Cureus. 2023 Dec 30;15(12):e51335. doi: 10.7759/cureus.51335. eCollection 2023 Dec.

ABSTRACT

Background and aim Antidepressant drugs are commonly used to treat depressive disorders and anxiety. However, they can cause side effects, including drug-induced serotonin syndrome, which is a potentially life-threatening condition. It is essential to understand the level of knowledge of healthcare professionals who are likely to prescribe and administer these medications. This article aims to assess the knowledge of Saudi medical, nursing, and pharmacy students and interns regarding antidepressant drugs and drug-induced serotonin syndrome. Methods A cross-sectional survey was conducted among medical, nursing, and pharmacy students and interns in Saudi Arabia. A self-administered questionnaire was used to collect data from participants. The questionnaire consisted of three sections: demographic information, knowledge about antidepressants, and knowledge about serotonin syndrome. Results A total of 425 participants were included in the study. The median knowledge score for antidepressants and serotonin syndrome was moderate to good, with median scores of 18 out of 23 (IQR: 16-20) and eight out of 12 (IQR: 6-10), respectively. However, more than half of the participants had sufficient knowledge about these topics, with only 227 (53.4%) and 264 (62.1%) having sufficient knowledge about antidepressants and serotonin syndrome, respectively. Regarding serotonin syndrome, males had a significantly higher proportion of sufficient knowledge compared to females, 86 (70.5%) out of 122 vs. 178 (58.7%) out of 303 (p=0.024), respectively. Medical students/interns had a significantly higher proportion of sufficient knowledge about antidepressants compared to nursing students/interns. According to the academic year, interns had the highest proportion of sufficient knowledge. Conclusion The current study revealed that Saudi medical, nursing, and pharmacy students and interns had moderate to good levels of knowledge about antidepressants and serotonin syndrome. The participating students had slightly better knowledge about serotonin syndrome in comparison to knowledge about antidepressants. Further research is needed to identify the causes of the knowledge gap and develop targeted interventions to address these causes. Educational efforts to ensure the safe and effective use of antidepressants are needed.

PMID:38161564 | PMC:PMC10757576 | DOI:10.7759/cureus.51335

Sr Care Pharm. 2024 Jan 1;39(1):14-21. doi: 10.4140/TCP.n.2024.14.

ABSTRACT

Background Older people have higher risk of experiencing medication-related problems (MRPs), leading to increased morbidity, health care use, and mortality. Few studies have examined the pathway between limited English proficiency (LEP) among older people and health service use through MRPs. Objective This study aimed to explore the association of LEP among Latino older people with MRPs and their relationship to emergency room (ER) visits. Methods Researchers used secondary enrollment data from a community medication program for older people (N = 180). Researchers conducted linear regression to examine the relationship between ethnicity/English proficiency and MRPs, and logistic regression to explore the association between MRPs and ER visits. Generalized structural equation modeling (GSEM) with bootstrapping was used to test the indirect effect between LEP Latino through MRPs to ER visits. Results The sample included 70% non-Latino participants, 12% English-speaking Latinos, and 18% LEP Latinos. Analysis LEP Latinos were associated with having 3.4 more MRPs than non-Latino participants, after controlling for covariates. Additionally, each additional MRP was associated with a 10% increased probability of having an ER visit. The GSEM results illustrated there was a significant indirect effect between LEP through MRPs to ER visits (β = 0.27, 95% CI 0.07-0.61). Conclusion Though LEP was not directly related to increased ER visits, it may have inhibited the ability of Latinos to read and understand medication instructions, contributing to their elevated risk of experiencing MRPs, thus indirectly increasing potential risks of having ER visits.

PMID:38160237 | DOI:10.4140/TCP.n.2024.14

Ter Arkh. 2023 Aug 17;95(6):494-499. doi: 10.26442/00403660.2023.06.202297.

ABSTRACT

AIM: To evaluate the efficacy and safety of a combination of virus-neutralizing monoclonal antibodies - MAB (casirivimab and imdevimab) in patients with mild to moderate COVID-19 with risk factors in real word settings.

MATERIALS AND METHODS: A non-interventional non-comparative observational study with primary prospective data collection included 108 patients with mild to moderate COVID-19 (mean age 61 years), who had risk factors for developing severe disease. All patients (n=108) were treated with a combination of MAB casirivimab and imdevimab intravenous single infusion 1200 mg (600 mg of each component). The efficacy and safety of MAB were assessed at 7, 14, and 28 days after infusion.

RESULTS: Efficacy. Indications for hospitalization by day 7 from the moment of MAB administration were in 0.9% (n=1), by day 14 - in 1.9% (n=2), by day 28 - in 0.9% of patients; to stay in the intensive care units by the 7th day - in 4.6% (n=5), by the 14th day - in 0.9% (n=1), by the 28th day - in 0.9% (n=1) patients. During 28 days of follow up, the need for mechanical ventilation and extracorporeal membrane oxygenation was registered in 2/108 (1.8%) patients. There were no deaths directly related to COVID-19 in the assessed cohort of patients. Safety. By the 28th day of the follow up, no adverse effects due to MAB therapy were registered.

CONCLUSION: An analysis of the results of a non-interventional observational study summarized in this article showed the high efficacy and safety of virus-neutralizing MAB combination (casirivimab and imdevimab) in patients with mild to moderate COVID-19 with of risk factors for severe COVID-19 in real word settings.

PMID:38158969 | DOI:10.26442/00403660.2023.06.202297

Med Oncol. 2023 Dec 29;41(1):40. doi: 10.1007/s12032-023-02267-4.

ABSTRACT

Efforts in cancer immunotherapy aim to counteract evasion mechanisms and stimulate the immune system to recognise and attack cancer cells effectively. Combination therapies that target multiple aspects of immune evasion are being investigated to enhance the overall efficacy of cancer immunotherapy. PD-1 (Programmed Cell Death Protein 1), CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), LAG-3 (Lymphocyte-Activation Gene 3), and TIM-3 (T Cell Immunoglobulin and Mucin Domain-Containing Protein3) are all immune checkpoint receptors that play crucial roles in regulating the immune response and maintaining self-tolerance often exploited by cancer cells to evade immune surveillance. Antibodies targeted against immune checkpoint inhibitors such as anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-CTLA-4 antibodies (e.g., Ipilimumab), and experimental drugs targeting LAG-3 and TIM-3, aim to block these interactions and unleash the immune system's ability to recognise and destroy cancer cells. The US FDA has approved different categories of immune checkpoint inhibitors that have been utilised successfully in some patients with metastatic melanoma, renal cell carcinoma, head and neck cancers, and non-small lung cancer. Although several immune checkpoint inhibitor antibodies have been developed, they exhibited immune-related adverse effects, resulting in hypophysitis, diabetes, and neurological issues. These adverse effects of antibodies can be reduced by developing aptamer against the target. Aptamers offer several advantages over traditional antibodies, such as improved specificity, reduced immunogenicity, and flexible design for reduced adverse effects that specifically target and block protein-protein or receptor-ligand interactions involved in immune checkpoint pathways. The current study aims to review the function of particular immune checkpoint inhibitors along with developed aptamer-mediated antitumor cytotoxicity in cancer treatment.

PMID:38158454 | DOI:10.1007/s12032-023-02267-4

Int J Antimicrob Agents. 2023 Dec 27:107075. doi: 10.1016/j.ijantimicag.2023.107075. Online ahead of print.

ABSTRACT

INTRODUCTION: 9MW1411 is a humanized monoclonal antibody against S. aureus alpha toxin. The safety, pharmacokinetics (PK) and immunogenicity of 9MW1411 should be characterized in humans before further clinical development.

METHODS: A single-centre, randomised, double-blind, placebo-controlled phase I clinical study was conducted in humans for the first time. A total of 42 healthy Chinese subjects were randomised to receive single ascending dose of 9MW1411 (200, 600, 1500, 3000 or 5,000 mg) or placebo. Safety, PK parameters, anti-drug antibody (ADA) were analysed. Monte Carlo simulations (MCS) were performed to predict the probability of target attainment (PTA) after single dose IV administration of 1500, 3000 and 5000 mg of 9MW1411.

RESULTS: Thirty-four subjects received 9MW1411, completed the study, and were included in data analysis. Five cases of drug-related AEs occurred in 4 subjects. All the adverse events (AEs) were mild or moderate. The Cmax, AUC0-t, and AUC0-∞ of 9MW1411 increased with dose after IV administration of 200 to 5000 mg 9MW1411. The mean Cmax increased from 85.40 ± 5.43 to 2082.11 ± 343.10 μg/mL, and AUC0-∞ from 29511.68 ± 5550.91 to 729985.49 ± 124932.18 h·μg/mL. The elimination half-life (T1/2) was 19-23 days. 9MW1411 ADA was positive in 3 subjects. MCS indicated that single dose of 3000 or 5000 mg 9MW1411 could achieve PTA > 90% for S. aureus.

CONCLUSIONS: 9MW1411 has shown a good safety profile in healthy Chinese subjects after single dose up to 5000 mg. Single dose of 3000 mg 9MW1411 is appropriate for use in subsequent studies.

PMID:38157918 | DOI:10.1016/j.ijantimicag.2023.107075

Nagoya J Med Sci. 2023 Nov;85(4):668-681. doi: 10.18999/nagjms.85.4.668.

ABSTRACT

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treating pain and inflammation. Spontaneous adverse drug reaction (ADR) reports represent a rich data source for the detection of unknown and rare ADRs. This cross-sectional study aimed to analyze the characteristics of ADRs due to NSAIDs in Thailand. All ADR reports of NSAIDs for systemic use from 2015 to 2019 were extracted from the national database in Thailand. Patient characteristics, drug use information, adverse event information, and source of senders in 32,857 reports were analyzed. The annual number of ADR reports due to NSAIDs decreased from 7,008 in 2015 to 5,922 in 2019. The most frequently reported drug was ibuprofen (n=12,645, 38.5%) followed by diclofenac (n=7,795, 23.7%), most patients were 40-59 years old, and the major adverse reaction was angioedema (n=7,513, 22.9%). Serious reactions were recorded in 20.7% (n=6,801) of the total ADRs. Most patients (n=20,593, 62.7%) recovered without sequelae, but there were 5,420 patients (16.5%) who could not recover and 3,109 patients (9.5%) who were recovering. Eight patients (0.02%) died of Stevens-Johnson syndrome (n=3), toxic epidermal necrolysis (n=4), and anaphylactic shock (n=1), which were possibly related to ADRs. The number of ADR reports due to NSAIDs decreased from 2015 to 2019 in Thailand. Serious ADRs and death cases accounted for 20.7% and 0.02%, respectively. Most fatal cases exhibited severe drug-induced skin reactions.

PMID:38155619 | PMC:PMC10751502 | DOI:10.18999/nagjms.85.4.668

Cureus. 2023 Nov 28;15(11):e49548. doi: 10.7759/cureus.49548. eCollection 2023 Nov.

ABSTRACT

Corticosteroid-induced myopathy is the most common drug-induced myopathy and could appear during the treatment of diseases where corticosteroids are the mainstay of treatment. We present a clinical case of a patient treated with corticosteroids who presented with proximal muscle weakness, myalgias, marked elevation of muscle enzymes, and acute kidney injury due to rhabdomyolysis. The definitive diagnosis was only possible through a muscle biopsy.

PMID:38156153 | PMC:PMC10753519 | DOI:10.7759/cureus.49548

BMJ Open. 2023 Dec 28;13(12):e076028. doi: 10.1136/bmjopen-2023-076028.

ABSTRACT

OBJECTIVE: Investigate risk for falls, fractures and syncope in older adult patients treated with nortriptyline compared with paroxetine and alternative medications.

DESIGN: Retrospective cohort study.

SETTING: The electronic medical record and prescription drug database of a large integrated healthcare system in Southern California.

PARTICIPANTS: Ambulatory patients, age ≥65 years diagnosed with depression, anxiety disorder or peripheral neuropathy, dispensed one or more of ten study medications between 1 January 2008 and 31 December 2018.

MAIN OUTCOME MEASURES: HR for falls, fractures and syncope with exposure to study medications adjusted for patient demographic variables and comorbidities.

RESULTS: Among 195 207 subjects, 19 305 falls, 15 088 fractures and 11 313 episodes of syncope were observed during the study period. Compared with the reference medication, nortriptyline, the adjusted HRs (aHRs) for falls were statistically significantly greater for: paroxetine (aHR 1.48, 95% CI 1.39 to 1.57), amitriptyline (1.20, 95% CI 1.08 to 1.33), venlafaxine (1.44, 95% CI 1.34 to 1.56), duloxetine (1.25, 95% CI 1.12 to 1.40), fluoxetine (1.51, 95% CI 1.44 to 1.59), sertraline (1.53, 95% CI 1.44 to 1.62), citalopram (1.61, 95% CI 1.52 to 1.71) and escitalopram (1.37, 95% CI 1.21 to 1.54), but not gabapentin (0.95, 95% CI 0.89 to 1.02). For fractures, compared with nortriptyline, aHRs were significantly greater for: paroxetine, venlafaxine, duloxetine, fluoxetine, sertraline, citalopram, escitalopram and gabapentin, with aHRs ranging from 1.30 for gabapentin to 1.82 for escitalopram; risk was statistically similar for amitriptyline. For syncope, the aHRs were significantly greater for: paroxetine, venlafaxine, fluoxetine, sertraline and citalopram, with aHRs ranging from 1.19 for fluoxetine and paroxetine up to 1.30 for citalopram and sertraline; risk was similar for amitriptyline, duloxetine, escitalopram and gabapentin.

CONCLUSIONS: Compared with therapeutic alternatives, nortriptyline was found to represent a lower risk for falls, fractures and syncope, versus comparator medications, except for a few instances that had equivalent risk. The risk for these adverse events from paroxetine was comparable to the alternative medications.

PMID:38154883 | DOI:10.1136/bmjopen-2023-076028

Support Care Cancer. 2023 Dec 28;32(1):68. doi: 10.1007/s00520-023-08275-4.

ABSTRACT

BACKGROUND: In the field of exercise oncology, there is a need to quantify the potential benefits of moderate, self-directed physical activity during active treatment. In a pooled analysis of three identical single-arm intervention studies, we investigate the association of activity tracker steps with patient-reported toxicities during chemotherapy.

METHODS: Women with early breast cancer who were enrolled in the intervention studies reported their symptom severity every 2-3 weeks throughout chemotherapy, and daily steps were documented through a Fitbit activity tracker. Relative risks (RR) and 95% confidence intervals (CI) were calculated using Poisson regression models with robust variance. For outcomes significant in unadjusted models, adjusted RRs were calculated controlling for race, age, and education level. Tracker step cut point (high step, low step) was determined by the means. Cumulative incidence functions of moderate, severe, and very severe (MSVS) symptoms were estimated using the Kaplan-Meier method and compared using a Cox proportional hazard model.

RESULTS: In a sample of 283 women, mean age was 56 years and 76% were White. Mean tracker-documented steps/week were 29,625, with 55% walking below the mean (low step) and 45% above (high step). In multivariable analysis, high step patients had lower risk for fatigue [RR 0.83 (0.70, 0.99)] (p = 0.04), anxiety [RR 0.59 (0.42, 0.84)] (p = 0.003), nausea [RR 0.66 (0.46, 0.96)] (p = 0.03), depression [RR 0.59 (0.37, 0.03)] (p = 0.02), and ≥ 6 MSVS symptoms [RR 0.73 (0.54, 1.00)] (p = 0.05) and had 36% lower risk for dose reductions [RR 0.64 (95% CI 0.43, 0.97)] (p = 0.03).

CONCLUSION: Self-directed walking at a rate of at least 30,000 steps/week may moderate the severity of treatment side effects during chemotherapy for early breast cancer.

TRIAL NUMBERS: NCT02167932, NCT02328313, NCT03761706.

PMID:38153568 | DOI:10.1007/s00520-023-08275-4

Arch Microbiol. 2023 Dec 28;206(1):46. doi: 10.1007/s00203-023-03776-6.

ABSTRACT

We examined literature on Mycobacterium tuberculosis (Mtb) subsequent to its genome release, spanning years 1999-2020. We employed scientometric mapping, entity mining, visualization techniques, and PubMed and PubTator databases. Most popular keywords, most active research groups, and growth in quantity of publications were determined. By gathering annotations from the PubTator, we determined direction of research in the areas of drug hypersensitivity, drug resistance (AMR), and drug-related side effects. Additionally, we examined the patterns in research on Mtb metabolism and various forms of tuberculosis, including skin, brain, pulmonary, extrapulmonary, and latent tuberculosis. We discovered that 2011 had the highest annual growth rate of publications, at 19.94%. The USA leads the world in publications with 18,038, followed by China with 14,441, and India with 12,158 publications. Studies on isoniazid and rifampicin resistance showed an enormous increase. Non-tuberculous mycobacteria also been the subject of more research in effort to better understand Mtb physiology and as model organisms. Researchers also looked at co-infections like leprosy, hepatitis, plasmodium, HIV, and other opportunistic infections. Host perspectives like immune response, hypoxia, and reactive oxygen species, as well as comorbidities like arthritis, cancer, diabetes, and kidney disease etc. were also looked at. Symptomatic aspects like fever, coughing, and weight loss were also investigated. Vitamin D has gained popularity as a supplement during illness recovery, however, the interest of researchers declined off late. We delineated dominant researchers, journals, institutions, and leading nations globally, which is crucial for aligning ongoing and evolving landscape of TB research efforts. Recognising the dominant patterns offers important information about the areas of focus for current research, allowing biomedical scientists, clinicians, and organizations to strategically coordinate their efforts with the changing priorities in the field of tuberculosis research.

PMID:38153595 | DOI:10.1007/s00203-023-03776-6

Cureus. 2023 Nov 27;15(11):e49494. doi: 10.7759/cureus.49494. eCollection 2023 Nov.

ABSTRACT

Drug-induced long QT syndrome (LQTS) is defined as prolonged corrected QT interval (QTc ≥460 ms) plus polymorphic ventricular arrhythmia fitting the description of torsades de pointes temporally associated with the administration of a drug or combination of drugs. Amiodarone therapy is a known uncommon cause of acquired QT interval prolongation that should not be underestimated. We present a case of an iatrogenic electrical storm with atrial fibrillation (AF) in which amiodarone was administered to attempt chemical cardioversion, resulting in an unnoticed prolongation of the QT interval, with subsequent repeated polymorphic ventricular tachycardia, managed with isoproterenol. Concomitant drugs and slight electrolyte disturbances potentiated this phenomenon. Given the widespread use of this drug in the emergency department, our case highlights a pertinent matter for all medical emergency practitioners. Additionally, it stresses the significance of potential precipitating factors, such as electrolyte imbalances, which are clinical conditions very frequent in the emergency context, along with the importance of recognizing drug interactions. Finally, this case also emphasizes the vital importance of closely monitoring the patient's receiving amiodarone.

PMID:38152805 | PMC:PMC10751592 | DOI:10.7759/cureus.49494

Curr Drug Res Rev. 2023 Dec 22. doi: 10.2174/0125899775259326231212073240. Online ahead of print.

ABSTRACT

BACKGROUND: After allogeneic organ transplantation, in order to reduce the risk of rejection, tacrolimus is given. In fact, infection is reported as one of the most common side effects of tacrolimus that might be associated with graft failure.

OBJECTIVE: This study aims to review the association between the occurrence of infections due to toxicity following the administration of tacrolimus in organ transplant recipients.

METHODS: Scientific literature on the pharmacotherapy of tacrolimus after organ transplantation, infections, and neurotoxicity were searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/), Web of Science, and Scopus (n=108). All articles were screened, and the data associated with the topic of interest was extracted. The primary outcome was infection and neurotoxicity.

RESULTS: Total area under the curve exposure, the ratio of parent drug/metabolites of tacrolimus was reported to be correlated with aggressive events such as infection episodes. A trough/dose ratio may demonstrate the net state of immunosuppression and drug-related events. The most frequent infectious complication of tacrolimus after organ transplantation was reported as urinary tract infections (UTIs). Virulent strains of recombinant Listeria monocytogenes, in addition to an increase in bacterial burden in the liver and spleen tissues, were reported in experimental animal studies. Patient survival was significantly lower in recipients with UTIs in the first post-transplant month. A higher degree of immunosuppression was associated with recurrent UTIs and drug-resistant organisms. By inhibiting the cerebral immune system, tacrolimus could cause neurodegeneration.

CONCLUSION: Transplant type, gut dysmotility, acute or chronic condition before transplant surgery, use of azole, antifungal, hematocrit, tacrolimus methods of detection, the total area under the curve, and duration of hospital stay could define the risk of infection through the first month of transplant surgery. In addition, neurological and infectious complications could be associated with the higher amounts of tacrolimus trough levels (C0). Polypharmacy based on tacrolimus, antiviral, and antifungal drugs, in addition to neurotoxicity, could increase the risk of opportunistic infections such as cytomegalovirus within the first year of organ transplantation.

PMID:38151846 | DOI:10.2174/0125899775259326231212073240

J Chem Inf Model. 2024 Jan 8;64(1):57-75. doi: 10.1021/acs.jcim.3c01613. Epub 2023 Dec 27.

ABSTRACT

Drug discovery is time-consuming, expensive, and predominantly follows the "one drug → one target → one disease" paradigm. With the rapid development of systems biology and network pharmacology, a novel drug discovery paradigm, "multidrug → multitarget → multidisease", has emerged. This new holistic paradigm of drug discovery aligns well with the essence of networks, leading to the emergence of network-based methods in the field of drug discovery. In this Perspective, we initially introduce the concept and data sources of networks and highlight classical methodologies employed in network-based methods. Subsequently, we focus on the practical applications of network-based methods across various areas of drug discovery, such as target prediction, virtual screening, prediction of drug therapeutic effects or adverse drug events, and elucidation of molecular mechanisms. In addition, we provide representative web servers for researchers to use network-based methods in specific applications. Finally, we discuss several challenges of network-based methods and the directions for future development. In a word, network-based methods could serve as powerful tools to accelerate drug discovery.

PMID:38150548 | DOI:10.1021/acs.jcim.3c01613

Front Pharmacol. 2023 Dec 12;14:1294579. doi: 10.3389/fphar.2023.1294579. eCollection 2023.

ABSTRACT

The World Health Organization has recommended dolutegravir (DTG) as a preferred first-line treatment for treatment naive and experienced people living with human immunodeficiency virus type one (PLWHIV). Based on these recommendations 15 million PLWHIV worldwide are expected to be treated with DTG regimens on or before 2025. This includes pregnant women. Current widespread use of DTG is linked to the drug's high potency, barrier to resistance, and cost-effectiveness. Despite such benefits, potential risks of DTG-linked fetal neurodevelopmental toxicity remain a concern. To this end, novel formulation strategies are urgently needed in order to maximize DTG's therapeutic potentials while limiting adverse events. In regard to potential maternal fetal toxicities, we hypothesized that injectable long-acting nanoformulated DTG (NDTG) could provide improved safety by reducing drug fetal exposures compared to orally administered native drug. To test this notion, we treated pregnant C3H/HeJ mice with daily oral native DTG at a human equivalent dosage (5 mg/kg; n = 6) or vehicle (control; n = 8). These were compared against pregnant mice injected with intramuscular (IM) NDTG formulations given at 45 (n = 3) or 25 (n = 4) mg/kg at one or two doses, respectively. Treatment began at gestation day (GD) 0.5. Magnetic resonance imaging scanning of live dams at GD 17.5 was performed to obtain T1 maps of the embryo brain to assess T1 relaxation times of drug-induced oxidative stress. Significantly lower T1 values were noted in daily oral native DTG-treated mice, whereas comparative T1 values were noted between control and NDTG-treated mice. This data reflected prevention of DTG-induced oxidative stress when delivered as NDTG. Proteomic profiling of embryo brain tissues harvested at GD 17.5 demonstrated reductions in oxidative stress, mitochondrial impairments, and amelioration of impaired neurogenesis and synaptogenesis in NDTG-treated mice. Pharmacokinetic (PK) tests determined that both daily oral native DTG and parenteral NDTG achieved clinically equivalent therapeutic plasma DTG levels in dams (4,000-6,500 ng/mL). Importantly, NDTG led to five-fold lower DTG concentrations in embryo brain tissues compared to daily oral administration. Altogether, our preliminary work suggests that long-acting drug delivery can limit DTG-linked neurodevelopmental deficits.

PMID:38149054 | PMC:PMC10750158 | DOI:10.3389/fphar.2023.1294579

HIV Med. 2023 Dec 26. doi: 10.1111/hiv.13593. Online ahead of print.

ABSTRACT

BACKGROUND: Real-world evidence is an essential component of evidence-based medicine. The aim of the BICSTaR (BICtegravir Single Tablet Regimen) study is to assess effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in antiretroviral treatment-naïve (TN) and treatment-experienced (TE) people with HIV.

METHODS: BICSTaR is a prospective, observational cohort study. Participants (≥18 years) are being followed for 24 months. A pooled analysis is presented at 12 months, with the primary endpoint of effectiveness (HIV-1 RNA <50 copies/mL) and secondary endpoints of safety and tolerability (as per protocol). An exploration of patient-reported outcome measures using standardized questionnaires is included.

RESULTS: Between June 2018 and May 2021, 1552 people with HIV were enrolled across 12 countries. The analysed population comprised 1509 individuals (279 TN, 1230 TE); most were white (76%), male (84%) and had one or more comorbid conditions (68%). Median age was 47 years. After 12 months of B/F/TAF treatment, HIV-1 RNA was <50 copies/mL in 94% (221/236) of TN participants and 97% (977/1008) of TE participants. Median CD4 cell count increased by 214 cells/μL (p < 0.001) in TN participants and 13 cells/μL (p = 0.014) in TE participants; median CD4/CD8 ratios increased by 0.30 and 0.03, respectively (both p < 0.001). Persistence was high at 12 months (TN, 97%; TE, 95%). No resistance to B/F/TAF emerged. Study drug-related adverse events occurred in 13% of participants through 12 months, leading to B/F/TAF discontinuation in 6%.

CONCLUSIONS: The findings of this study provide robust real-world evidence to support the broad use of B/F/TAF in both TN and TE people with HIV.

PMID:38148567 | DOI:10.1111/hiv.13593

Inquiry. 2023 Jan-Dec;60:469580231218625. doi: 10.1177/00469580231218625.

ABSTRACT

Optimal medication management is important during hospitalization and at discharge because post-discharge adverse drug events (ADEs) are common, often preventable, and contribute to patient harms, healthcare utilization, and costs. Conduct a cost analysis of a comprehensive pharmacist-led transitions-of-care medication management intervention for older adults during and after hospital discharge. Twelve intervention components addressed medication reconciliation, medication review, and medication adherence. Trained, experienced pharmacists delivered the intervention to older adults with chronic comorbidities at 2 large U.S. academic centers. To quantify and categorize time spent on the intervention, we conducted a time-and-motion analysis of study pharmacists over 36 sequential workdays (14 519 min) involving 117 patients. For 40 patients' hospitalizations, we observed all intervention activities. We used the median minutes spent and pharmacist wages nationally to calculate cost per hospitalization (2020 U.S. dollars) from the hospital perspective, relative to usual care. Pharmacists spent a median of 66.9 min per hospitalization (interquartile range 46.1-90.1), equating to $101 ($86 to $116 in sensitivity analyses). In unadjusted analyses, study site was associated with time spent (medians 111 and 51.8 min) while patient primary language, discharge disposition, number of outpatient medications, and patient age were not. In this cost analysis, comprehensive medication management around discharge cost about $101 per hospitalization, with variation across sites. This cost is at least an order of magnitude less than published costs associated with ADEs, hospital readmissions, or other interventions designed to reduce readmissions. Work is ongoing to assess the current intervention's effectiveness.

PMID:38146178 | DOI:10.1177/00469580231218625

BioDrugs. 2023 Dec 27. doi: 10.1007/s40259-023-00637-y. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: QX006N is a novel, humanized, IgG4κ monoclonal antibody targeting IFNAR1, developed for the treatment of systemic lupus erythematosus. This study aims to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of QX006N when administered intravenously to healthy Chinese individuals.

METHODS: A double-blind, randomized, placebo-controlled, single-ascending-dose, phase I clinical trial was conducted comprising five cohorts (n = 10 per cohort, except n = 5 for the first cohort). Subjects in each cohort were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of QX006N (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 6.0 mg/kg, or 10.0 mg/kg) or placebo for 30 minutes. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. The serum concentration of QX006N was measured using the enzyme-linked immunosorbent assay method, and the anti-drug antibodies were detected using the electrochemiluminescence assay method.

RESULTS: QX006N demonstrated a favorable safety and tolerability profile throughout the study. All treatment-emergent adverse events were of Grade 1-2 (CTCAE Version 5.0), and no serious adverse events, deaths, or drug discontinuations because of treatment-emergent adverse events were observed. All drug-related treatment-emergent adverse events showed no clear dose-related trends. Following an intravenous infusion of QX006N at doses that ranged from 0.3 mg/kg to 10 mg/kg, the half-life increased from 24.7 to 208 hours in a dose-dependent manner, while clearance decreased from 0.0828 to 0.0065 L/h. The maximum concentration exhibited nearly dose-proportional increases, and the area under the curve displayed a more than dose-proportional increment with non-linear pharmacokinetic characteristics. The incidence of anti-drug antibodies was observed to increase over time for doses that ranged from 1.0 mg/kg to 10.0 mg/kg of QX006N, reaching its peak at day 57 (range 62.50-87.50%). Conversely, the incidence of anti-drug antibodies in the QX006N 0.3-mg/kg and placebo cohorts remained low.

CONCLUSIONS: QX006N demonstrated acceptable safety, tolerability, and pharmacokinetic characteristics in healthy subjects when administered as a single intravenous infusion at doses that ranged from 0.3 mg/kg to 10.0 mg/kg. Based on the pharmacokinetic and safety outcomes, a recommended effective dose of 300 mg is proposed for future phase Ib studies.

CLINICAL TRIAL REGISTRATION: This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20212834.

PMID:38148466 | DOI:10.1007/s40259-023-00637-y

HIV Med. 2023 Dec 26. doi: 10.1111/hiv.13588. Online ahead of print.

ABSTRACT

OBJECTIVES: Cabotegravir + rilpivirine (CAB + RPV) dosed monthly or every 2 months is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virological suppression. This post hoc analysis summarizes outcomes for Asian participants through week 96.

METHODS: Data from Asian participants naive to CAB + RPV randomized to receive dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) in the FLAIR (NCT02938520) and ATLAS-2M (NCT03299049) phase 3/3b studies were pooled. The proportion of participants with plasma HIV-1 RNA ≥50 and <50 copies/mL (per FDA Snapshot algorithm), incidence of confirmed virological failure (CVF; two consecutive HIV-1 RNA ≥200 copies/mL), pharmacokinetics, safety, and tolerability through week 96 were assessed.

RESULTS: Overall, 41 Asian participants received CAB + RPV (Q8W, n = 17; Q4W, n = 24). At week 96, 83% (n = 34/41) of participants maintained HIV-1 RNA <50 copies/mL, none had HIV-1 RNA ≥50 copies/mL, and 17% (n = 7/41) had no virological data. No Asian participant met the CVF criterion. Drug-related adverse events occurred in 44% (n = 18/41) of participants; none were Grade ≥3. All injection site reactions were Grade 1 or 2; median duration was 2 days and most resolved within 7 days (90%, n = 390/435). CAB and RPV trough concentrations remained well above their respective protein-adjusted 90% inhibitory concentrations (CAB, 0.166 μg/mL; RPV, 12 ng/mL) through week 96.

CONCLUSIONS: CAB + RPV LA demonstrated high efficacy, with no participants having CVF, and an acceptable safety profile in Asian participants through week 96. These data support CAB + RPV LA as a complete regimen for the maintenance of HIV-1 virological suppression in Asian individuals.

PMID:38147871 | DOI:10.1111/hiv.13588

J Gastrointestin Liver Dis. 2023 Dec 22;32(4):488-496. doi: 10.15403/jgld-5045.

ABSTRACT

BACKGROUND AND AIMS: Immune checkpoint inhibitors may cause various types of organ damage as immune-related adverse events, of which, liver damage is the most common. Herein, we evaluated the clinicopathological features of immune checkpoint inhibitor-related liver injury and investigated the differences between immune checkpoint inhibitor-related liver injury and drug-induced liver injury or autoimmune hepatitis.

METHODS: We selected patients with ≥ grade 3 liver injury who were diagnosed with immune checkpoint inhibitor-related liver injury (n=15). Liver biopsies were performed in 10 of the 15 cases. We also selected cases in which a liver biopsy was performed and drug-induced liver injury (n=7) or autoimmune hepatitis [n=21: acute exacerbation (n=13) was diagnosed and cases of acute onset (n=8), in which liver function test results corresponded to ≥ grade 3].

RESULTS: Portal fibrosis and periportal activity scores were significantly higher in the acute exacerbation autoimmune hepatitis group than in the other groups. Portal and lobular activity were not different between the groups. Plasma cell infiltration showed a higher trend in the autoimmune hepatitis group than in the other groups. Granuloma formations were seen in 90% of immune checkpoint inhibitor-related liver injury cases. The CD4/8 ratio was significantly lower in the immune checkpoint inhibitor-related liver injury group than in the other groups. Patients with bile duct injury had poorer response to corticosteroid therapy than those without.

CONCLUSIONS: There are some obvious differences among immune checkpoint inhibitor-related liver injury, drug-induced liver injury, and autoimmune hepatitis in liver histology. Liver biopsy is helpful for the diagnosis and severity evaluation of liver injury.

PMID:38147620 | DOI:10.15403/jgld-5045

Lancet Haematol. 2023 Dec 21:S2352-3026(23)00344-7. doi: 10.1016/S2352-3026(23)00344-7. Online ahead of print.

ABSTRACT

BACKGROUND: In a pivotal phase 3 trial of cytomegalovirus prophylaxis with letermovir for up to 100 days after allogeneic haematopoietic stem-cell transplantation (HSCT), 12% of participants developed clinically significant cytomegalovirus infection after letermovir was discontinued. We aimed to evaluate the efficacy and safety of extending the duration of letermovir prophylaxis for clinically significant cytomegalovirus infection from 100 days to 200 days following HSCT.

METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 32 sites in six countries (France, Germany, Italy, Japan, the UK, and the USA). Cytomegalovirus‑seropositive HSCT recipients (aged ≥18 years) who had received letermovir prophylaxis for up to 100 days following HSCT and who remained at high risk of late clinically significant cytomegalovirus infection (with no previous history of clinically significant cytomegalovirus infection, defined as initiation of pre-emptive therapy for documented cytomegalovirus viraemia, onset of cytomegalovirus end-organ disease, or both) were eligible. Participants were randomly assigned (2:1) to receive either an additional 100 days (ie, a total of 200 days; letermovir group) of oral or intravenous letermovir 480 mg once daily, adjusted to 240 mg once daily for participants on cyclosporin A, or 100 days of a placebo comparator for letermovir (ie, a total of 100 days of letermovir; placebo group), following HSCT. Randomisation was done using a central interactive response technology system, stratified by study centre and haploidentical donor (yes or no). Participants, investigators, and sponsor personnel were masked to the treatment allocation. The primary efficacy endpoint was the proportion of participants from randomisation to week 28 (200 days after HSCT) with clinically significant cytomegalovirus infection, analysed using the full analysis set population (ie, those who received at least one dose of study intervention). Safety was analysed in all participants as treated (ie, those who received at least one dose according to the study intervention they were assigned to). This study is registered with ClinicalTrials.gov, NCT03930615, and is complete.

FINDINGS: Between June 21, 2019, and March 16, 2022, 255 patients were screened for eligibility and 220 (86%) were randomly assigned (145 [66%] in the letermovir group and 75 [34%] in the placebo group). Between randomisation and week 28, four (3%) of 144 participants in the letermovir group and 14 (19%) of 74 in the placebo group developed clinically significant cytomegalovirus infection (treatment difference -16·1% [95% CI -25·8 to -6·5]; p=0·0005). The most common adverse events among participants in the letermovir group versus the placebo group were graft-versus-host disease (43 [30%] vs 23 [31%]), diarrhoea (17 [12%] vs nine [12%]), nausea (16 [11%] vs 13 [18%]), pyrexia (13 [9%] vs nine [12%]), and decreased appetite (six [4%] vs nine [12%]). The most frequently reported serious adverse events were recurrent acute myeloid leukaemia (six [4%] vs none) and pneumonia (three [2%] vs two [3%]). No deaths were considered to be drug-related by the investigator.

INTERPRETATION: Extending the duration of letermovir prophylaxis to 200 days following HSCT is efficacious and safe in reducing the incidence of late clinically significant cytomegalovirus infection in patients at risk.

FUNDING: Merck Sharp & Dohme LLC.

PMID:38142695 | DOI:10.1016/S2352-3026(23)00344-7