Front Endocrinol (Lausanne). 2023 Jan 24;14:1027905. doi: 10.3389/fendo.2023.1027905. eCollection 2023.

ABSTRACT

PURPOSE: Three dopamine agonists [bromocriptine, cabergoline, and quinagolide (CV)] have been used for hyperprolactinemia treatment for decades. Several studies have reviewed the efficacy and safety of bromocriptine and cabergoline. However, no systematic review or meta-analysis has discussed the efficacy and safety of CV in hyperprolactinemia and prolactinoma treatment.

METHODS: Five medical databases (PubMed, Web of Science, Embase, Scopus, and Cochrane Library) were searched up to 9 May 2022 to identify studies related to CV and hyperprolactinemia. A meta-analysis was implemented by using a forest plot, funnel plot, sensitivity analysis, meta-regression, and Egger's test via software R 4.0 and STATA 12.

RESULTS: A total of 1,211 studies were retrieved from the five medical databases, and 33 studies consisting of 827 patients were finally included in the analysis. The pooled proportions of patients with prolactin concentration normalization and tumor reduction (>50%) under CV treatment were 69% and 20%, respectively, with 95% confidence intervals of 61%-76% and 15%-28%, respectively. The pooled proportion of adverse effects was 13%, with a 95% confidence interval of 11%-16%.

CONCLUSION: Our study showed that CV is not less effective than cabergoline and bromocriptine in treating hyperprolactinemia, and the side effects were not significant. Hence, this drug could be considered an alternative first-line or rescue treatment in treating hyperprolactinemia in the future.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022347750.

PMID:36761195 | PMC:PMC9902948 | DOI:10.3389/fendo.2023.1027905

Transl Cancer Res. 2023 Jan 30;12(1):194-200. doi: 10.21037/tcr-22-1983. Epub 2023 Jan 6.

ABSTRACT

BACKGROUND: Dasatinib is an effective 2nd generation tyrosine kinase inhibitor for the treatment of newly diagnosed or intolerant to imatinib chronic myeloid leukemia (CML), and in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). The most common adverse effects of dasatinib include gastrointestinal upset, pancytopenia, skin rash, diarrhea and fluid retention. Pleural effusion (PE), which occurs in almost 15-35% of patients, is the most frequent manifestation of fluid retention. However, Dasatinib-induced chylothorax is extremely rare. There are solely 13 cases of dasatinib-related chylothorax in adults in the literature, while only one pediatric patient has been reported. The preferred treatment options are usually with systemic steroids, diuretics, and dasatinib discontinuation. We report the second pediatric case and propose the hypothesis of its mechanism and summarize the relevant cases to facilitate the understanding of the pathophysiology, clinical manifestation, management and prognosis of dasatinib-induced chylothorax.

CASE DESCRIPTION: An 11-year-old boy diagnosed with breakpoint cluster region-Abelson (BCR-ABL) fusion was treated with dasatinib. After 38 months, the patient was admitted for dyspnea characterized by decreased breath sounds on both lungs during physical examination. Computed tomography (CT) showed bilateral PE with local insufficiency of both lungs. Drug-induced chylothorax was presumed based on clinical manifestations, excluding other possible causes. Dasatinib was withdrawn, diuretics as well as steroids were given for supportive therapy and octreotide was administered to decrease fat absorption in the intestine. However, the chylous fluid did not decrease significantly. The patient was then being fasted. Unexpectedly, after fasted for two days, the chylous fluid became clear and the drainage volume was decreased. The patient was advised to use nilotinib. We followed up the patient for 8 months, and there was no recurrence of chylothorax.

CONCLUSIONS: Our patient had a shorter treatment course for chylothorax than those in the literature. In addition to dasatinib withdrawal, fasting treatment was also utmost critical. We summarize the literature of known existing cases to improve the understanding of the side effects and management of dasatinib in the treatment of CML.

PMID:36760377 | PMC:PMC9906050 | DOI:10.21037/tcr-22-1983

Hepatol Commun. 2023 Feb 9;7(3):e0064. doi: 10.1097/HC9.0000000000000064. eCollection 2023 Mar 1.

ABSTRACT

INTRODUCTION: Homeopathic remedies are highly diluted formulations without proven clinical benefits, traditionally believed not to cause adverse events. Nonetheless, published literature reveals severe local and non-liver-related systemic side effects. We present the first series on homeopathy-related severe drug-induced liver injury (DILI) from a single center.

METHODS: A retrospective review of records from January 2019 to February 2022 identified 9 patients with liver injury attributed to homeopathic formulations. Competing causes were comprehensively excluded. Chemical analysis was performed on retrieved formulations using triple quadrupole gas chromatography-mass spectrometry and inductively coupled plasma atomic emission spectroscopy.

RESULTS: Males predominated with a median age of 54 years. The most typical clinical presentation was acute hepatitis, followed by acute on chronic liver failure. All patients developed jaundice, and ascites were notable in one-third of the patients. Five patients had underlying chronic liver disease. COVID-19 prevention was the most common indication for homeopathic use. Probable DILI was seen in 77.8%, and hepatocellular injury predominated (66.7%). Four (44.4%) patients died (3 with chronic liver disease) at a median follow-up of 194 days. Liver histopathology showed necrosis, portal and lobular neutrophilic inflammation, and eosinophilic infiltration with cholestasis. A total of 29 remedies were consumed between 9 patients, and 15 formulations were analyzed. Toxicology revealed industrial solvents, corticosteroids, antibiotics, sedatives, synthetic opioids, heavy metals, and toxic phyto-compounds, even in 'supposed' ultra-dilute formulations.

CONCLUSION: Homeopathic remedies potentially result in severe liver injury, leading to death in those with underlying liver disease. The use of mother tinctures, insufficient dilution, poor manufacturing practices, adulteration and contamination, and the presence of direct hepatotoxic herbals were the reasons for toxicity. Physicians, the public, and patients must realize that Homeopathic drugs are not 'gentle placebos.'

PMID:36757412 | DOI:10.1097/HC9.0000000000000064

PLoS One. 2023 Feb 8;18(2):e0281466. doi: 10.1371/journal.pone.0281466. eCollection 2023.

ABSTRACT

BACKGROUND: Polypharmacy can be a consequence of overprescribing that is prevalent in older adults with multimorbidity. Polypharmacy can cause adverse reactions and result in hospital admission. This study predicted risks of adverse drug reaction (ADR)-related and emergency hospital admissions by medicine classes.

METHODS: We used electronic health record data from general practices of Clinical Practice Research Datalink (CPRD GOLD) and Aurum. Older patients who received at least five medicines were included. Medicines were classified using the British National Formulary sections. Hospital admission cases were propensity-matched to controls by age, sex, and propensity for specific diseases. The matched data were used to develop and validate random forest (RF) models to predict the risk of ADR-related and emergency hospital admissions. Shapley Additive eXplanation (SHAP) values were calculated to explain the predictions.

RESULTS: In total, 89,235 cases with polypharmacy and hospitalised with an ADR-related admission were matched to 443,497 controls. There were over 112,000 different combinations of the 50 medicine classes most implicated in ADR-related hospital admission in the RF models, with the most important medicine classes being loop diuretics, domperidone and/or metoclopramide, medicines for iron-deficiency anaemias and for hypoplastic/haemolytic/renal anaemias, and sulfonamides and/or trimethoprim. The RF models strongly predicted risks of ADR-related and emergency hospital admission. The observed Odds Ratio in the highest RF decile was 7.16 (95% CI 6.65-7.72) in the validation dataset. The C-statistics for ADR-related hospital admissions were 0.58 for age and sex and 0.66 for RF probabilities.

CONCLUSIONS: Polypharmacy involves a very large number of different combinations of medicines, with substantial differences in risks of ADR-related and emergency hospital admissions. Although the medicines may not be causally related to increased risks, RF model predictions may be useful in prioritising medication reviews. Simple tools based on few medicine classes may not be effective in identifying high risk patients.

PMID:36753492 | PMC:PMC9907844 | DOI:10.1371/journal.pone.0281466

PLoS One. 2023 Feb 7;18(2):e0269765. doi: 10.1371/journal.pone.0269765. eCollection 2023.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADR) challenge successful anti-tuberculosis treatment (ATT). The aim of this study was to evaluate the impact of ATT-associated ADR and related factors on ATT outcomes.

METHODS: A prospective cohort study of persons with tuberculosis (TB) at a referral center in Rio de Janeiro, Brazil, from 2010 to 2016. Baseline information: race, sex, schooling, economic status, tobacco, drugs and alcohol abuse, HIV-infection status and comorbidities were captured during TB screening and diagnosis. Laboratory exams were performed to confirm TB diagnosis and monitor ADRs, favorable (cure and treatment completion) and unfavorable (death, loss to follow up and failure) outcomes were prospectively captured. The Kaplan-Meier curve was used to estimate the probability of ADR-free time. A logistic regression analysis (backward elimination) was performed to identify independent associations with unfavorable outcomes.

RESULTS: 550 patients were enrolled, 35.1% were people living with HIV (PLHIV) and ADR occurred in 78.6% of all participants. Smoking (OR: 2.32; 95% CI:1.34-3.99) and illicit-drug use (OR:2.02; 95% CI:1.15-3.55) were independent risk factors for unfavorable outcomes. In PLHIV, alcohol abuse and previous ART use were associated with unfavorable outcomes. In contrast, ADR increased the odds of favorable outcomes in the overall population. PLHIV more frequently experienced grade 3/4-ADR (18.36%), especially "liver and biliary system disorders". Lower CD4 counts (<100 cells/uL) were associated with hepatotoxicity (p = 0.03). ART-naïve participants presented a higher incidence of ADR in comparison with ART-experienced patients.

CONCLUSION: Substance use was associated with unfavorable outcomes, highlighting the need for better strategies to reduce this habit. In contrast, ADRs were associated with favorable outcomes. Attention to the occurrence of ADR in PLHIV is essential, especially regarding hepatotoxicity in those with high immunosuppression.

PMID:36749743 | DOI:10.1371/journal.pone.0269765

J Med Internet Res. 2023 Feb 7;25:e43734. doi: 10.2196/43734.

ABSTRACT

BACKGROUND: Machine learning offers new solutions for predicting life-threatening, unpredictable amiodarone-induced thyroid dysfunction. Traditional regression approaches for adverse-effect prediction without time-series consideration of features have yielded suboptimal predictions. Machine learning algorithms with multiple data sets at different time points may generate better performance in predicting adverse effects.

OBJECTIVE: We aimed to develop and validate machine learning models for forecasting individualized amiodarone-induced thyroid dysfunction risk and to optimize a machine learning-based risk stratification scheme with a resampling method and readjustment of the clinically derived decision thresholds.

METHODS: This study developed machine learning models using multicenter, delinked electronic health records. It included patients receiving amiodarone from January 2013 to December 2017. The training set was composed of data from Taipei Medical University Hospital and Wan Fang Hospital, while data from Taipei Medical University Shuang Ho Hospital were used as the external test set. The study collected stationary features at baseline and dynamic features at the first, second, third, sixth, ninth, 12th, 15th, 18th, and 21st months after amiodarone initiation. We used 16 machine learning models, including extreme gradient boosting, adaptive boosting, k-nearest neighbor, and logistic regression models, along with an original resampling method and 3 other resampling methods, including oversampling with the borderline-synthesized minority oversampling technique, undersampling-edited nearest neighbor, and over- and undersampling hybrid methods. The model performance was compared based on accuracy; Precision, recall, F1-score, geometric mean, area under the curve of the receiver operating characteristic curve (AUROC), and the area under the precision-recall curve (AUPRC). Feature importance was determined by the best model. The decision threshold was readjusted to identify the best cutoff value and a Kaplan-Meier survival analysis was performed.

RESULTS: The training set contained 4075 patients from Taipei Medical University Hospital and Wan Fang Hospital, of whom 583 (14.3%) developed amiodarone-induced thyroid dysfunction, while the external test set included 2422 patients from Taipei Medical University Shuang Ho Hospital, of whom 275 (11.4%) developed amiodarone-induced thyroid dysfunction. The extreme gradient boosting oversampling machine learning model demonstrated the best predictive outcomes among all 16 models. The accuracy; Precision, recall, F1-score, G-mean, AUPRC, and AUROC were 0.923, 0.632, 0.756, 0.688, 0.845, 0.751, and 0.934, respectively. After readjusting the cutoff, the best value was 0.627, and the F1-score reached 0.699. The best threshold was able to classify 286 of 2422 patients (11.8%) as high-risk subjects, among which 275 were true-positive patients in the testing set. A shorter treatment duration; higher levels of thyroid-stimulating hormone and high-density lipoprotein cholesterol; and lower levels of free thyroxin, alkaline phosphatase, and low-density lipoprotein were the most important features.

CONCLUSIONS: Machine learning models combined with resampling methods can predict amiodarone-induced thyroid dysfunction and serve as a support tool for individualized risk prediction and clinical decision support.

PMID:36749620 | DOI:10.2196/43734

J Investig Med High Impact Case Rep. 2023 Jan-Dec;11:23247096231154640. doi: 10.1177/23247096231154640.

ABSTRACT

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used in the treatment of solid and hematologic malignancies. Immune checkpoint inhibitors target the T-cell deactivation system via the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor, programmed cell death protein 1 (PD-1) receptor, and programmed cell death ligand 1 (PD-L1). As a result, the activated T-cell enhances the host tumor response. However, even with their essential clinical benefits, ICIs are associated with a broad spectrum of adverse effects that can be generalized or tissue-specific inflammatory responses known as immune-related adverse events (irAEs). The most common dermatologic toxicity manifests mainly as maculopapular rash and pruritus. Understanding the complexity of immune-mediated response and the importance of clinical histopathologic correlation in recognizing irAEs allows for appropriate intervention and patient care due. We present the case of a 71-year-old African American male diagnosed with a large-cell poorly differentiated neuroendocrine tumor in the gastroesophageal junction of the stomach with mediastinal lymphadenopathy. He was treated with carboplatin, etoposide, and atezolizumab for 4 cycles. However, he developed vitiligo while on maintenance atezolizumab, which is rarely seen with atezolizumab use. Despite the improving clinical outcomes in oncology with ICIs, their adverse effects should not be ignored. When promptly recognized and treated, patients on ICI monotherapy may not need treatment interruption or discontinuation.

PMID:36748760 | DOI:10.1177/23247096231154640

Brief Bioinform. 2023 Feb 7:bbad041. doi: 10.1093/bib/bbad041. Online ahead of print.

ABSTRACT

Drug-drug interactions (DDIs) are compound effects when patients take two or more drugs at the same time, which may weaken the efficacy of drugs or cause unexpected side effects. Thus, accurately predicting DDIs is of great significance for the drug development and the drug safety surveillance. Although many methods have been proposed for the task, the biological knowledge related to DDIs is not fully utilized and the complex semantics among drug-related biological entities are not effectively captured in existing methods, leading to suboptimal performance. Moreover, the lack of interpretability for the predicted results also limits the wide application of existing methods for DDIs prediction. In this study, we propose a novel framework for predicting DDIs with interpretability. Specifically, we construct a heterogeneous information network (HIN) by explicitly utilizing the biological knowledge related to the procedure of inducing DDIs. To capture the complex semantics in HIN, a meta-path-based information fusion mechanism is proposed to learn high-quality representations of drugs. In addition, an attention mechanism is designed to combine semantic information obtained from meta-paths with different lengths to obtain final representations of drugs for DDIs prediction. Comprehensive experiments are conducted on 2410 approved drugs, and the results of predictive performance comparison show that our proposed framework outperforms selected representative baselines on the task of DDIs prediction. The results of ablation study and cold-start scenario indicate that the meta-path-based information fusion mechanism red is beneficial for capturing the complex semantics among drug-related biological entities. Moreover, the results of case study demonstrate that the designed attention mechanism is able to provide partial interpretability for the predicted DDIs. Therefore, the proposed method will be a feasible solution to the task of predicting DDIs.

PMID:36750041 | DOI:10.1093/bib/bbad041

J Drugs Dermatol. 2023 Feb 1;22(2):197-202. doi: 10.36849/JDD.7151.

ABSTRACT

Calcipotriol, a vitamin D analogue is widely used in the treatment of psoriasis. However, poor adherence to topical therapy has led to an ineffective use of the medication and built a barrier to the treatment's success. A water-free lipid-based formulation system has been developed to improve dosage and cosmetic properties along with patient compliance. This study was conducted to evaluate the efficacy and cutaneous safety of water-free lipid-based formulations containing calcipotriol (50 &mu;g/g) as compared to their corresponding vehicles and marketed calcipotriol formulations in a psoriasis plaque test. In total, 24 subjects with chronic psoriasis vulgaris were enrolled in this single-center, randomized, vehicle, and comparator-controlled clinical trial and treated once daily over a 12-day period (10 applications). The anti-psoriatic effect was evaluated by sonographic measurement of psoriatic infiltrate and investigators' clinical efficacy assessments. The mean reduction in psoriatic infiltrate from baseline to day 12 (end of trial) with lipid-based calcipotriol formulations (-34% and -37%) was statistically significant (P&lt;0.0001) when compared to their corresponding vehicles (6% and -4%) but not when compared with marketed calcipotriol solution and cream (-34% and -49% respectively). Mean total clinical assessment scores of these lipid-based calcipotriol formulations (1.7 each) were between those of the two comparators - greater than marketed calcipotriol solution (1.3) but lower than cream (2.0). Overall, nine mild non-serious treatment-emergent adverse effects related to all calcipotriol formulations were reported in four subjects, but all recovered at the follow-up visit. Therefore, novel lipid-based formulations of calcipotriol were clearly more efficacious than their corresponding vehicles and considered as safe therapy against psoriasis vulgaris. J Drugs Dermatol. 2023;22(2):197-202. doi:10.36849/JDD.7151Citation:&nbsp;Holmb&auml;ck J, Carlsson A, Rinwa P. Efficacy and safety of water-free lipid formulation system containing calcipotriol against psoriasis vulgaris. J Drugs Dermatol. 2023;22(2):197-202. doi:10.36849/JDD.7151 &nbsp.

PMID:36745360 | DOI:10.36849/JDD.7151

Afr J Prim Health Care Fam Med. 2023 Jan 18;15(1):e1-e9. doi: 10.4102/phcfm.v15i1.3659.

ABSTRACT

BACKGROUND: Spontaneous reporting is regarded as a cornerstone of pharmacovigilance (PV) but presents many limitations, including varying quality and completeness of information, which is essential for causality assessment.

AIM: This study aimed to evaluate the completeness of adverse drug reaction (ADR) reports in South Africa based on the vigiGrade completeness score.

SETTING: The South African Health Products Regulatory Authority (SAHPRA).

METHODS: A cross-sectional, descriptive study of all reports received by SAHPRA and submitted to VigiBase® in 2017 was conducted. A report with a vigiGrade score 0.8 is considered well-documented.

RESULTS: The mean completeness score for the 8438 reports received was 0.456 (s.d. = 0.221). Only 11.3% of reports had a completeness score 0.8. The completeness of reports submitted by consumers professionals did not significantly differ from reports by physicians, pharmacists or other healthcare professionals (d ≤ 0.2). Reports of reactions that resulted in death (M = 0.572, s.e. = 0.007), disability (M = 0.491, s.e. 0.033) or were life threatening (M = 0.474, s.e. = 0.013) had a medium to large practically significant effect (0.5 ≥ d ≤ 0.8) on the completeness score compared with reports of congenital anomaly (M = 0.348, s.e. = 0.089).

CONCLUSION: The completeness of reports submitted by consumers is comparable to those submitted by healthcare professionals. The completeness of reports was low and multiple measures to improve reporting are recommended.Contribution: This study describes the completeness of ADR reports in South Africa and the results can be used to improve training.

PMID:36744452 | DOI:10.4102/phcfm.v15i1.3659

Anesth Pain Med (Seoul). 2023 Jan;18(1):11-20. doi: 10.17085/apm.22259. Epub 2023 Jan 25.

ABSTRACT

Due to unknown safety concerns, sugammadex should not be administered to patients withend-stage renal disease (ESRD). However, because the supply of benzylisoquinolinium-typeneuromuscular blocking agents (NMBAs) has been discontinued, rocuronium is the onlynon-depolarizing NMBA that can be used in clinical settings in some countries, includingSouth Korea. The administration of sugammadex cannot be avoided to achieve rapid andcomplete neuromuscular recovery in patients with ESRD or renal transplantation after rocuronium administration. Although there has been a limited number of clinical studies involving the use of sugammadex in patients with ESRD, studies have shown that sugammadexcan effectively and safely reverse rocuronium-induced neuromuscular blockade (NMB) inpatients with ESRD, however recovery of neuromuscular function in patients with ESRD isslower than in patients with normal renal function. Nonetheless, safety-concerns are yet tobe addressed. Considering the small number of clinical studies, high heterogeneity amongstudies, and insufficient safety information, more extensive data on the efficacy and safetyof sugammadex in patients with ESRD are needed. In particular, it is important to securedata on safety, including residual NMB after surgery, recurarization and cardiorespiratorycomplications, anaphylactic reactions, and long-term morbidity and mortality. Furthermore,anesthesiologists should remember that performing proper quantitative neuromuscularmonitoring and neuromuscular management based on the monitoring signs are the mostessential requirements when using sugammadex in patients with ESRD.

PMID:36746897 | DOI:10.17085/apm.22259

J Clin Aesthet Dermatol. 2023 Jan;16(1):14-17.

ABSTRACT

OBJECTIVE: We sought to describe skin injuries associated with unapproved topical mole and skin tag removers containing concentrated salicylic acid, Sanguinaria canadensis, or other caustic agents.

METHODS: We identified skin injuries associated with unapproved non-device topical mole and skin tag removers reported to the US Food and Drug Administration (FDA) through October 30, 2021 or described in Amazon consumer product reviews between 2019 and 2021.

RESULTS: We identified 38 cases, including 30 from Amazon consumer product reviews and eight reported to the FDA. Twenty-eight were from 2021. The most common reason for use was for mole and/or skin tag removal. Listed ingredients included salicylic acid, Sanguinaria canadensis, botanicals (includes homeopathic products), and calcium oxide. Seven cases involved products without ingredients listed. Adverse events included burns, pain, and ulceration, some resulting in permanent scarring and disfigurement. There were 14 facial injuries, including four adjacent to the eye. Reported treatments included antibiotics, hospital care, wound care, and dermatology advice to have a skin graft.

LIMITATIONS: Limitations include underreporting of adverse events to the FDA, limited clinical details and potential bias in consumer reviews, and poor replicability of review searches due to the dynamic nature of the Amazon website.

CONCLUSION: Unapproved, non-device topical mole and skin tag removers are associated with serious skin injuries. We found Amazon consumer reviews to be a novel and useful data source for safety surveillance of these types of skin products. When dermatologists are consulted about skin injuries, exposure to these products should be considered in the differential diagnosis.

PMID:36743972 | PMC:PMC9891211

Lancet. 2023 Feb 4;401(10374):347-356. doi: 10.1016/S0140-6736(22)01841-4.

ABSTRACT

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.

METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.

FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001).

INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.

FUNDING: European Union Horizon 2020.

PMID:36739136 | DOI:10.1016/S0140-6736(22)01841-4

Br J Community Nurs. 2023 Feb 2;28(2):74-76. doi: 10.12968/bjcn.2023.28.2.74.

ABSTRACT

Adverse cutaneous drug reactions (ACDR) are relatively common, especially in multimorbid populations who take a range of medications. Francesca Ramadan provides an overview of several common types of ACDR and their most frequently associated drugs, alongside some options for diagnosis and management.

PMID:36735364 | DOI:10.12968/bjcn.2023.28.2.74

Med Oncol. 2023 Feb 3;40(3):88. doi: 10.1007/s12032-023-01954-6.

ABSTRACT

Chemotherapy is one of the widely used anticancer treatments that involves the use of powerful cytotoxic drugs to stop tumor growth by targeting rapidly dividing cells through various mechanisms, which will be elucidated in this review. Introduced during the early twentieth century, chemotherapy has since lengthened the longevity of innumerable cancer patients. However, the increase in lifespan is at the expense of quality of life as patients are at risk of developing short-term and long-term side effects following chemotherapy, such as alopecia (hair loss), chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting, cardiotoxicity, diarrhea, infertility, and chemo brain. Currently, a number of these chemotherapy-induced adverse effects are managed through supportive care and approved treatments, while the rest of the side effects are unavoidable. Hence, chemotherapeutic drugs associated with inevitable side effects are only administered when their therapeutic role outweighs their chemotoxicity, thus severely limiting the potency of chemotherapy in treating malignancy. Therein, the potential approaches to alleviating side effects of chemotherapy ranging from pharmaceutical drugs to alternative therapies will be discussed in this review in hopes of increasing the tolerance and effectiveness of future chemotherapeutic treatments.

PMID:36735206 | DOI:10.1007/s12032-023-01954-6

Eur J Hosp Pharm. 2023 Feb 3:ejhpharm-2023-003701. doi: 10.1136/ejhpharm-2023-003701. Online ahead of print.

NO ABSTRACT

PMID:36737228 | DOI:10.1136/ejhpharm-2023-003701

J Environ Pathol Toxicol Oncol. 2023;42(1):1-16. doi: 10.1615/JEnvironPatholToxicolOncol.2022042088.

ABSTRACT

Melatonin is a serotonin-derived pineal gland hormone with many biological functions like regulating the sleep-wake cycle, circadian rhythm, menstrual cycle, aging, immunity, and antioxidants. Melatonin synthesis and release are more pronounced during the night, whereas exposure to light decreases it. Evidence is mounting in favor of the therapeutic effects of melatonin in cancer prevention, treatment and delayed onset in various cancer subtypes. Melatonin exerts its anticancer effect through modification of its receptors such as melatonin 1 (MT1), melatonin 2 (MT2), and inhibition of cancer cell proliferation, epigenetic alterations (DNA methylation/demethylation, histone acetylation/deacetylation), metastasis, angiogenesis, altered cellular energetics, and immune evasion. Melatonin performs a significant function in immune modulation and enhances innate and cellular immunity. In addition, melatonin has a remarkable impact on epigenetic modulation of gene expression and alters the transcription of genes. As an adjuvant to cancer therapies, it acts by decreasing the side effects and boosting the therapeutic effects of chemotherapy. Since current treatments produce drug-induced unwanted toxicities and side effects, they require alternate therapies. A recent review article attempts to summarize the mechanistic perspective of melatonin in different cancer subtypes like skin cancer, breast cancer, hepatic cancer, renal cell cancer, non-small cell lung cancer (NSCLC), colon oral, neck, and head cancer. The various studies described in this review will give a firm basis for the future evolution of anticancer drugs.

PMID:36734949 | DOI:10.1615/JEnvironPatholToxicolOncol.2022042088

Pharmacol Res Perspect. 2023 Feb;11(1):e01040. doi: 10.1002/prp2.1040.

ABSTRACT

This study assessed the safety, tolerability, and pharmacokinetics of single and multiple oral doses of DA-8010, a muscarinic M3 receptor antagonist, in healthy subjects. This was a randomized, double-blind, placebo-controlled, ascending single (Part A: 1, 2.5, 5, 20, and 40 mg QD fasted and 10 mg QD fasted and fed) and multiple doses (Part B: 5, 10, and 20 mg QD from Days 1 to 7 fasted), sequential-group study. Safety data were analyzed descriptively, time to maximum plasma concentration (tmax ) nonparametrically, and pharmacokinetic parameters using power and mixed models and ANOVA. Of 109 subjects randomized (Part A = 69 and Part B = 40; each part consisted a female group), 31 (44.9%) in Part A and 29 (72.5%) in Part B experienced treatment-emergent adverse events (TEAEs) in a dose-related manner. Common drug-related TEAEs in Part A and B were dizziness (8.7% and 15.0%), headache (5.8% and 12.5%) and blurred vision (8.7% and 20%). One male (20 mg) and one female (10 mg) from Part B discontinued the study due to a confusional state, and nausea and vomiting. Irrespective of sex, DA-8010 was steadily absorbed following single and multiple doses in the fasted state with increased systemic exposure in a dose-proportional manner with maximum plasma concentration occurring at a median tmax between 4.0 and 6.0 h. A high-fat meal increased systemic exposure. DA-8010 was safe, well tolerated, and well absorbed at lower doses and moderately tolerated at higher doses without any notable effects of food and sex.

PMID:36734627 | DOI:10.1002/prp2.1040

Med J Aust. 2023 Feb 2. doi: 10.5694/mja2.51841. Online ahead of print.

NO ABSTRACT

PMID:36733993 | DOI:10.5694/mja2.51841

Eur J Hosp Pharm. 2023 Feb 2:ejhpharm-2022-003453. doi: 10.1136/ejhpharm-2022-003453. Online ahead of print.

ABSTRACT

A female patient in her early 30s was treated with imatinib and high-dose methotrexate (HD-MTX) for Philadelphia chromosome-positive acute lymphoblastic leukaemia. The patient developed delayed MTX clearance and grade 3 acute kidney injury characterised by elevated creatinine (114% increase from baseline). After intensified calcium folinate rescue therapy and hydration, the MTX serum level was appropriately decreased 72 hours after the start of MTX infusion, and renal function returned to normal. Medication analysis by a clinical pharmacist suggested that the concomitant treatment with imatinib likely contributed to the delayed MTX clearance and caused the acute kidney injury.

PMID:36732034 | DOI:10.1136/ejhpharm-2022-003453