Drug-induced Adverse Events

Neutropenia in pediatric solid organ transplant

Sat, 2022-08-20 06:00

Pediatr Transplant. 2022 Aug 20:e14378. doi: 10.1111/petr.14378. Online ahead of print.

ABSTRACT

Neutropenia is generally defined as an absolute neutrophil count in the circulation of less than 1500/mm3 and occurs in up to 25%-30% of pediatric solid organ transplant recipients (SOT) within the first year after transplantation. In the SOT population, neutropenia is most often a result of drug-induced bone marrow suppression but can also be secondary to viral infection, nutritional deficiencies, lymphoproliferative infiltrate, and inherited causes. Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Management of neutropenia should begin by addressing the underlying cause, including reducing or removing medications when appropriate, treating infections, and addressing nutrient deficiencies; however, consultation with an experienced pediatric hematologist and use of granulocyte colony-stimulating factor (G-CSF) may be helpful in some cases. Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with infections or severe neutropenia.

PMID:35986635 | DOI:10.1111/petr.14378

Categories: Literature Watch

Herb-anticancer drug interactions in real life based on VigiBase, the WHO global database

Fri, 2022-08-19 06:00

Sci Rep. 2022 Aug 19;12(1):14178. doi: 10.1038/s41598-022-17704-z.

ABSTRACT

Cancer patients could combine herbal treatments with their chemotherapy. We consulted VigiBase, a WHO database of individual case safety reports (ICSRs) which archives reports of suspected Adverse Drug Reactions (ADRs) when herbal products are used in conjunction with anti-cancer treatment. We focused on the possible interactions between antineoplastic (L01 ATC class) or hormone antagonists (L02B ATC class) with 10 commonly used herbs (pineapple, green tea, cannabis, black cohosh, turmeric, echinacea, St John's wort, milk thistle and ginger) to compare ADRs described in ICSRs with the literature. A total of 1057 ICSRs were extracted from the database but only 134 were complete enough (or did not concern too many therapeutic lines) to keep them for analysis. Finally, 51 rationalizable ICSRs could be explained, which led us to propose a pharmacokinetic or pharmacodynamic interaction mechanism. Reports concerned more frequently women and half of the rationalizable ICSRs involved Viscum album and Silybum marianum. 5% of the ADRs described could have been avoided if clinicians had had access to the published information. It is also important to note that in 8% of the cases, the ADRs observed were life threatening. Phytovigilance should thus be considered more by health care professionals to best treat cancer patients and for better integrative care.

PMID:35986023 | DOI:10.1038/s41598-022-17704-z

Categories: Literature Watch

Emergency Department Visits Due to Dyspnea: Association with Inhalation Therapy in COPD and Cases with Adverse Drug Reactions

Fri, 2022-08-19 06:00

Int J Chron Obstruct Pulmon Dis. 2022 Aug 11;17:1827-1834. doi: 10.2147/COPD.S367062. eCollection 2022.

ABSTRACT

PURPOSE: Dyspnea is a leading symptom of COPD that causes presentations in emergency departments or negatively impacts on them. Guideline-based inhalation therapies are intended to reduce dyspnea in COPD patients. This study analyzed how common guideline recommended inhalation therapy regimens are occurring in clinical practice among COPD patients presenting to emergency departments due to adverse drug reactions in polytherapy using data of the German ADRED database.

PATIENTS AND METHODS: In total, 269 COPD cases were identified. In a further analysis, all cases were analyzed for documented GOLD stage and guideline-recommended inhalation therapy for COPD. Dyspnea and other symptoms identified during ED presentation were analyzed and compared between patients who did and did not receive the guideline's recommended inhalation therapy.

RESULTS: In this observation, 41% (n = 46) of all 112 cases with a documented COPD and GOLD stage received an underdosed therapy according to current guidelines. Dyspnea was the most common identified symptom (32%, n = 36) in this cohort and occurred more often in patients who received an underdosage of inhalation therapy (p < 0.01).

CONCLUSION: Patients with COPD presenting to ED with ADRs show a high rate of non-guideline-recommended inhalation therapy and present more often with dyspnea compared to those COPD patients who received an adequate dosing of inhalation therapy.

PMID:35983166 | PMC:PMC9379107 | DOI:10.2147/COPD.S367062

Categories: Literature Watch

The role of OATP1B1 and OATP1B3 transporter polymorphisms in drug disposition and response to anticancer drugs: a review of the recent literature

Fri, 2022-08-19 06:00

Expert Opin Drug Metab Toxicol. 2022 Aug 19. doi: 10.1080/17425255.2022.2113380. Online ahead of print.

ABSTRACT

INTRODUCTION: Members of the solute carrier family of organic anion transporting polypeptides are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. In particular, the polymorphic transporters OATP1B1 and OATP1B3 are highly expressed in the liver and have been identified as critical regulators of hepatic eliminaton. As these transporters are also expressed in cancer cells, the function alteration of these proteins have important consequences for an individual's susceptibility to certain drug-induced side effects, drug-drug interactions, and treatment efficacy.

AREAS COVERED: In this mini-review, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of genetic variants in OATP1B1 and OATP1B3 to the transport of anticancer drugs, the role of these carriers in regulation of their disposition and toxicity profiles, and recent advances in attempts to integrate information on transport function in patients to derive individualized treatment strategies.

EXPERT OPINION: Based on currently available data, it appears imperative that different aspects of disease, physiology, and drugs of relevance should be evaluated along with an individual's genetic signature, and that tools such as biomarker levels can be implemented to achieve the most reliable prediction of clinically relevant pharmacodynamic endpoints.

PMID:35983889 | DOI:10.1080/17425255.2022.2113380

Categories: Literature Watch

Perceptions, practices and barriers to reporting of adverse drug reactions among HIV infected patients and their doctors in 3 public sector hospitals of the Ethekwini Metropolitan, Kwa-Zulu Natal: a cross sectional and retrospective analysis

Thu, 2022-08-18 06:00

BMC Health Serv Res. 2022 Aug 18;22(1):1054. doi: 10.1186/s12913-022-08395-3.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) remain a global public health concern. Pharmacovigilance practises are essential in ensuring patients safety and post drug marketing surveillance. This study aimed to describe practices, perceptions and barriers towards ADR reporting practices amongst People Living with HIV/AIDS (PLWHA), who are on Highly Active Anti-Retroviral Therapy (HAART) and their doctors.

METHODS: The study took place at 3 public sector hospitals. The first phase of the study was a quantitative cross-sectional study using a closed ended questionnaire that was given to PLWHA. Phase two was a retrospective analysis of these patients' medical files, whilst phase 3 included a descriptive statistics to determine the frequencies and percentages for variables such as ADR reporting practices by doctors.

RESULTS: Spontaneous reporting, was evident with 202 patients (48%) indicating that they reported experiencing ADRs to their doctors. Ten doctors (77%) indicated that they received PV training. Eight (62%) doctors indicated that the completed ADR reporting forms were submitted to the pharmacy manager in the hospital for forwarding to the regulatory authority, with 2 (15%) indicating that they submitted directly to the South African Health Products Regulatory Authority. Four (31%) doctors stated that the system of reporting ADRs is ineffective with the majority of the doctors 12 (92%) responding that the reporting of ADRs is very important/critical. A barrier cited by 4 patients (0.9%) for non-reporting of their ADRs was transport cost. Whilst doctors' barriers included reporting being time consuming (31%), and a lack of availability of reporting forms (31%).

CONCLUSION: Patients and doctors are reporting ADRs but more education and easier reporting process should be available to strengthen the knowledge and reporting of ADRs. Doctors agree that it is critical to report ADRs. Electronic reporting should be encouraged to lessen the time it takes to report ADRs.

PMID:35982442 | PMC:PMC9389709 | DOI:10.1186/s12913-022-08395-3

Categories: Literature Watch

Reply: Side Effects of Amiodarone

Thu, 2022-08-18 06:00

JACC Clin Electrophysiol. 2022 Aug;8(8):1049-1050. doi: 10.1016/j.jacep.2022.07.002.

NO ABSTRACT

PMID:35981796 | DOI:10.1016/j.jacep.2022.07.002

Categories: Literature Watch

Side Effects of Amiodarone

Thu, 2022-08-18 06:00

JACC Clin Electrophysiol. 2022 Aug;8(8):1048. doi: 10.1016/j.jacep.2022.05.019.

NO ABSTRACT

PMID:35981795 | DOI:10.1016/j.jacep.2022.05.019

Categories: Literature Watch

Rebuilding trust in proton pump inhibitor therapy

Thu, 2022-08-18 06:00

World J Gastroenterol. 2022 Jun 28;28(24):2667-2679. doi: 10.3748/wjg.v28.i24.2667.

ABSTRACT

Introduction of proton pump inhibitor (PPI) therapy into clinical practice has revolutionized treatment approach to acid-related diseases. With its clinical success came a widespread use of PPI therapy. Subsequently, several studies found that PPIs were oftentimes overprescribed in primary care and emergency setting, likely attributed to seemingly low side-effect profile and physicians having low threshold to initiate therapy. However, now there is a growing concern over PPI side-effect profile among both patients and providers. We would like to bring more awareness to the currently available guidelines on PPI use, discuss clinical indications for PPIs and the evidence behind the reported side-effects. We hope that increased awareness of proper PPI use will make the initiation or continuation of therapy a well informed and an evidence-based decision between patient and physician. We also hope that discussing evidence behind the reported side-effect profile will help clarify the growing concerns over PPI therapy.

PMID:35979162 | PMC:PMC9260870 | DOI:10.3748/wjg.v28.i24.2667

Categories: Literature Watch

An Unusual Case of Drug-Induced Liver Injury Secondary to Nitrofurantoin Use

Thu, 2022-08-18 06:00

Cureus. 2022 Jul 15;14(7):e26882. doi: 10.7759/cureus.26882. eCollection 2022 Jul.

ABSTRACT

Nitrofurantoin is a commonly prescribed antibiotic for uncomplicated urinary tract infections. Despite a number of side effects, it is increasingly prescribed due to its low cost, high efficacy, and minimal antimicrobial resistance. One of the rare, however significant side effects of nitrofurantoin is idiosyncratic drug-induced liver toxicity. It commonly presents with abdominal pain and elevated liver enzymes. Interestingly, it can cause either an acute or a chronic hepatitis-like syndrome that can be severe and lead to liver failure or cirrhosis. We present a case of a healthy 24-year-old female who presented with epigastric abdominal pain, which was found to be drug-induced liver injury (DILI) secondary to her recent nitrofurantoin use.

PMID:35978742 | PMC:PMC9375953 | DOI:10.7759/cureus.26882

Categories: Literature Watch

Methotrexate Toxicity: A Case Series from a Tertiary Care Center in Northern India

Wed, 2022-08-17 06:00

Skinmed. 2022 Aug 31;20(4):274-281. eCollection 2022.

ABSTRACT

Methotrexate is widely prescribed by various specialists, including internists, dermatologists, rheumatologists, orthopedics, and oncologists. The clinical features of acute methotrexate toxicity vary and are influenced by the acute cumulative dose, duration of methotrexate, associated risk factors, comorbidities, and drug interactions. We present a series of six patients with acute methotrexate toxicity. The characteristics of their clinical presentation, diagnoses, and risk factors are highlighted. All patients were given intravenous leucovorin and other supportive treatments. This series highlights the importance of thorough counseling for patients regarding the course of disease for which methotrexate is prescribed and the dosing, schedule, and adverse effects that are associated with methotrexate. Physician awareness, diagnosis, and treatment are crucial for mitigating the complications of methotrexate toxicity. (SKINmed. 2022;20:274-281).

PMID:35976016

Categories: Literature Watch

HORNBILL: a phase I/IIa trial examining the safety, tolerability and early response of BI 764524 in patients with diabetic retinopathy and diabetic macular ischaemia-rationale, study design and protocol

Wed, 2022-08-17 06:00

Trials. 2022 Aug 17;23(1):669. doi: 10.1186/s13063-022-06527-y.

ABSTRACT

BACKGROUND: Diabetic macular ischaemia (DMI) is a complication of diabetic retinopathy that leads to irreversible vision loss. DMI is characterised by reduced retinal vessel density and enlargement of the foveal avascular zone (FAZ). Despite its clinical burden, there is no formal consensus on the definition of DMI, and no approved treatment. Semaphorin 3A (Sema3A) is an axonal guidance molecule that blocks revascularisation of the ischaemic retina. Sema3A modulation is therefore a promising mechanism of action for the treatment of ischaemic eye diseases. BI 764524 is an intravitreal anti-Sema3A ischaemia modulator agent.

METHODS: HORNBILL (NCT04424290) is a phase I/IIa trial comprising a non-randomised, open-label, single rising dose (SRD) part and a randomised, masked, sham-controlled multiple dose (MD) part to investigate the safety, tolerability and early biological response of ischaemia modulator BI 764524 in adults (≥18 years) with DMI. DMI will be defined using optical coherence tomography angiography (OCTA) as either any degree of disruption in the retinal vascularity (SRD) or a FAZ of ≥0.5 mm2 (MD). Subjects in the SRD part will receive 0.5, 1.0 or 2.5 mg of BI 764524; the maximum tolerated dose will then be used in the MD part. A minimum of 12 subjects will be enrolled into the SRD part; planned enrollment is 30 for the MD part. The primary endpoint of the SRD part is the number of subjects with dose-limiting adverse events (AEs) until day 8. The primary endpoint of the MD part is the number of subjects with drug-related AEs from baseline to end of study, and secondary endpoints include change from baseline in the size of the FAZ, best-corrected visual acuity and central retinal thickness.

DISCUSSION: DMI is a poorly defined condition with no treatment options. HORNBILL is the first clinical trial to assess a treatment for DMI and to use OCTA as a means to define and examine DMI. The OCTA data generated in this trial could form the basis of formal diagnostic criteria for DMI. Furthermore, the novel mechanism of action (Sema3A modulation) explored in this trial has the potential to revolutionise the treatment landscape for patients with DMI.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04424290 ; EudraCT 2019-004432-28. Registered on 9 June 2020.

PMID:35978329 | DOI:10.1186/s13063-022-06527-y

Categories: Literature Watch

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer

Wed, 2022-08-17 06:00

Nat Commun. 2022 Aug 17;13(1):4829. doi: 10.1038/s41467-022-31859-3.

ABSTRACT

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

PMID:35977936 | DOI:10.1038/s41467-022-31859-3

Categories: Literature Watch

RECAM: A New and Improved, Computerized Causality Assessment Tool for DILI Diagnosis

Tue, 2022-08-16 06:00

Am J Gastroenterol. 2022 Sep 1;117(9):1387-1389. doi: 10.14309/ajg.0000000000001836. Epub 2022 May 25.

NO ABSTRACT

PMID:35973138 | DOI:10.14309/ajg.0000000000001836

Categories: Literature Watch

HLA pharmacogenetic markers of drug hypersensitivity from the perspective of the populations of the Greater Middle East

Tue, 2022-08-16 06:00

Pharmacogenomics. 2022 Aug;23(12):695-708. doi: 10.2217/pgs-2022-0078. Epub 2022 Aug 16.

ABSTRACT

Specific HLA associations with drug hypersensitivity may vary between geographic regions and ethnic groups. There are little to no data related to HLA-drug hypersensitivity on populations who reside in the Greater Middle East (GME), a vast region spanning from Morocco in the west to Pakistan in the east. In this review, the authors intended to summarize the significant HLA alleles associated with hypersensitive drug reactions induced by different drugs, as have been found in different populations, and to summarize the prevalence of these alleles in the specific and diverse populations of the GME. For example, HLA-B*57:01 allele prevalence, associated with abacavir-induced hypersensitivity, ranges from 1% to 3%, and HLA-DPB1*03:01 prevalence, associated with aspirin-induced asthma, ranges from 10% to 14% in the GME population. Studying pharmacogenomic associations in the ethnic groups of the GME may allow the discovery of new associations, confirm ones found with a low evidence rate and enable cost-effectiveness analysis of allele screening before drug use.

PMID:35971864 | DOI:10.2217/pgs-2022-0078

Categories: Literature Watch

Effects of side-effect risk framing strategies on COVID-19 vaccine intentions: a randomized controlled trial

Tue, 2022-08-16 06:00

Elife. 2022 Aug 16;11:e78765. doi: 10.7554/eLife.78765.

ABSTRACT

BACKGROUND: Fear over side-effects is one of the main drivers of COVID-19 vaccine hesitancy. A large literature in the behavioral and communication sciences finds that how risks are framed and presented to individuals affects their judgments of its severity. However, it remains unknown whether such framing changes can affect COVID-19 vaccine behavior and be deployed as policy solutions to reduce hesitancy.

METHODS: We conducted a pre-registered randomized controlled trial among 8998 participants in the United States and the United Kingdom to examine the effects of different ways of framing and presenting vaccine side-effects on individuals' willingness to get vaccinated and their perceptions of vaccine safety.

RESULTS: Adding a descriptive risk label ('very low risk') next to the numerical side-effect and providing a comparison to motor-vehicle mortality increased participants' willingness to take the COVID-19 vaccine by 3.0 percentage points (p=0.003) and 2.4 percentage points (p=0.049), respectively. These effects were independent and additive and combining both framing strategies increased willingness to receive the vaccine by 6.1 percentage points (p<0.001). Mechanistically, we find evidence that these framing effects operate by increasing individuals' perceptions of how safe the vaccine is.

CONCLUSIONS: Low-cost side-effect framing strategies can meaningfully affect vaccine intentions at a population level.

FUNDING: Heidelberg Institute of Global Health.

CLINICAL TRIAL NUMBER: German Clinical Trials Registry (#DRKS00025551).

PMID:35971757 | DOI:10.7554/eLife.78765

Categories: Literature Watch

Drug-related problem characterization and the solved status associated factor analysis in a pharmacist-managed anticoagulation clinic

Mon, 2022-08-15 06:00

PLoS One. 2022 Aug 15;17(8):e0270263. doi: 10.1371/journal.pone.0270263. eCollection 2022.

ABSTRACT

Drug-related problems (DRPs) in a pharmacist-managed anticoagulation clinic (AC) have not been extensively studied. We aimed to characterize the DRPs in a pharmacist-managed AC, identify the factors associated with the solved status of DRPs, and analyze the secondary outcomes, including the safety and efficacy of AC service. The patients receiving services at a pharmacist-managed AC in a medical center for the first time from March 2019 to August 2020 were reviewed retrospectively. The DRPs were retrieved from a self-developed Intelligent AC Service System and classified according to the Pharmaceutical Care Network Europe Foundation v9.0 classification system. Logistic regression models were performed to identify the potential factors associated with the solved status of DRPs. A total of 78 direct oral anticoagulant (DOAC) and 34 warfarin users were included. The major types of DRPs identified at the initial service were adverse drug events (ADEs) (68.4%) and untreated symptoms or indications (14.8%) in the DOAC group, and ADEs (51.6%) and suboptimal effect of drug treatment (38.7%) in the warfarin group. The rates of totally solved DRPs were 56.8% and 51.6% in the DOAC and warfarin groups, respectively. According to the multivariable analysis, receiving AC services 3 times or more in 180 days (OR 3.11, 95% CI 1.30-7.44) was associated with the totally solved status of DRPs in the DOAC group, but no relevant factor was identified in the warfarin group. The secondary outcomes showed that DOAC users demonstrated fewer thromboembolism events, major bleeding, and bleeding-related hospitalizations after AC services, whereas the warfarin users increased percentage time in therapeutic range (TTR% 55.0% vs. 74.6%, P = 0.006) after AC services. These findings may be utilized to develop DOAC and warfarin AC services.

PMID:35969589 | PMC:PMC9377620 | DOI:10.1371/journal.pone.0270263

Categories: Literature Watch

Adverse Effects of Sit and Stand Workstations on the Health Outcomes of Assembly Line Workers: A Cross-sectional Study

Mon, 2022-08-15 06:00

J Prev Med Hyg. 2022 Jul 31;63(2):E344-E350. doi: 10.15167/2421-4248/jpmh2022.63.2.1567. eCollection 2022 Jun.

ABSTRACT

INTRODUCTION: Sitting and standing workstations can affect individual's health outcomes differently. This study aimed to assess the effects of sit and stand workstations on energy expenditure and blood parameters, including glucose and triglyceride, musculoskeletal symptoms/pain and discomfort, fatigue, and productivity among workers of assembly line of a belt factory.

METHODS: This cross-sectional study was conducted on 47 male assembly line workers (24 workers in sitting workstation and 23 workers in standing workstation) with at least one year of working experience. Data were gathered via demographic/occupational characteristics, Fitbit system, medical records, the Persian version of the Nordic Musculoskeletal Questionnaire (P-NMQ), the Persian version of the Numeric Rating Scale (P-NRS), the Persian version of the Swedish Occupational Fatigue (P-SOFI), and Persian version of the Health and Work Questionnaire (P-HWQ).

RESULTS: The results showed that there were no statistically significant between the demographic/occupational details of the participants in sitting and standing groups, except work experience. The findings of the present study revealed that the energy expenditure, and blood glucose/triglyceride there are not statistically differences between sitting and standing groups. In addition, the prevalence of musculoskeletal symptoms in the neck, lower back, knees, and ankles/feet in standing group was significantly higher than the sitting group. The means of severity of discomfort/pain in all body regions were significantly higher in standing group compared to other group. Generally, occupational fatigue was higher among the standing group compared to sitting group. About productivity, the 'concentration/focus' and 'impatience/irritability' subscales in sitting group were higher than the standing group. Contrariwise, other subscales of the productivity, including 'productivity', 'supervisor relations', 'non-work satisfaction', 'work satisfaction' in the standing group were higher than the sitting group.

CONCLUSIONS: To reduce the adverse effects of sitting and standing workstations on individual's health outcomes, planning to use sit-stand workstations is recommended.

PMID:35968062 | PMC:PMC9351412 | DOI:10.15167/2421-4248/jpmh2022.63.2.1567

Categories: Literature Watch

In vitro/in silico prediction of drug induced steatosis in relation to oral doses and blood concentrations by the Nile Red assay

Sat, 2022-08-13 06:00

Toxicol Lett. 2022 Sep 1;368:33-46. doi: 10.1016/j.toxlet.2022.08.006. Epub 2022 Aug 10.

ABSTRACT

The accumulation of lipid droplets in hepatocytes is a key feature of drug-induced liver injury (DILI) and can be induced by a subset of hepatotoxic compounds. In the present study, we optimized and evaluated an in vitro technique based on the fluorescent dye Nile Red, further named Nile Red assay to quantify lipid droplets induced by the exposure to chemicals. The Nile Red assay and a cytotoxicity test (CTB assay) were then performed on cells exposed concentration-dependently to 60 different compounds. Of these, 31 were known to induce hepatotoxicity in humans, and 13 were reported to also cause steatosis. In order to compare in vivo relevant blood concentrations, pharmacokinetic models were established for all compounds to simulate the maximal blood concentrations (Cmax) at therapeutic doses. The results showed that several hepatotoxic compounds induced an increase in lipid droplets at sub-cytotoxic concentrations. To compare how well (1) the cytotoxicity test alone, (2) the Nile Red assay alone, and (3) the combination of the cytotoxicity test and the Nile Red assay (based on the lower EC10 of both assays) allow the differentiation between hepatotoxic and non-hepatotoxic compounds, a previously established performance metric, the Toxicity Separation Index (TSI) was calculated. In addition, the Toxicity Estimation Index (TEI) was calculated to determine how well blood concentrations that cause an increased DILI risk can be estimated for hepatotoxic compounds. Our findings indicate that the combination of both assays improved the TSI and TEI compared to each assay alone. In conclusion, the study demonstrates that inclusion of the Nile Red assay into in vitro test batteries may improve the prediction of DILI compounds.

PMID:35963427 | DOI:10.1016/j.toxlet.2022.08.006

Categories: Literature Watch

Statins Neuromuscular Adverse Effects

Fri, 2022-08-12 06:00

Int J Mol Sci. 2022 Jul 28;23(15):8364. doi: 10.3390/ijms23158364.

ABSTRACT

Statins are drugs widely prescribed in high-risk patients for cerebrovascular or cardiovascular diseases and are, usually, safe and well tolerated. However, these drugs sometimes may cause neuromuscular side effects that represent about two-third of all adverse events. Muscle-related adverse events include cramps, myalgia, weakness, immune-mediated necrotizing myopathy and, more rarely, rhabdomyolysis. Moreover, they may lead to peripheral neuropathy and induce or unmask a preexisting neuromuscular junction dysfunction. A clinical follow up of patients assuming statins could reveal early side effects that may cause neuromuscular damage and suggest how to better modulate their use. In fact, statin dechallenge or cessation, or the alternative use of other lipid-lowering agents, can avoid adverse events. This review summarizes the current knowledge on statin-associated neuromuscular adverse effects, diagnosis, and management. It is conceivable that the incidence of neuromuscular complications will increase because, nowadays, use of statins is even more diffused than in the past. On this purpose, it is expected that pharmacogenomic and environmental studies will help to timely predict neuromuscular complications due to statin exposure, leading to a more personalized therapeutic approach.

PMID:35955495 | PMC:PMC9369175 | DOI:10.3390/ijms23158364

Categories: Literature Watch

2-deoxyglucose transiently inhibits yeast AMPK signaling and triggers glucose transporter endocytosis, potentiating the drug toxicity

Thu, 2022-08-11 06:00

PLoS Genet. 2022 Aug 11;18(8):e1010169. doi: 10.1371/journal.pgen.1010169. eCollection 2022 Aug.

ABSTRACT

2-deoxyglucose is a glucose analog that impacts many aspects of cellular physiology. After its uptake and its phosphorylation into 2-deoxyglucose-6-phosphate (2DG6P), it interferes with several metabolic pathways including glycolysis and protein N-glycosylation. Despite this systemic effect, resistance can arise through strategies that are only partially understood. In yeast, 2DG resistance is often associated with mutations causing increased activity of the yeast 5'-AMP activated protein kinase (AMPK), Snf1. Here we focus on the contribution of a Snf1 substrate in 2DG resistance, namely the alpha-arrestin Rod1 involved in nutrient transporter endocytosis. We report that 2DG triggers the endocytosis of many plasma membrane proteins, mostly in a Rod1-dependent manner. Rod1 participates in 2DG-induced endocytosis because 2DG, following its phosphorylation by hexokinase Hxk2, triggers changes in Rod1 post-translational modifications and promotes its function in endocytosis. Mechanistically, this is explained by a transient, 2DG-induced inactivation of Snf1/AMPK by protein phosphatase 1 (PP1). We show that 2DG-induced endocytosis is detrimental to cells, and the lack of Rod1 counteracts this process by stabilizing glucose transporters at the plasma membrane. This facilitates glucose uptake, which may help override the metabolic blockade caused by 2DG, and 2DG export-thus terminating the process of 2DG detoxification. Altogether, these results shed a new light on the regulation of AMPK signaling in yeast and highlight a remarkable strategy to bypass 2DG toxicity involving glucose transporter regulation.

PMID:35951639 | PMC:PMC9398028 | DOI:10.1371/journal.pgen.1010169

Categories: Literature Watch

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