Viruses. 2023 Apr 10;15(4):936. doi: 10.3390/v15040936.

ABSTRACT

BACKGROUND: The high effectiveness and safety of the two-drug (2DRs) strategy using dolutegravir (DTG) plus lamivudine (3TC) have led to international guidelines recommending their use for treatment-naive HIV patients. In virologically suppressed patients, de-escalating from 3DRs to DTG plus either rilpivirine (RPV) or 3TC has shown high rates of virological suppression.

OBJECTIVES: This study aimed to compare the real-life data of two multicenter Spanish cohorts of PLWHIV treated with DTG plus 3TC (SPADE-3) or RPV (DORIPEX) as a switch strategy, not only in terms of virological suppression, safety, and durability but also in terms of immune restoration. The primary endpoint was the percentage of patients with virological suppression on DTG plus 3TC and DTG plus RPV at weeks 24 and 48. The secondary outcomes included the proportion of patients who experienced the protocol-defined loss of virological control by week 48; changes in immune status in terms of CD4+ and CD8+ T lymphocyte counts and the CD4+/CD8+ ratio; the rate, incidence, and reasons for discontinuation of treatment over the 48-week study period; and safety profiles at weeks 24 and 48.

METHODS: We conducted a retrospective, observational, multicenter study of 638 and 943 virologically suppressed HIV-1-infected patients in two cohorts who switched to 2DRs with DTG plus RPV or DTG plus 3TC.

RESULTS: The most frequent reasons for starting DTG-based 2DRs were treatment simplification/pill burden or drug decrease. The virological suppression rates were 96.9%, 97.4%, and 99.1% at weeks 24, 48, and 96, respectively. The proportion of patients with virological failure over the 48-week study period was 0.01%. Adverse drug reactions were uncommon. Patients treated with DTG+3TC increased CD4, CD8, and CD4/CD8 parameters at 24 and 48 weeks.

CONCLUSIONS: We conclude that DTG-based 2DRs (combined with 3TC or RPV) in clinical practice were effective and safe as a switching strategy, with a low VF and high viral suppression rates. Both regimens were well tolerated, and ADR rates were low, including neurotoxicity and induced treatment discontinuations.

PMID:37112915 | PMC:PMC10145987 | DOI:10.3390/v15040936

Sensors (Basel). 2023 Apr 13;23(8):3962. doi: 10.3390/s23083962.

ABSTRACT

Possible drug-food constituent interactions (DFIs) could change the intended efficiency of particular therapeutics in medical practice. The increasing number of multiple-drug prescriptions leads to the rise of drug-drug interactions (DDIs) and DFIs. These adverse interactions lead to other implications, e.g., the decline in medicament's effect, the withdrawals of various medications, and harmful impacts on the patients' health. However, the importance of DFIs remains underestimated, as the number of studies on these topics is constrained. Recently, scientists have applied artificial intelligence-based models to study DFIs. However, there were still some limitations in data mining, input, and detailed annotations. This study proposed a novel prediction model to address the limitations of previous studies. In detail, we extracted 70,477 food compounds from the FooDB database and 13,580 drugs from the DrugBank database. We extracted 3780 features from each drug-food compound pair. The optimal model was eXtreme Gradient Boosting (XGBoost). We also validated the performance of our model on one external test set from a previous study which contained 1922 DFIs. Finally, we applied our model to recommend whether a drug should or should not be taken with some food compounds based on their interactions. The model can provide highly accurate and clinically relevant recommendations, especially for DFIs that may cause severe adverse events and even death. Our proposed model can contribute to developing more robust predictive models to help patients, under the supervision and consultants of physicians, avoid DFI adverse effects in combining drugs and foods for therapy.

PMID:37112302 | PMC:PMC10143839 | DOI:10.3390/s23083962

Nutrients. 2023 Apr 7;15(8):1807. doi: 10.3390/nu15081807.

ABSTRACT

Supplementation is known to enhance the immune response and reduce infection. Therefore, the association between immune nutrients and vaccine side effects needs to be investigated. Our aim was to analyze the relationship between vaccination side effects and supplement intake among the Italian population. The study included a questionnaire asking for personal data, anthropometric information, COVID-19 infection and immunity response, and COVID-19 vaccination and supplementation. The survey was conducted from 8 February to 15 June 2022. In the study, 776 respondents were included, aged between 18 and 86 (71.3% females). We observed a statistically significant correlation between supplement consumption and side effects at the end of the vaccination cycle (p = 0.000), which was also confirmed by logistic regression (p = 0.02). Significant associations were observed between supplement intake and side effects of diarrhea and nausea at the end of the vaccination cycle (p = 0.001; p = 0.04, respectively). Significant associations were observed between side effects and omega-3 and mineral supplementation at the start of the vaccination cycle (p = 0.02; p = 0.001, respectively), and between side effects and vitamin supplementation at the end of the vaccination cycle (p = 0.005). In conclusion, our study shows a positive impact of supplementation on vaccination response, increasing host immune defenses, and reducing side effects.

PMID:37111026 | PMC:PMC10141698 | DOI:10.3390/nu15081807

Drug Ther Bull. 2023 May;61(5):66. doi: 10.1136/dtb.2023.000021.

NO ABSTRACT

PMID:37116907 | DOI:10.1136/dtb.2023.000021

Cancer Immunol Immunother. 2023 Apr 28. doi: 10.1007/s00262-023-03434-2. Online ahead of print.

ABSTRACT

MSB2311 is a novel pH-dependent humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody. This phase I study primarily aimed to determine the maximum tolerated dose (MTD)/recommended phase 2 dose level (RP2D) of MSB2311 in patients with advanced solid tumors or lymphoma. MSB2311 was intravenously administered at 3, 10, and 20 mg/kg every 3 weeks (Q3W) and 10 mg/kg every 2 weeks (Q2W) using 3 + 3 design. During expansion phase, eligible patients with either PD-L1 overexpression, Epstein-Barr Virus positive, microsatellite instability high/mismatch repair deficient, or high tumor mutation burden tumors were treated at RP2D. A total of 37 Chinese patients were treated, including 31 with solid tumors and 6 lymphoma. No dose limiting toxicity was reported and MTD was not reached. The trial was expanded at 20 mg/kg Q3W or 10 mg/kg Q2W, both of which were determined as RP2D. Most common drug-related treatment-emergent adverse events were anemia (43.2%), aspartate aminotransferase increase (27.0%), proteinuria (21.6%), alanine aminotransferase increase and hypothyroidism (18.9% each), thyroid stimulating hormone increased and hyperglycemia (16.2% each). Out of 20 efficacy evaluable patients with biomarker positive solid tumors, 6 achieved confirmed partial response with the median duration of response of 11.0 months (95% CI 7.0-11.4) and 4 had stable disease, resulting an objective response rate of 30.0% (95% CI 11.9, 54.3) and disease control rate of 50.0% (95% CI 27.2, 72.8). One partial response was also observed among 6 patients with lymphoma. MSB2311 demonstrated a manageable safety profile and promising antitumor activity in patients with advanced solid tumors and lymphomas.

PMID:37115210 | DOI:10.1007/s00262-023-03434-2

Therap Adv Gastroenterol. 2023 Apr 20;16:17562848231167858. doi: 10.1177/17562848231167858. eCollection 2023.

ABSTRACT

BACKGROUND: Vonoprazan, a novel acid-suppressive drug, is non-inferior to proton pump inhibitors (PPIs) for the management of gastric acid-related diseases. However, the safety of vonoprazan has not been systematically evaluated yet.

OBJECTIVES: To elucidate the incidence and type of adverse events (AEs) in patients taking vonoprazan.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES AND METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for all studies reporting the safety of vonoprazan. The incidences of any AEs, drug-related AEs, serious AEs, AEs leading to drug discontinuation, and common AEs were pooled. Odds ratios (ORs) were calculated to compare the incidence of AEs between patients taking vonoprazan and PPIs.

RESULTS: Seventy-seven studies were included. The pooled incidences of any AEs, drug-related AEs, serious AEs, and AEs leading to drug discontinuation were 20, 7, 1, and 1%, respectively. The incidences of any AEs (OR = 0.96, p = 0.66), drug-related AEs (OR = 1.10, p = 0.44), serious AEs (OR = 1.14, p = 0.36), and AEs leading to drug discontinuation (OR = 1.09, p = 0.55) were not significantly different between patients taking vonoprazan and PPIs. In subgroup analyses, patients with peptic ulcer disease (PUD) had higher incidences of any AEs, serious AEs, and AEs leading to drug discontinuation than those with gastroesophageal reflux disease (GERD), Helicobacter pylori (H. pylori) infection, and artificial ulcer after gastric endoscopic submucosal dissection (ESD), but patients with H. pylori infection had a higher incidence of drug-related AEs than those with PUD, GERD, and artificial ulcer after gastric ESD. The incidence of AEs was higher in patients taking long-term use of vonoprazan than those taking short-term use of vonoprazan.

CONCLUSION: Vonoprazan is well tolerated and shows similar safety compared to PPIs. The safety of vonoprazan may be primarily influenced by its indications and duration.

REGISTRATION: PROSPERO CRD42022314982.

PMID:37113190 | PMC:PMC10126681 | DOI:10.1177/17562848231167858

Medicina (Kaunas). 2023 Apr 17;59(4):780. doi: 10.3390/medicina59040780.

ABSTRACT

Background and objectives: Drug-drug interactions and drug-related problems in patients with vascular diseases are common. To date, very few studies have focused on these important problems. The aim of the present study is to investigate the most common drug-drug interactions and DRPs in patients with vascular diseases. Materials and Methods: The medications of 1322 patients were reviewed manually in the time period from 11/2017 to 11/2018; the medications of 96 patients were entered into a clinical decision support system. Potential drug problems were identified, and a read-through consensus was reached between a clinical pharmacist and a vascular surgeon during the clinical curve visits; possible modifications were implemented. The focus was on additional dose adjustment and drug antagonization on drug interactions. Interactions were classified as contraindicated/high-risk combination (drugs must not be combined), clinically serious (interaction can be potentially life-threatening or have serious, possibly irreversible consequences), or potentially clinically relevant and moderate (interaction can lead to therapeutically relevant consequences). Results: A total of 111 interactions were observed. Of these, 6 contraindicated/high-risk combinations, 81 clinically serious interactions, and 24 potentially clinically relevant and moderate interactions were identified. Furthermore, 114 interventions were recorded and categorized. Discontinued use of the drug (36.0%) and drug dose adjustment (35.1%) were the most common interventions. Mostly, antibiotic therapy was continued unnecessarily (10/96; 10.4%), and the adjustment of the dosage to kidney function was overlooked in 40/96; 41.7% of the cases. In the most common cases, a dose reduction was not considered necessary. Here, unadjusted doses of antibiotics were found in 9/96, 9.3% of the cases. Notes for medical professionals summarized information that did not require direct intervention but rather increased attention on the part of the ward doctor. It was usually necessary to monitor laboratory parameters (49/96, 51.0%) or the patients for side effects (17/96, 17.7%), which were expected with the combinations used. Conclusions: This study could help identify problematic drug groups and develop prevention strategies for drug-related problems in patients with vascular diseases. A multidisciplinary collaboration between the different professional groups (clinical pharmacists and surgeons) might optimize the medication process. Collaborative care could have a positive impact on therapeutic outcomes and make drug therapy safer for patients with vascular diseases.

PMID:37109738 | DOI:10.3390/medicina59040780

Pestic Biochem Physiol. 2023 May;192:105391. doi: 10.1016/j.pestbp.2023.105391. Epub 2023 Mar 15.

ABSTRACT

The use of arsenic in arsenic-based pesticides has been common in many countries in the past and today. There is considerable evidence linking arsenic exposure to hepatotoxicity and diabetes. Destructive phenomena such as hepatic oxidative stress and inflammation can interfere with glucose uptake and insulin function. In the present study, the antioxidant, anti-inflammatory, and molecular mechanism of citicoline against sodium arsenite-induced hepatotoxicity and glucose intolerance were investigated in mice. Citicoline improved glucose tolerance impaired by sodium arsenite. Citicoline increased the hepatic activity of catalase, superoxide dismutase, and glutathione peroxidase enzymes. Moreover, we found that citicoline prevents an increase in the levels of thiobarbituric acid reactive substances. Citicoline reduced levels of caspase 3, tumor necrosis factor-alpha, and interleukin 6 in sodium arsenite intoxicated groups. It was shown that citicoline increased the expression of arsenite methyltransferase, vesicle-associated membrane protein 2, peroxisome proliferator-activated receptor gamma, and sirtuin 3 to combat sodium arsenite toxicity. Citicoline reduced glucose intolerance, which was disrupted by sodium arsenite, by affecting the pancreatic and extra-pancreatic pathways involved in insulin production, secretion, and action. Based on our results, citicoline can be considered a modulating agent against arsenic-induced hepatotoxicity and hyperglycemia. Considering the relationship between arsenic exposure and the occurrence of side effects such as liver toxicity and diabetes, it is necessary to monitor and awareness of arsenic residues from sources such as drinking water.

PMID:37105618 | DOI:10.1016/j.pestbp.2023.105391

In Vivo. 2023 May-Jun;37(3):1260-1265. doi: 10.21873/invivo.13203.

ABSTRACT

BACKGROUND/AIM: Interstitial lung disease (ILD) is a serious adverse event (AE) associated with the use of immune checkpoint inhibitors (ICIs). However, the risk factors for developing ICI-related ILD remain poorly understood. Therefore, this study investigated the effect of concomitant analgesics on developing ICI-related ILD using the Japanese Adverse Drug Event Report (JADER) database.

PATIENTS AND METHODS: All the reported AE data were downloaded from the Pharmaceuticals and Medical Devices Agency website, and the JADER data between January 2014 and March 2021 were analysed. The relationship between ICI-related ILD and concomitant use of analgesics was assessed using reporting odds ratio (ROR) and 95% confidence interval. We investigated whether the effect of developing ILD varied according to the type of analgesics used during ICI treatment.

RESULTS: Positive signals for ICI-related ILD development were detected for the concomitant use of the narcotic analgesics codeine, fentanyl and oxycodone, but not with morphine. In contrast, there were no positive signals for the concomitant use of the non-narcotic analgesics celecoxib, acetaminophen, loxoprofen and tramadol. An increased ROR for ICI-related ILD in cases with concomitant use of narcotic analgesics was observed in a multivariate logistic analysis adjusted by sex and age.

CONCLUSION: These results suggest that the concomitant use of narcotic analgesics is involved in the development of ICI-related ILD.

PMID:37103090 | DOI:10.21873/invivo.13203

Immun Inflamm Dis. 2023 Apr;11(4):e804. doi: 10.1002/iid3.804.

ABSTRACT

BACKGROUND: After introducing Covid-19 vaccines, a few side effects were reported, pityriasis rosea being one of them. Therefore, this study will systematically review its manifestation afteradministration.

METHODS: Databases were searched, covering a timeline from December 1, 2019 to February 28, 2022. Data were independently extracted and accessed for bias. SPSS statistical software version 25 was used for appropriate inferential statistics.

RESULTS: Thirty-one studies were included for data extraction after screening following the eligibility criteria. A total of 111 people were identified to have developed pityriasis rosea or pityriasis rosea-like eruptions after vaccination, out of which 36 (55.38%) were female. The average age of incidence was calculated to be 44.92 years, and 63 (62.37%) people presented after administration of the first dose. It was found popularly in the trunk area, either asymptomatically or with mild symptoms. Meantime the onset, was 8.58 days, and meantime it took to recover, was 6.44 weeks.

CONCLUSION: The association between pityriasis rosea and pityriasis rosea-like eruptions after Covid-19 vaccines was established, but given the scarcity of studies, there is a need to conduct different clinical trials to confirm this association further and study the etiology and mechanism of the disease.

PMID:37102660 | DOI:10.1002/iid3.804

Eur J Hosp Pharm. 2023 Apr 27:ejhpharm-2023-003694. doi: 10.1136/ejhpharm-2023-003694. Online ahead of print.

ABSTRACT

OBJECTIVES: Vancomycin therapeutic drug monitoring is challenging, especially in the paediatric population where evidence is scarce. The main objective of this study was to analyse the achievement of therapeutic concentrations of vancomycin in paediatric patients and to evaluate the current monitoring method (trough levels), doses used, and the time required to achieve target concentrations.

METHODS: Paediatric patients on treatment and monitored with vancomycin from November 2019 to December 2021 were included. Those with only one determination of serum vancomycin concentration were excluded. Demographic variables, analytical and microbiological parameters and toxicity data were collected. Pharmacokinetic parameters were assessed at baseline and during treatment.

RESULTS: 225 patients (40.9% female; 108 neonates, 49 infants and 68 children or adolescents) were included in the study. The main indications for vancomycin treatment were sepsis (33.9%) and fever of unknown origin (29.3%). Microbiological cultures were positive in 71.1%, mostly with Gram-positive bacteria (60.4%). Therapeutic levels of vancomycin were reached in only 20.1% of the participants in the first determination. After pharmacokinetic monitoring, 81.7% of patients reached therapeutic concentrations, requiring a 23% increase in the initial dose, a 2-day lag time and 1-2 dosage adjustments until the therapeutic concentration was reached. Of the total patients, 13 developed nephrotoxicity, nine neutropenia and one patient developed red man syndrome.

CONCLUSIONS: In our sample of paediatric patients, the recommended doses of vancomycin were insufficient to achieve therapeutic concentrations. Revision of the recommendations and/or a change in the method of pharmacokinetic monitoring is crucial to optimise treatment in this population.

PMID:37105712 | DOI:10.1136/ejhpharm-2023-003694

Hematology. 2023 Dec;28(1):2205739. doi: 10.1080/16078454.2023.2205739.

ABSTRACT

OBJECTIVES: To determine the impact of pretransplant measurable residual disease (pre-MRD) and the efficacy of maintenance therapy in t(8;21) acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (allo-HCT).

METHODS: We retrospectively analyzed 100 t(8;21) AML patients who underwent allo-HCT between 2013 and 2022. 40 patients received pre-emptive therapy including immunosuppressant adjustment, azacitidine, and donor lymphocyte infusion (DLI) combined with chemotherapy. 23 patients received prophylactic therapy, including azacitidine or chidamide.

RESULTS: Patients with a positive pre-MRD (pre-MRDpos) had a higher 3-year cumulative incidence of relapse (CIR) (25.90% [95% CI, 13.87%-39.70%] vs 5.00% [95% CI, 0.88%-15.01%]; P = 0.008). Pre-MRDpos patients were less likely to have a superior 3-year disease-free survival (DFS) (40.83% [95% CI, 20.80%-80.16%]) if their MRD was still positive at 28 days after transplantation (post-MRD28pos). The 3-year DFS and CIR were 53.17% (95% CI, 38.31% - 73.80%) and 34.87% (95% CI, 18.84% - 51.44%), respectively, for patients receiving pre-emptive interventions after molecular relapse. The 3-year DFS and CIR were 90.00% (95%CI, 77.77% - 100%) and 5.00% (95%CI, 0.31% - 21.10%), respectively, for high-risk patients receiving prophylactic therapy. In most patients, epigenetic-drug-induced adverse events were reversible with dose adjustment or temporary discontinuation.

CONCLUSION: Patients with pre-MRDpos and post-MRD28pos were more likely to have higher rates of relapse and inferior DFS, even after receiving pre-emptive interventions. Prophylactic therapy may be a better option for high-risk t(8;21) AML patients; however, this warrants further investigation.

PMID:37104677 | DOI:10.1080/16078454.2023.2205739

Exp Brain Res. 2023 Apr 27. doi: 10.1007/s00221-023-06616-7. Online ahead of print.

ABSTRACT

This study used transcranial magnetic stimulation (TMS) to determine if muscarinic receptor blockade affects muscle responses during voluntary contractions. Motor evoked potentials (MEPs) were recorded from biceps brachii in 10 subjects (age: 23 ± 2) during 10%, 25%, 50%, 75%, and 100% maximal voluntary contractions (MVCs). Each contraction intensity was examined under non-fatigued and fatigued conditions. All measurements were obtained post-ingestion of 25 mg promethazine or placebo. MEP area and the duration of the TMS-evoked silent period (SP) were calculated for all contractions. No drug-related differences were detected for MEP area during non-fatigued or fatigued contractions. A main effect of drug was detected for the SP (p = 0.019) where promethazine increased SP duration by an average of 0.023 [Formula: see text] 0.015 s. This drug effect was only identified for the unfatigued contractions and not following the sustained fatiguing contractions (p = 0.105). The cholinergic system does not influence corticospinal excitability during voluntary muscle contractions, but instead affects neural circuits associated with the TMS-evoked SP. Given the prevalence of cholinergic properties in prescription and over-the-counter medications, the current study enhances our understanding of mechanisms that may contribute to motor side-effects.

PMID:37103494 | DOI:10.1007/s00221-023-06616-7

Infect Dis Rep. 2023 Mar 30;15(2):180-187. doi: 10.3390/idr15020019.

ABSTRACT

Clostridioides difficile infection (CDI) is one of the most common hospital-acquired infections. Its incidence has increased during the last decade in the community among individuals with no previous risk factors; however, morbidity and mortality are still considered high in elderly patients. Oral Vancomycin and Fidaxomicin are the first lines of treatment for CDI. The systemic bioavailability of oral Vancomycin is thought to be undetectable due to its poor absorption in the gastrointestinal tract; therefore, routine monitoring is not warranted. Only 12 case reports were found in the literature that described adverse reactions associated with oral Vancomycin and its related risk factors. We present a case of a 66-year-old gentleman with severe CDI and acute renal failure who was started on oral Vancomycin upon admission. On day five of treatment, he developed leukocytosis associated with neutrophilia, eosinophilia, and atypical lymphocytes, with no evidence of active infection. Three days later, he developed a pruritic maculopapular rash in more than 50% of his body surface area. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) was ruled out since the patient only had three inclusion criteria for this diagnosis. No clear inciting agent was found. Oral Vancomycin was stopped and supportive treatment was supplied for a presumed Vancomycin-induced allergic reaction. The patient had an excellent response, with complete resolution of the rash and leukocytosis in less than 48 h. By reporting this case, we want to raise awareness among clinicians to remember that, albeit rare, oral Vancomycin can be the cause of adverse drug reactions in patients with severe illnesses.

PMID:37102979 | DOI:10.3390/idr15020019

J Clin Pharmacol. 2023 Apr 27. doi: 10.1002/jcph.2253. Online ahead of print.

ABSTRACT

This study aimed to evaluate the efficacy and safety of evening primrose oil(EPO) for cervical ripening before gynecologic procedures and compare it to misoprostol. In this study,40 hysteroscopy, dilation and curettage (D&C) candidates were enrolled. Patients were randomly assigned to receive either 2000 mg vaginal EPO (n = 20) or 200 μg vaginal misoprostol (n = 20) two hours before the expected procedure. The measured outcomes were the size of the Hegar dilator that passed through the cervix effortlessly, uterine cervicovaginal complications, and Drug-related side effects. The two groups were not significantly different in age, number of gravity, parity, type of delivery, and menopausal status (P>0.05). The mean ±SD size of the first dilator was 5.25 ± 1.55 in the misoprostol group and 7.30 ± 1.08 in the EPO group (P<0.001). The pain complaint in the EPO group was significantly lower (P = 0.027) but the two groups were not significantly different in terms of other complications. No cases of uterine or cervical rupture were seen in either group. The present study showed that 2000 mg vaginal EPO was significantly more effective for cervical ripening than 200 μg of vaginal misoprostol before gynecological surgery. Therefore, it is recommended to use EPO as an alternative to misoprostol. This article is protected by copyright. All rights reserved.

PMID:37102338 | DOI:10.1002/jcph.2253

Cureus. 2023 Mar 24;15(3):e36650. doi: 10.7759/cureus.36650. eCollection 2023 Mar.

ABSTRACT

Our case report highlights the importance of understanding various mechanisms of an atrioventricular block (AVB) and recognizing potential iatrogenic culprits. Despite the prevalent use of second-generation antipsychotics and the growing popularity of long-acting formulations, it is not routinely recognized as a cause for AVB. Second-generation antipsychotics such as risperidone have a dose-dependent pro-arrhythmic effect and are known to cause first-degree AVB. Our case presents an opportunity to recognize an unappreciated cause for AVB and switch to safer alternatives. In the era of long-acting injectables, it is important to monitor for these effects prior to escalating doses and risking high-degree AVB.

PMID:37101998 | PMC:PMC10123026 | DOI:10.7759/cureus.36650

Front Pharmacol. 2023 Apr 10;14:1158222. doi: 10.3389/fphar.2023.1158222. eCollection 2023.

ABSTRACT

Introduction: Tyrosine kinase inhibitor drugs (TKIs) are highly effective cancer drugs, yet many TKIs are associated with various forms of cardiotoxicity. The mechanisms underlying these drug-induced adverse events remain poorly understood. We studied mechanisms of TKI-induced cardiotoxicity by integrating several complementary approaches, including comprehensive transcriptomics, mechanistic mathematical modeling, and physiological assays in cultured human cardiac myocytes. Methods: Induced pluripotent stem cells (iPSCs) from two healthy donors were differentiated into cardiac myocytes (iPSC-CMs), and cells were treated with a panel of 26 FDA-approved TKIs. Drug-induced changes in gene expression were quantified using mRNA-seq, changes in gene expression were integrated into a mechanistic mathematical model of electrophysiology and contraction, and simulation results were used to predict physiological outcomes. Results: Experimental recordings of action potentials, intracellular calcium, and contraction in iPSC-CMs demonstrated that modeling predictions were accurate, with 81% of modeling predictions across the two cell lines confirmed experimentally. Surprisingly, simulations of how TKI-treated iPSC-CMs would respond to an additional arrhythmogenic insult, namely, hypokalemia, predicted dramatic differences between cell lines in how drugs affected arrhythmia susceptibility, and these predictions were confirmed experimentally. Computational analysis revealed that differences between cell lines in the upregulation or downregulation of particular ion channels could explain how TKI-treated cells responded differently to hypokalemia. Discussion: Overall, the study identifies transcriptional mechanisms underlying cardiotoxicity caused by TKIs, and illustrates a novel approach for integrating transcriptomics with mechanistic mathematical models to generate experimentally testable, individual-specific predictions of adverse event risk.

PMID:37101545 | PMC:PMC10123273 | DOI:10.3389/fphar.2023.1158222

Sci Rep. 2023 Apr 26;13(1):6826. doi: 10.1038/s41598-023-33967-6.

ABSTRACT

The aging of patients with tuberculosis and better therapeutic management for them are recent concerns. This study aimed to identify risk factors for adverse drug reactions (ADRs) or death in very elderly patients with pulmonary tuberculosis and to assess the association between the dosage of antituberculosis drugs and outcomes. We conducted a multicenter retrospective study at two hospitals. Hospitalized patients (≥ 80 years old) with pulmonary tuberculosis who were treated with antituberculosis drugs were enrolled. Multivariate analysis was performed to assess factors associated with ADRs or death within 60 days after treatment initiation. In total, 632 patients were included. The primary endpoint occurred in 268 patients (190 ADRs and 78 deaths). A serum albumin level < 2.5 g/dL, respiratory failure, and dependent activities of daily living were independent risk factors for ADRs or death. However, a low dosage (< 8 mg/kg/day) of rifampicin was associated with a lower risk of the primary outcomes. Delayed time to negative sputum culture conversion was not observed in the lower dosage of rifampicin group. Very elderly hospitalized tuberculosis patients with the aforementioned risk factors should be carefully monitored to receive safer treatment. Rifampicin dosage reduction may be considered for very elderly tuberculosis patients to prevent ADRs/death.

PMID:37100850 | PMC:PMC10133295 | DOI:10.1038/s41598-023-33967-6

Nat Commun. 2023 Apr 26;14(1):2177. doi: 10.1038/s41467-023-37709-0.

ABSTRACT

Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies.

PMID:37100783 | PMC:PMC10133246 | DOI:10.1038/s41467-023-37709-0

Indian J Tuberc. 2023 Apr;70(2):226-231. doi: 10.1016/j.ijtb.2022.05.008. Epub 2022 May 28.

ABSTRACT

INTRODUCTION: In the context of changing over from an intermittent treatment regimen to a daily regimen, it becomes crucial to understand the impact of a daily regimen on the treatment process and outcome. It enables health professionals to strengthen strategies, to enhance the quality of treatment as well as the quality of life of TB patients. The perspective of each stakeholder involved in the process is important in assessing the impact of the daily regimen.

OBJECTIVES: To understand patients' and providers' perspectives on the daily regimen of Tuberculosis treatment.

METHODOLOGY: A qualitative study was conducted between March 2020 to June 2020, including in-depth interviews with TB patients on treatment and DOT providers, and Key Informant Interview(KII) with TB Health Visitors(TBHV) and family members of TB patients. A thematic-network analysis approach was utilized to get the results.

RESULTS: Two sub-themes emerged: (i) Acceptance of the daily regimen of treatment; (ii) operational difficulties of the daily regimen. No injections in the regimen, fewer side effects of drugs as dose depends on weight band, family members can be treatment supporter, awareness about disease and treatment, the drugs are as same as private drugs available, adherence has improved, monthly DBT were found to some of the enablers in the study. The Barriers found in the study were traveling daily to get drugs, loss of daily wages, accompanying patients daily, tracing private patients, pyridoxine is not given free in this regimen, increased workload for treatment providers, etc. CONCLUSION: The study points out that acceptance of the patient to the daily regimen is better as they have lesser side effects. The operational difficulties in the implementation of the daily regimen can be addressed by providing family members as treatment supporters.

PMID:37100580 | DOI:10.1016/j.ijtb.2022.05.008