DDIs between ARV and anticancer drugs, primarily mediated through CYP450 enzymes. Dolutegravir based regimens offer the safest DDI profile for concurrent use with anticancer drugs. However, there are substantial gaps in our knowledge, and this study serves to highlight the need for additional research to better define these interactions and their effect on drug exposure, as attention to these DDIs is a relatively simple intervention that could lead to optimizing disease treatment.

Adverse Reactions of Proton Pump Inhibitors: A Literature Review

Gastroesophageal reflux disease (GRD) is the most common form of esophagitis, where proton pump inhibitors are the most widely used drugs. This study aimed to perform a literature review about the clinical use and adverse reactions of proton pump inhibitors (PPIs). Treatment of GRD evolved in the 1970s, when the first PPI, timoprazole, was discovered and in 1979, omeprazole originated, with a high action on the proton bomb. The most potent drugs in gastric suppression are proton pump inhibitors where they act irreversibly in the proton pump H +, K +, - ATPase, the suppression of acid secretion lasts for 24-48 hr. PPIs with prolonged use are associated with changes in the intestinal microbiota, which can be compared to changes seen with antimicrobials, in addition to altering the absorption of iron and Vitamin b12 and the metabolism of calcium and magnesium. The population most susceptible to the appearance of the side effects of PPIs is the elderly, age is a factor that predisposes to the appearance of various pathologies and it is necessary to use many medications thus constituting a polypharmacy, in addition, may increase the risks of drug toxicity due to the hepatic metabolism of the elderly being compromised, this is a worrying condition, as it can cause, in addition to the side effects of PPIs, drug interactions, making pharmacotherapeutic follow-up essential, thus being able to make dose adjustments and assess possible drug-related problems and adverse drug reactions. Key words: Adverse effects, Proton pump inhibitors, Pharmacotherapy, Pharmacovigilance, Reflux diseases.

Therapeutic Drug Monitoring in Non-Tuberculosis Mycobacteria Infections.

Nontuberculous mycobacteria can cause minimally symptomatic self-limiting infections to progressive and life-threatening disease of multiple organs. Several factors such as increased testing and prevalence have made this an emerging infectious disease. Multiple guidelines have been published to guide therapy, which remains difficult owing to the complexity of therapy, the potential for acquired resistance, the toxicity of treatment, and a high treatment failure rate. Given the long duration of therapy, complex multi-drug treatment regimens, and the risk of drug toxicity, therapeutic drug monitoring is an excellent method to optimize treatment. However, currently, there is little available guidance on therapeutic drug monitoring for this condition. The aim of this review is to provide information on the pharmacokinetic/pharmacodynamic targets for individual drugs used in the treatment of nontuberculous mycobacteria disease. Lacking data from randomized controlled trials, in vitro, in vivo, and clinical data were aggregated to facilitate recommendations for therapeutic drug monitoring to improve efficacy and reduce toxicity.

Kratom: An Emerging Issue and Need for Regulations in the United States.

To understand and highlight the current issues, emerging trends, and regulations of kratom in the United States. PubMed and PubMed Central of the National Library of Medicine, MEDLINE, PsycINFO, and ClinicalTrials.gov databases were utilized. Studies published between January 1, 2000, and June 30, 2020, were accessed by using the MeSH term mitragyna in the context of toxicity, safety, and legislation and jurisprudence. The final qualitative synthesis included 11 studies by following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement guidelines. The US Drug Enforcement Administration (DEA) initially proposed to place kratom under Schedule I of the Controlled Substances Act, but the DEA later withdrew the intent, and kratom is still a legal substance in most of the United States. A low to moderate kratom dose produces mild stimulant properties, whereas large doses produce sedative effects that are identical to opiates. Its regular use at a higher dose is associated with dependence. Management of overdose is similar to that of patients presenting with opioid abuse, although kratom may potentially pose a higher risk for drug toxicity and organ injury compared to opioids due to intrinsic properties and adulteration. There is no clinical evidence for its safety and efficacy. The US Food and DEA do not recognize any legitimate medical use of kratom. Kratom is an emerging public health concern and is abused as an alternative to opioids. Stringent policies and public awareness campaigns are required to curb the perception of its safe use, which needs to be substantiated with well-designed clinical trials.

Progress in the Application of Nano- and Micro-based Drug Delivery Systems in Pulmonary Drug Delivery

Abstract Nanotechnology is associated with the development of particles in the nano-size range that can be used in a wide range of applications in the medical field. It has gained more importance in the pharmaceutical research field particularly in drug delivery, as it results in enhanced therapeutic drug performance, improved drug solubility, targeted drug delivery to the specific sites, minimized side effects, and prolonged drug retention time in the targeted site. To date, the application of nanotechnology continues to offer several benefits in the treatment of various chronic diseases and results in remarkable improvements in treatment outcomes. The use of nano-based delivery systems such as liposomes, micelles, and nanoparticles in pulmonary drug delivery have shown to be a promising strategy in achieving drug deposition and maintained controlled drug release in the lungs. They have been widely used to minimize the risks of drug toxicity in vivo. In this review, recent advances in the application of nano- and micro-based delivery systems in pulmonary drug delivery for the treatment of various pulmonary diseases, such as lung cancer, asthma, and chronic obstructive pulmonary disease, are highlighted. Limitations in the application of these drug delivery systems and some key strategies in improving their formulation properties to overcome challenges encountered in drug delivery are also discussed.