J Clin Oncol. 2021 Apr 6:JCO2003088. doi: 10.1200/JCO.20.03088. Online ahead of print.

ABSTRACT

PURPOSE: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking.

METHODS: Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug-related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience.

RESULTS: Two hundred two patients were included. Antitumor drug-related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group.

CONCLUSION: Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects.

PMID:33822650 | DOI:10.1200/JCO.20.03088

Contemp Clin Trials. 2021 Apr 2:106391. doi: 10.1016/j.cct.2021.106391. Online ahead of print.

ABSTRACT

Cancer-related symptoms, like depression, nausea, and pain, are common and negatively affect quality of life. Unfortunately, there is large inter-individual variability in response to supportive care medications for these symptoms. Pharmacogenomics may inform prescribing by identification of those genetically at risk for drug related adverse events or therapeutic failure. While such information can be applied to many drugs, there are specific oncology populations that could greatly benefit from pharmacogenomics-guided supportive care management due to high symptom burden, including those receiving palliative medicine and hematopoietic stem cell transplantation. The goal of this paper is to provide an overview of, and lessons learned from, the development of two prospective pharmacogenomics-guided interventional trials ("Supportive Care PGx Trial" and "Transplant PGx Trial") across two different clinical settings at the Levine Cancer Institute: the Department of Supportive Oncology and the Transplant and Cellular Therapy section. Key considerations included the appropriate study design and endpoints (balancing study goals and resources), dissemination and application of individual pharmacogenetics results, technical details about assay development, and overall care coordination to minimize clinic disruption.

PMID:33819640 | DOI:10.1016/j.cct.2021.106391

Front Oncol. 2021 Mar 17;11:662318. doi: 10.3389/fonc.2021.662318. eCollection 2021.

ABSTRACT

BACKGROUND: Previous studies, both in vitro and in vivo, have established that apatinib has anti-tumor properties. However, insufficient empirical evidence of the efficacy and safety of apatinib has been published for bone and soft tissue sarcoma, the reported results differing widely. Here, we conducted a meta-analysis to assess the efficacy and toxicity of apatinib for the treatment of bone and soft tissue sarcoma.

METHODS: Pubmed, Medline, Web of Science, ScienceDirect, Ovid, Embase, Cochrane Library, Scopus, Vip (China), Cnki (China), Wanfang (China), and CBM (China) databases and literature from conferences were searched for studies of apatinib for the treatment of bone and soft tissue sarcomas, published from the inception of each database to Sep 1, 2020, without language restrictions. Primary outcomes were efficacy and toxicity of apatinib for the treatment of bone and soft tissue sarcoma, including treatment response, progression-free survival (PFS), and the incidence of adverse events. After extraction of data and methodological quality evaluation, random or fixed-effects models, as appropriate, were selected to calculate pooled effect estimates using R software (Version 3.4.1).

RESULTS: A total of 21 studies with 827 participants were included in the present meta-analysis. The mean MINORS score was 10.48 ± 1.75 (range: 7-13), indicating evidence of moderate quality. Pooled outcomes indicated that overall response rate (ORR) and disease control rate (DCR) were 23.85% (95% CI: 18.47%-30.21%) and 79.16% (95% CI: 73.78%-83.68%), respectively. Median PFS ranged from 3.5 to 13.1 months, with a mean of 7.08 ± 2.98 months. Furthermore, the rates of PFS (PFR) after 1, 6, and 12 months were 99.31%, 44.90%, and 14.31%, respectively. Drug-related toxicity appears to be common in patients administered apatinib, for which hand-foot syndrome (41.13%), hypertension (36.15%), and fatigue (20.52%) ranked the top three most common adverse events. However, the incidence of grade 3-4 adverse events was relatively low and manageable.

CONCLUSIONS: Based on the best evidence currently available, apatinib demonstrates promising clinical efficacy and an acceptable safety profile for the treatment of advanced bone and soft tissue sarcoma, although additional high-quality clinical studies are required to further define its properties and toxicity.

PMID:33816318 | PMC:PMC8010174 | DOI:10.3389/fonc.2021.662318

JFMS Open Rep. 2021 Mar 22;7(1):2055116921999595. doi: 10.1177/2055116921999595. eCollection 2021 Jan-Jun.

ABSTRACT

CASE SUMMARY: This case report documents the clinical appearance, diagnosis and novel treatment of a central Texas cat with cutaneous leishmaniosis. The cat presented with a linear erosion on the right pinnal margin, an ulcerated exophytic nodule on the right hock and a swelling in the right nostril. Cytological and histopathological findings were consistent with leishmaniosis. PCR confirmed the presence of Leishmania mexicana, a species endemic to Texas. An epidemiological investigation was conducted by trapping sandflies from the cat's environment. Sandflies collected were identified as Lutzomyia species, known vectors of Leishmania species. Given the lack of validated medical therapies for L mexicana in cats, treatments typically prescribed for canine leishmaniosis were administered. Allopurinol achieved clinical success but was discontinued due to suspected drug-related neutropenia. Topical imiquimod also improved lesional skin but was not sustainable due to application difficulty. Oral administration of artemisinin resulted in significant clinical improvement of cutaneous lesions without reported adverse events. Nearly 8 months after the initiation of artemisinin therapy, the cat remained systemically healthy with stable lesions.

RELEVANCE AND NOVEL INFORMATION: This case report demonstrates endemic feline leishmaniosis in central Texas and provides the clinician with alternative therapeutic options for medical management.

PMID:33815814 | PMC:PMC7995465 | DOI:10.1177/2055116921999595

JACC Clin Electrophysiol. 2021 Mar 25:S2405-500X(21)00120-1. doi: 10.1016/j.jacep.2021.01.020. Online ahead of print.

ABSTRACT

OBJECTIVES: This study sought to compare the efficacy of ivabradine and amiodarone in the management of postoperative junctional ectopic tachycardia (JET) after cardiac surgery in children.

BACKGROUND: JET is a serious arrhythmia occurring in children after cardiac surgery and requires aggressive management. Amiodarone has been conventionally used in its treatment. Recent studies have reported the utility of ivabradine in this regard.

METHODS: In this open-label randomized controlled trial, 94 children (age ≤18 years) who developed postoperative JET were allocated to receive either amiodarone or ivabradine. The primary end point was restoration of normal sinus rhythm.

RESULTS: Sinus rhythm was achieved in 43 out of the 46 patients (93.5%) in the amiodarone group and 46 out of the 48 patients (95.8%) in the ivabradine group (mean difference of treatment effect: 2.3%; 95% confidence interval: -6.7% to 11.5%). The median (interquartile range) time taken to achieve sinus rhythm conversion was similar in both the groups: 21.5 (17-30.2) versus 22 (13.4-38.5) hours (p = 0.36)]. The time taken to rate control of JET was significantly less in the amiodarone group: median 7.0 (5.5-9.5) versus 8.0 (5.8-10.8) hours (p = 0.02)]. No drug-related adverse events were observed in the ivabradine group.

CONCLUSIONS: Oral ivabradine is not inferior to intravenous amiodarone in converting postoperative JET to sinus rhythm. There was no difference in time taken to sinus rhythm conversion between the groups, although the rate control was earlier in patients who received amiodarone. Monotherapy with ivabradine may be considered as an alternative to amiodarone in the management of postoperative JET. (Comparison of Two Drugs, Ivabradine and Amiodarone, in the Management of Junctional Ectopic Tachycardia, an Abnormality in Cardiac Rhythm in Patients Under 18 years Who Undergo Cardiac Surgery: CTRI/2018/08/015182).

PMID:33812837 | DOI:10.1016/j.jacep.2021.01.020

Life (Basel). 2021 Mar 28;11(4):288. doi: 10.3390/life11040288.

ABSTRACT

Diabetes mellitus (DM) is the most severe metabolic disease that reached the level of a global pandemic and is associated with high cardiovascular morbidity. Statins are the first-line lipid-lowering therapy in diabetic patients with or without a history of atherosclerotic disease. Although well tolerated, chronic treatment may result in side effects that lead to treatment interruption. Mitochondrial dysfunction has emerged as a central pathomechanism in DM- and statin-induced side effects. Assessment of mitochondrial respiration in peripheral platelets has been increasingly used as a mirror of organ mitochondrial dysfunction. The present study aimed to assess the: (i) changes in mitochondrial respiration elicited by statins in patients with type 2 DM and (ii) the effects of cell-permeable succinate (NV118) on respiratory parameters in platelets harvested from these patients. No significant changes were found in global mitochondrial respiration of intact platelets isolated from diabetic patients treated with either atorvastatin or rosuvastatin. Similarly, no significant changes in mitochondrial respiration of permeabilized platelets were found between diabetic patients treated with atorvastatin and healthy controls. Acute ex vivo administration of NV118 significantly improved respiration in isolated platelets. These results prompt further research on the role of permeable succinate as a therapeutic alternative for improving mitochondrial function in metabolic pathologies and point to the role of peripheral platelets as a potential biomarker of treatment response.

PMID:33800630 | PMC:PMC8065590 | DOI:10.3390/life11040288

Int J Environ Res Public Health. 2021 Mar 5;18(5):2600. doi: 10.3390/ijerph18052600.

ABSTRACT

While the clinical approval process is able to filter out medications whose utility does not offset their adverse drug reaction profile in humans, it is not well suited to characterizing lower frequency issues and idiosyncratic multi-drug interactions that can happen in real world diverse patient populations. With a growing abundance of real-world evidence databases containing hundreds of thousands of patient records, it is now feasible to build machine learning models that incorporate individual patient information to provide personalized adverse event predictions. In this study, we build models that integrate patient specific demographic, clinical, and genetic features (when available) with drug structure to predict adverse drug reactions. We develop an extensible graph convolutional approach to be able to integrate molecular effects from the variable number of medications a typical patient may be taking. Our model outperforms standard machine learning methods at the tasks of predicting hospitalization and death in the UK Biobank dataset yielding an R2 of 0.37 and an AUC of 0.90, respectively. We believe our model has potential for evaluating new therapeutic compounds for individualized toxicities in real world diverse populations. It can also be used to prioritize medications when there are multiple options being considered for treatment.

PMID:33807714 | PMC:PMC7967515 | DOI:10.3390/ijerph18052600

Int J Environ Res Public Health. 2021 Mar 7;18(5):2674. doi: 10.3390/ijerph18052674.

ABSTRACT

There is a consensus that elderly individuals are quite vulnerable to adverse drug reactions (ADRs), and headaches are one of the most frequent clinical presentations of central nervous system problems in the general population, which can be an ADR. The purpose of our work was to analyze reports of "headache" associated ADRs in the elderly sent to the Portuguese Pharmacovigilance System (PPS), and also which drugs were more frequently associated with this adverse reaction. A retrospective analysis of suspected ADR reports involving patients aged 65 years or older received by the PPS in the last 10 years was conducted. A search of all the terms associated with the High Level Term "headache" was performed. All duplicate reports were excluded from the analysis. A total of 155 ADRs reports were included, in which 15 reported isolated "headache" as suspected ADR, while the remaining 140 ADRs reports reported "headache" together with several other adverse reactions. Most reports of "headache" ADR occurred in women (74.8%; n = 116). About half (46.5%; n = 72) of the ADR reports were considered serious. Anti-viral medication, anti-depressants, anti-dyslipidemic agents and central nervous system-acting analgesics were the most frequent drugs associated with "headache" ADR reports in this population. In elderly patients, most ADR reports involving headaches occurred in women and a high percentage (46.5%) were considered serious. Thus, it is important that healthcare professionals pay more attention to headaches reported as ADRs in the elderly and drugs suspected to cause them, in order to increase knowledge about this type of reaction and contribute towards safely using drugs in this age group.

PMID:33799926 | PMC:PMC7967518 | DOI:10.3390/ijerph18052674

Hepatology. 2021 Apr 2. doi: 10.1002/hep.31841. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic hepatitis C virus (HCV)-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of glecaprevir (GLE) and pibrentasvir (PIB) in children ages 3 - < 12 years old.

APPROACH AND RESULTS: Children with chronic HCV infection, genotype (GT) 1-6, with or without compensated cirrhosis, were divided into 3 cohorts by age, cohort 2 (9 - < 12 years), cohort 3 (6 - < 9 years), and cohort 4 (3 - < 6 years) and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were SVR12 and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 kg to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 kg to < 30 kg), and 150 mg GLE + 60 mg PIB (12 kg to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by post-treatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two non-responders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to adults.

CONCLUSIONS: A pediatric formulation of GLE/PIB was highly efficacious and well-tolerated in chronic HCV-infected children 3 - < 12 years old.

PMID:33811356 | DOI:10.1002/hep.31841

Molecules. 2021 Mar 3;26(5):1349. doi: 10.3390/molecules26051349.

ABSTRACT

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug's bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.

PMID:33802579 | DOI:10.3390/molecules26051349

Int J Mol Sci. 2021 Mar 27;22(7):3464. doi: 10.3390/ijms22073464.

ABSTRACT

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

PMID:33801659 | DOI:10.3390/ijms22073464

Pharmacotherapy. 2021 Apr 2. doi: 10.1002/phar.2523. Online ahead of print.

ABSTRACT

STUDY OBJECTIVE: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed.

DESIGN: Open-label, Phase-1 pharmacokinetic study SETTING: Research Study Center PATIENTS: Twenty-three matched subjects were included, seven with "Normal" renal function (creatinine clearance >90 mL/min), eight with "Severe" renal impairment (glomerular filtration rate <30 mL/min/1.73 m2), and eight subjects requiring hemodialysis.

MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On-dialysis), as well as, on a non-dialysis day (Off-dialysis). Plasma, urine, and dialysate fluid was collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during On- and Off-dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate.

CONCLUSION: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.

PMID:33797776 | DOI:10.1002/phar.2523

Sci Rep. 2021 Apr 1;11(1):7362. doi: 10.1038/s41598-021-86826-7.

ABSTRACT

Multimodal pain management protocol effectively relieves pain following simultaneous bilateral total knee arthroplasty (SBTKA) but is associated with administration of large amounts of opioids in the perioperative period. In this prospective, randomized, assessor-blinded, single-surgeon clinical trial, the goal was to validate the efficacy of an opioid-sparing protocol for SBTKA with a reduced opioid dose, while achieving similar pain relief with few adverse events. Fifty-six patients who had undergone SBTKA were randomly allocated to receive either an opioid-sparing or opioid-based protocol. The primary outcome parameters were visual analogue scale (VAS) scores at rest, with movement, and cumulative morphine dose, through time. Secondary outcome parameters included drug-related adverse events and range of motion with continuous passive motion device, through time. In the opioid-sparing group, a lower VAS score with movement at postoperative 24 and 72 h was observed compared with the opioid-based group, but the difference did not reach the minimal clinically importance difference. A reduced cumulative morphine dose was noted in the opioid-sparing group at postoperative 24, 48 and 72 h. In conclusion, the opioid-sparing protocol may be used as an alternative modality for pain management following SBTKA. Similar pain relief effects may be achieved utilizing a reduced cumulative opioid dose, with few opioid related adverse events.

PMID:33795787 | DOI:10.1038/s41598-021-86826-7

Int J Antimicrob Agents. 2021 Mar 27:106329. doi: 10.1016/j.ijantimicag.2021.106329. Online ahead of print.

ABSTRACT

Data supporting oral step-down therapy in methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are sparse; linezolid offers potential in this setting. This study aimed to determine the effectiveness and safety of oral step-down linezolid compared with standard parenteral therapy (SPT) in MRSA-BSI. This was a retrospective cohort performed in adults receiving step-down/outpatient linezolid or SPT (vancomycin, daptomycin) for MRSA-BSI from 2011-2019. Primary outcome was 90-day infection-related re-admission (IRR) from clinical worsening/relapse or infection recurrence. 215 patients included (54 linezolid, 161 SPT). Infection sources were skin (34%), bone/joint (15%), endocarditis (13%), other (32%), multiple (6%). Patients receiving SPT more commonly had complicated bacteraemia (72% vs. 41%; P < 0.0001) and metastatic foci (45% vs. 20%; P = 0.001). 90-day IRR occurred in 17% and 26% of linezolid and SPT groups, respectively (P = 0.159). When accounting for disease severity, linezolid use was not independently associated with 90-day IRR (adjOR, 1.0, 95% CI 0.24-4.3; P = 0.986). There were no differences in all-cause 90-day mortality (4% vs. 6%, P = 0.487) or overall incidence of drug-related adverse events (AEs) (17% vs. 16%; P = 0.843) between the groups. More patients in the SPT group developed an AE requiring re-hospitalisation (12% vs. 2%; P = 0.024), most commonly line-related complications. Oral step-down linezolid demonstrated similar clinical and safety outcomes compared with SPT for MRSA-BSI, except linezolid was associated with fewer AEs requiring re-hospitalisation. Additional research is needed exploring step-down linezolid in MRSA-BSI, particularly in patients requiring shorter durations of outpatient therapy.

PMID:33785363 | DOI:10.1016/j.ijantimicag.2021.106329

Medicine (Baltimore). 2021 Apr 2;100(13):e25402. doi: 10.1097/MD.0000000000025402.

ABSTRACT

Nivolumab has shown good prognosis in renal cell carcinoma (RCC) patients previously treated with targeted therapy. We aimed to study irAE (immune-related adverse event) due to nivolumab and numbers of previous treatment lines in RCC patients. Between October 2016 and November 2019, 114 patients were treated with nivolumab as second- and later-line therapy. Among them, 110 patients with complete data were evaluated in this retrospective observational study. The primary endpoint was the relation between irAE and numbers of previous targeted therapies. Secondary endpoints were the relation of irAE with the duration of nivolumab treatment and with best overall response. For the primary analysis, proportional odds logistic regression was used to assess the effect of the number of prior therapies on the grade of any irAE as the ordinal variable. For the secondary analysis, binomial logistic regression models adjusted for the covariates were prepared to confirm the association between the incidence of irAE and the number of courses, number of nivolumab treatments and best overall response. Overall, 69, 66, 33, 13, 9 and 9 patients were treated with sunitinib, axitinib, pazopanib, sorafenib, temsirolimus and everolimus, respectively, prior to nivolumab. In total, 60 adverse events (Grade 1, 21; Grade 2, 21; Grade 3, 14; Grade 4, 2; not evaluated, 2) were identified in the patients treated with nivolumab. Ordered logistic regression analysis showed that the adjusted odds ratios of numbers of prior treatment for grade of irAE were 1.12 (numbers of prior treatment: 2 to 1) and 1.31 (3 to 1). Odds ratios of the numbers of nivolumab treatments and best overall response for the incidence of irAE were not significant. No statistically significant relations were found between grade of irAE and numbers of treatments prior to nivolumab. Patients treated with nivolumab should be closely monitored for irAE regardless number of previous therapies.

PMID:33787647 | PMC:PMC8021322 | DOI:10.1097/MD.0000000000025402

Database (Oxford). 2021 Mar 31;2021:baab017. doi: 10.1093/database/baab017.

ABSTRACT

Understanding the underlying molecular and structural similarities between seemingly heterogeneous sets of drugs can aid in identifying drug repurposing opportunities and assist in the discovery of novel properties of preclinical small molecules. A wealth of information about drug and small molecule structure, targets, indications and side effects; induced gene expression signatures; and other attributes are publicly available through web-based tools, databases and repositories. By processing, abstracting and aggregating information from these resources into drug set libraries, knowledge about novel properties of drugs and small molecules can be systematically imputed with machine learning. In addition, drug set libraries can be used as the underlying database for drug set enrichment analysis. Here, we present Drugmonizome, a database with a search engine for querying annotated sets of drugs and small molecules for performing drug set enrichment analysis. Utilizing the data within Drugmonizome, we also developed Drugmonizome-ML. Drugmonizome-ML enables users to construct customized machine learning pipelines using the drug set libraries from Drugmonizome. To demonstrate the utility of Drugmonizome, drug sets from 12 independent SARS-CoV-2 in vitro screens were subjected to consensus enrichment analysis. Despite the low overlap among these 12 independent in vitro screens, we identified common biological processes critical for blocking viral replication. To demonstrate Drugmonizome-ML, we constructed a machine learning pipeline to predict whether approved and preclinical drugs may induce peripheral neuropathy as a potential side effect. Overall, the Drugmonizome and Drugmonizome-ML resources provide rich and diverse knowledge about drugs and small molecules for direct systems pharmacology applications. Database URL: https://maayanlab.cloud/drugmonizome/.

PMID:33787872 | PMC:PMC8011435 | DOI:10.1093/database/baab017

Cureus. 2021 Mar 25;13(3):e14099. doi: 10.7759/cureus.14099.

ABSTRACT

The mRNA-1273 vaccine, popularly called the "Moderna vaccine" is being widely administered in the United States for the prevention of COVID-19 infection since December 2020. Mild to moderate intensity side effects like low-grade fever, myalgia, chills and malaise were reported in the trials related to the vaccine. With this case report, we report a case of purpuric rash and thrombocytopenia after receiving the first dose of the m-RNA-1273 vaccine. The patient, in this case, is a 60-year-old male patient who received the first vaccine dose and within two days, he developed diffuse papular rash associated with some thrombocytopenia. He had a history of tobacco use, Hepatitis C liver cirrhosis, chronic kidney disease stage 4, untreated hypertension and systolic congestive heart failure at the baseline. With review of the limited literature related to the vaccine and its side effect profile and with no other etiology explaining the sudden onset of rash, we attribute this thrombocytopenia and purpuric rash as the side effects of the mRNA-1273 vaccine.

PMID:33786251 | PMC:PMC7996471 | DOI:10.7759/cureus.14099

Neurology. 2021 Mar 30;96(13):639. doi: 10.1212/WNL.0000000000011659.

NO ABSTRACT

PMID:33782166 | DOI:10.1212/WNL.0000000000011659

Neurology. 2021 Mar 30;96(13):638. doi: 10.1212/WNL.0000000000011672.

NO ABSTRACT

PMID:33782165 | DOI:10.1212/WNL.0000000000011672

Drug Ther Bull. 2021 Mar 29:dtb-2021-000010. doi: 10.1136/dtb.2021.000010. Online ahead of print.

ABSTRACT

DTB commentaries provide an overview of, and commentary on, a clinical trial, systematic review or observational study.

PMID:33782047 | DOI:10.1136/dtb.2021.000010