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

Medicina (Kaunas). 2023 Dec 4;59(12):2119. doi: 10.3390/medicina59122119.

ABSTRACT

Background and objectives: Cyclophosphamide (CPA) is an alkylating agent that is used for the management of various types of malignancies and as an immunosuppressive agent for the treatment of immunological disorders. However, its use is limited by its potential to cause a wide range of pulmonary toxicities. Amentoflavone (AMV) is a flavonoid that had proven efficacy in the treatment of disease states in which oxidative stress, inflammation, and apoptosis may play a pathophysiologic role. This study investigated the potential ameliorative effects of the different doses of AMV on CPA-induced pulmonary toxicity, with special emphasis on its antioxidant, anti-inflammatory, and apoptosis-modulating effects. Materials and methods: In a rat model of CPA-induced pulmonary toxicity, the effect of AMV at two dose levels (50 mg/kg/day and 100 mg/kg/day) was investigated. The total and differential leucocytic counts, lactate dehydrogenase activity, and levels of pro-inflammatory cytokines in the bronchoalveolar lavage fluid were estimated. Also, the levels of oxidative stress parameters, sirtuin-1, Keap1, Nrf2, JAK2, STAT3, hydroxyproline, matrix metalloproteinases 3 and 9, autophagy markers, and the cleaved caspase 3 were assessed in the pulmonary tissues. In addition, the histopathological and electron microscopic changes in the pulmonary tissues were evaluated. Results: AMV dose-dependently ameliorated the pulmonary toxicities induced by CPA via modulation of the SIRT-1/Nrf2/Keap1 axis, mitigation of the inflammatory and fibrotic events, impaction of JAK-2/STAT-3 axis, and modulation of the autophagic and apoptotic signals. Conclusions: AMV may open new horizons towards the mitigation of the pulmonary toxicities induced by CPA.

PMID:38138222 | PMC:PMC10744450 | DOI:10.3390/medicina59122119

Medicina (Kaunas). 2023 Dec 1;59(12):2109. doi: 10.3390/medicina59122109.

ABSTRACT

Background and Objectives: In addition to a suboptimal and rapidly diminishing response to the coronavirus disease 2019 (COVID-19) vaccine, hemodialysis (HD) patients are at risk for developing a severe COVID-19 infection. In 2022, the combination of cilgavimab and tixagevimab (Evusheld, AstraZeneca) was approved for COVID-19 preexposure prophylaxis in high-risk groups. The purpose of this study was to evaluate the humoral response and short-term safety of this antibody combination in a group of HD patients. Materials and Methods: Seventy-three adult maintenance hemodialysis patients were recruited from a tertiary-care hospital for this double-blinded, non-randomized, placebo-controlled study. Patients were placed into two groups: the intervention group (n = 43) received a single 300 mg dosage of cilgavimab and tixagevimab, while the control group (n = 30) received a saline placebo. The titer of COVID-19-neutralizing antibodies was measured at baseline and after 1 and 6 months. The patients were evaluated for any drug-related adverse effects and monitored for six months for the emergence of any COVID-19-related events. Results: Patients in the intervention group were substantially older and had been on HD for longer (p = 0.002 and 0.006, respectively). The baseline antibody levels were higher in the Evusheld group. The antibody level in the intervention group increased significantly after 1 month and remained consistent for 6 months, whereas the antibody level in the control group fell significantly after 6 months during the study period (Wald χ2 = 30.620, p < 0.001). The drug-related adverse effects were modest and well-tolerated, and only seven patients experienced them. Six months after study enrollment, 10 patients in the intervention group and 6 patients in the control group had been infected with COVID-19, respectively. In the control group, ICU admission and mortality were observed, but in the intervention group, the infection was milder with no aggressive consequences. Conclusions: This study demonstrated the short-term safety and efficacy of tixagevimab-cilgavimab for COVID-19 preexposure prophylaxis in HD patients. These findings require more studies with more HD patients and longer follow-up periods.

PMID:38138212 | PMC:PMC10744812 | DOI:10.3390/medicina59122109

Medicina (Kaunas). 2023 Nov 21;59(12):2052. doi: 10.3390/medicina59122052.

ABSTRACT

Background and Objectives: Schizophrenia, a debilitating mental illness, is often associated with significant physical health risks. Many second-generation antipsychotics increase the risk of metabolic syndrome and cardiovascular disease. Community pharmacists are highly accessible and could play a role in monitoring cardiometabolic adverse drug events in people with schizophrenia. However, it remains uncertain whether mental health professionals perceive this as valuable. This study aimed to explore the opinions of mental healthcare professionals regarding the role of community pharmacists in reducing the incidence of cardiometabolic adverse events in people with schizophrenia and their integration into a multidisciplinary mental health team. Materials and Methods: Qualitative semi-structured interviews were conducted with Australian psychiatrists, mental health nurses and mental health pharmacists. Transcription of the interviews underwent thematic analysis using an inductive approach. Results: Eleven mental healthcare professionals from metropolitan and regional areas across Australia were interviewed, leading to the identification of five overarching themes. These themes encompassed the following aspects: the benefits of community pharmacists' involvement in managing cardiometabolic adverse drug events in people with schizophrenia, improving communication pathways with community pharmacists, defining roles and responsibilities for monitoring cardiometabolic parameters and managing adverse cardiometabolic drug events, fostering collaboration between community pharmacists and mental health care professionals, and recognising the acceptance of community pharmacists' integration within a multidisciplinary team. Mental health professionals believed that community pharmacists could play a role in reducing the incidence of cardiometabolic adverse events in schizophrenia. However, they underscored the need for enhanced communication and collaboration pathways with other healthcare professionals, emphasised the importance of more comprehensive mental health first aid training, and identified potential barriers for community pharmacists such as remuneration, workload, and staff resources. Conclusions: Mental health professionals acknowledged the benefits of incorporating community pharmacists into multidisciplinary teams as a strategy to reduce the incidence of adverse events among individuals with schizophrenia. They recognise the competence of community pharmacists in monitoring cardiometabolic adverse events. However, these professionals have also highlighted specific perceived barriers to the complete integration of community pharmacists within these teams. Notably, there are concerns related to remuneration, staff resources, time constraints, acceptance by other healthcare professionals and patients, and the need for improved communication pathways. Addressing these barriers and providing targeted training could facilitate the valuable inclusion of community pharmacists in the comprehensive care of people with schizophrenia.

PMID:38138155 | PMC:PMC10744378 | DOI:10.3390/medicina59122052

Lancet HIV. 2023 Dec 20:S2352-3018(23)00258-8. doi: 10.1016/S2352-3018(23)00258-8. Online ahead of print.

ABSTRACT

BACKGROUND: In two phase 3 trials for first-line therapy in adults with HIV-1, doravirine showed non-inferior efficacy, a favourable safety profile, and a superior lipid profile to darunavir and efavirenz through to 48 and 96 weeks. Here we report 192-week results from both studies.

METHODS: DRIVE-FORWARD and DRIVE-AHEAD are multicentre, double-blind, randomised, active comparator-controlled, phase 3 trials of first-line antiretroviral treatment in adults with HIV-1. Eligible participants (aged ≥18 years) were naive to antiretroviral therapy, had plasma HIV-1 RNA 1000 copies per mL or more at screening, had no known resistance to any of the trial drugs, and had creatinine clearance 50 mL per min or more. DRIVE-FORWARD was conducted at 125 sites in 15 countries and compared doravirine (100 mg) with ritonavir-boosted darunavir (ritonavir [100 mg] and darunavir [800 mg]), each administered orally once daily with two nucleoside or nucleotide reverse transcriptase inhibitors (tenofovir disoproxil fumarate [300 mg] and emtricitabine [200 mg] or abacavir sulfate [600 mg] and lamivudine [300 mg]). DRIVE-AHEAD was conducted at 126 sites in 23 countries and compared doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg) with that of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), all administered orally once daily. DRIVE-FORWARD enrolment was between Dec 1, 2014, and June 1, 2020, and DRIVE-AHEAD enrolment was between June 10, 2015, and Aug 10, 2020. After the 96-week double-blind phase, eligible participants could enter an open-label extension and either continue doravirine or switch from comparator to doravirine for an additional 96 weeks. Efficacy (HIV-1 RNA <50 copies per mL) and safety assessments (adverse events and changes in laboratory parameters) were pooled. The DRIVE-FORWARD and DRIVE-AHEAD trials were registered with ClinicalTrials.gov, NCT02275780 and NCT02403674.

FINDINGS: Of 1494 participants treated in the double-blind phase (1261 [84%] male and 233 [16%] female), 550 continued doravirine and 502 switched to doravirine in the extension. Using the FDA snapshot approach, HIV-1 RNA less than 50 copies per mL was maintained in 457 (83%) of 550 participants who continued doravirine and 404 (80%) of 502 participants who switched to doravirine. Protocol-defined virological failure and development of resistance were low, occurring mainly before week 96. Two (<1%) of 550 participants who continued doravirine reported serious drug-related adverse events, and three (1%) who continued doravirine and one (<1%) of 502 who switched to doravirine discontinued due to drug-related adverse events. Participants continuing or switching to doravirine showed generally favourable lipid profiles, little weight gain, and small decreases in estimated glomerular filtration rates, with no discontinuations due to increased creatinine or renal adverse events.

INTERPRETATION: Favourable efficacy and safety profiles for doravirine at week 96 were maintained through to week 192 in participants who continued or switched to doravirine, supporting use of doravirine for long-term first-line HIV-1 treatment and for virologically suppressed adults switching therapy.

FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

PMID:38141637 | DOI:10.1016/S2352-3018(23)00258-8

J Pers Med. 2023 Dec 14;13(12):1706. doi: 10.3390/jpm13121706.

ABSTRACT

Introduction: Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor-recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. Area covered: Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.

PMID:38138933 | DOI:10.3390/jpm13121706

Prim Care Companion CNS Disord. 2023 Dec 14;25(6):23cr03605. doi: 10.4088/PCC.23cr03605.

NO ABSTRACT

PMID:38134407 | DOI:10.4088/PCC.23cr03605

Mult Scler. 2023 Dec 22:13524585231215268. doi: 10.1177/13524585231215268. Online ahead of print.

ABSTRACT

BACKGROUND: Despite increasing evidence that Epstein-Barr virus (EBV) plays a causal role in MS, no treatments have been shown to reduce EBV turnover. We studied the effect of famciclovir on salivary EBV shedding in people with MS (NCT05283551) in a pilot, proof-of-concept study.

METHODS: People with MS receiving natalizumab provided weekly saliva samples for 12 weeks before starting famciclovir 500 mg twice daily for 12 weeks. Twelve saliva samples were provided on treatment and 12 following treatment. A real-time qPCR Taqman assay was used to detect EBV DNA in saliva. The proportion of saliva samples containing EBV DNA was compared using the Friedman test.

RESULTS: Of 30 participants (19 F; mean age 41 years; median EDSS 3.5), 29 received famciclovir, and 24 completed the 12-week course. Twenty-one participants provided at least one usable saliva sample in all epochs. Ten of the 21 had shedding in at least one sample pre-drug; 7/21 when taking famciclovir (not significant). No difference in EBV DNA copy number was seen. There were no drug-related serious adverse events.

CONCLUSION: No significant effect of famciclovir on EBV shedding was seen in this small pilot study. Given the low numbers, a small effect of famciclovir cannot be excluded. Salivary EBV shedding in this natalizumab-treated cohort was lower than in previous studies, which requires replication.

PMID:38131621 | DOI:10.1177/13524585231215268

World J Clin Cases. 2023 Dec 16;11(35):8425-8430. doi: 10.12998/wjcc.v11.i35.8425.

ABSTRACT

BACKGROUND: This case report addresses the dearth of effective therapeutic interventions for central nervous system metastases in patients with HER2-negative breast cancer. It presents a unique case of a woman with estrogen receptor-positive, HER2-negative breast cancer who developed brain metastasis. The report highlights her initial favorable response to abemaciclib and letrozole therapy prior to the discontinuation due to drug-induced lung damage (DILD).

CASE SUMMARY: In this comprehensive case summary, we present the clinical course of a woman in her 60s, who 11 years following primary breast cancer surgery, was diagnosed with multiple brain metastases. As a third-line systemic therapy, she underwent treatment with abemaciclib and letrozole. This treatment approach yielded a near-partial response in her metastatic brain lesions. However, abemaciclib administration ceased due to the emergence of DILD, as confirmed by a computed tomography scan. The DILD improved after 1 mo of cessation. Despite ongoing therapeutic efforts, the patient's condition progressively deteriorated, ultimately resulting in death due to progression of the brain metastases.

CONCLUSION: This case underscores the challenge of managing adverse events in responsive brain metastasis patients, given the scarcity of therapeutic options.

PMID:38130622 | PMC:PMC10731188 | DOI:10.12998/wjcc.v11.i35.8425

Korean J Pain. 2023 Dec 22. doi: 10.3344/kjp.23246. Online ahead of print.

ABSTRACT

BACKGROUND: : Failed back surgery syndrome (FBSS) is a chronic condition that is characterized by persistent back pain following one or more spinal surgeries. Pharmacological interventions, such as the use of opioids and gabapentinoids, are frequently used in the treatment of FBSS. However, prolonged and excessive use of these medications can lead to dependence and adverse effects. This study investigates trends in opioid and gabapentinoid prescriptions among patients with FBSS in Korea from 2016 to 2020.

METHODS: : Data from the Health Insurance and Review Agency were analyzed, and claims listing FBSS were selected for the study. Prescription patterns of opioids and gabapentinoids were classified based on the number of days prescribed per year.

RESULTS: : Of the 390,095 patients diagnosed with FBSS, 41.6% of the patients were prescribed gabapentinoids, and 42.0% of them were prescribed opioids, while 10.6% of the patients were classified as long-term gabapentinoid users, 11.4% as long-term opioid users, and 7.4% of the patients were found to have long-term prescriptions for both drugs. The proportion of patients who received both gabapentinoid and opioid prescriptions increased annually. The doses of opioids prescribed have also increased along with the increase in the number of patients receiving opioid prescriptions.

CONCLUSIONS: : The prescription rates of opioids and gabapentinoids among patients with FBSS in Korea continue to increase steadily, posing potential risks of addiction and adverse effects. Further research is needed to better understand the actual status of addiction in patients with FBSS.

PMID:38130090 | DOI:10.3344/kjp.23246