BMC Health Serv Res. 2021 Aug 6;21(1):779. doi: 10.1186/s12913-021-06808-3.

ABSTRACT

BACKGROUND: A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program for certain medications with serious safety concerns required by the U.S. Food and Drug Administration (FDA) of manufacturers to implement to help ensure the benefits of the medication outweigh its risks. FDA is encouraging "the research community to develop novel methods for assessing REMS," conveying the unmet need for a standardized evaluation method of these regulatory-mandated healthcare programs. The objective of this research is to evaluate FDA REMS assessment plans using established implementation science frameworks and identify opportunities for strengthening REMS evaluation.

METHODS: A content analysis was conducted of publicly available assessment plans for all REMS programs (N = 23) approved 1/1/2014-12/31/2018 for new drug applications (NDAs) and biologics license applications (BLAs) requiring FDA-mandated Elements to Assure Safe Use (ETASU). Blinded reviewers critically appraised REMS assessment measures (n = 674) using three established implementation science frameworks: RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance); PRECEDE-PROCEED (Predisposing, Reinforcing, and Enabling Constructs in Educational/Environmental Diagnosis and Evaluation - Policy, Regulatory, and Organizational Constructs in Educational and Environmental Development); and CFIR (Consolidated Framework for Implementation Research). Framework constructs were mapped to REMS Assessment categories as defined by FDA Guidance for Industry to evaluate congruence.

RESULTS: REMS assessment measures demonstrated strong congruence (> 90% mapping rate) with the evaluative constructs of RE-AIM, PRECEDE-PROCEED, and CFIR. Application of the frameworks revealed that REMS assessment measures heavily emphasize implementation and operations, focus less on health outcomes, and do not evaluate program context and design assumptions.

CONCLUSIONS: Implementation science frameworks have utility for evaluating FDA-mandated drug safety programs including the selection of primary measures to determine whether REMS goals are being met and of secondary measures to evaluate contextual factors affecting REMS effectiveness in varying organizational settings.

PMID:34362367 | PMC:PMC8348874 | DOI:10.1186/s12913-021-06808-3

J Clin Med. 2021 Jul 21;10(15):3202. doi: 10.3390/jcm10153202.

ABSTRACT

We aimed to investigate the incidence of sugammadex-induced anaphylaxis in a large Korean population. We retrospectively investigated the incidence of sugammadex-induced anaphylaxis between 2013 and 2019 from the database of the Korea Institute of Drug Safety-Risk Management-Korea Adverse Event Reporting System (KIDS-KAERS). We estimated the incidence of sugammadex-induced anaphylaxis from the KIDS-KAERS database, assuming that the reporting efficiency was 10%, 50%, and 100%, respectively. We also investigated its annual sales volume in Korea and assumed that the exposure to sugammadex was 95% of the estimated sales volume. During the study period, 1,401,630 sugammadex vials were sold, and 19 cases of sugammadex-induced anaphylaxis were identified in the KIDS-KAERS database. The estimated incidence of sugammadex-induced anaphylaxis was 0.0143%, 0.00279%, and 0.0014%, assuming a reporting efficiency of 10%, 50%, and 100%, respectively. All patients, except for one with a missing record, fully recovered after anaphylaxis. The incidence of sugammadex-induced anaphylaxis identified in the national pharmacovigilance database was lower than previously reported rates in other countries. Therefore, its use in general anesthesia should not be hindered by concerns about the resulting risk of anaphylaxis in Korea.

PMID:34361989 | DOI:10.3390/jcm10153202

Microorganisms. 2021 Jul 14;9(7):1505. doi: 10.3390/microorganisms9071505.

ABSTRACT

Beta-lactams are the most commonly prescribed antimicrobials in intensive care unit (ICU) settings and remain one of the safest antimicrobials prescribed. However, the misdiagnosis of beta-lactam-related adverse events may alter ICU patient management and impact clinical outcomes. To describe the clinical manifestations, risk factors and beta-lactam-induced neurological and renal adverse effects in the ICU setting, we performed a comprehensive literature review via an electronic search on PubMed up to April 2021 to provide updated clinical data. Beta-lactam neurotoxicity occurs in 10-15% of ICU patients and may be responsible for a large panel of clinical manifestations, ranging from confusion, encephalopathy and hallucinations to myoclonus, convulsions and non-convulsive status epilepticus. Renal impairment, underlying brain abnormalities and advanced age have been recognized as the main risk factors for neurotoxicity. In ICU patients, trough concentrations above 22 mg/L for cefepime, 64 mg/L for meropenem, 125 mg/L for flucloxacillin and 360 mg/L for piperacillin (used without tazobactam) are associated with neurotoxicity in 50% of patients. Even though renal complications (especially severe complications, such as acute interstitial nephritis, renal damage associated with drug induced hemolytic anemia and renal obstruction by crystallization) remain rare, there is compelling evidence of increased nephrotoxicity using well-known nephrotoxic drugs such as vancomycin combined with beta-lactams. Treatment mainly relies on the discontinuation of the offending drug but in the near future, antimicrobial optimal dosing regimens should be defined, not only based on pharmacokinetics/pharmacodynamic (PK/PD) targets associated with clinical and microbiological efficacy, but also on PK/toxicodynamic targets. The use of dosing software may help to achieve these goals.

PMID:34361942 | DOI:10.3390/microorganisms9071505

Int J Environ Res Public Health. 2021 Jul 25;18(15):7859. doi: 10.3390/ijerph18157859.

ABSTRACT

BACKGROUND: Coronavirus disease (COVID-19) vaccine-related side effects have a determinant role in the public decision regarding vaccination. Therefore, this study has been designed to actively monitor the safety and effectiveness of COVID-19 vaccines globally.

METHODS: A multi-country, three-phase study including a cross-sectional survey to test for the short-term side effects of COVID-19 vaccines among target population groups. In the second phase, we will monitor the booster doses' side effects, while in the third phase, the long-term safety and effectiveness will be investigated. A validated, self-administered questionnaire will be used to collect data from the target population; Results: The study protocol has been registered at ClinicalTrials.gov, with the identifier NCT04834869.

CONCLUSIONS: CoVaST is the first independent study aiming to monitor the side effects of COVID-19 vaccines following booster doses, and the long-term safety and effectiveness of said vaccines.

PMID:34360156 | DOI:10.3390/ijerph18157859

Cancers (Basel). 2021 Jul 22;13(15):3675. doi: 10.3390/cancers13153675.

ABSTRACT

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2-DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

PMID:34359577 | DOI:10.3390/cancers13153675

Front Pharmacol. 2021 Jul 20;12:706329. doi: 10.3389/fphar.2021.706329. eCollection 2021.

ABSTRACT

Lamotrigine (LTG), a wide-spectrum antiepileptic drug, is frequently associated with cutaneous side-effects, whereas hematological side-effects such as leukopenia have rarely been reported for it. We report the case of a 15-year-old Chinese female epileptic patient weighing 60 kg who developed combined asymptomatic leukopenia after receiving concomitant therapy with LTG and valproate acid (VPA). In this case report, antiepileptic drug-related leukopenia may have occurred in definite relation to an increase in LTG concentration and reversed with the discontinuation of VPA. Monte Carlo (MC) simulations were performed to estimate the steady-state serum concentrations (C ss ) of LTG for different dosing regimens in adolescent Chinese epileptic patients weighing the same as the patient considered in the case study, based on pharmacokinetic (PK) models published in past research. Adjustments to the dosage of LTG for the patient were analyzed to illustrate the application of MC simulations and verify the results. The predicted LTG concentrations within a prediction interval between the 10th and 90th percentiles that represented 80% of the simulated populations, could adequately capture the measured LTG concentrations of the patient, indicating that MC simulations are a useful tool for estimating drug concentrations. Clinicians may benefit from the timely probabilistic predictions of the range of drug concentration based on an MC simulation that considers a large sample of virtual patients. The case considered here highlights the importance of therapeutic drug monitoring (TDM) and implementing model-informed precision dosing in the course of a patient's individualized treatment to minimize adverse reactions.

PMID:34354594 | PMC:PMC8329375 | DOI:10.3389/fphar.2021.706329

Cir Cir. 2021;89(4):476-483. doi: 10.24875/CIRU.20000567.

ABSTRACT

ANTECEDENTES: En una cesárea se puede emplear analgesia epidural con bupivacaína 0.125% and lidocaína 1.5% ó bupivacaína 0.25% and lidocaína 1.0%. Una concentración mayor de bupivacaína alcanza mayor analgesia con más eventos adversos.

OBJETIVO: evaluar la analgesia y seguridad de bupivacaína 0.125% and lidocaína 1.5% ó bupivacaína 0.25% and lidocaína 1.0%.

MATERIALES Y MÉTODOS: Cohorte prospectivo estratificado según ambas concentraciones de bupivacaína.

RESULTADOS: Se recuperó cien gestantes a término (cincuenta por cohorte). A los 20 y 30 minutos tras la administración epidural hubo más casos con mayor bloqueo motor en quienes se empleó bupivacaína 0.125% and lidocaína 1.5% (p = 0.0229 y p = 0.0006, respectivamente). No hubo diferencia significativa respecto al bloqueo sensitivo. Bupivacaína 0.25% and lidocaína 1.5% mostró una tencencia a la hipotensión (p < 0.001) y a la bradicardia (p = 0.4100). De la cohorte de bupivacaína 0.125% and lidocaína 1.5%, 25 casos (50%) presentaron cuando menos un evento adverso, en contraste con 44/50 (88%) de la cohorte de bupivacaína 0.25% and lidocaína 1.0% (p < 0.001).

CONCLUSIÓN: En la analgesia epidural durante cesárea, bupivacaína 0.125% and lidocaína 1.5% está asociado con un efecto analgésico similar a bupivacaína 0.25% and lidocaína 1.0%. Sin embargo, mayores concentraciones están significativamente relacionadas con mayor tasa de eventos adversos (especialmente hipotensión).

BACKGROUND: In a cesarean section, epidural analgesia with 0.125% bupivacaine and 1.5% lidocaine or 0.25% bupivacaine with 1.0% lidocaine concentrations can be used. A higher concentration of bupivacaine reaches better analgesia but with a higher rate of drug-related adverse events.

AIM: The aim of the study was to assess analgesia and safety of 0.125% bupivacaine and 1.5% lidocaine or 0.25% bupivacaine with 1.0% lidocaine during cesarean.

MATERIALS AND METHODS: Prospective cohort stratified following both bupivacaine concentrations.

RESULTS: One hundred women with full-term pregnancies were selected (fifty per cohort). At 20 and 30 min after epidural administration, there was a higher proportion of motor blockade cases from the 0.125% bupivacaine and 1.5% lidocaine cohort (p = 0.0229 and p = 0.0006, respectively). There was no significant difference among sensitive blockage. A 0.25% bupivacaine and 1.0% lidocaine concentration showed a tendency to hypotension (p < 0.001) and bradycardia (p = 0.4100). From 0.125% bupivacaine and 1.5% lidocaine cohort, 25 cases (50%) presented at least one adverse event; in contrast with 44/50 (88%) from 0.25% bupivacaine and 1.0% lidocaine cohort (p < 0.001).

CONCLUSION: In epidural analgesia during cesarean, using 0.125% bupivacaine and 1.5% lidocaine presented similar analgesia than 0.25% bupivacaine and 1.0% lidocaine. However, a higher bupivacaine concentration is significantly related to more frequent drug-related adverse events (especially hypotension).

PMID:34352874 | DOI:10.24875/CIRU.20000567

Cancer Rep (Hoboken). 2021 Aug 5:e1520. doi: 10.1002/cnr2.1520. Online ahead of print.

ABSTRACT

BACKGROUND: Combination molecular targeted therapy with dabrafenib plus trametinib has been shown to improve progression-free survival and overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. In general, these agents are well tolerated. Kidney related adverse events are uncommon with only three case reports of acute interstitial nephritis and one case of a serious acute kidney injury. We report another case of interstitial nephritis related to these drugs.

CASE: A 37-year-old man diagnosed with metastatic melanoma (BRAF V600E mutation) who developed acute interstitial nephritis 5 years into his treatment with combination dabrafenib plus trametinib therapy. He presented with an asymptomatic acute kidney injury on routine surveillance pathology with a creatinine of 174 μmol/L (from baseline 80 μmol/L) and a corresponding estimated glomerular filtration rate (eGFR) of 42 ml/min/1.73 m2 (from a baseline >90 ml/min/1.73 m2 ) and microalbuminuria (albumin creatinine ratio [ACR] 8.5 mg/mmol). Renal biopsy revealed a granulomatous interstitial nephritis likely drug related. He was treated with prednisolone 1 mg/kg and ceased his targeted therapy with improvement in his renal function.

CONCLUSION: Although rare, recognition of acute interstitial nephritis, a possible serious adverse outcome due to dabrafenib and trametinib is important and needs to be incorporated into current Australian cancer therapy guidelines.

PMID:34350734 | DOI:10.1002/cnr2.1520

J Anaesthesiol Clin Pharmacol. 2021 Apr-Jun;37(2):272-278. doi: 10.4103/joacp.JOACP_405_20. Epub 2021 Jul 15.

ABSTRACT

BACKGROUND AND AIMS: Transdermal opioids are newer modality in use for the control of postoperative pain, because of its noninvasiveness, longer duration of action, sustained blood levels, and with minimal side effects. The study was aimed to evaluate the efficacy of analgesia of buprenorphine patch 10, 20 μg·h-1 and fentanyl patch 25 μg·h-1 for relief of pain in the postoperative period in patients undergoing arthroscopic lower limb surgeries.

MATERIALS AND METHODS: It was a randomized, double-blinded, prospective study in which adult patients undergoing lower limb arthroscopic surgery were randomly segregated into three groups. In Group 1 (fentanyl patch 25 μg·h-1), Group 2 (buprenorphine patch 10 μg·h-1), and Group 3 (buprenorphine patch 20 μg·h-1), transdermal patches were applied 12 h prior to surgery. Mean NRS score, total rescue analgesic requirement, drug-related adverse effects, and hemodynamic status were evaluated till 72 h in the postoperative period.

RESULTS: Out of 175 screened patients, 150 patients were finally analyzed. Baseline characteristics were the same among all the three groups. Median NRS score was lowest in Group 3 [P value < 0.05 at 2, 4, 8, 12, and 24 h after surgery (Kruskal Wallis test). The total consumption of postoperative rescue analgesic diclofenac was the lowest in Group 3 as compared to other groups without any significant increase in adverse events.

CONCLUSIONS: In arthroscopic lower limb surgery, buprenorphine patch (20 μg·h-1) applied 12 h prior to surgery is an effective postoperative analgesic and it is not associated with any significant adverse effects.

PMID:34349379 | PMC:PMC8289665 | DOI:10.4103/joacp.JOACP_405_20

Mult Scler J Exp Transl Clin. 2021 Jul 13;7(3):20552173211024298. doi: 10.1177/20552173211024298. eCollection 2021 Jul-Sep.

ABSTRACT

BACKGROUND: Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets.

OBJECTIVE: To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies.

METHODS: This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation.

RESULTS: By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%).

CONCLUSION: Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation.

PMID:34345436 | PMC:PMC8283088 | DOI:10.1177/20552173211024298

Elife. 2021 Aug 3;10:e65543. doi: 10.7554/eLife.65543.

ABSTRACT

The discovery of a drug requires over a decade of intensive research and financial investments - and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug-drug and drug-metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.

PMID:34340747 | PMC:PMC8331181 | DOI:10.7554/eLife.65543

Int J Surg Case Rep. 2021 Jul 27;85:106239. doi: 10.1016/j.ijscr.2021.106239. Online ahead of print.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Prolonged air leakage after pulmonary resection is a common complication, and fibrin glue is used as a sealant to reduce this. Fibrin glue-induced adverse events are generally rare. Herein, we describe a rare case of fibrin glue-induced eosinophilic pleural effusion (EPE).

CASE PRESENTATION: A 77-year-old man underwent partial pulmonary resection for right lower lobe lung cancer, and the pulmonary staple stump was subsequently covered with fibrin glue. Antibacterial drugs were administered for the treatment of postoperative pneumonia. However, re-elevation of the inflammatory cell number was observed, and computed tomography revealed an increase in right pleural effusion. Although thoracoscopy was performed based on a possibility of empyema, no empyema was observed. The eosinophil count in the pleural effusion was 11%; thus, the patient was diagnosed with EPE, which was resolved after thoracic drainage, without corticosteroid administration. Fibrin glue was identified as the causative agent, using a drug-induced lymphocyte stimulation test.

CLINICAL DISCUSSION: EPE is defined as an eosinophil count of ≥10% in the pleural effusion. If pleural effusion on the surgical side, with fever or an elevated inflammatory cell number, is observed in the early postoperative period after pulmonary resection, empyema should be considered foremost. In this case, the administration of antibacterial drugs was ineffective, and the patient was eventually diagnosed with EPE.

CONCLUSION: EPE should be considered as a rare fibrin glue-induced adverse event after pulmonary resection. It is recommended that the leukocyte fraction be examined, if pleural effusion is collected for postoperative pleural effusion.

PMID:34340047 | DOI:10.1016/j.ijscr.2021.106239

Eur Rev Med Pharmacol Sci. 2021 Jan;25(14):4746-4756. doi: 10.26355/eurrev_202101_26386.

ABSTRACT

OBJECTIVE: Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients, and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors, Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs.

MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles.

RESULTS: Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage-gated calcium channel blockers (gabapentin, pregabalin) and opioids may be effective.

CONCLUSIONS: Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzodiazepines or gabapentinoids for symptomatic relief is the basis of management.

PMID:34337722 | DOI:10.26355/eurrev_202101_26386

Front Endocrinol (Lausanne). 2021 Jul 14;12:662865. doi: 10.3389/fendo.2021.662865. eCollection 2021.

ABSTRACT

INTRODUCTION/PURPOSE: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS).

MATERIALS AND METHODS: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%).

RESULTS: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred.

CONCLUSIONS: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

PMID:34335465 | PMC:PMC8317576 | DOI:10.3389/fendo.2021.662865

J Toxicol Sci. 2021;46(8):359-369. doi: 10.2131/jts.46.359.

ABSTRACT

Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the anti-hepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was withdrawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addition, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.

PMID:34334557 | DOI:10.2131/jts.46.359

Vaccine. 2021 Aug 23;39(36):5087-5090. doi: 10.1016/j.vaccine.2021.07.047. Epub 2021 Jul 22.

ABSTRACT

INTRODUCTION: COVID-19 vaccination seems to be the most pertinent pharmacologic public health measure to control the pandemic. Reactogenicity symptoms were frequent in vaccine recipients mostly mild to moderate and commonly reported after the second dose. However, there is a lack of data in patients with a previous diagnosis of Covid-19.

METHODS: We analysed side effects of 311 patients after the first dose of Pfizer-BioNTech COVID-19 vaccine, in a french university hospital. We compared patients with COVID-19 history to naive individuals. All the data collected are based on self-reported, including COVID-19 exposure status.

RESULTS: Overall, 229 (74%) patients reported at least one side effect. Among participants with history of Covid-19, 95% reported at least one adverse event versus 70% in naive patients (p < 0.01). However, symptom intensity was not different between the 2 groups.

CONCLUSION: Vaccine recipients with prior COVID-19 reported more, but no more serious, side effects than naive participants.

PMID:34332800 | PMC:PMC8295016 | DOI:10.1016/j.vaccine.2021.07.047

Bioorg Chem. 2021 Jul 21;115:105198. doi: 10.1016/j.bioorg.2021.105198. Online ahead of print.

ABSTRACT

Farnesoid X receptor (FXR) has been considered as an attractive target for metabolic disorder and liver injury, while many current FXR agonists suffer from undesirable side effects, such as pruritus. Therefore, it is urgent to develop new structure types different from current FXR agonists. In this study, a series of structural optimizations were introduced to displace the unstable coumarin and geraniol scaffolds of auraptene (AUR), a novel and safe FXR agonist. All of these efforts led to the identification of compound 14, a potent FXR agonist with nearly fourfold higher activity than AUR. Molecular modeling study suggested that compound 14 fitted well with binding pocket, and formed the key ionic bond with His291 and Arg328. In acetaminophen-induced acute liver injury model, compound 14 exerts better therapeutic effect than that of AUR, which highlighting its pharmacological potential in the treatment of drug-induced liver injury.

PMID:34333419 | DOI:10.1016/j.bioorg.2021.105198

West Afr J Med. 2021 Jul 29;38(7):634-645.

ABSTRACT

BACKGROUND: Nigeria is yet to achieve the internationally recommended number of Adverse Drug Reactions (ADRs) reports.

OBJECTIVE: This study evaluated the impact of an educational lecture followed by repeated text messages via the Short Messaging System (SMS) on ADR reporting.

METHODS: Six teaching hospitals in the South-South zone of Nigeria were randomized in 1:1 ratio into intervention and non-intervention hospitals. The intervention hospitals received an educational lecture followed by monthly SMS reinforcements over 12 months. The number and quality of ADR reports from the local pharmacovigilance centers of each teaching hospital over the 12 months before and after the intervention were described.

RESULTS: A total of 4912 healthcare professionals were working in the 6 hospitals at the time of the study (3099 in the intervention and 1813 in the control) and the educational intervention was conducted between January and March 2016. In the intervention hospitals, the number of ADR reports increased from 57 in the pre-intervention period (from January 1st 2015) to 75 in the post- intervention period. However, the proportion of serious ADRs decreased slightly from 26(45.6%) to 33(44%). Post-intervention, the report of suspected drug details in the ADR report form also improved.

CONCLUSION: There was a trend to increased absolute number and quality of reports following educational intervention and SMS reminders.

PMID:34330932

Adv Ther. 2021 Jul 30. doi: 10.1007/s12325-021-01850-3. Online ahead of print.

ABSTRACT

INTRODUCTION: Achieving target blood pressure (BP) goals in patients with chronic kidney disease (CKD) and uncontrolled hypertension is a challenge. Various studies have shown the efficacy of nifedipine gastrointestinal therapeutic system (GITS) 60 mg in patients with hypertension. However, there is a paucity of clinical studies in patients with CKD. Hence, we conducted this study to evaluate the effectiveness and tolerability of nifedipine GITS 60 mg in Chinese patients with CKD and uncontrolled hypertension in real-world clinical settings.

METHODS: In a prospective, multicenter, observational study, Chinese patients with CKD and uncontrolled hypertension were given nifedipine GITS 60 mg with a primary endpoint of change in office systolic BP (SBP) at 12 weeks. The secondary endpoints included changes at 12 weeks in office diastolic BP (DBP), office SBP and DBP in SBP subgroups (140-160 mmHg and ≥ 160 mmHg) and CKD stages subgroups, SBP and DBP control rate, and the adverse events (AEs). Statistical analysis was performed using SAS® version 9.4.

RESULTS: In total, 871 and 622 patients were included in the safety analysis set and efficacy analysis set respectively. The mean office SBP and DBP at baseline were 162.9 and 97.3 mmHg, respectively. At week 12, the mean change in SBP was - 24.0 mmHg (95% confidence interval [CI] - 25.32, - 22.65 mmHg); after missing data were accounted for, it was - 23.9 mmHg (95% CI - 25.25, - 22.60 mmHg). Marked decreases in DBP, and office SBP and DBP in baseline SBP subgroups as well as CKD stages were observed at week 12. The BP control rate at week 12 was 50.0%. Twenty-three (2.6%) patients reported at least one drug-related AEs. No event of hypotension or death occurred during the study.

CONCLUSION: Nifedipine GITS 60 mg showed effectiveness and tolerability in reducing office SBP and DBP in Chinese patients with CKD and uncontrolled hypertension.

TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03194633.

PMID:34331258 | DOI:10.1007/s12325-021-01850-3

Lancet Haematol. 2021 Aug;8(8):e593-e604. doi: 10.1016/S2352-3026(21)00167-8.

ABSTRACT

Progressive multifocal leukoencephalopathy (PML) is a serious and usually fatal CNS infection caused by the John Cunningham virus. CD4+ and CD8+ T-cell lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are primary risk factors for PML. Following its introduction in 1997, the immunomodulatory anti-CD20 monoclonal antibody, rituximab, has received regulatory approval worldwide for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, chronic lymphocytic leukaemia, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulagris. Rituximab leads to prolonged B-lymphocyte depletion, potentially allowing John Cunningham viral infection to occur. Six unexpected cases of PML infection developing in rituximab-treated patients were first reported in 2002. We review 20 years of information on clinical findings, pathology, epidemiology, proposed pathogenesis, and risk-management issues associated with PML infection developing after rituximab treatment. Since the first case series report of 52 cases of rituximab-associated PML among patients with non-Hodgkin lymphoma or chronic lymphocytic leukaemia in 2009, updated and diligent pharmacovigilance efforts have provided reassurance that this fatal toxicity is a rare clinical event with concurring causal factors. International harmonisation of safety warnings around rituximab-associated PML should be considered, with these notifications listing rituximab-associated PML under a section titled warnings and precautions as is the case in most countries, rather than a boxed warning as is the case in the USA.

PMID:34329579 | DOI:10.1016/S2352-3026(21)00167-8