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Drug Safety Apr 2024Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach.
METHODS
The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I statistics. Publication bias was examined through funnel plots and Egger's test.
RESULTS
A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID.
CONCLUSIONS
A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.
Topics: Male; Female; Humans; Aged, 80 and over; Natalizumab; Leukoencephalopathy, Progressive Multifocal; Canada; Immunologic Factors; Multiple Sclerosis; HIV Infections
PubMed: 38321317
DOI: 10.1007/s40264-023-01383-4 -
Molecular Metabolism Jan 2024Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct...
OBJECTIVE
Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5'tRF transfer RNA fragments and microRNA miR-194-5p.
METHODS
Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5'tRF and miR-194-5p.
RESULTS
Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5'tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5'tRF levels.
CONCLUSION
Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.
Topics: Animals; Humans; Mice; Lysine; MicroRNAs; Non-alcoholic Fatty Liver Disease; Oleic Acid; Perilipin-2
PubMed: 38141848
DOI: 10.1016/j.molmet.2023.101856 -
Oncology (Williston Park, N.Y.) Dec 2023Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods... (Review)
Review
Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.
Topics: Aged; Female; Humans; Male; Middle Aged; Danazol; Myelodysplastic Syndromes
PubMed: 38133562
DOI: 10.46883/2023.25921009 -
Journal of Computer-aided Molecular... Dec 2023Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques...
Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles. All-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.
Topics: Micelles; Molecular Dynamics Simulation; Colloids; Surface-Active Agents
PubMed: 38103089
DOI: 10.1007/s10822-023-00541-1 -
Behavioural Brain Research Mar 2024In recent years, central precocious puberty (CPP) in children is becoming more common, which seriously affects their physical and psychological health and requires...
In recent years, central precocious puberty (CPP) in children is becoming more common, which seriously affects their physical and psychological health and requires finding a safe and effective treatment method. The aim of this study was to investigate the therapeutic effect of melatonin on CPP. A CPP model was established by subcutaneous injection of 300 micrograms of danazol into 5-day-old female mice, followed by treatment with melatonin and leuprolide. The vaginal opening was checked daily. Mice were weighed, gonads were weighed, gonadal index was calculated, and gonadal development was observed by hematoxylin and eosin (HE) staining. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E) levels were measured by ELISA. By using RT-PCR and Western blotting, the mRNA and protein expression of the hypothalamus Kiss-1, Kiss-1 receptor (Kiss1R), gonadotropin-releasing hormone (GnRH), and pituitary GnRH receptor (GnRHR) were identified. The results showed that melatonin delayed vaginal opening time and reduced body weight, gonadal weight and indices in female CPP mice. Melatonin treatment prevents uterine wall thickening and ovarian luteinization in female CPP mice. Melatonin treatment reduces serum concentrations of FSH, LH, and E in female CPP mice. Melatonin suppressed the expressions of Kiss-1, Kiss1R and GnRH in the hypothalamus, and the expression of GnRHR in the pituitary of the female CPP mice. Our results suggest that melatonin can inhibit the hypothalamic-pituitary-gonadal (HPG) axis by down-regulating the Kiss-1/Kiss1R system, thereby treating CPP in female mice.
Topics: Humans; Child; Female; Mice; Animals; Puberty, Precocious; Melatonin; Kisspeptins; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Follicle Stimulating Hormone; Hypothalamus
PubMed: 38029845
DOI: 10.1016/j.bbr.2023.114783 -
Psychological Assessment and Treatment Effectiveness in Mastalgia: Developing a Treatment Algorithm.Cureus Oct 2023Background Mastalgia often impairs the physical, social, and sexual lives of women. It may manifest in both cyclical or acyclical patterns. The psychoneurotic...
Background Mastalgia often impairs the physical, social, and sexual lives of women. It may manifest in both cyclical or acyclical patterns. The psychoneurotic association of mastalgia has been claimed for a long time in various available literature. Several treatment options have been used and are available in the market for mastalgia, but no specific guidelines are currently in place at the global or local levels. This study aims to evaluate the psychological status and effectiveness of various treatment options in women presenting with mastalgia. Methods This study was conducted in the General Surgery outpatient department from February 1 to November 30, 2021, at King George's Medical University, Lucknow, India. Females of all age groups presenting to the General Surgery outpatient department with unilateral/bilateral breast pain and/or chest wall pain were considered for this study. Pregnant patients, those with a history of allergy to drugs, or those who were lost to follow-up were excluded from the study. The psychological status of patients was assessed using the Depression Anxiety and Stress Scale (DASS-42) scale. Pain assessment was performed using a visual analog scale (VAS). Patients were divided into five categories: (i) isolated chest wall pain, (ii) isolated breast pain, (iii) both chest wall and breast pain, (iv) pain with an associated lump(s), and (v) pain and tenderness isolated over the lump, and two groups: Group-A: VAS≤4, and Group-B: VAS>4. Group B patients in Category iv were randomized into two groups: topical non-steroidal anti-inflammatory drugs (NSAIDs) or evening primrose oil+vitamin E. The next line of treatment was tamoxifen 10mg followed by danazol 100mg followed by ormeloxifene 30mg. Results The mean age of 106 participants enrolled was 31.59±10.52 years. The mean scores, using the DASS-42 scale, for depression, anxiety, and stress were 7.31±8.53, 7.08±6.57, and 11.15±8.07, respectively. The depression, anxiety, and stress scores had no significant correlation with pain scores (p =0.84, 0.99, and 0.97 for depression, anxiety, and stress, respectively), or duration (p=0.69, 0.66, and 0.85 for depression, anxiety, and stress, respectively). Twenty-nine of 43 patients (67.44%) responded to topical NSAIDs as first-line treatment, and out of the remaining, 6.98% responded to evening primrose oil + vitamin E, 18.60% to tamoxifen, and 4.65% to danazol. Twenty-nine of 32 patients (90.63%) responded to evening primrose oil+vitamin E as first-line treatment, while 6.25% and 3.12% responded to tamoxifen and danazol, respectively. Conclusions Both topical NSAIDs and evening primrose oil + vitamin E were found effective first-line treatment options in the majority of patients. Hence, it is always advisable to start such patients on topical NSAIDs, or evening primrose oil + vitamin E, before switching over (if no resolution of pain is reported with these drugs) to higher and more severe treatment options. The duration or severity of pain did not correlate with the psychological condition of the patient.
PubMed: 38021953
DOI: 10.7759/cureus.46838 -
Obstetrics and Gynecology Jan 2024To estimate the effect of medical management on the size of ovarian endometriomas. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To estimate the effect of medical management on the size of ovarian endometriomas.
DATA SOURCE
Online databases were searched from inception to October 2022, including Ovid MEDLINE, Ovid EMBASE, PubMed, EBM Reviews-Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov , and Web of Science.
METHODS OF STUDY SELECTION
Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we included all English-language, full-text articles that reported on change in endometrioma size (either diameter or volume) after medical interventions. Studies evaluating surgical interventions or postoperative recurrence were excluded. All screening and data extraction were performed independently by two authors. Risk of bias assessment was performed with either the Cochrane Risk of Bias Tool for randomized controlled trials or a modified Newcastle-Ottawa Scale for observational studies.
TABULATION, INTEGRATION, AND RESULTS
After removal of duplicates, 9,332 studies were screened, with 33 full-text articles deemed eligible for inclusion. In the meta-analysis, dienogest showed significant reduction in cyst diameter (reduction 1.32 cm, 95% CI, 0.91-1.73, eight studies, n=418 cysts) and volume (mean difference of log-transformed volume 1.35, 95% CI, 0.87-1.83, seven studies, n=282 cysts). Similarly, significant reductions were seen with the oral contraceptive pill (OCP) (1.06 cm, 95% CI, 0.59-1.53, nine studies, n=455), gonadotropin-releasing hormone (GnRH) agonists (1.17 cm, 95% CI, 0.42-1.92, four studies, n=128 cysts), norethindrone acetate (0.6 cm, 95% CI, 0.27-0.94, two studies, n=88 cysts), and danazol (1.95 cm, 95% CI, 1.18-2.73, two studies, n=34 cysts). Norethindrone acetate with aromatase inhibitor was also effective in reducing endometrioma volume (mean difference of log-transformed volume 1.47, 95% CI, 0.16-2.78, two studies, n=34 cysts).
CONCLUSION
Medical management with dienogest, OCPs, GnRH agonists, norethindrone acetate, norethindrone acetate with aromatase inhibitor, or danazol can reduce the size of ovarian endometriomas.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, CRD 42022363319.
Topics: Female; Humans; Endometriosis; Danazol; Norethindrone Acetate; Aromatase Inhibitors; Gonadotropin-Releasing Hormone; Cysts
PubMed: 37944155
DOI: 10.1097/AOG.0000000000005444 -
Revista Alergia Mexico (Tecamachalco,... Sep 2023Hereditary angioedema type 1 (HAE1) is an autosomal dominant disorder, characterized by quantitative and qualitative deficiency of C1 inhibitor, excessive production of...
BACKGROUND
Hereditary angioedema type 1 (HAE1) is an autosomal dominant disorder, characterized by quantitative and qualitative deficiency of C1 inhibitor, excessive production of bradykinin and causing recurrent angioedema in varying degrees of severity that affects quality of life and life itself. from the patients. Lanadelumab is a human monoclonal antibody, a specific inhibitor of plasma kallikrein, approved for long-term prophylaxis of HAE1.
CASE REPORT
A 59-year-old female patient, diagnosed with HAE 1 since November 1987, without therapeutic response to danazol, fresh frozen plasma, or C1 inhibitor derived from intravenous plasma, requiring 3 to 9 monthly vials of icatibant acetate due to angioedema. laryngeal, cutaneous and visceral with highly altered quality of life indices. Lanadelumab 300 mg subcutaneously every 14 days was started. At the start of treatment, the AECT1 score was 1 point; AE-Qol2: 57 points, AAS3: 32 points, being followed up at 5, 10 and 12 months. After one year of treatment, the records showed an AECT1 of 19 points; AE-Qol2: 36 points and AAS3: 5 points. The requirement for icatibant acetate has been no more than 3 vials per month.
CONCLUSION
In accordance with the literature, lanadelumab offered a significant decrease in angioedema activity and a significantly positive impact on the pa- tient's quality of life, confirming that lanadelumab is an effective option for long-term HAE prophylaxis. .
Topics: Female; Humans; Middle Aged; Quality of Life; Antibodies, Monoclonal, Humanized; Angioedema; Angioedemas, Hereditary
PubMed: 37933935
DOI: 10.29262/ram.v70i3.1270 -
British Journal of Haematology Mar 2024By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF),...
By whole exome sequencing, we identified a homozygous c.2086 C→T (p.R696C) TERT mutation in patients who present with a spectrum of variable bone marrow failure (BMF), raccoon eyes, dystrophic nails, rib anomalies, fragility fractures (FFs), high IgE level, extremely short telomere lengths (TLs), and skewed numbers of cytotoxic T cells with B and NK cytopenia. Haploinsufficiency in the other family members resulted in short TL and osteopenia. These patients also had the lowest bone mineral density Z-score compared to other BMF-patients. Danazol/zoledronic acid improved the outcomes of BMF and FFs. This causative TERT variant has been observed in one family afflicted with dyskeratosis congenita (DC), and thus, we also define a second report and new phenotype related to the variant which should be suspected in severe cases of DC with co-existent BMF, FFs, high IgE level and rib anomalies.
Topics: Humans; Rib Fractures; Telomere; Pancytopenia; Mutation; Dyskeratosis Congenita; Immunoglobulin E; Telomerase
PubMed: 37926112
DOI: 10.1111/bjh.19176 -
Hematology (Amsterdam, Netherlands) Dec 2023This study aimed to evaluate the efficacy of azacitidine (AZA) combined with danazol (DNZ) and thalidomide (THD) maintenance therapy after intensive chemotherapy (IC) in...
OBJECTIVE
This study aimed to evaluate the efficacy of azacitidine (AZA) combined with danazol (DNZ) and thalidomide (THD) maintenance therapy after intensive chemotherapy (IC) in patients with acute myeloid leukemia (AML).
METHODS
we retrospectively analyzed the clinical data of 11 patients treated with AZA combined with DNZ and THD as maintenance therapy after IC at the Baiyun Hospital were between February 2017 and March 2021. The patients' clinical features, relapse-free survival (RFS), and overall survival (OS) were analyzed.
RESULTS
Eleven cases fulfilled the AML criteria per the 2016 World Health Organization classification. Of the 11 patients, five were females, and six were males, with a median age of 45 years (range, 23-65 years). Ten patients were in the first complete remission (CR1), and one patient was in the second complete remission (CR2). All patients received AZA combined with DNZ and THD maintenance therapy after IC. The median number of AZA cycles received was 7 (6-12). Until June 2022, the median follow-up period was 37 (14-63) months; one patient had a relapse, and three died. RFS at 1 year and 3 years was 100% and 71.1%, respectively, and OS at 3 years was 100%.
CONCLUSION
AZA combined with DNZ and THD maintenance therapy is effective for patients with AML who are ineligible for allogeneic hematopoietic stem cell transplantation. Further studies with large sample sizes and randomized are needed to verify these findings.
Topics: Male; Female; Humans; Young Adult; Adult; Middle Aged; Aged; Azacitidine; Thalidomide; Danazol; Antimetabolites, Antineoplastic; Retrospective Studies; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Recurrence
PubMed: 37916643
DOI: 10.1080/16078454.2023.2276550