Fertil Steril. 2021 Dec 8:S0015-0282(21)02214-7. doi: 10.1016/j.fertnstert.2021.11.013. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of 40-mg relugolix (REL) compared with those of leuprorelin (LEU) in women with endometriosis-associated pain.

DESIGN: Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study in Japanese patients.

SETTING: Hospitals and clinics.

PATIENT(S): Women aged ≥20 years with regular menstrual cycles (25-38 days) experiencing endometriosis or ovarian endometrioma and reporting pelvic pain.

INTERVENTION(S): In the REL group, 40 mg of REL was orally administered once a day for 24 weeks. In the LEU group, 3.75 or 1.88 mg of LEU was subcutaneously injected every 4 weeks for 24 weeks.

MAIN OUTCOME MEASURE(S): The primary endpoint was the change in the maximum visual analog scale score for pelvic pain from baseline until 28 days before the end of treatment.

RESULT(S): Changes in the maximum visual analog scale score were -52.6 ± 1.3 for REL and -57.5 ± 1.4 for LEU. Ovarian endometrioma decreased by 12.26 ± 17.52 cm3 for REL and 14.10 ± 18.81 cm3 for LEU. Drug-related treatment emergent adverse events with an incidence of >10% for both groups were hot flush, metrorrhagia, headache, and genital hemorrhage. Discontinuations from treatment emergent adverse events were 2.9% for REL and 4.3% for LEU.

CONCLUSION(S): Relugolix was noninferior to LEU for treating endometriosis-associated pelvic pain. Safety profiles of both medications were comparable, although menses returned earlier in patients taking REL, a huge benefit for women who plan to conceive after treatment.

CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03931915.

PMID:34895700 | DOI:10.1016/j.fertnstert.2021.11.013

Lancet Respir Med. 2021 Dec 8:S2213-2600(21)00439-2. doi: 10.1016/S2213-2600(21)00439-2. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiogenic shock has a high mortality on optimal therapy. Adrenomedullin is released during cardiogenic shock and is involved in its pathophysiological processes. This study assessed treatment with the humanised, monoclonal, non-neutralising, adrenomedullin antibody adrecizumab, increasing circulating concentrations of adrenomedullin in cardiogenic shock.

METHODS: In this investigator-initiated, placebo-controlled, double-blind, multicentre, randomised trial (ACCOST-HH), patients were recruited from four university hospitals in Germany. Patients were eligible if they were 18 years old or older and hospitalised for cardiogenic shock within the last 48 h. Exclusion criteria were resuscitation for longer than 60 min and cardiogenic shock due to sustained ventricular tachycardia or bradycardia. Adult patients in cardiogenic shock were randomly assigned (1:1) to intravenous adrecizumab (8 mg/kg bodyweight) or placebo using an internet-based software. A block randomisation procedure was applied with stratification by age (older vs younger than 65 years), sex (male vs female), and type of underlying cardiogenic shock (acute myocardial infarction vs other entities). Investigators, patients, and medical staff involved in patient care were masked to group assignment. The primary endpoint was number of days up to day 30 without the need for cardiovascular organ support, defined as vasopressor therapy, inotropes, or mechanical circulatory support (or both) assessed in the intention-to-treat population. Safety outcomes included therapy-emergent serious adverse events, severe adverse events, adverse events, suspected unexpected serious adverse reactions, study drug-related mortality, and total mortality. The trial was registered at ClinicalTrials.gov, NCT03989531, and EudraCT, 2018-002824-17, and is now complete.

FINDINGS: Between April 5, 2019, and Jan 13, 2021, 150 patients were enrolled: 77 (51%) were randomly assigned to adrecizumab and 73 (49%) to placebo. All patients received the allocated treatment. The number of days without the need for cardiovascular organ support was not different between patients receiving adrecizumab or placebo (12·37 days [95% CI 9·80-14·94] vs 14·05 [11·41-16·69]; adjusted mean difference -1·69 days [-5·37 to 2·00]; p=0·37). Serious adverse events occurred in 59 patients receiving adrecizumab and in 57 receiving placebo (odds ratio 0·92 [95% CI 0·43-1·98]; p=0·83). Mortality was not different between groups at 30 days (hazard ratio 0·99 [95% CI 0·60-1·65]; p=0·98) or 90 days (1·10 [0·68-1·77]; p=0·71).

INTERPRETATION: Adrecizumab was well tolerated in patients with cardiogenic shock but did not reduce the need for cardiovascular organ support or improve survival at days 30 and 90.

FUNDING: Adrenomed AG and University Hospital of Hamburg.

PMID:34895483 | DOI:10.1016/S2213-2600(21)00439-2

Chin Med. 2021 Dec 11;16(1):135. doi: 10.1186/s13020-021-00543-x.

ABSTRACT

Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs.

PMID:34895294 | DOI:10.1186/s13020-021-00543-x

BMC Biol. 2021 Dec 11;19(1):260. doi: 10.1186/s12915-021-01164-4.

ABSTRACT

BACKGROUND: The integrity of microtubule filament networks is essential for the roles in diverse cellular functions, and disruption of its structure or dynamics has been explored as a therapeutic approach to tackle diseases such as cancer. Microtubule-interacting drugs, sometimes referred to as antimitotics, are used in cancer therapy to target and disrupt microtubules. However, due to associated side effects on healthy cells, there is a need to develop safer drug regimens that still retain clinical efficacy. Currently, many questions remain open regarding the extent of effects on cellular physiology of microtubule-interacting drugs at clinically relevant and low doses. Here, we use super-resolution microscopies (single-molecule localization and optical fluctuation based) to reveal the initial microtubule dysfunctions caused by nanomolar concentrations of colcemid.

RESULTS: We identify previously undetected microtubule (MT) damage caused by clinically relevant doses of colcemid. Short exposure to 30-80 nM colcemid results in aberrant microtubule curvature, with a trend of increased curvature associated to increased doses, and curvatures greater than 2 rad/μm, a value associated with MT breakage. Microtubule fragmentation was detected upon treatment with ≥ 100 nM colcemid. Remarkably, lower doses (< 20 nM after 5 h) led to subtle but significant microtubule architecture remodelling characterized by increased curvature and suppression of microtubule dynamics.

CONCLUSIONS: Our results support the emerging hypothesis that microtubule-interacting drugs induce non-mitotic effects in cells, and establish a multi-modal imaging assay for detecting and measuring nanoscale microtubule dysfunction. The sub-diffraction visualization of these less severe precursor perturbations compared to the established antimitotic effects of microtubule-interacting drugs offers potential for improved understanding and design of anticancer agents.

PMID:34895240 | DOI:10.1186/s12915-021-01164-4

Mutat Res Rev Mutat Res. 2021 Jul-Dec;788:108391. doi: 10.1016/j.mrrev.2021.108391. Epub 2021 Jul 17.

ABSTRACT

Breast cancer (BC) is the most frequent neoplasm and one of the main causes of death in women. The pharmacological treatment of BC consists of hormonal therapy, chemotherapeutic agents and targeted therapy. The response to BC therapy is highly variable in clinical practice. This variability can be explained by the presence of genetic polymorphisms in genes involved in the pharmacokinetics, pharmacodynamics or immune response of patients. The abundant evidence of associations between low-activity alleles CYP2D6*3, *4, *5, *6, *10 and *41 and poor results with tamoxifen therapy, and between DPYD gene polymorphisms rs3918290, rs55886062, rs67376798 and rs75017182 and increased risk of toxicity to fluoropyrimidine therapy, justify the existence of clinical pharmacogenetic guidelines. The NQO1 rs1800566 polymorphism is related to poorer results in BC therapy with chemotherapy agents. The polymorphism rs1695 of the GSTP1 gene has been associated with the effectiveness and toxicity of fluorouracil, cyclophosphamide and epirubicin therapy. Finally, the HLA-DQA1*02:01 allele is significantly associated with the occurrence of liver toxicity events in patients receiving lapatinib. There is moderate evidence to support the aforementioned associations and, therefore, a high probability of these being considered as future predictive genetic biomarkers of response. However, further studies are required to reinforce or clarify their clinical relevance.

PMID:34893156 | DOI:10.1016/j.mrrev.2021.108391

Drug Ther Bull. 2021 Dec 10:dtb-2021-000065. doi: 10.1136/dtb.2021.000065. Online ahead of print.

ABSTRACT

Overview of: The Blood Pressure Lowering Treatment Triallists' Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet 2021;397:1625-36.

PMID:34893501 | DOI:10.1136/dtb.2021.000065

Drug Ther Bull. 2021 Dec 10:dtb-2021-000064. doi: 10.1136/dtb.2021.000064. Online ahead of print.

NO ABSTRACT

PMID:34893500 | DOI:10.1136/dtb.2021.000064

Drug Ther Bull. 2021 Dec 10:dtb-2021-000066. doi: 10.1136/dtb.2021.000066. Online ahead of print.

ABSTRACT

Overview of: Yang W, Sun C, He SQ et al The efficacy and safety of disease-modifying osteoarthritis drugs for knee and hip osteoarthritis-a systematic review and network meta-analysis. J Gen Intern Med 2021;36:2085-93.

PMID:34893499 | DOI:10.1136/dtb.2021.000066

Int J Environ Res Public Health. 2021 Nov 25;18(23):12411. doi: 10.3390/ijerph182312411.

ABSTRACT

Inhaled medication used for treatment of chronic obstructive lung diseases (asthma, chronic obstructive pulmonary disease-COPD, and Asthma-COPD overlap) may be associated with adverse drug reactions (ADRs). The aim of this study was to characterise spontaneous reports (SRs) of suspected ADRs received by the Portuguese Pharmacovigilance System (PPS), from 2007 to 2017.

METHODS: Retrospective observational study of SRs associated with single substance and combination inhalers, analysed in terms of pharmacological class of the involved drugs, sex and age range of the involved patients, and seriousness and type of ADRs.

RESULTS: 230 SRs were analysed, accounting for a total of 599 suspected ADRs. Inhaled corticosteroid/long-acting beta-2 agonist combination had the highest frequency in SRs (32.2%) and in ADRs (32.7%). There was a slight predominance in men (51.3%) and non-elderly adults were the most affected age group (39.1%). Most SRs were serious (70.4%). In total, "respiratory, thoracic and mediastinal diseases" ADRs were the most reported (19.5%), with "dyspnea" being the most frequent (4.8%).

CONCLUSIONS: Most SRs were associated with controller medications and were expected. Most ADRs involved non-elderly adults, were serious and of respiratory nature and many were due to overuse of reliever medication.

PMID:34886135 | PMC:PMC8656767 | DOI:10.3390/ijerph182312411

Psychopharmacol Bull. 2021 Nov 3;51(4):105-116.

ABSTRACT

Antiepileptic drugs (AEDs) are used in various pathologies such as including epilepsy, migraine, neuropathic pain, etc. They can improve symptoms but cause adverse events (ADRs). Case reports have reported that one rare but serious AED-induced adverse reaction that has appeared in case reports is myotoxicity from rhabdomyolysis. Rhabdomyolysis can be induced by a therapeutically dosed occur with therapeutic doses of antiepileptic drugs and is in most cases reversible, although rarely it can cause serious complications. Clinical manifestations of rhabdomyolysis range from a single isolated asymptomatic rise in serum CK levels to severe electrolyte imbalances, cardiac arrhythmia, acute and disseminated renal failure, intravascular coagulation, and other symptoms. Many clinical cases reported that both conventional older and newer AEDs, as well as propofol, can cause rhabdomyolysis, even if there are no conclusive data. It has recently been shown that genetic factors certainly contribute to adverse reactions of antiepileptic drugs. A study of genetic polymorphism in patients with AED-induced rhabdomyolysis may be useful to explain the rarity of this adverse event and to improve the treatment of these AED patients, in terms of AED type and dose adjustment.

PMID:34887602 | PMC:PMC8601760

J Med Internet Res. 2021 Dec 10;23(12):e27188. doi: 10.2196/27188.

ABSTRACT

BACKGROUND: Existing systems to document adverse drug events often use free text data entry, which produces nonstandardized and unstructured data that are prone to misinterpretation. Standardized terminology may improve data quality; however, it is unclear which data standard is most appropriate for documenting adverse drug event symptoms and diagnoses.

OBJECTIVE: This study aims to compare the utility, strengths, and weaknesses of different data standards for documenting adverse drug event symptoms and diagnoses.

METHODS: We performed a mixed methods substudy of a multicenter retrospective chart review. We reviewed the research records of prospectively diagnosed adverse drug events at 5 Canadian hospitals. A total of 2 pharmacy research assistants independently entered the symptoms and diagnoses for the adverse drug events using four standards: Medical Dictionary for Regulatory Activities (MedDRA), Systematized Nomenclature of Medicine (SNOMED) Clinical Terms, SNOMED Adverse Reaction (SNOMED ADR), and International Classification of Diseases (ICD) 11th Revision. Disagreements between research assistants regarding the case-specific utility of data standards were discussed until a consensus was reached. We used consensus ratings to determine the proportion of adverse drug events covered by a data standard and coded and analyzed field notes from the consensus sessions.

RESULTS: We reviewed 573 adverse drug events and found that MedDRA and ICD-11 had excellent coverage of adverse drug event symptoms and diagnoses. MedDRA had the highest number of matches between the research assistants, whereas ICD-11 had the fewest. SNOMED ADR had the lowest proportion of adverse drug event coverage. The research assistants were most likely to encounter terminological challenges with SNOMED ADR and usability challenges with ICD-11, whereas least likely to encounter challenges with MedDRA.

CONCLUSIONS: Usability, comprehensiveness, and accuracy are important features of data standards for documenting adverse drug event symptoms and diagnoses. On the basis of our results, we recommend the use of MedDRA.

PMID:34890351 | DOI:10.2196/27188

Medicine (Baltimore). 2021 Dec 10;100(49):e28140. doi: 10.1097/MD.0000000000028140.

ABSTRACT

RATIONALE: Drug-induced liver injury (DILI) is the leading cause of acute liver injury (ALI), market withdrawal of a drug, and rejection of applications for marketing licenses. The incidence of DILI is very low, with a value between 1 and 19 per 100,000 patient years. All antidepressants may induce DILI even at low therapeutic doses. In this report, we present a case of ALI after venlafaxine administration.

PATIENT CONCERNS: A 27-year-old Chinese Han woman was admitted for depression. Several serum liver function indices in this patient were abnormal after antidepressant treatment. The Roussel Uclaf Causality Assessment Method (RUCAM) causality assessment score was 8, and the R value was 31.18.

DIAGNOSES: The patient was diagnosed with hepatocellular ALI, which was derived from venlafaxine-related adverse events.

INTERVENTIONS: First, all medications were stopped to block the progression of DILI. Then, a hepatoprotective strategy and proper psychological treatment were performed to recover the impaired hepatic function.

OUTCOMES: Liver function was fully recovered as indicated by liver function indices and ultrasound imaging.

LESSONS: The possibility of DILI should not be overlooked during the long-term use of antipsychotic drugs. In response, regular liver function monitoring should be performed in a timely manner to avoid missing diagnoses and delayed treatment. Furthermore, the necessary medical treatment needs to be conducted after the occurrence of ALI.

PMID:34889278 | DOI:10.1097/MD.0000000000028140

World J Gastroenterol. 2021 Nov 7;27(41):7190-7206. doi: 10.3748/wjg.v27.i41.7190.

ABSTRACT

BACKGROUND: Despite the popularity of immune checkpoint inhibitors (ICIs) in the treatment of advanced cancer, patients often develop gastrointestinal (GI) and non-GI immune-related adverse events (irAEs). The clinical characteristics and survival outcomes of GI-irAEs have not been fully elucidated in previous reports. This necessitates the evaluation of the impact of GI-irAEs on patients receiving ICI treatment.

AIM: To evaluate the clinical characteristics of GI-irAEs and their impact on survival in patients treated with ICIs.

METHODS: In this single-center, retrospective, observational study, we reviewed the records of 661 patients who received ICIs for various cancers at Nagoya University Hospital from September 2014 to August 2020. We analyzed the clinical characteristics of patients who received ICI treatment. We also evaluated the correlation between GI-irAE development and prognosis in non-small cell lung cancer (LC) and malignant melanoma (MM). Kaplan-Meier analysis was used to compare the median overall survival (OS). Multivariate Cox proportional hazards models were used to identify prognostic factors. A P value < 0.05 was considered statistically significant.

RESULTS: GI-irAEs occurred in 34 of 605 patients (5.6%) treated with an anti-programmed cell death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) antibody alone and in nine of 56 patients (16.1%) treated with an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies. The cumulative incidence and median daily diarrhea frequency were significantly higher in patients receiving anti-CTLA-4 antibodies (P < 0.05). In 130 patients with MM, OS was significantly prolonged in the group that continued ICI treatment despite the development of GI-irAEs compared to the group that did not experience GI-irAEs (P = 0.035). In contrast, in 209 patients with non-small cell LC, there was no significant difference in OS between the groups. The multivariate analyses showed that a performance status of 2-3 (hazard ratio: 2.406; 95% confidence interval: 1.125-5.147; P = 0.024) was an independent predictive factor for OS in patients with MM.

CONCLUSION: Patients receiving anti-CTLA-4 antibodies develop GI-irAEs more frequently and with higher severity than those receiving anti-PD-1/PD-L1 antibodies. Continuing ICI treatment in patients with MM with GI-irAEs have better OS.

PMID:34887637 | PMC:PMC8613649 | DOI:10.3748/wjg.v27.i41.7190

Int J Mol Sci. 2021 Nov 25;22(23):12765. doi: 10.3390/ijms222312765.

ABSTRACT

The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.

PMID:34884570 | DOI:10.3390/ijms222312765

BMJ. 2021 Dec 8;375:e066588. doi: 10.1136/bmj-2021-066588.

ABSTRACT

OBJECTIVE: To evaluate the effectiveness of remote proactive management of toxicities during chemotherapy for early stage breast cancer.

DESIGN: Pragmatic, cluster randomised trial.

SETTING: 20 cancer centres in Ontario, Canada, allocated by covariate constrained randomisation to remote management of toxicities or routine care.

PARTICIPANTS: All patients starting adjuvant or neoadjuvant chemotherapy for early stage breast cancer at each centre. 25 patients from each centre completed patient reported outcome questionnaires.

INTERVENTIONS: Proactive, standardised, nurse led telephone management of common toxicities at two time points after each chemotherapy cycle.

MAIN OUTCOME MEASURES: The primary outcome, cluster level mean number of visits to the emergency department or admissions to hospital per patient during the whole course of chemotherapy treatment, was evaluated with routinely available administrative healthcare data. Secondary patient reported outcomes included toxicity, self-efficacy, and quality of life.

RESULTS: Baseline characteristics of participants were similar in the intervention (n=944) and control arms (n=1214); 22% were older than 65 years. Penetration (that is, the percentage of patients who received the intervention at each centre) was 50-86%. Mean number of visits to the emergency department or admissions to hospital per patient was 0.91 (standard deviation 0.28) in the intervention arm and 0.94 (0.40) in the control arm (P=0.94); 47% (1014 of 2158 patients) had at least one visit to the emergency department or a hospital admission during chemotherapy. Among 580 participants who completed the patient reported outcome questionnaires, at least one grade 3 toxicity was reported by 48% (134 of 278 patients) in the intervention arm and by 58% (163 of 283) in the control arm. No differences in self-efficacy, anxiety, or depression were found. Compared with baseline, the functional assessment of cancer therapy trial outcome index decreased by 6.1 and 9.0 points in the intervention and control participants, respectively.

CONCLUSIONS: Proactive, telephone based management of toxicities during chemotherapy did not result in fewer visits to the emergency department or hospital admissions. With the rapid rise in remote care because of the covid-19 pandemic, identifying scalable strategies for remote management of patients during cancer treatment is particularly relevant.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02485678.

PMID:34880055 | DOI:10.1136/bmj-2021-066588

Eur J Hosp Pharm. 2021 Dec 8:ejhpharm-2021-003091. doi: 10.1136/ejhpharm-2021-003091. Online ahead of print.

NO ABSTRACT

PMID:34880102 | DOI:10.1136/ejhpharm-2021-003091

Am J Emerg Med. 2021 Dec;50:646-653. doi: 10.1016/j.ajem.2021.09.051. Epub 2021 Sep 25.

ABSTRACT

INTRODUCTION: Tranexamic acid, as a traditional hemostatic agent, is commonly used to treat or prevent excessive blood loss. However, the role of tranexamic acid in promoting good clinical outcomes and reducing mortality and risk of adverse events during the treatment of aneurysmal subarachnoid hemorrhage remains unclear.

METHODS: In strict accordance with the inclusion and exclusion criteria, Cochrane Library, Embase, Web of Science, and PubMed databases were assessed for randomized controlled trials (published between 1980 and 2021). Data were analyzed using STATA 16.0 and RevMan 5.3. In addition, the fixed-effects model (M-H method) and effect size (risk difference; RD) were used as a pooled measure to combine data. We also performed a post hoc sensitivity analysis and subgroup analysis to evaluate each outcome with low heterogeneity.

RESULTS: A meta-analysis revealed that although tranexamic acid was related to less rebleeding (RD = -0.06; 95% CI [-0.09, -0.03]; P = 0.0006), there is evidence that it has no an effect on good clinical outcomes or mortality (RD = -0.01; 95% CI [-0.05, 0.02]; P = 0.51; RD = 0.00; 95% CI [-0.03, 0.04]; P = 0.91). Tranexamic acid was associated with increased hydrocephalus (RD = 0.04; 95% CI [0.01, 0.08]; P = 0.02) and seizure (RD = 0.04; 95% CI [0.00, 0.08]; P = 0.05). The incidence of thromboembolic complications or delayed cerebral ischemia was not different in the two groups (RD = -0.01; 95% CI [-0.04, 0.03]; P = 0.62; RD = 0.00; 95% CI [-0.03, 0.03]; P = 0.96), and significant drug-related overall adverse events were identified (RD = 0.02; 95% CI [0.00, 0.04]; P = 0.03).

CONCLUSIONS: These findings indicate that the routine use of tranexamic acid is not suggested for patients with aneurysmal subarachnoid hemorrhage.

PMID:34879481 | DOI:10.1016/j.ajem.2021.09.051

Infect Dis Ther. 2021 Dec 8. doi: 10.1007/s40121-021-00572-x. Online ahead of print.

ABSTRACT

INTRODUCTION: We aimed to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of a single dose of LY-CovMab in Chinese healthy adults.

METHODS: We conducted a phase 1, randomized, dose-escalation, placebo-controlled trial in 42 volunteers, 18-45 years of age, and 40 out of 42 received a single dose of LY-CovMab or placebo with LY-CovMab at a dose of 30 mg, 150 mg, 600 mg, 1200 mg, and 2400 mg. There were ten subjects in each group receiving LY-CovMab or placebo in a 4:1 ratio with the exception that the 30 mg group had two subjects both receiving LY-CovMab.

RESULTS: Among the 42 randomized participants, 40 received an injection with 32 administered LY-CovMab and 8 administered placebo. A total of 18 drug-related treatment-emergent adverse events (TEAEs) were reported in 12 subjects (30.0%), including protein urine present (25%, 10/40) and blood creatinine increased (7.5%, 3/40). The incidence of drug-related TEAE in each dosage group was as follows: 150 mg (28.6%, 2/7), 600 mg (25%, 2/8), 1200 mg (14.3%, 1/7), 2400 mg (50%, 4/8), and placebo (37.5%, 3/8). All drug-related TEAEs were grade 1, and most of them were recovering/resolving or recovered/resolved without taking action. The serum exposure of LY-CovMab (Cmax, AUC0-last, AUC0-inf) after intravenous infusion increased in an approximately proportional manner as the dose increased from 150 to 2400 mg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 28.5 days.

CONCLUSIONS: A single dose of LY-CovMab was shown to be safe and well tolerated in Chinese healthy adults. The pharmacokinetic (PK) profiles of LY-CovMab in healthy adults showed typical monoclonal antibody distribution and elimination characteristics. LY-CovMab demonstrated dose proportionality.

TRIAL REGISTRATION: ClinicalTrial.gov Identifier NCT04973735.

PMID:34878625 | DOI:10.1007/s40121-021-00572-x

Open Forum Infect Dis. 2021 Nov 17;8(12):ofab542. doi: 10.1093/ofid/ofab542. eCollection 2021 Dec.

ABSTRACT

Numerous studies have detected a greater likelihood of excess weight gain with specific antiretrovirals (ARVs), particularly tenofovir alafenamide and integrase inhibitors, as compared with other agents and classes. The long-term implications and potential reversibility for individuals who have experienced substantial ARV-associated weight accumulation remain poorly understood. Furthermore, the underlying mechanism remains controversial: Is the explanation mitochondrial toxicity and weight suppression from the older agents or direct effects of the newer drugs on appetite, adipocytes, or other unintended targets? This review discusses proposed mechanisms and evidence to date and argues that the question about mechanism is highly clinically relevant because it carries significant implications for ARV management. The existing literature suggests that older ARVs, such as tenofovir disoproxil fumarate and efavirenz, suppress weight gain, but also that integrase inhibitors may stimulate excess weight gain through several plausible biologic pathways. Confirming the mechanisms of ARV-associated excess weight gain should be high priority for future research.

PMID:34877366 | PMC:PMC8643706 | DOI:10.1093/ofid/ofab542

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