Muscle Nerve. 2023 Mar 16. doi: 10.1002/mus.27819. Online ahead of print.

ABSTRACT

INTRODUCTION/AIMS: Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in ALS; the aim of this report is to share the design, operational features, and costs of an EAP program for ALS.

METHODS: The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs.

RESULTS: From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 months. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs.

CONCLUSION: EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs. This article is protected by copyright. All rights reserved.

PMID:36929648 | DOI:10.1002/mus.27819

ANZ J Surg. 2023 Mar 16. doi: 10.1111/ans.18361. Online ahead of print.

ABSTRACT

BACKGROUND: Multimodal therapy (MMT) for analgesia following joint arthroplasty continues to reduce cost and the requirement of strong opioids post-operatively. Tramadol immediate release is an important MMT component providing synergistic pain relief via dual μ-opioid agonism and serotonin and noradrenaline reuptake inhibition. Case reports have shown tramadol when combined with antidepressants cause serotonin syndrome, but this has yet to be demonstrated in larger studies. We undertook a pilot study assessing the functional outcomes and incidence of side effects associated with tramadol in lower limb arthroplasty patients with a focus on those taking concomitant antidepressants.

METHODS: Primary and revision hip and knee arthroplasties performed in 2018-2019 by a senior surgeon were included (n = 364). Patient records were assessed to determine pain scores, length of hospitalization, prescription of tramadol and antidepressants, self-reported side effects and previous adverse reactions associated with tramadol.

RESULTS: Nine-five percentage of patients had been prescribed tramadol, and 16% had concurrent prescription of tramadol and one or more antidepressants. The total rate of adverse effects associated with tramadol before and during the study was 7% (n = 25) including two cases of concomitant tramadol and antidepressant use. For patients on tramadol, median 2-week post-operative pain score was 1.5 (IQR 1-2.5) out of 10 and hospitalization length was 1 (IQR 1-2) days.

CONCLUSION: Tramadol immediate release appears to be well tolerated among our patient population with no significantly increased prevalence of side effects when co-administered with low and moderate dose antidepressants.

PMID:36929136 | DOI:10.1111/ans.18361

Reg Anesth Pain Med. 2023 Mar 16:rapm-2023-104398. doi: 10.1136/rapm-2023-104398. Online ahead of print.

ABSTRACT

INTRODUCTION: The addition of adjuvants to short-acting local anesthetics (LA) is common practice in clinical routine to speed up block onset and decrease pain on injection. In a previous study, we observed the development of microscopic crystal precipitations after bupivacaine or ropivacaine were mixed with adjuvants; this follow-up study is intended to clarify whether crystallization (A) also occurs in short-acting or intermediate-acting LA-adjuvant mixtures, (B) changes over time, and (C) is associated with the solutions' pH.

METHODS: Lidocaine 2%, prilocaine 2%, mepivacaine 2%, procaine 2% and chloroprocaine 2% were individually mixed with clonidine, dexamethasone, dexmedetomidine, epinephrine, fentanyl, morphine or sodium bicarbonate 8.4% in clinically established ratios. For each mixture, we measured initial pH and recorded crystallization patterns at 0, 15, 30 and 60 min using a standardized, semiquantitative light microscopy approach.

RESULTS: Lidocaine 2% and mepivacaine 2% plus sodium bicarbonate 8.4%, and mepivacaine 2% plus dexamethasone developed delayed grade 5 crystallization over 1 hour. Prilocaine-based, procaine-based and chloroprocaine-based mixtures showed much less pronounced crystallization, with a maximum of grade 2. Initial pH and grade of crystallization showed weak monotonic relationships at time points t0, t15 and t30 (ρ=-0.17, 0.31 and 0.32, (all p>0.05)) and a moderate relationship time point t60 (ρ=0.57 (p=0.0003)) CONCLUSIONS: Our study revealed high grades of crystallization in lidocaine/mepivacaine-bicarbonate and mepivacaine-dexamethasone mixtures, although these were previously considered safe for local, perineural or neuraxial use. Our findings cast particular doubt on the safety of preparing these formulations for later use.

PMID:36928300 | DOI:10.1136/rapm-2023-104398

Ned Tijdschr Geneeskd. 2023 Mar 8;167:D7402.

ABSTRACT

Statins are effective drugs that can reduce the risk of new cardiovascular events. Although in randomized, placebo-controlled trials statins are associated with a low risk of mild muscle complaints such as myalgia, in daily practice up to 30% of patients report complaints attributed to statin use. Two recent studies have shown statin-associated muscle complaints are mainly related to the nocebo effect. The nocebo effect is a decrease in benefit and/or a new onset or worsening of adverse effects due to an expectation of harm associated with the treatment. Statins face reputational challenges due to a vast amount of negative attention on the internet. We need to address the nocebo effect by managing the perception of statins and provide patients with objective information about statin treatment, reduce the negative expectations, and placing discussion about the likelihood of adverse effects into the context of treatment benefit.

PMID:36920298

Tidsskr Nor Laegeforen. 2023 Mar 13;143(4). doi: 10.4045/tidsskr.22.0758. Print 2023 Mar 14.

NO ABSTRACT

PMID:36919290 | DOI:10.4045/tidsskr.22.0758

BMC Public Health. 2023 Mar 14;23(1):488. doi: 10.1186/s12889-023-15346-y.

ABSTRACT

BACKGROUND: Although patients frequently use patient information leaflets (PILs) to obtain information about medicine, their confidence in using it may be diminished after reading it. This study aimed to assess the public perception of PIL's quality and the perceived impact of its use on medication adherence.

METHODS: A community-based cross-sectional study of 1,138 adult individuals in Saudi Arabia, April-May 2020, was conducted via Survey Monkey using an anonymous validated e-questionnaire. Data were collected on personal characteristics, PIL readership and preferences, perception towards PIL quality and impact of its use on taking medication, and reasons for not reading PIL. In addition, logistic regression analysis was performed to identify the significant predictors of reading PIL. Significance was considered at p < 0.05.

RESULTS: Nearly all participants (91.1%) reported reading PIL. The more read PIL's sections were directions of use (52.7%) and side effects (30.3%). Female gender (OR = 5.64, 95%CI: 3.53,9.02), age over 40 years (OR = 2.80, 95%CI: 1.69,4.64), and secondary education or more (OR = 1.74, 95%CI: 1.06,2.85) were the significant predictors of reading PIL. The majority of PIL readers reported their preference for verbal information (65.8%), hard copy presentation (77%), adding graphics (71.1%), and concise content of PIL (68.8%). In addition, most participants reported PIL always/usually adds to their knowledge of medicines (70.6%) and said that PIL reading positively impacted their medication adherence (64.9%). For only 8.8%, PIL reading negatively impacted their adherence, primarily because of reading information on medicine's side effects and complications (74.4%). More than one-half of participants perceived the PIL quality as good/excellent in terms of; font size (51.3%), language comprehensiveness (64.9%), paper quality (68.0%), and general appearance (64.9%). Getting sufficient information from doctors and pharmacists was the main reason for not reading the PIL (59.2%). Most participants (92.5%) agreed on standardizing how information is displayed in the PIL among all PILs of all companies.

CONCLUSION: PIL is read by nearly all the study sample, especially females, older, and educated subjects. It was perceived as beneficial in upgrading medication adherence. Effective designing of PILs should focus on patients' literacy level and age. Standardization of the PIL structure in all pharmaceutical companies is recommended.

PMID:36918823 | DOI:10.1186/s12889-023-15346-y

BMC Bioinformatics. 2023 Mar 14;24(1):93. doi: 10.1186/s12859-023-05212-4.

ABSTRACT

BACKGROUND: Drug-drug interactions (DDIs) prediction is vital for pharmacology and clinical application to avoid adverse drug reactions on patients. It is challenging because DDIs are related to multiple factors, such as genes, drug molecular structure, diseases, biological processes, side effects, etc. It is a crucial technology for Knowledge graph to present multi-relation among entities. Recently some existing graph-based computation models have been proposed for DDIs prediction and get good performance. However, there are still some challenges in the knowledge graph representation, which can extract rich latent features from drug knowledge graph (KG).

RESULTS: In this work, we propose a novel multi-view feature representation and fusion (MuFRF) architecture to realize DDIs prediction. It consists of two views of feature representation and a multi-level latent feature fusion. For the feature representation from the graph view and KG view, we use graph isomorphism network to map drug molecular structures and use RotatE to implement the vector representation on bio-medical knowledge graph, respectively. We design concatenate-level and scalar-level strategies in the multi-level latent feature fusion to capture latent features from drug molecular structure information and semantic features from bio-medical KG. And the multi-head attention mechanism achieves the optimization of features on binary and multi-class classification tasks. We evaluate our proposed method based on two open datasets in the experiments. Experiments indicate that MuFRF outperforms the classic and state-of-the-art models.

CONCLUSIONS: Our proposed model can fully exploit and integrate the latent feature from the drug molecular structure graph (graph view) and rich bio-medical knowledge graph (KG view). We find that a multi-view feature representation and fusion model can accurately predict DDIs. It may contribute to providing with some guidance for research and validation for discovering novel DDIs.

PMID:36918766 | DOI:10.1186/s12859-023-05212-4

Sci Transl Med. 2023 Mar 15;15(687):eabn2110. doi: 10.1126/scitranslmed.abn2110. Epub 2023 Mar 15.

ABSTRACT

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

PMID:36921036 | DOI:10.1126/scitranslmed.abn2110

J Ethnopharmacol. 2023 Jun 12;309:116383. doi: 10.1016/j.jep.2023.116383. Epub 2023 Mar 12.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The use of herbal medicines for prophylaxis, prevention, and treatment of various ailments is rising throughout the world because they are thought to be safer than allopathic treatments, which they are. However, several investigations have documented the toxicity and adverse drug reactions (ADR) of certain formulations and botanicals if not consumed wisely.

AIM OF THE STUDY: The goal of the current study is to address herbal medication pharmacovigilance (PV) modeling and related considerations for improved patient safety. Also, focus is laid on the comprehensive and critical analysis of the current state of PV for herbal medications at the national and international levels.

MATERIALS AND METHODS: Targeted review also known as focused literature review methodology was utilized for exploring the data from various scientific platforms such as Science Direct, Wiley Online Library, Springer, PubMed, Google Scholar using "pharmacovigilance, herbal medicine, traditional medicine, ADR, under reporting, herb toxicity, herb interactions" as keywords along with standard literature pertaining to herbal medicines that is published by the WHO and other international and national organizations etc. The botanical names mentioned in the present article were authenticated using World Flora Online database.

RESULTS: The historical developments paving the way for PV in regulatory setup were also discussed, along with various criteria's for monitoring herbal medicine, ADR of herbs, phytoconstituents, and traditional medicines, herb-drug interactions, modes of reporting ADR, databases for reporting ADR's, provisions of PV in regulatory framework of different nations, challenges and way forward in PV are discussed in detail advocating a robust drug safety ecosystem for herbal medicines.

CONCLUSION: Despite recent efforts to encourage the reporting of suspected ADRs linked to herbal medicines, such as expanding the programme and adding community pharmacists and other healthcare professionals as recognized reporters, the number of herbal ADR reports received by the regulatory bodies remains comparatively low. Since users often do not seek professional advice or report if they have side effects, under-reporting, is anticipated to be significant for herbal medications. There are inadequate quality control methods, poor regulatory oversight considering herbs used in food and botanicals, and unregulated distribution channels. In addition, botanical identity, traceability of herbs, ecological concerns, over-the-counter (OTC) herbal medicines, patient-physicians barriers requires special focus by the regulatory bodies for improved global safety of herbal medicines.

PMID:36918049 | DOI:10.1016/j.jep.2023.116383

J Oral Facial Pain Headache. 2023 Winter;37(1):27-34. doi: 10.11607/ofph.3163.

ABSTRACT

Aims: To present a review of the mechanisms of action, available clinical data, and safety profiles of novel migraine therapeutics to inform practice. Methods: PubMed, Medline, and Google Scholar were searched for randomized controlled trials (24 publications), review articles (15 publications), and other pertinent literature (16 publications) discussing the novel migraine therapeutics available between the years 2010 and 2021. All publications were reviewed to assess the mechanism of action, relevant clinical data, and side effect profile for each novel treatment. Therapeutic gain was also recorded in studies that included a placebo arm. Results: A total of 55 studies were included in the final analysis. In the preventive treatment of migraine, novel medications target calcitonin gene-related peptide (CGRP) and fall into either the monoclonal anti-CGRP or gepant class. For the acute treatment of migraine, novel medications fall into either the ditan or gepant class. Several medical devices have been developed for the acute and preventive treatment of migraine. Conclusion: Novel therapeutics are available for both the prevention and acute treatment of migraine headaches. These new medications and neuromodulatory devices appear overall to be safe and effective in the management of migraine headaches.

PMID:36917235 | DOI:10.11607/ofph.3163

Allergol Immunopathol (Madr). 2023 Mar 1;51(2):184-190. doi: 10.15586/aei.v51i2.778. eCollection 2023.

ABSTRACT

BACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that manifests in skin dryness, severe itching, and eczema, and can significantly impact a patient's quality of life. Current treatment regimens do not prevent the recurrence of the disease and are associated with adverse effects. Here, we report two cases of moderate-to-severe AD in children that were treated with dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, in combination with mite allergen-specific immunotherapy.

CASE SUMMARY: Both patients presented with the diagnosis of AD that was not adequately controlled by the conventional treatment regimen, including topical corticosteroids (TCS), topical calcineurin inhibitors, emollients, and the traditional Chinese medicine treatments. In both patients, AD-associated skin irritation impacted the quality of life, disturbed sleep patterns, and caused stress and anxiety.Patients received treatment with dupilumab and mite allergen-specific immunotherapy in addition to the baseline treatment regimen of external glucocorticoids (TCS) and oral antihistamines. Nine months after beginning of treatment, clinical symptoms, signs, medication scores, and evaluation scale scores of both children significantly improved, and the treatment was associated with an overall good tolerance.

CONCLUSION: A combination of dupilumab and mite allergen-specific immunotherapy in addition to the standard anti-AD treatment improves clinical symptoms and is not associated with increased incidence of adverse effects.

PMID:36916105 | DOI:10.15586/aei.v51i2.778

Allergol Immunopathol (Madr). 2023 Mar 1;51(2):11-16. doi: 10.15586/aei.v51i2.774. eCollection 2023.

ABSTRACT

BACKGROUND: Asthma is the most common chronic lung disease among children. International guidelines recommend inhaled corticosteroids (ICS) as the first-line daily controller therapy for children with asthma and leukotriene receptor antagonists (LTRA) as the second alternative therapy. Adherence to treatment is the most significant component to optimize the benefits of therapy in asthma.

OBJECTIVE: This study aims to investigate the frequency of drug discontinuation due to adverse drug reactions (ADRs) that affect adherence to treatment in children with asthma or asthma and allergic rhinitis using LTRA or ICS as monotherapy.

METHODS: The subjects aged 4-18 years with asthma or asthma and allergic rhinitis and using montelukast or ICS as monotherapy were included in the study. They were evaluated in terms of ADRs affecting adherence to treatment in the first and third months of treatment.

RESULTS: A total of 468 cases, 356 of whom received montelukast monotherapy and 112 of whom received ICS treatment, with a mean age of 9.10 ± 3.08 (4-17) years, were included in the study. Males constituted 65.6% of the total cases (n = 307). In the first month of follow-up of the cases, it was observed that 4.8% (n = 17) of the patients in the montelukast group could not continue the treatment due to ADR. It was determined that the drug discontinuation rate in the montelukast group in the first month was significantly higher than in the ICS group (P = 0.016), and the risk of drug discontinuation due to ADR in the montelukast group was 1.333 (95% CI, 1.26-1.40) times higher.

CONCLUSIONS: As a result, it was observed that the drug was discontinued due to ADR at a higher rate in children with asthma who received montelukast monotherapy compared to those who received ICS monotherapy.

PMID:36916083 | DOI:10.15586/aei.v51i2.774

Oncol Ther. 2023 Mar 14. doi: 10.1007/s40487-023-00224-9. Online ahead of print.

ABSTRACT

Breast cancer is the most frequently diagnosed malignancy in patients worldwide and the main cause of cancer-related death. Though still incurable, metastatic breast cancer's prognosis has been considerably improved in the past 10 years due to the introduction of new targeted agents, such as immune checkpoint inhibitors (ICI). However, these medications are associated with unique side effects known as immune-mediated adverse events (irAE). In this paper, we review the clinical evidence for the use of ICIs in breast cancer, in both the metastatic as well as neoadjuvant/adjuvant setting, followed by a review of irAE most commonly seen, and the medications used to treat them. Our opinion is that any cancer specialist treating patients with breast cancer should be aware of these side effects for early detection and management, and oncologists should be the leaders of the multidisciplinary team that will take care of them.

PMID:36917399 | DOI:10.1007/s40487-023-00224-9

Transl Vis Sci Technol. 2023 Mar 1;12(3):7. doi: 10.1167/tvst.12.3.7.

ABSTRACT

PURPOSE: Evaluation of safety and efficacy of topical ocular SAF312 (Libvatrep) in post-photorefractive keratectomy (PRK) pain.

METHODS: In this placebo (vehicle)-controlled, participant- and investigator-masked study, 40 participants were randomized (1:1) to two treatment sequences in a bilateral PRK crossover design (SAF312 2.5% followed by vehicle [or vice versa], one eye drop, four times daily for 72 hours after PRK). Primary endpoints were visual analog scale (VAS) pain scores at 6 hours after first drop of study drug and average VAS scores over 0 to 12 hours postoperatively. Secondary endpoints included postoperative oral rescue medication (ORM) use and adverse events (AEs).

RESULTS: All 40 participants completed the study. Both primary endpoints were met; mean difference in VAS pain scores between SAF312- and vehicle-treated eyes was -11.13 (P = 0.005, -25%) at 6 hours postoperatively and -8.56 (P = 0.017, -22%) over 0 to 12 hours. Mean VAS pain scores with SAF312 were consistently lower than with vehicle from 1 hour postoperatively up to 30 hours (P ≤ 0.10 observed in 8/11 time points). Less ORM was taken with SAF312 up to 0 to 72 hours postoperatively, with a trend of fewer participants taking ORM at 0 to 24 hours postoperatively with SAF312 versus vehicle. No serious AEs were reported. All ocular AEs were mild and transient, and none were drug related. SAF312-treated eyes showed no delay in wound healing and had a lower grade 4 conjunctival hyperemia 24 hours postoperatively versus vehicle-treated eyes.

CONCLUSIONS: SAF312 was well tolerated and effective in reducing ocular pain post-PRK.

TRANSLATIONAL RELEVANCE: Topical SAF312 presents a new therapeutic option for patients undergoing PRK.

PMID:36917119 | DOI:10.1167/tvst.12.3.7

Cochrane Database Syst Rev. 2023 Mar 14;3:CD015769. doi: 10.1002/14651858.CD015769.

ABSTRACT

BACKGROUND: Mpox was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on 23 July 2022, following the identification of thousands of cases in several non-endemic countries in previous months. There are currently no licenced therapeutics for treating mpox; however, some medications may be authorized for use in an outbreak. The efficacy and safety of possible therapeutic options has not been studied in humans with mpox. There is a need to investigate the evidence on safety and effectiveness of treatments for mpox in humans; should any therapeutic option be efficacious and safe, it may be approved for use around the world.

OBJECTIVES: There are two parts to this Cochrane Review: a review of evidence from randomized controlled trials (RCTs), and a narrative review of safety data from non-randomized studies. Randomized controlled trials review To systematically review the existing evidence on the effectiveness of therapeutics for mpox infection in humans compared to: a) another different therapeutic for mpox, or b) placebo, or c) supportive care, defined as the treatment of physical and psychological symptoms arising from the disease. Non-randomized studies review To assess the safety of therapeutics for mpox infection from non-randomized studies (NRS).

SEARCH METHODS: Randomized controlled trials review We searched the following databases up to 25 January 2023: MEDLINE (OVID), Embase (OVID), Biosis previews (Web of Science), CAB Abstracts (Web of science), and Cochrane CENTRAL (Issue 1 2023). We conducted a search of trial registries (Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP)) on 25 January 2023. There were no date or language limits placed on the search. We undertook a call to experts in the field for relevant studies or ongoing trials to be considered for inclusion in the review. Non-randomized studies review We searched the following databases on 22 September 2022: Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9 of 12, 2022), published in the Cochrane Library; MEDLINE (Ovid); Embase (Ovid); and Scopus (Elsevier). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress.

SELECTION CRITERIA: For the RCT review and the narrative review, any therapeutic for the treatment of mpox in humans was eligible for inclusion, including tecovirimat, brincidofovir, cidofovir, NIOCH-14, immunomodulators, and vaccine immune globulin. Randomized controlled trials review Studies were eligible for the main review if they were of randomized controlled design and investigated the effectiveness or safety of therapeutics in human mpox infection. Non-randomized studies review Studies were eligible for inclusion in the review of non-randomized studies if they were of non-randomized design and contained data concerning the safety of any therapeutic in human mpox infection.

DATA COLLECTION AND ANALYSIS: Randomized controlled trials review Two review authors independently applied study inclusion criteria to identify eligible studies. If we had identified any eligible studies, we planned to assess the risk of bias, and report results with 95% confidence intervals (CI). The critical outcomes were serious adverse events, development of disease-related complications, admission to hospital for non-hospitalized participants, pain as judged by any visual or numerical pain scale, level of virus detected in clinical samples, time to healing of all skin lesions, and mortality. We planned to perform subgroup analysis to explore whether the effect of the therapeutic on the planned outcomes was modified by disease severity and days from symptom onset to therapeutic administration. We also intended to explore the following subgroups of absolute effects: immunosuppression, age, and pre-existing skin disease. Non-randomized studies review One review author applied study inclusion criteria to identify eligible studies and extracted data. Studies of a non-randomized design containing data on the safety of therapeutics could not be meta-analyzed due to the absence of a comparator; we summarized these data narratively in an appendix.

MAIN RESULTS: Randomized controlled trials review We did not identify any completed RCTs investigating the effectiveness of therapeutics for treating mpox for the main review. We identified five ongoing trials that plan to assess the effectiveness of one therapeutic option, tecovirimat, for treating mpox in adults and children. One of these ongoing trials intends to include populations with, or at greater risk of, severe disease, which will allow an assessment of safety in more vulnerable populations. Non-randomized studies review Three non-randomized studies met the inclusion criteria for the narrative review, concerning data on the safety of therapeutics in mpox. Very low-certainty evidence from non-randomized studies of small numbers of people indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection, but a possible safety signal for brincidofovir. All three participants who received brincidofovir had raised alanine aminotransferase (ALT), but not bilirubin, suggesting mild liver injury. No study reported severe drug-induced liver injury with brincidofovir.

AUTHORS' CONCLUSIONS: Randomized controlled trials review This review found no evidence from randomized controlled trials concerning the efficacy and safety of therapeutics in humans with mpox. Non-randomized studies review Very low-certainty evidence from non-randomized studies indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection. In contrast, very low-certainty evidence raises a safety signal that brincidofovir may cause liver injury. This is also suggested by indirect evidence from brincidofovir use in smallpox. This warrants further investigation and monitoring. This Cochrane Review will be updated as new evidence becomes available to assist policymakers, health professionals, and consumers in making appropriate decisions for the treatment of mpox.

PMID:36916727 | DOI:10.1002/14651858.CD015769

Br J Clin Pharmacol. 2023 Mar 13. doi: 10.1111/bcp.15713. Online ahead of print.

ABSTRACT

AIM: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants.

METHODS: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4 mg, 8 mg or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH)-stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing.

RESULTS: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4 mg, 8 mg, 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-hour aldosterone suppression after 8 days of treatment, unlike the 8 mg and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge).

CONCLUSIONS: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.

PMID:36914591 | DOI:10.1111/bcp.15713

Front Immunol. 2023 Feb 23;14:1133207. doi: 10.3389/fimmu.2023.1133207. eCollection 2023.

ABSTRACT

In recent years, a wide range of cancer immunotherapies have been developed and have become increasingly important in cancer treatment across multiple oncologic diseases. In particular, immune checkpoint inhibitors (ICIs) offer promising options to improve patient outcomes. However, a major limitation of these treatments consists in the development of immune-related adverse events (irAEs) occurring in potentially any organ system and affecting up to 76% of the patients. The most frequent toxicities involve the skin, gastrointestinal tract, and endocrine system. Although mostly manageable, potentially life-threatening events, particularly due to neuro-, cardiac, and pulmonary toxicity, occur in up to 30% and 55% of the patients treated with ICI-monotherapy or -combination therapy, respectively. Imaging, in particular computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT), plays an important role in the detection and characterization of these irAEs. In some patients, irAEs can even be detected on imaging before the onset of clinical symptoms. In this context, it is particularly important to distinguish irAEs from true disease progression and specific immunotherapy related response patterns, such as pseudoprogression. In addition, there are irAEs which might be easily confused with other pathologies such as infection or metastasis. However, many imaging findings, such as in immune-related pneumonitis, are nonspecific. Thus, accurate diagnosis may be delayed underling the importance for adequate imaging features characterization in the appropriate clinical setting in order to provide timely and efficient patient management. 18F-FDG-PET/CT and radiomics have demonstrated to reliably detect these toxicities and potentially have predictive value for identifying patients at risk of developing irAEs. The purpose of this article is to provide a review of the main immunotherapy-related toxicities and discuss their characteristics on imaging.

PMID:36911692 | PMC:PMC9995973 | DOI:10.3389/fimmu.2023.1133207

Front Endocrinol (Lausanne). 2023 Feb 23;14:1125187. doi: 10.3389/fendo.2023.1125187. eCollection 2023.

ABSTRACT

DISCLOSURE SUMMARY: Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose.

BACKGROUND: Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity.

OBJECTIVE: The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity.

METHODS: In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase.

RESULTS: Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month.

CONCLUSION: Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT04209075.

PMID:36909343 | PMC:PMC9996666 | DOI:10.3389/fendo.2023.1125187

J Intern Med. 2023 Mar 13. doi: 10.1111/joim.13627. Online ahead of print.

ABSTRACT

BACKGROUND: Findings of liver enzyme elevations in recent cannabidiol studies have raised concerns over liver safety. This study aimed to determine the association between cannabidiol use, liver enzyme elevation, and drug-induced liver injury (DILI).

METHODS: In this systematic review and meta-analysis, a search of EMBASE, CENTRAL, CINAHL, Clinicaltrials.gov, Medline, medRxiv, and Web of Science of records up to February 2022 was conducted. Clinical trials initiating daily cannabidiol treatment with serial liver enzyme measures were included. The proportion of liver enzyme elevations and DILI were independently extracted from published reports. Pooled proportions and probability meta-analyses were conducted.

RESULTS: Cannabidiol use was associated with an increased probability of liver enzyme elevation (N = 12 trials, n = 1229; OR = 5.85 95% CI = 3.84-8.92, p < 0.001) and DILI (N = 12 trials, n = 1229; OR = 4.82 95% CI = 2.46-9.45, p < 0.001) compared to placebo controls. In participants taking cannabidiol (N = 28 trials, n = 1533), the pooled proportion of liver enzyme elevations was 0.074 (95% CI 0.0448-0.1212), and DILI was 0.0296 (95% CI 0.0136-0.0631). High-dose CBD (≥1000 mg/day or ≥20 mg/kg/day) and concomitant antiepileptic drug use were identified as risk factors. No cases were reported in adults using cannabidiol doses <300 mg/day. No cases of severe DILI were reported.

CONCLUSIONS: Cannabidiol-associated liver enzyme elevations and DILI meet the criteria of common adverse drug events. Clinicians are encouraged to screen for cannabidiol use and monitor liver function in patients at increased risk.

PMID:36912195 | DOI:10.1111/joim.13627

HIV Med. 2023 Mar;24(3):290-300. doi: 10.1111/hiv.13386. Epub 2022 Aug 17.

ABSTRACT

OBJECTIVES: Data on switching to bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) in virologically suppressed Asian people living with HIV are limited. We performed a pooled analysis of virologically suppressed Asian participants from three international phase III trials to evaluate the efficacy and safety of switching to B/F/TAF.

METHODS: Virologically suppressed people living with HIV were randomized to switch to B/F/TAF or to stay on baseline regimens. The primary endpoint was the proportion of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48. We analysed the incidence of adverse events (AEs), laboratory abnormalities, and changes in relevant tolerability parameters through 48 weeks.

RESULTS: Overall, 136 Asian participants were included. The proportions of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48 were low in both arms (0% for B/F/TAF vs 1.4% for those who stayed on baseline regimens). Those who switched to B/F/TAF had virological suppression rates similar to those who stayed on baseline regimens (100% vs 95.9%, p = 0.2485), with no treatment-emergent resistance. Drug-related AEs occurred in three participants in each arm; none were serious. No participants discontinued the study drug because of AEs, and no deaths were observed. No significant differences were observed between the arms in the median changes in estimated glomerular filtration rate, body weight, and most lipid parameters. Switching from tenofovir disoproxil fumarate-containing regimens to B/F/TAF resulted in a significant decrease in tubular proteinuria compared with those who stayed on baseline regimens (p < 0.01).

CONCLUSIONS: Virologically suppressed Asian people living with HIV who switched to B/F/TAF maintained 100% virological suppression at week 48, with no treatment-emergent drug resistance and safety profiles comparable to those seen in people who stayed on baseline regimens.

CLINICAL TRIAL NUMBER: ClinicalTrials.gov (NCT02603120, NCT02652624, and NCT02603107).

PMID:36912172 | DOI:10.1111/hiv.13386