Cell Rep Med. 2021 May 18;2(5):100281. doi: 10.1016/j.xcrm.2021.100281. eCollection 2021 May 18.

ABSTRACT

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

PMID:34095883 | PMC:PMC8149471 | DOI:10.1016/j.xcrm.2021.100281

Haemophilia. 2021 Jun 5. doi: 10.1111/hae.14350. Online ahead of print.

ABSTRACT

INTRODUCTION: SCT800 is a recombinant human B-domain-deleted coagulation factor VIII (BDDrFVIII) developed in China.

AIM: To evaluate the repeat pharmacokinetics (PKs), efficacy, and safety of SCT800 in previously treated Chinese adolescent and adult patients with severe haemophilia A.

METHODS: A phase III, multicentre, prospective, open-label, single-arm trial was conducted at 12 medical centres. Subjects received treatment for 24 weeks. PKs were assessed at the initial and repeated dosing 24 weeks later. The primary endpoint was annualized bleeding rate (ABR). Breakthrough bleeding episodes and inhibitor development were assessed.

RESULTS: A total of 71 of 73 patients completed the study, and 18 were enrolled for the repeat PK investigation. Total exposure was 5643 exposure days. Overall, SCT800 showed comparable repeat PK profiles. The total ABR was 2.82 (95% confidence interval 2.01-3.96). During prophylaxis, 43.8% of patients had no bleeding episodes. The majority (89.4%) of bleeding episodes were controlled with 1-2 injections of SCT800, the success rate (defined as 'excellent' or 'good' haemostatic response) for the treatment of bleeding episodes was 92.6%. The incidence of treatment-related adverse events was 53.4%. Drug-related AE incidence was 4.1%. The observed AEs were similar to those of other coagulation factor VIII, but lower in frequency. No subject developed an inhibitor, and no other safety concerns were identified.

CONCLUSIONS: SCT800 has robust PK characteristics, and is safe and efficacious for the prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult patients with severe haemophilia A.

PMID:34089210 | DOI:10.1111/hae.14350

BMJ Evid Based Med. 2021 Jun 4:bmjebm-2020-111573. doi: 10.1136/bmjebm-2020-111573. Online ahead of print.

NO ABSTRACT

PMID:34088713 | DOI:10.1136/bmjebm-2020-111573

MMW Fortschr Med. 2021 Jun;163(11):26. doi: 10.1007/s15006-021-0067-5.

NO ABSTRACT

PMID:34086218 | DOI:10.1007/s15006-021-0067-5

J Thorac Oncol. 2021 Jun 1:S1556-0864(21)02188-2. doi: 10.1016/j.jtho.2021.05.017. Online ahead of print.

ABSTRACT

Pulmonary immune-related adverse events represent rare but potentially severe side effects of immunotherapies. Diagnosis is often challenging, as symptoms and imaging features are not specific and may mimic other lung diseases, thus potentially delaying appropriate patient management. In this setting, an accurate imaging evaluation is essential for a prompt detection as well as correct management of these drug-induced lung diseases. The purpose of this article is to review the different types of pulmonary immune-related adverse events, describe their imaging characteristics on both HRCT and PET/CT, and stress their underlying diagnostic challenge by presenting the mimickers.

PMID:34087477 | DOI:10.1016/j.jtho.2021.05.017

Blood. 2021 Jun 4:blood.2021011725. doi: 10.1182/blood.2021011725. Online ahead of print.

ABSTRACT

End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor (F) XI and blocks its activation by factor XIIa but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis (www.clinicaltrials.gov #NCT03612856). Patients were randomized to receive a single pre-dialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio and safety and preliminary efficacy were compared to placebo and to observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer.

PMID:34086880 | DOI:10.1182/blood.2021011725

Eur J Hosp Pharm. 2021 Jun 2:ejhpharm-2021-002880. doi: 10.1136/ejhpharm-2021-002880. Online ahead of print.

NO ABSTRACT

PMID:34083222 | DOI:10.1136/ejhpharm-2021-002880

Eur J Hosp Pharm. 2021 Jun 3:ejhpharm-2021-002785. doi: 10.1136/ejhpharm-2021-002785. Online ahead of print.

ABSTRACT

OBJECTIVE: The use of biological agents in the treatment of ocular Behçet's disease has recently become more frequent. The use of two agents, infliximab (IFX) and adalimumab (ADA), for the treatment of Behçet's disease requires prior approval by the Turkish Medicines and Medical Devices Agency. We report on a review of such applications with a view to informing on how such agents are used off-label in Turkey.

METHODS: Prescriptions for off-label use of IFX or ADA sent from hospitals in Turkey to the Turkish Medicines and Medical Devices Agency in 2018 were evaluated. Demographic data, previous treatment regimens and reasons for referral were extracted from the files of the cases.

RESULTS: A total of 662 patients were considered for off-label use of IFX or ADA for the treatment of ocular Behçet's disease. The mean age of the patients was 35.7±10.8 years (range 12-76); 61.5% of patients were men and 38.5% were women. Of the applications, 345 (52.1%) were for IFX and 317 (47.9%) for ADA. Among the referring hospitals, the public university hospitals ranked first, accounting for 77.9% of IFX and 88.6% of ADA prescriptions. Most applications were made after the failure of conventional therapy, which included steroids and immunosuppressive agents.

CONCLUSION: IFX and ADA are rarely used as initial therapy. Stepwise treatment is still preferred in the treatment of ocular Behçet's disease in Turkey. Our report informs on the management of this difficult-to-treat condition.

PMID:34083220 | DOI:10.1136/ejhpharm-2021-002785

Rev Med Liege. 2021 May;76(5-6):408-412.

ABSTRACT

Cardio-oncology is a new interdisciplinary specialty that has emerged over the past ten years. With the development of increasingly potent cancer therapies which improve cancer survival, but at the cost of cardiovascular toxicity, the demand for specialized cardio-oncology services has emerged. Also, cardiovascular diseases are more common and more serious in cancer patients than in the general population. Cardio-oncology focuses on the prevention, detection, monitoring, and treatment of cardiovascular diseases in cancer patients, mostly those occurring as a side effect of chemo- and radiotherapy.

PMID:34080372

Rev Med Liege. 2021 May;76(5-6):403-407.

ABSTRACT

Immunotherapy has revolutionized cancer management in recent years and is affecting more and more patients. Immunotherapy side effects are specific, immune-related, and their early recognition and management are essential. Here we describe the main adverse effects of immunotherapy and their general principles of management.

PMID:34080371

Rev Med Liege. 2021 May;76(5-6):380-386.

ABSTRACT

The «one size fits all» approach is seriously challenged by rapid progression of medical knowledge, especially in the field of individual genome expression. It is currently known that the anti-tumour effect of a given treatment and possible side effects at the level of healthy tissues, can at least partly be predicted and explained by individual variations of gene expression. However, most of us realize that these differences in response are also linked to a variety of other individual characteristics, such as for example the environment and socio-economic factors. Without any possible doubt, there are multiple problems (technical, administrative, financial, cultural and ethical) to be solved, before we witness the real irruption of precision medicine and its holistic individualized approach in our daily oncological practice. It has to start with an international effort, disregarding borders of individual countries, in order to obtain very large amounts of data (with a high degree of variability to avoid bias). This holistic approach, at both societal and individual levels, is the entrance door for a personalized approach in care, whether this is curative, predictive or preventive.

PMID:34080367

Hellenic J Cardiol. 2021 May 31:S1109-9666(21)00109-3. doi: 10.1016/j.hjc.2021.05.003. Online ahead of print.

ABSTRACT

BACKGROUND: This study evaluated the prognostic significance of cardiac magnetic resonance myocardial feature tracking (CMR-FT) in patients with Brugada syndrome (BrS) to detect subclinical alterations and predict major adverse events (MAE).

METHODS: CMR was performed in 106 patients with BrS and 25 healthy controls. Biventricular global strain analysis was assessed using CMR-FT. Patients were followed over a median of 11.6 [8.8 ± 13.8] years.

RESULTS: The study cohort was subdivided according to the presence of a spontaneous type 1 ECG (sECG), into sBrS (BrS with sECG, n=34 (32.1%)) and diBrS (BrS with drug-induced type 1 ECG, n=72 (67.9%)). CMR-FT revealed morphological differences between sBrS and diBrS patients regarding right ventricular (RV) strain (circumferential (%) (sBrS -7.9 ± 2.9 vs diBrS -9.5 ± 3.1, p=0.02) and radial (%) (sBrS 12.0 ± 4.3 vs diBrS 15.4 ± 5.4, p=0.004)). During follow-up, MAE occurred in 11 patients (10.4%). Multivariable analysis was performed to identify independent predictors for the occurrence of events during follow-up. The strongest predictive value was found for RV circumferential strain (OR 3.2 (95%CI 1.4 to 6.9), p=0.02) and RVOT/BSA (OR 3.1 (95%CI 1.0 to 7.0), p=0.03).

CONCLUSIONS: Myocardial strain analysis detected early subclinical alterations, prior to apparent changes in myocardial function, in patients with BrS. While usual functional parameters were within the normal range, CMR-FT revealed pathological results in patients with a sECG. Moreover, RV circumferential strain and RVOT size provided additional prognostic information on the occurrence of MAE during follow-up, reflecting electrical vulnerability.

PMID:34082115 | DOI:10.1016/j.hjc.2021.05.003

Molecules. 2021 May 23;26(11):3113. doi: 10.3390/molecules26113113.

ABSTRACT

Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

PMID:34070985 | PMC:PMC8197169 | DOI:10.3390/molecules26113113

Int J Geriatr Psychiatry. 2021 Jun 2. doi: 10.1002/gps.5587. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the association of benzodiazepines and antidepressants on the risk of hospitalization and hip fracture in patients with dementia initiating antipsychotic drug treatment.

METHODS: A register-based retrospective cohort study using data on all incident dementia cases (≥ 65 years) initiating antipsychotic treatment as monotherapy or in combination with benzodiazepines and/or antidepressants in Denmark from 2000 to 2015. The outcomes of interest were all-cause hospitalization and hip fracture. Cox proportional hazards models with adjustment for multiple variables were used to investigate risk of hospitalization and hip fracture within 180 days.

RESULTS: The risk of all-cause hospitalization during 180-day follow-up was significantly increased by 55% (adjusted HR: 1.55, 95% CI: 1.29-1.86, p<0.0001), when antipsychotic use was combined with benzodiazepines, when compared to antipsychotic monotherapy. The association between the combination of antipsychotics and benzodiazepines with the risk of hip fracture did not reach statistical significance (adjusted HR: 1.50, 95% CI: 0.99-2.26, p=0.0534).

CONCLUSIONS: The observed increased risk of all-cause hospitalization and hip fracture may indicate increased drug-related adverse events. Thus, careful and regular monitoring is needed to assess response to treatment and decrease the risk of adverse events, when antipsychotics are combined with BZDs, albeit confounding cannot be fully excluded within the current design. This article is protected by copyright. All rights reserved.

PMID:34076293 | DOI:10.1002/gps.5587

Clin Sci (Lond). 2021 Jun 11;135(11):1333-1351. doi: 10.1042/CS20200309.

ABSTRACT

Recent advances in treatment have transformed the management of cancer. Despite these advances, cardiovascular disease remains a leading cause of death in cancer survivors. Cardio-oncology has recently evolved as a subspecialty to prevent, diagnose, and manage cardiovascular side effects of antineoplastic therapy. An emphasis on optimal management of comorbidities and close attention to drug interactions are important in cardio-oncologic care. With interdisciplinary collaboration among oncologists, cardiologists, and pharmacists, there is potential to prevent and reduce drug-related toxicities of treatments. The cytochrome P450 (CYP450) family of enzymes and the P-glycoprotein (P-g) transporter play a crucial role in drug metabolism and drug resistance. Here we discuss the role of CYP450 and P-g in drug interactions in the field of cardio-oncology, provide an overview of the cardiotoxicity of a spectrum of cancer agents, highlight the role of precision medicine, and encourage a multidisciplinary treatment approach for patients with cancer.

PMID:34076246 | DOI:10.1042/CS20200309

Mol Biol Rep. 2021 Jun 1. doi: 10.1007/s11033-021-06444-4. Online ahead of print.

ABSTRACT

Drug-induced liver injury significantly caused by synthetic drugs, and other xenobiotics contribute to clinical hepatic dysfunction, which has been a substantial challenge for both patients and physicians. Traditional medicines used as an alternative therapy because of their pharmacological benefits, less or no side effects, and enormous availability in nature. Phytochemicals are essential ingredients of plants that reduce necrotic cell death, restore the antioxidant defence mechanism, limit oxidative stress, and prevent the inflammation of tissue and dysfunction of the mitochondria. In this review, we principally focused on the potential effect of the herbal plants and their phytochemicals in treating drug-induced hepatotoxicity.

PMID:34075538 | DOI:10.1007/s11033-021-06444-4

Nutrients. 2021 May 24;13(6):1784. doi: 10.3390/nu13061784.

ABSTRACT

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.

PMID:34073784 | DOI:10.3390/nu13061784

Int J Mol Sci. 2021 May 26;22(11):5654. doi: 10.3390/ijms22115654.

ABSTRACT

Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish (Danio rerio) studies. Zebrafish have proven to be an excellent research tool for studying dyslipidaemias as a model of these pathological conditions. This system enables in-vivo characterization of drug and gene candidates to further the understanding of disease aetiology and develop new therapeutic strategies. Our review also considers important environmental issues arising from the indiscriminate use of LLDs worldwide. The widespread use and importance of drugs such as statins and fibrates justify the need for the meticulous study of their mechanism of action and the side effects they cause.

PMID:34073503 | DOI:10.3390/ijms22115654

Med Clin North Am. 2021 Jul;105(4):757-782. doi: 10.1016/j.mcna.2021.04.011.

ABSTRACT

Connective tissue diseases (CTDs) encompass a broad spectrum of clinical presentations that involve multidisciplinary management. Cutaneous findings are common in CTD and careful examination of these features aids in appropriate diagnosis and subsequent evaluation. Thorough work-up of CTD is crucial to properly identify disease subtypes and systemic involvement. Management plans can be developed based on diagnosis and systemic manifestations of disease. Disease management often requires treatment with pharmacotherapies with potential for toxicities, further underscoring the importance of diagnostic accuracy in this patient population. Evolving research strives to better elucidate the pathogenic mechanisms of CTDs allowing for more targeted treatment modalities.

PMID:34059249 | DOI:10.1016/j.mcna.2021.04.011

Med Clin North Am. 2021 Jul;105(4):577-597. doi: 10.1016/j.mcna.2021.04.001.

ABSTRACT

Severe cutaneous adverse reactions to medications (SCARs) include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. They are all non-immunoglobulin E mediated hypersensitivity reaction patterns, distinguished from simple cutaneous drug eruptions by immunologic pathogenesis and internal organ involvement. Herein the clinical features, diagnostic workup, and management considerations are presented for each of these major SCARs.

PMID:34059239 | DOI:10.1016/j.mcna.2021.04.001