Transplant Cell Ther. 2021 Dec 4:S2666-6367(21)01409-3. doi: 10.1016/j.jtct.2021.11.022. Online ahead of print.

ABSTRACT

We recently demonstrated that TCRαβ+/CD19+ graft depletion successfully prevents severe acute and chronic GVHD in pediatric patients with primary immunodeficiencies (PID) receiving transplants from both matched unrelated and mismatched related donors. However, in all patients, short-term post-HSCT immunosuppressive therapy (IST) was used. There are limited data on TCRαβ+/CD19+ graft depletion with no post-HSCT IST implementation. In the current study were included 74 PID patients who underwent first HSCT from matched unrelated (n=51) or mismatched related donors (n=23) with TCRαβ+/CD19+ graft depletion. All received in conditioning regimen a combination of treosulfan with fludarabine and either melphalan or thiotepa. In all, thymoglobulin 5 mg/kg (days -5, -4, -3) and rituximab at day -1 were used. In 48 patients, various approaches to short-term post-transplant IST were used and 26 patients received no post-HSCT IST. The rates of engraftment, acute and chronic GVHD, survival and mortality were similar in those who received and did not receive IST, with a slightly higher incidence of graft rejection in patients not receiving IST: 19% in the non-IST group against 13% in the IST group (p=0.41). The incidence of CMV reactivation was 50% and 39% (p=0.5) and EBV reactivation 10% and 0 (p=0.2) in the IST and non-IST groups, respectively. No grade 4 adverse events were seen in both groups, although in 19/40 (47.5%) patients receiving calcineurin inhibitors, the therapy was discontinued before day +45. More robust immune recovery with both T- and B- lymphocytes was observed in the non-IST group. To conclude, TCRαβ+/CD19+ in combination with particular serotherapy effectively prevents severe acute and chronic GVHD in PID. Regarding remaining risks of infectious complications and additional drug-related toxicity, there are no benefits to post-HSCT IST use in these patients.

PMID:34875404 | DOI:10.1016/j.jtct.2021.11.022

Best Pract Res Clin Gastroenterol. 2021 Oct-Dec;54-55:101760. doi: 10.1016/j.bpg.2021.101760. Epub 2021 Jul 3.

ABSTRACT

Human liver possesses a persistent and tightly regulated immune response. Maintaining this homeostatic state is the key to prevent pathological processes, as a failure in clearing dangerous stimuli, is associated with tissue damage. A dysregulation of the liver immune homeostasis is involved in many disease processes and the use of the immunosuppression aims to control the inflammatory response, where the physiologic mechanisms failed. The use of steroids which targets broadly the inflammatory cascade and the immune system activation have been extensively employed in both acute and chronic liver diseases. They currently are the backbone of the treatment of autoimmune diseases such as autoimmune hepatitis or IgG4 sclerosing cholangitis. The steroid use in acute liver injury, especially alcohol mediated and drug induced liver injury (DILI), have been debated, despite the biological rationale. The immunosuppression molecules currently employed in liver diseases target the immune system broadly, causing multiple side effects either intrinsic in the mechanisms of the drug or secondary to off-target toxicity. The future of immunosuppressant treatment is moving towards more selective strategies, targeting disease specific pathways. This review aims to explore the rationale of use of immunosuppression in non-transplant hepatology. A broad summary of the immune biology of liver immune mediated diseases will be provided to the readers in order to highlight the potential therapeutic targets. An extensive description of the molecules employed in liver diseases will follow and the clinical evidences in AIH, IgG4 related cholangitis, alcoholic hepatitis and DILI will be reviewed.

PMID:34874849 | DOI:10.1016/j.bpg.2021.101760

J Cancer Res Clin Oncol. 2021 Dec 7. doi: 10.1007/s00432-021-03870-6. Online ahead of print.

ABSTRACT

PURPOSE: Immune checkpoint inhibitor (ICI)-induced hepatitis belongs to the frequently occurring immune-related adverse events (irAEs), particularly with the combination therapy involving ipilimumab and nivolumab. However, predisposing factors predicting the occurrence of ICI-induced hepatitis are barely known. We investigated the association of preexisting autoantibodies in the development of ICI-induced hepatitis in a prospective cohort of cancer patients.

METHODS: Data from a prospective biomarker cohort comprising melanoma and non-small cell lung cancer (NSCLC) patients were used to analyze the incidence of ICI-induced hepatitis, putatively associated factors, and outcome.

RESULTS: 40 patients with melanoma and 91 patients with NSCLC received ICI between July 2016 and May 2019. 11 patients developed ICI-induced hepatitis (8.4%). Prior to treatment, 45.5% of patients in the hepatitis cohort and 43.8% of the control cohort showed elevated titers of autoantibodies commonly associated with autoimmune liver diseases (p = 0.82). We found two nominally significant associations between the occurrence of ICI-induced hepatitis and HLA alleles associated with autoimmune liver diseases among NSCLC patients. Of note, significantly more patients with ICI-induced hepatitis developed additional irAEs in other organs (p = 0.0001). Neither overall nor progression-free survival was affected in the hepatitis group.

CONCLUSION: We found nominally significant associations of ICI-induced hepatitis with two HLA alleles. ICI-induced hepatitis showed no correlation with liver-specific autoantibodies, but frequently co-occurred with irAEs affecting other organs. Unlike other irAEs, ICI-induced hepatitis is not associated with a better prognosis.

PMID:34874490 | DOI:10.1007/s00432-021-03870-6

J Am Heart Assoc. 2021 Dec 7:e022247. doi: 10.1161/JAHA.121.022247. Online ahead of print.

ABSTRACT

Background Anticancer therapies have significantly improved patient outcomes; however, cardiac side effects from cancer therapies remain a significant challenge. Cardiotoxicity following treatment with proteasome inhibitors such as carfilzomib is known in clinical settings, but the underlying mechanisms have not been fully elucidated. Methods and Results Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a cell model for drug-induced cytotoxicity in combination with traction force microscopy, functional assessments, high-throughput imaging, and comprehensive omic analyses, we examined the molecular mechanisms involved in structural and functional alterations induced by carfilzomib in hiPSC-CMs. Following the treatment of hiPSC-CMs with carfilzomib at 0.01 to 10 µmol/L, we observed a concentration-dependent increase in carfilzomib-induced toxicity and corresponding morphological, structural, and functional changes. Carfilzomib treatment reduced mitochondrial membrane potential, ATP production, and mitochondrial oxidative respiration and increased mitochondrial oxidative stress. In addition, carfilzomib treatment affected contractility of hiPSC-CMs in 3-dimensional microtissues. At a single cell level, carfilzomib treatment impaired Ca2+ transients and reduced integrin-mediated traction forces as detected by piconewton tension sensors. Transcriptomic and proteomic analyses revealed that carfilzomib treatment downregulated the expression of genes involved in extracellular matrices, integrin complex, and cardiac contraction, and upregulated stress responsive proteins including heat shock proteins. Conclusions Carfilzomib treatment causes deleterious changes in cellular and functional characteristics of hiPSC-CMs. Insights into these changes could be gained from the changes in the expression of genes and proteins identified from our omic analyses.

PMID:34873922 | DOI:10.1161/JAHA.121.022247

Reg Anesth Pain Med. 2021 Dec 6:rapm-2021-103294. doi: 10.1136/rapm-2021-103294. Online ahead of print.

NO ABSTRACT

PMID:34873025 | DOI:10.1136/rapm-2021-103294

Postgrad Med. 2021 Dec 7. doi: 10.1080/00325481.2021.2015221. Online ahead of print.

ABSTRACT

Pain following brain surgery can compromise the result of surgery. Several pharmacological interventions have been used to prevent postoperative pain in adults undergoing brain surgery. Pain following craniotomy is considered to be moderate to severe during the first two post-operative days. Opioids have been historically the mainstay and are the current prominent strategy for pain treatment. They produce analgesia, but may alter respiratory, cardiovascular, gastrointestinal and neuroendocrine functions. All these side effects may affect the normal postoperative course of craniotomy, by affecting neurological function and increasing intracranial pressure. Therefore their use in neurosurgery is limited and opioids are used in case of strict necessity or as rescue medication. In addition to opioids, drugs with differing mechanisms of actions target pain pathways resulting in additive and/or synergistic effects. Some of these agents inclde acetaminophen/non-steroidal anti-inflammatory drugs (NSAIDs), alpha 2 agonists, NMDA receptor antagonists, gabapentinoids, and local anesthesia techniques. Multimodal analgesia should be a balance between adequate analgesia and less drug induced sedation, respiratory depression, hypercapnia, nausea and vomiting, which may increase intracranial pressure. Non-opioid analgesics can be an useful pharmacological alternative in multimodal regimes to manage post craniotomy pain. This narrative review aims to outline the current clinical evidence of multimodal analgesia for post craniotomy pain control.

PMID:34872428 | DOI:10.1080/00325481.2021.2015221

Front Immunol. 2021 Nov 19;12:688930. doi: 10.3389/fimmu.2021.688930. eCollection 2021.

ABSTRACT

Acute anaphylaxis to small molecule drugs is largely considered to be antibody-mediated with immunogloblin E (IgE) and mast cell activation being key. More recently, a role for drug-reactive immunoglobulin G (IgG) with neutrophil activation has also been suggested, at least in reactions to neuromuscular blocking agents (NMBAs). However, the mast cell receptor MRGPRX2 has also been highlighted as a possible triggering mechanism in acute anaphylaxis to many clinically used drugs. Significantly, MRGPRX2 activation is not dependent upon the presence of drug-recognising antibody. Given the reasonable assumption that MRGPRX2 is expressed in all individuals, the corollary of this is that in theory, anybody could respond detrimentally to triggering drugs (recently suggested to be around 20% of a drug-like compound library). But this clearly is not the case, as the incidence of acute drug-induced anaphylaxis is very low. In this mini-review we consider antibody-dependent and -independent mechanisms of mast cell activation by small molecule drugs with a focus on the MRGPRX2 pathway. Moreover, as a juxtaposition to these adverse drug actions, we consider how increased understanding of the role of MRGPRX2 in anaphylaxis is important for future drug development and can complement exploration of this receptor as a drug target in broader clinical settings.

PMID:34867939 | PMC:PMC8639860 | DOI:10.3389/fimmu.2021.688930

Anesth Analg. 2021 Dec 2. doi: 10.1213/ANE.0000000000005811. Online ahead of print.

ABSTRACT

BACKGROUND: Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension.

METHODS: We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively.

RESULTS: We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg.

CONCLUSIONS: A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.

PMID:34872102 | DOI:10.1213/ANE.0000000000005811

Front Pharmacol. 2021 Nov 18;12:756582. doi: 10.3389/fphar.2021.756582. eCollection 2021.

ABSTRACT

Background and Objective: Over the past few years, mirabegron has been increasingly used as a therapeutic option for neurogenic lower urinary tract dysfunction. Here, we carried out a meta-analysis to investigate the efficacy and safety of mirabegron for the treatment of neurogenic lower urinary tract dysfunction. Methods: We used a range of databases to retrieve randomized controlled trials (RCTs) relating to mirabegron in patients with neurogenic lower urinary tract dysfunction: PubMed, Embase, and Cochrane Library; our strategy conformed to the PICOS (populations, interventions, comparators, outcomes, and study designs) strategy. Results: Our analyses involved four RCTs involving 245 patients. We found that mirabegron treatment resulted in a significant improvement in bladder compliance [mean difference (MD) = 19.53, 95% confidence interval (CI): 14.19 to 24.87, P < 0.00001], urinary incontinence episodes (MD = -0.78, 95% CI: -0.89 to -0.67, P < 0.00001) and Incontinence Quality of Life (I-QOL) (MD = 8.02, 95% CI: 3.20 to 12.84, P = 0.001). Significant differences were detected in terms of Patient Perception of Bladder Condition (PPBC) (MD = -0.54, 95% CI: -1.46 to 0.39, P = 0.26) and urinary urgency episodes (MD = -0.72, 95% CI: -3.1 to 1.66, P = 0.55). With regard to safety, there were no significant differences between mirabegron and control groups in terms of the incidence of drug-related adverse events [odds ratio (OR): 0.83, 95% CI: 0.43 to 1.59, P = 0.57], arrhythmias (OR: 1.27, 95% CI: 0.37 to 4.38, P = 0.70), hypertension (OR: 0.70, 95% CI: 0.13 to 3.82, P = 0.68), or post-voiding residual volume (MD: 1.62, 95% CI: -9.00 to 12.24, P = 0.77). Conclusion: Mirabegron is an efficacious and safe treatment for patients with neurogenic lower urinary tract dysfunction.

PMID:34867373 | PMC:PMC8636815 | DOI:10.3389/fphar.2021.756582

Expert Rev Anti Infect Ther. 2021 Dec 4. doi: 10.1080/14787210.2022.2015326. Online ahead of print.

ABSTRACT

BACKGROUND: Hydroxychloroquine had attracted significant attention in the initial phases of the COVID-19 pandemic but current recommendations do not support its use. However, the evidence against its use as pre-exposure prophylaxis have been of low to moderate quality and have been limited by high risk of bias.

METHODS: Following institutional ethics committee approval, healthcare workers (n=1294) completing their first week-long COVID in-patient duty, subsequent institutional quarantine and RT-PCR testing for COVID-19 infection were included for this prospective cohort study. Demographic data, hydroxychloroquine usage and related adverse effects were captured through a "Caring for the Caregivers" surveillance system. Chi-Square test of independence was used to determine the effect of hydroxychloroquine prophylaxis.

RESULTS: Among the 1294 participants (Age: 31±7 years, 61% women), 273 (21.1%) healthcare workers used hydroxychloroquine prophylaxis as per Indian Council Medical Research recommendations and 83/1294 (6.4%) tested positive after their duty. There was no significant difference in COVID-19 incidence between those on hydroxychloroquine prophylaxis and those not on it (5.9% vs 6.6%, χ2=0.177, p=0.675; RR=0.89, 95% CI - 0.53 to 1.52). There were no significant adverse effects to hydroxychloroquine usage.

CONCLUSION: This study demonstrated no benefit of hydroxychloroquine prophylaxis and provides quality evidence against its use in COVID-19 prevention.

PMID:34865592 | DOI:10.1080/14787210.2022.2015326

J Crohns Colitis. 2021 Dec 3:jjab213. doi: 10.1093/ecco-jcc/jjab213. Online ahead of print.

ABSTRACT

BACKGROUND: Immunomediated adverse events (IAEs) are the most frequently reported infliximab-related adverse events. Combination therapy may reduce their incidence, although this strategy is not recommended in elderly patients.

AIMS: To compare the rates of infliximab-related IAE and loss of response (LOR) in elderly and younger patients.

METHODS: Adult patients in the ENEIDA registry who had received a first course of infliximab therapy were identified and grouped into two cohorts regarding age at the beginning of treatment (over 60 and between 18-50 years). The rates of IAEs and LOR were compared.

RESULTS: Nine hundred thirty-nine patients (12%) who started infliximab over 60 years of age and 6,844 (88%) below 50 years of age were included. Elderly patients presented a higher proportion of AEs related to IFX (23.2% vs. 19%; P=0.002), infections (7.1% vs. 4.3%; P<0.001) and neoplasms (2.2% vs. 0.5%; P<0.001). In contrast, the rates of IAE (14.8% vs. 14.8%, P=0.999), infusion reactions (8.1% vs. 8.1%, P=0.989), late hypersensitivity (1.3% vs. 1.2%, P=0.895), paradoxical psoriasis (1% vs. 1.5%; P=0.187) and drug-induced lupus erythematosus (0.6% vs. 0.7%; P=0.947) were similar in elderly and younger patients. LOR rates were also similar between both groups (20.5% vs. 19.3%; P=0.438). In the logistic regression analysis, infliximab monotherapy, extraintestinal manifestations and female gender were the only risk factors for IAEs, whereas infliximab monotherapy, extraintestinal manifestations and Crohn's disease were risk factors for LOR.

CONCLUSIONS: Elderly patients with IBD have a similar risk of developing infliximab-related IAEs and LOR to that of younger patients.

PMID:34864947 | DOI:10.1093/ecco-jcc/jjab213

Cleve Clin J Med. 2021 Dec 2;88(12):644-645. doi: 10.3949/ccjm.88b.12021.

NO ABSTRACT

PMID:34857595 | DOI:10.3949/ccjm.88b.12021

Eur J Oncol Nurs. 2021 Nov 20;56:102066. doi: 10.1016/j.ejon.2021.102066. Online ahead of print.

ABSTRACT

PURPOSE: Chemotherapy-induced adverse drug reactions (ADRs) are common and diverse, and not only affect changes or interruptions to treatment schedules, but also negatively affect the patient's quality of life. This study aimed to predict eight chemotherapy-induced ADRs based on electronic health records (EHR) data using machine-learning algorithms.

METHODS: We used EHR data of 6812 chemotherapy cycles for 935 adult patients receiving four different chemotherapy regimens (FOLFOX, 5-fluorouracil + oxaliplatin + leucovorin; FOLFIRI, 5-fluorouracil + irinotecan + leucovorin; paclitaxel; and GP, gemcitabine + cisplatin) at a tertiary teaching hospital between January 2015 and June 2016. The predicted ADRs included nausea-vomiting, fatigue-anorexia, diarrhea, peripheral neuropathy, hypersensitivity, stomatitis, hand-foot syndrome, and constipation. Three machine learning algorithms were used to developed prediction models: logistic regression, decision tree, and artificial neural network. We compared the performance of the models with area of under the ROC (Receiver Operating Characteristic) curve (AUC) and accuracy.

RESULTS: The AUCs of the logistic regression, decision tree, and artificial neural network models were 0.62-0.83, 0.61-0.83, and 0.62-0.83, respectively, and the accuracies were 0.59-0.84, 0.55-0.88, and 0.57-0.88, respectively. Among the algorithms, the logistic regression models performed best and had the highest AUC for six ADRs (range 0.67-0.83). The nausea-vomiting prediction models performed best with an AUC of 0.83 for the three algorithms.

CONCLUSIONS: The prediction models for chemotherapy-induced ADRs were able to predict eight ADRs using EHR data. The logistic regression models were best suited to predict ADRs. The models developed in this study can be used to predict the risk of ADRs in patients receiving chemotherapy.

PMID:34861529 | DOI:10.1016/j.ejon.2021.102066

Front Pharmacol. 2021 Nov 9;12:747416. doi: 10.3389/fphar.2021.747416. eCollection 2021.

ABSTRACT

Objective: To describe the frequency and spectrum of treatment-related adverse events (TRAEs) of immunotherapy combined with antiangiogenic therapy in patients with melanoma. Methods: This retrospective cohort study included three clinical trials on patients with stage III/IV melanoma treated with anti-PD 1 and antiangiogenic therapy. Results: We analyzed data from 72 patients with a median follow-up time of 25.9 months (95% CI, 9.1-42.7 m). The median treatment duration was 7.5 months (range, 0.7-42.8 m), and the median of treatment cycles was 11.0 (range, 1-90). Most patients (70 of 72 or 97.2%) experienced TRAEs (mostly grades 1 or 2). No drug-related deaths were reported. Most TRAEs were hepatic (75%), endocrine (72.2%), skin (65.3%), and gastrointestinal tract (59.7%) manifestations, followed by myelosuppression (55.6%), renal dysfunction (55.6%), and dyslipidaemia (54.2%). The adverse event (AE) spectra were similar between regimens. Using multivariate Cox proportional risk models showed that hypertension was associated with a long PFS. According to our multivariable logistic regression models, TRAEs were not associated with ORR. Conclusion: We found that the prevalence of AEs was higher than that of anti-PD-1 monotherapy. Most of the AEs were mild. The AE spectra were similar to those seen after anti-PD-1 or antiangiogenic therapy monotherapy, without unexpected AEs. Immunotherapy combined with antiangiogenic therapy was well tolerated. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03955354.

PMID:34858178 | PMC:PMC8630676 | DOI:10.3389/fphar.2021.747416

Anticancer Res. 2021 Dec;41(12):6067-6076. doi: 10.21873/anticanres.15426.

ABSTRACT

BACKGROUND/AIM: We describe a pharmacological strategy for selectively targeting glioblastoma using a redox-active combination drug menadione/ascorbate (M/A), compared to the chemotherapeutic standard-of-care temozolomide (TMZ).

MATERIALS AND METHODS: Experiments were conducted on glioblastoma mice (GS9L cell transplants - intracranial model), treated with M/A or TMZ. Tumor growth was monitored by magnetic resonance imaging. Effects of M/A and TMZ on cell viability and overproduction of mitochondrial superoxide were also evaluated on isolated glioblastoma cells (GS9L) and normal microglial cells (EOC2).

RESULTS: M/A treatment suppressed tumor growth and increased survival without adverse drug-related side effects that were characteristic of TMZ. Survival was comparable with that of TMZ at the doses we have tested so far, although the effect of M/A on tumor growth was less pronounced than that of TMZ. M/A induced highly specific cytotoxicity accompanied by dose-dependent overproduction of mitochondrial superoxide in glioblastoma cells, but not in normal microglial cells.

CONCLUSION: M/A differentiates glioblastoma cells from normal microglial cells, causing redox alterations and oxidative stress only in the tumor. This easier-to-tolerate treatment has a potential to support the surgery and conventional therapy of glioblastoma.

PMID:34848461 | DOI:10.21873/anticanres.15426

Ann Rheum Dis. 2021 Nov 29:annrheumdis-2021-221163. doi: 10.1136/annrheumdis-2021-221163. Online ahead of print.

ABSTRACT

Non-adherence challenges efficacy and costs of healthcare. Knowledge of the underlying factors is essential to design effective intervention strategies.

OBJECTIVES: To estimate the prevalence of treatment adherence in rheumatoid arthritis (RA) and to evaluate its predictors.

METHODS: A 6-month prospective cohort study of patients with RA selected by systematic stratified sampling (33% on first disease-modifying rheumatic drug (DMARD), 33% on second-line DMARD and 33% on biologics). The outcome measure was treatment adherence, defined by a score greater than 80% both in the Compliance Questionnaire in Rheumatology and the Reported Adherence to Medication scale, and was estimated with 95% CIs. Predictive factors included sociodemographic, psychological, clinical, drug-related, patient-doctor relationship related and logistic. Their effect on 6-month adherence was examined by multilevel logistic models adjusted for baseline covariates.

RESULTS: 180 patients were recruited (77% women, mean age 60.8). The prevalence of adherence was 59.1% (95% CI 48.1% to 71.8%). Patients on biologics showed higher adherence and perceived a higher medication need than the others; patients on second-line DMARDs had experienced more adverse events than the others. The variables explaining adherence in the final multivariate model were the type of treatment prescribed (second-line DMARDs OR=5.22, and biologics OR=3.76), agreement on treatment (OR=4.57), having received information on treatment adaptation (OR=1.42) and the physician perception of patient trust (OR=1.58). These effects were independent of disease activity.

CONCLUSION: Treatment adherence in RA is far from complete. Psychological, communicational and logistic factors influence treatment adherence in RA to a greater extent than sociodemographic or clinical factors.

PMID:34844924 | DOI:10.1136/annrheumdis-2021-221163

Invest New Drugs. 2021 Nov 29. doi: 10.1007/s10637-021-01202-6. Online ahead of print.

ABSTRACT

BACKGROUND: EPI-506 is the first of a new class of drugs targeting the N-terminal domain (NTD) of the androgen receptor (AR), potentially overcoming known resistance mechanisms to androgen receptor pathway inhibitors (ARPIs) among men with metastatic castration resistant prostate cancer (mCRPC).

METHODS: Patients with mCRPC who had progressed on prior ARPI were enrolled in this phase 1 open-label, adaptive 3 + 3 dose escalation study. The primary outcome was safety and tolerability of oral EPI-506. Secondary objectives included determination of the maximal tolerated dose (MTD), pharmacokinetic profile, and antitumor efficacy.

RESULTS: 28 mCRPC patients were enrolled into 7 dose cohorts of EPI-506 ranging from 80-3600 mg given once daily and 1800 mg given twice daily. Six DLTs occurred in 4 patients; Grade 4 elevated amylase; Grade 3 abdominal pain; Grade 3 elevated ALT and Grade 3 elevated AST; Grade 2 nausea and Grade 1 vomiting which resulted in study drug intake of < 75% of the expected dose during the DLT assessment period. The most common drug-related adverse events included diarrhea, nausea and fatigue. Six patients had a PSA decline not meeting PSA response criteria. The study was terminated prior to reaching the MTD due to poor oral bioavailability.

CONCLUSIONS: This phase 1 trial established the safety of EPI-506 and provides proof of concept for targeting the AR NTD. Next generation compounds with improved bioavailability and potency are in clinical development.

PMID:34843005 | DOI:10.1007/s10637-021-01202-6

Toxicol Appl Pharmacol. 2021 Nov 25:115812. doi: 10.1016/j.taap.2021.115812. Online ahead of print.

ABSTRACT

Cardiovascular toxicity represents one of the most common reasons for clinical trial failure. Consequently, early identification of novel cardioprotective strategies could prevent the later-stage drug-induced cardiac side effects. The use of zebrafish (Danio rerio) in preclinical studies has greatly increased. High-throughput and low-cost of assays make zebrafish model ideal for initial drug discovery. A common strategy to induce heart failure is a chronic β-adrenergic (βAR) stimulation. Herein, we set out to test a panel of βAR agonists to develop a pharmacological heart failure model in zebrafish. We assessed βAR agonists with respect to the elicited mortality, changes in heart rate, and morphological alterations in zebrafish larvae according to Fish Embryo Acute Toxicity Test. Among the tested βAR agonists, epinephrine elicited the most potent onset of heart stimulation (EC50 = 0.05 mM), which corresponds with its physiological role as catecholamine. However, when used at ten-fold higher dose (0.5 mM), the same compound caused severe heart rate inhibition (-28.70 beats/min), which can be attributed to its cardiotoxicity. Further studies revealed that isoetharine abolished body pigmentation at the sublethal dose of 7.50 mM. Additionally, as a proof of concept that zebrafish can mimic human cardiac physiology, we tested βARs antagonists (propranolol, carvedilol, metoprolol, and labetalol) and verified that they inhibited fish heart rate in a similar fashion as in humans. In conclusion, we proposed two novel pharmacological models in zebrafish; i.e., epinephrine-dependent heart failure and isoetharine-dependent transparent zebrafish. We provided strong evidence that the zebrafish model constitutes a valuable tool for cardiovascular research.

PMID:34838787 | DOI:10.1016/j.taap.2021.115812

Pak J Pharm Sci. 2021 Sep;34(5(Supplementary)):1957-1962.

ABSTRACT

The COVID-19 pandemic has brought attention back to its spread in medical staff. A survey-based study was conducted to combine general information related to COVID-19 exposures, acceptances, vaccines received, and side effects. The majority (62.3%) of healthcare professionals had acquired COVID-19 infection from hospital environment (51.5%) mainly who treated (64%) COVID-19 patients. 54% healthcare respondents expressed 'high acceptance' towards COVID-19 vaccines. 88% received COVID-19 vaccination. The majority of healthcare personnel received SinoPharm (65%). 82.3% did not acquire COVID-19 post-vaccination. 38% mild side effects were observed from vaccination. Following were the general side-effects: myalgia (18.2%), the feeling of sickness (16%), fever (15.6%), dizziness (7.8%), joint pain (7.4%), chills (4.8%), and flu (4.8%). Following were the common neurological side-effects reported: headache (18.2%), fatigue (16.5%), muscle pain (16%), numbness/tingling (3%), and migraine (2.6%). Nausea and diarrhoea were reported in only 3.5% of respondents. Bad taste was reported in only 3% of respondents. The 1.7% reported rash and itching. The majority of the healthcare professionals did not report significant side effects related to neurological, gastroenterological, skin and oral categories. To assess the vaccines' potential for substantial and long-term or chronic effects, more study with a larger sample size and a longer follow-up time is required.

PMID:34836866

Clin Exp Nephrol. 2021 Nov 27. doi: 10.1007/s10157-021-02159-9. Online ahead of print.

ABSTRACT

BACKGROUND: Azilsartan is an angiotensin II receptor blocker indicated for the treatment of adult hypertension. A previous single-dose study suggested that azilsartan may also be a promising agent for paediatric hypertension. However, the long-term safety and efficacy of azilsartan in children have not been established.

METHODS: We conducted a phase 3, single-arm, open-label, prospective study to evaluate the safety and efficacy of azilsartan in pediatric patients with hypertension. Twenty-seven patients aged 6-15 years were treated with once-daily azilsartan for 52 weeks. The starting dose was 2.5 mg for patients weighing < 50 kg (N = 22) and 5 mg for patients weighing ≥ 50 kg (N = 5), with doses titrated up to a maximum of 20 and 40 mg, respectively.

RESULTS: Azilsartan showed acceptable tolerability at doses up to 20 mg in patients weighing < 50 kg and 40 mg in those weighing ≥ 50 kg. Most drug-related adverse events (AEs) were mild, with one patient (3.7%) experiencing a severe and serious drug-related AE (acute kidney injury). One patient (3.7%) had a mild increase in serum creatinine level, which resolved after treatment discontinuation. The blood pressure-lowering effect of azilsartan was observed as early as Week 2. Overall, approximately half of the patients achieved their target blood pressure at the end of azilsartan treatment.

CONCLUSIONS: Our study suggests that azilsartan has an acceptable safety profile in hypertensive patients aged 6-15 years. Azilsartan may be a promising agent for treating paediatric hypertension.

PMID:34837606 | DOI:10.1007/s10157-021-02159-9