Molecules. 2021 Apr 25;26(9):2506. doi: 10.3390/molecules26092506.

ABSTRACT

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

PMID:33923028 | PMC:PMC8123278 | DOI:10.3390/molecules26092506

Int J Mol Sci. 2021 Apr 24;22(9):4443. doi: 10.3390/ijms22094443.

ABSTRACT

The hepatotoxic potential of drugs is one of the main reasons why a number of drugs never reach the market or have to be withdrawn from the market. Therefore, the evaluation of the hepatotoxic potential of drugs is an important part of the drug development process. The aim of this work was to evaluate the relative abilities of different supervised self-organizing algorithms in classifying the hepatotoxic potential of drugs. Two modifications of standard counter-propagation training algorithms were proposed to achieve good separation of clusters on the self-organizing map. A series of optimizations were performed using genetic algorithm to select models developed with counter-propagation neural networks, X-Y fused networks, and the two newly proposed algorithms. The cluster separations achieved by the different algorithms were evaluated using a simple measure presented in this paper. Both proposed algorithms showed a better formation of clusters compared to the standard counter-propagation algorithm. The X-Y fused neural network confirmed its high ability to form well-separated clusters. Nevertheless, one of the proposed algorithms came close to its clustering results, which also resulted in a similar number of selected models.

PMID:33923145 | DOI:10.3390/ijms22094443

Med Clin North Am. 2021 May;105(3):425-444. doi: 10.1016/j.mcna.2021.02.003.

ABSTRACT

When prescribing medications, it is important to consider the ocular side effects of common systemic therapy as well as potential systemic side effects of ocular medications. Although not an exhaustive list of medications/classes of medications, this article does include many commonly used drugs and also provides information on some topical therapies commonly used by ophthalmologists. These ocular medications may result in systemic effects and/or alter patients' management of systemic conditions.

PMID:33926639 | DOI:10.1016/j.mcna.2021.02.003

Lancet Rheumatol. 2021 Mar 9;3(5):e337-e346. doi: 10.1016/S2665-9913(21)00061-8. eCollection 2021 May.

ABSTRACT

BACKGROUND: Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts-cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics.

METHODS: Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR-European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0-6 h (AUC0-6) were measured. This study is registered with ISRCTN, ISRCTN36667085.

FINDINGS: Between Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18-0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0-6 were two-times higher in participants developing dose-limiting toxicities.

INTERPRETATION: The maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial.

FUNDING: UK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.

PMID:33928262 | PMC:PMC8062952 | DOI:10.1016/S2665-9913(21)00061-8

Cureus. 2021 Mar 24;13(3):e14091. doi: 10.7759/cureus.14091.

ABSTRACT

Regadenoson myocardial perfusion imaging (MPI) is a widely used screening study for patients with an intermediate pretest probability of coronary artery disease (CAD). Via selective agonism of the adenosine A2A receptor, regadenoson can induce coronary steal, revealing stenotic vessel territory through transient ischemia. Common side effects of this medication include chest pain, shortness of breath, nausea, vomiting, atrioventricular block, seizure, and allergic reactions. Here we present a case of severe shivering and chest tightness after the administration of regadenoson, along with a physiologic explanation and treatment.

PMID:33927915 | PMC:PMC8075772 | DOI:10.7759/cureus.14091

Malar J. 2021 Apr 29;20(1):206. doi: 10.1186/s12936-021-03735-w.

ABSTRACT

BACKGROUND: Post-artesunate delayed haemolysis (PADH) is common after severe malaria episodes. PADH is related to the "pitting" phenomenon and the synchronous delayed clearance of once-infected erythrocytes, initially spared during treatment. However, direct antiglobulin test (DAT) positivity has been reported in several PADH cases, suggesting a contribution of immune-mediated erythrocyte clearance. The aim of the present study was to compare clinical features of cases presenting a positive or negative DAT.

METHODS: Articles reporting clinical data of patients diagnosed with PADH, for whom DAT had been performed, were collected from PubMed database. Data retrieved from single patients were extracted and univariate analysis was performed in order to identify features potentially related to DAT results and steroids use.

RESULTS: Twenty-two studies reporting 39 PADH cases were included: median baseline parasitaemia was 20.8% (IQR: 11.2-30) and DAT was positive in 17 cases (45.5%). Compared to DAT-negative individuals, DAT-positive patients were older (49.5 vs 31; p = 0.01), had a higher baseline parasitaemia (27% vs 17%; p = 0.03) and were more commonly treated with systemic steroids (11 vs 3 patients, p = 0.002). Depth and kinetics of delayed anaemia were not associated with DAT positivity.

CONCLUSIONS: In this case series, almost half of the patients affected by PADH had a positive DAT. An obvious difference between the clinical courses of patients presenting with a positive or negative DAT was lacking. This observation suggests that DAT result may not be indicative of a pathogenic role of anti-erythrocytes antibodies in patients affected by PADH, but it may be rather a marker of immune activation.

PMID:33926462 | DOI:10.1186/s12936-021-03735-w

J Clin Med. 2021 Apr 1;10(7):1428. doi: 10.3390/jcm10071428.

ABSTRACT

BACKGROUND: COVID-19 vaccine side effects have a fundamental role in public confidence in the vaccine and its uptake process. Thus far, the evidence on vaccine safety has exclusively been obtained from the manufacturer-sponsored studies; therefore, this study was designed to provide independent evidence on Pfizer-BioNTech COVID-19 vaccine side effects.

METHODS: A cross-sectional survey-based study was carried out between January and February 2021 to collect data on the side effects following the COVID-19 vaccine among healthcare workers in the Czech Republic. The study used a validated questionnaire with twenty-eight multiple-choice items covering the participants' demographic data, medical anamneses, COVID-19-related anamneses, general, oral, and skin-related side effects.

RESULTS: Injection site pain (89.8%), fatigue (62.2%), headache (45.6%), muscle pain (37.1%), and chills (33.9%) were the most commonly reported side effects. All the general side effects were more prevalent among the ≤43-year-old group, and their duration was mainly one day (45.1%) or three days (35.8%) following the vaccine. Antihistamines were the most common drugs associated with side effects, thus requiring further investigation. The people with two doses were generally associated with a higher frequency of side effects.

CONCLUSIONS: The distribution of side effects among Czech healthcare workers was highly consistent with the manufacturer's data, especially in terms of their association with the younger age group and the second dose. The overall prevalence of some local and systemic side effects was higher than the manufacturer's report. Further independent studies on vaccine safety are strongly required to strengthen public confidence in the vaccine.

PMID:33916020 | DOI:10.3390/jcm10071428

Biomed Pharmacother. 2021 Apr 26;139:111617. doi: 10.1016/j.biopha.2021.111617. Online ahead of print.

ABSTRACT

BACKGROUND: The efficacy and safety of dexmedetomidine and olanzapine for delirium control in critically ill elderly patients without ventilation or surgery are not known.

METHODS: The efficacy and safety of dexmedetomidine and olanzapine for controlling delirium were evaluated in a retrospective cohort of critically illness by assessing the sedation level, drug dose/duration, combination rate with other sedatives, adverse effects, intubation rate and prognosis.

RESULT: The maximum (1.61 ± 1.56 vs. 2.70 ± 1.01, p < 0.001), average (-0.57 ± 0.88 vs. 0.88 ± 0.73, p < 0.001), and minimum (-1.67 ± 1.04 vs. -1.37 ± 1.01, p = 0.014) RASS scores of 263 patients were lower after treating with dexmedetomidine than treating with olanzapine. Drug use duration (4.83 ± 2.67 days vs. 5.87 ± 3.14 days, p = 0.005) and sedative combination rates (13.56% vs. 40.00%, p = 0.003) were lower when treating with dexmedetomidine than that with olanzapine. A comparison of adverse effects between dexmedetomidine and olanzapine revealed respiratory depression (16.95% vs. 2.84%, p < 0.001), hypoxia (13.56% vs. 2.76%, p < 0.001) and hypotension (11.02% vs. 3.45%, p = 0.007). Intubation rates (22.88% vs. 12.41%, p = 0.023) and the length of hospital stay (9.30 ± 4.90 days vs. 8.83 ± 3.34 days, p < 0.001) were higher in patients treated with dexmedetomidine than that with olanzapine. Mortality rates, cognitive prognosis, and delirium recurrence rates were similar between groups. Age, severe cardiopulmonary disease, APACHE II scores, dexmedetomidine dose, minimum RASS score and sedative combination were significantly (p < 0.05) associated with the adverse effects of dexmedetomidine. Respiratory depression, hypoxia and hypotension in the olanzapine group all occurred during combination with benzodiazepines.

CONCLUSIONS: Dexmedetomidine achieved more satisfactory sedative effects on delirium control, but olanzapine was safer.

PMID:33915500 | DOI:10.1016/j.biopha.2021.111617

Kidney Int Rep. 2021 Feb 3;6(4):1088-1098. doi: 10.1016/j.ekir.2021.01.029. eCollection 2021 Apr.

ABSTRACT

INTRODUCTION: Primary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage. LDHA inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. LDHA is mainly expressed in the liver and muscles.

METHODS: Nonclinical data in mice and nonhuman primates show that LDHA inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA inhibition.

RESULTS: Based on a literature review of human LDHA deficiency, we defined the phenotype as mainly muscle-related with no liver manifestations. Healthy volunteers treated with nedosiran experienced no drug-related musculoskeletal adverse events. There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function.

CONCLUSION: Phase I clinical data on nedosiran and published nonclinical data together provide substantial evidence that LDHA inhibition is a safe therapeutic mechanism for the treatment of all known types of PH.

PMID:33912759 | PMC:PMC8071644 | DOI:10.1016/j.ekir.2021.01.029

Drug Des Devel Ther. 2021 Apr 21;15:1633-1640. doi: 10.2147/DDDT.S305244. eCollection 2021.

ABSTRACT

BACKGROUND: An oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children.

METHODS: Eleven newly diagnosed and one relapsed pediatric patient (4-14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.

RESULTS: A total of 107 arsenic concentrations (0.1-75.0 µg L-1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63-82.18) L h-1 kg-1 and 230.37 (85.96-495.68) L kg-1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3-4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.

CONCLUSION: The pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.

PMID:33911851 | PMC:PMC8071704 | DOI:10.2147/DDDT.S305244

J Thromb Haemost. 2021 Apr 28. doi: 10.1111/jth.15352. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 Vaccine from AstraZeneca (AZD1222) is one of several vaccines introduced to provide immunity against SARS-CoV-2. Recently, more than 50 cases have been reported presenting a combination of thrombosis, thrombocytopenia and remarkably high levels of anti-PF4/polyanion antibodies post-AZD1222 vaccination. Now linked to the vaccine, the condition is referred to as vaccine-induced thrombotic thrombocytopenia (VITT). The European Medicines Agency still recommends vaccination with AZD1222, but several European countries have temporally paused and/or restricted its use because of the perceived risk of this severe side effect. As there is no description of PF4/polyanion antibody testing in the clinical trials, knowledge about the prevalence of such antibodies in a vaccinated cohort is needed.

OBJECTIVES: To investigate prevalence of thrombocytopenia and anti-PF4/polyanion antibodies in a population recently vaccinated with AZD1222.

PATIENTS/METHODS: 492 health care workers recently vaccinated with the first dose of AZD1222 were recruited from two hospitals in Norway. Study individuals were screened for thrombocytopenia and the presence of anti-PF4/polyanion antibodies with a PF4/PVS IgG ELISA immunoassay. Side effects after vaccination were registered.

RESULTS: The majority of study participants had normal platelet counts and negative immunoassay. Anti-PF4/polyanion antibodies without platelet activating properties were only detected in 6 individuals (OD ≥ 0.4, range 0.58-1.16), all with normal platelet counts. No subjects had severe thrombocytopenia.

CONCLUSIONS: We found low prevalence of both thrombocytopenia and antibodies to PF4/polyanion-complexes among Norwegian health care workers after vaccination with AZD1222.

PMID:33909350 | DOI:10.1111/jth.15352

Drug Ther Bull. 2021 May;59(5):73-76. doi: 10.1136/dtb.2020.000040.

ABSTRACT

The emergence of targeted and precision therapies has increased treatment options for people living with cancer. Of particular note is the development and approval of chimeric antigen receptor (CAR) T-cell therapies that involve the use of a patient's own immune system to treat cancers that have proven resistant to other approaches. Keeping abreast of treatment changes and practice guidelines is a challenge for all healthcare professionals, and the pressure of doing so becomes most acute with innovations in cancer therapeutics that have the potential to extend or save lives. Though uncommon, step changes like CAR T-cell therapy pose a challenge, often requiring completely new ways of thinking about efficacy evidence, basic science, ethics and service delivery. At a time when patients are able and empowered to readily access information about novel and exploratory treatments, healthcare professionals need to feel informed enough to help patients with life-changing or life-limiting cancers who approach them for advice. This article gives an overview of the basic principles of CAR T-cell therapy including how it is delivered, who is eligible to receive it in the UK, and a brief outline of current evidence of its efficacy and safety. The information is intended to provide healthcare professionals with an introduction to CAR T-cell therapy to help them advise potentially eligible patients or those already undergoing treatment about what to expect.

PMID:33906917 | DOI:10.1136/dtb.2020.000040

Medicina (B Aires). 2021;81(2):208-213.

ABSTRACT

The management of patients with immune-related adverse events (irAEs) frequently demands a multidisciplinary approach. We reviewed the causes and clinical course of medical visits and admissions at the Instituto Alexander Fleming due to irAEs between September 2015 and July 2019. Demographic data, diagnosis, toxicity and its severity, requirement of admission, treatment, mortality, and evaluation of the re-administration of immunotherapy were collected. We found 124 irAEs in 89 patients. Sixty-eight of them received monotherapy (76.4%) and 21 (23.6%) combination of drugs. Cutaneous manifestations were the most frequent cause of irAEs, followed by general manifestations, endocrine dysfunctions (hypothyroidism the most frequent), colitis, pneumonitis, neurologic disorders, and hepatitis. In 26 adverse events (in 25 patients), severity grade was = 3. Fifteen were admitted and 6 required ICU admission. One patient died. Thirty-four received glucocorticoids, 12 of them by intravenous route. One patient received mycophenolate and one IVIG. In 20, the treatment was discontinued; 8 were re-exposed, with definitive discontinuation in one patient. In this case series we report our experience in the diagnosis and management of adverse reactions related to a family of drugs whose use has grown in recent years.

PMID:33906139

Brain. 2021 Apr 26:awab167. doi: 10.1093/brain/awab167. Online ahead of print.

ABSTRACT

Strong evidence suggests that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits ER stress-induced eIF2α-phosphatase allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. Its efficacy and safety in ALS patients are unknown. To address these issues, we conducted a multicentre, randomised, double-blind trial, with futility design. ALS patients with onset of symptoms within the previous 18 months were randomly assigned to receive in a 1:1:1:1 ratio guanabenz 64 mg, 32 mg, 16 mg or placebo daily for 6 months as add-on therapy to riluzole. The purpose of the placebo group blinding was safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease in 6 months as measured by the ALS Milano-Torino staging compared to a historical cohort of 200 ALS patients. The secondary outcomes were the rate of decline in ALSFRS-R total score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary analysis of efficacy was performed by intention-to-treat. Guanabenz 64 mg and 32 mg arms, both alone and combined, reached the primary hypothesis of non-futility with proportions of patients who progressed to higher stage of disease at 6 months significantly lower than that expected under the hypothesis of non-futility and significantly lower difference in the median rate of change of the ALSFRS-R total score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those in guanabenz 16 mg (4/8; 50%), historical cohort alone (21/49; 43%; p = 0.001) or plus placebo (25/60; 42%; p = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having significantly higher proportion of drug-related side effects and the 64 mg arm significantly higher drop-out rate. The number of serious adverse events did not significantly differ between guanabenz arms and placebo. Our findings indicate that a larger trial with a molecule targeting the UPR pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.

PMID:33905493 | DOI:10.1093/brain/awab167

Immunopharmacol Immunotoxicol. 2021 Apr 27:1-17. doi: 10.1080/08923973.2021.1916525. Online ahead of print.

ABSTRACT

Aim: Major side effects of cyclophosphamide administration are immunosuppression and myelosuppression. The immunomodulatory effects of plant bioactive compounds on chemotherapy drug-induced immunosuppression may have significant effects in cancer treatment. For this reason, we investigated the immunomodulatory effect of myricetin, apigenin, and hesperidin in cyclophosphamide-induced immunosuppression in rats.Methods: In our study, a total of 64 rats were used, and divided into eight equal groups. These groups were: control, cyclophosphamide, cyclophosphamide + myricetin (100 mg/kg), cyclophosphamide + myricetin (200 mg/kg), cyclophosphamide + apigenin (100 mg/kg), cyclophosphamide + apigenin (200 mg/kg), cyclophosphamide + hesperidin (100 mg/kg), and cyclophosphamide + hesperidin (200 mg/kg). Myricetin, apigenin, and hesperidin pretreatments were performed for 14 d, while cyclophosphamide application (200 mg/kg) was performed only on the 4th day of the study. Levels of humoral antibody production, quantitative hemolysis, macrophage phagocytosis, splenic lymphocyte proliferation, and natural killer cell cytotoxicity were determined. In addition, we measured pro-inflammatory cytokines, and followed lipid peroxidation and antioxidant markers and examined the histology of bone marrow, liver and spleen in all groups.Results: During cyclophosphamide treatment, all three phytochemicals increased the levels of humoral antibody production, quantitative hemolysis, macrophage phagocytosis, splenic lymphocyte proliferation, antioxidant markers, and natural killer cell cytotoxicity. Moreover, the agents decreased the levels of pro-inflammatory cytokines and mediators, reduced lipid peroxidation markers, and reduced tissue damage in liver, spleen, and bone marrow.Conclusion: Our study demonstrated that myricetin, apigenin, and hesperidin can reduce the immunosuppressive effect of cyclophosphamide by enhancing both innate and adaptive immune responses, and these compounds may be useful immunomodulatory agents during cancer chemotherapy.

PMID:33905277 | DOI:10.1080/08923973.2021.1916525

Iran J Allergy Asthma Immunol. 2021 Apr 17;20(2):255-259.

ABSTRACT

Generalized bullous fixed drug eruption (GBFDE) is a specific variant of fixed drug eruption that belongs to severe cutaneous adverse reactions (SCARs) and its diagnosis is based mainly on clinical course and especially on the reoccurrence of typical bullous lesions in previous and new sites after re-administration of the offending drug. We present a well-documented case of fluconazole-induced GBFDE, with a positive patch test to fluconazole (30% weight/volume preparation) and clinical tolerance to itraconazole proven by negative oral provocation. Even in SCARs, patch testing represents a useful diagnostic tool, while oral provocation remains the gold standard in cases that an alternative but the chemically relevant drug must be administered.

PMID:33904684

Respir Med. 2021 Apr 14;182:106398. doi: 10.1016/j.rmed.2021.106398. Online ahead of print.

ABSTRACT

OBJECTIVE: Evidence of the efficacy of single-inhaler triple therapy in COPD patients inferred from RCTs has not been assessed in a real-world setting in Austria. In this non-interventional study (NIS) tolerability and effectiveness of extrafine beclometasone-dipropionate, formoterol-fumarate and glycopyrronium (Trimbow® 87/5/9 μg) was evaluated in COPD patients.

METHODS: A prospective NIS was conducted over 52 weeks in 24 sites in Austria. Eligible COPD patients had an indication for treatment with single-inhaler BDP/FF/G. In this study tolerability, lung function, exacerbation rate, symptom scores and CAT scores were recorded.

RESULTS: 265 patients with moderate to very severe airflow limitation (GOLD Grade 2-4: 96.2%) and persistent symptoms (GOLD B: 62.3%, GOLD D: 34%) according to the 2018 GOLD Report were included. After 52 weeks, a significant improvement was detected in lung function (FEV1, FEV1% predicted and FVC; p < 0.001) and symptoms (cough, sputum and shortness of breath; p < 0.001). A clinically relevant improvement in CAT score observed at 12 weeks persisted after 52 weeks in GOLD B and GOLD D patients (p < 0.001), paralleled by a significant reduction of moderate and severe exacerbations by 57.4% and 27.3%, respectively (p < 0.001). After 52 weeks, 93.7% of the patients continued the treatment. Of 21 adverse events reported 16 were non-serious, five were serious, none were deemed drug related.

CONCLUSIONS: The present results support the tolerability and effectiveness of extrafine BDP/FF/G in COPD patients in a real-world setting, showing an improvement in lung function, symptom control and a significant reduction in exacerbations.

PMID:33901786 | DOI:10.1016/j.rmed.2021.106398

J Patient Cent Res Rev. 2021 Apr 19;8(2):113-120. eCollection 2021 Spring.

ABSTRACT

PURPOSE: Many studies in preventing adverse drug events have been researcher-driven, yet few have engaged patients in the development of a project. This project aims to engage minority elderly patients with multiple chronic conditions in the development of research questions and strategies to improve medication safety.

METHODS: Elderly patients (≥65 years old) who were prescribed 7 or more chronic medications were recruited through a university-based aging resource network in a historically African American community in Houston, Texas. Patients and a caregiver participated in a multidisciplinary workgroup comprised of a physician, pharmacists, a nurse, health educators, and a social worker. Patients were engaged by utilizing the 4 patient-centered outcomes research engagement principles. The workgroup created a strategic plan, completed an environmental scan, identified research problems, and reviewed current evidence-based approaches in the literature. Workgroup findings were presented to a broader audience within a community town hall setting, and input was collected from a community-wide survey.

RESULTS: From April 2018 to July 2018, 3 patients and 1 caregiver participated in 5 multidisciplinary workgroup meetings. A total of 74 seniors attended the town hall meeting, and 69 completed the surveys. The most common drug-related problems among survey participants were doubts about drug advertisements (79%) and drug interactions (70%). Most participants (88%) were more comfortable in receiving face-to-face counseling compared to an app or virtual visits. Findings aided in developing 3 grant proposals.

CONCLUSIONS: This narrative provides a roadmap for conducting multidisciplinary, patient-centered participatory research to refine research strategies in minimizing drug-related problems.

PMID:33898643 | PMC:PMC8060036

Expert Opin Drug Saf. 2021 Apr 24. doi: 10.1080/14740338.2021.1922667. Online ahead of print.

ABSTRACT

INTRODUCTION: Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades saw a considerable expansion in antifungal drug research, resulting in the clinical development of different classes of antifungal agents with different pharmacologic properties. Among drug-specific characteristics of antifungal agents, renal disposition and nephrotoxicity are important clinical considerations as many patients requiring antifungal therapy have compromised organ functions or are receiving other potentially nephrotoxic medications.

AREAS COVERED: The present article reviews incidence, severity and mechanisms of nephrotoxicity associated with antifungal agents used for prevention and treatment of invasive fungal diseases by discussing distribution, metabolism, elimination and drug-related adverse events in the context of safety data from phase II and III clinical studies.

EXPERT OPINION: Based on the available data amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.

PMID:33896310 | DOI:10.1080/14740338.2021.1922667

Pediatr Allergy Immunol. 2021 Apr 24. doi: 10.1111/pai.13522. Online ahead of print.

ABSTRACT

BACKGROUND: H1-antihistamines (AHs) are widely used for the treatment of allergic diseases, being one of the most commonly prescribed classes of medications in pediatrics. Newer-generation AHs are associated with fewer adverse effects compared to first-generation. However, their relative harms in the pediatric population still need scrutiny.

METHODS: We performed a systematic review of randomized controlled trials (RCTs) which included comparisons of safety parameters between an orally administered newer-generation AH with another AH (first- or second- generation), montelukast or placebo in children aged≤12 years. We searched MEDLINE and CENTRAL, independently extracted data on study population, interventions, adverse events (AEs) and treatment discontinuations, and assessed the methodological quality of the included RCTs using the Cochrane's risk of bias tool.

RESULTS: Fourty-five RCTs published between 1989 and 2017 met eligibility criteria. The majority of RCTs included school-aged children with allergic rhinitis and had a follow-up period of up to a month. Four RCTs reported serious AEs in patients receiving a newer-generation AH, but only two patients experienced a possibly drug-related serious AE. The occurrence of AEs, drug-related AEs and treatment discontinuations due to AEs varied between RCTs. Most AEs reported were of mild intensity. Indirect evidence indicates that cetirizine is more sedating than the other newer-generation AHs.

CONCLUSION: Our findings confirm that newer-generation AHs have a favorable safety and tolerability profile. However, we could not draw firm conclusions regarding the comparative safety profile of the newer-generation AHs due to the paucity of head-to-head RCTs, variation in definitions and reporting of AEs, and short follow-up duration.

PMID:33894089 | DOI:10.1111/pai.13522