Danazol's use for menstrual suppression in transgender individuals: A retrospective multi-site cohort study.

BACKGROUND: Danazol is a synthetic progestin with androgenic effects that is approved by the Food and Drug Administration for treatment of endometriosis, benign fibrocystic breast disease, and hereditary angioedema. In recent years, increasing numbers of transgender and nonbinary individuals seeking menstrual suppression have been offered danazol due to its potential to both induce amenorrhea and cause reversible androgenic side effects including pigmentation of vellus hairs and voice changes, which may be desirable in this population. There are currently no studies assessing use of danazol within the transgender population for menstrual suppression. OBJECTIVE: This study's primary aim was to evaluate the use of danazol as a menstrual suppression agent in transgender patients. DESIGN: This was a retrospective multisite cohort study of all individuals who had been on danazol at two tertiary care centers between 2000 and 2022. METHODS: All patients prescribed danazol were identified using a search of the electronic medical records. For demographic purposes, comparisons were made between those who did and did not use danazol for the purpose of menstrual suppression. A detailed chart review was then performed to analyze the experiences of menstrual suppression in transgender and nonbinary patients. RESULTS: Most transgender and nonbinary patients on danazol for menstrual suppression remained on it at their most recent follow-up visit, and many charts noted improvements in gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy menstrual bleeding. Most transgender patients achieved amenorrhea. CONCLUSION: Danazol may be a reasonable option for menstrual suppression in transgender and nonbinary patients. Our findings show its potential to not only induce amenorrhea but cause desired androgenic symptoms and improve gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy bleeding. While the androgenic effects of danazol are less desirable in cisgender populations, it is an attractive option for menstrual suppression in transgender and nonbinary patients.

Using danazol to stop periods in transgender individualsDanazol has previously been used to help treat pain and bleeding related to endometriosis. However, danazol can have certain androgenic side effects (acne, deepening of the voice) that cisgender women (individuals who were assigned female at birth and identify with the female gender) often find undesirable, but that could be desirable in transgender patients seeking to affirm their gender by stopping periods. Our study looked at danazol use for period suppression, as well as for other reasons. We found that most transgender patients using danazol for period suppression found it to be successful and remained on it at follow-up appointments, and that many transgender patients saw improved gender dysphoria, pelvic pain, pain during periods, endometriosis, and heavy period bleeding. These findings suggest that danazol may be a good option for menstrual suppression in transgender individuals as any experienced androgenic effects may help with gender dysphoria, whether individuals are not yet ready to start testosterone or do not desire testosterone therapy at all.

Tumid lupus erythematosus in C1-inhibitor deficiency.

A case of a 28-year-old woman with known C1-inhibitor deficiency (functional, Type II) with persistent bilateral non-pruritic, mildly photosensitive facial rash for 10 months following delivery of her second child is presented. Histology of the skin was suggestive of tumid lupus erythematosus (LE), but no other features of systemic LE (ANA, dsDNA negative) were evident. She had stopped danazol which was controlling the underlying disease, and once this was restarted and treatment for tumid lupus was started, she improved. More rigorous control preventing all C1-inhibitor deficiency-related attacks proved successful. The hypothesis that uncontrolled classical pathway complement activation that led to the lupus-like skin lesions is being presented as a clinical case, highlighting the complex interrelationships between immunodeficiency and autoimmunity in inborn errors in immunity.

Maintenance therapy with a combination of azacitidine, danazol, and thalidomide after intensive chemotherapy in patients with acute myeloid leukemia.

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.

Efficacy and safety of different subsequent therapies after fertility preserving surgery for endometriosis: A systematic review and network meta-analysis.

BACKGROUND: Endometriosis (EMT) is a benign and common estrogen-dependent disease. Hormonal therapy improves pain symptoms in most women with EMT. However, in many cases, laparoscopic fertility preservation surgery is considered a common treatment for EMT. The present study aimed to evaluate the efficacy and safety of dienogest, leuprolide, danazol, gestrinone, mifepristone and levonorgestrel intrauterine system (LNG-IUS) in relieving symptoms and delaying the recurrence of EMT cysts after fertility protection surgery. METHODS: We searched PubMed, the Cochrane Library, Web of Science, EMBase, China National Knowledge Infrastructure, VIP Database, China Biology Medicine disc, WanFang Data databases to collect randomized controlled trials (RCT) related to dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS as a follow-up treatment after fertility preserving surgery for EMT. After literature screening, data extraction and quality evaluation, effective rate, recurrence rate, pregnancy rate and adverse reaction rate were used as outcome indicators to evaluate the efficacy and safety of drugs. Evidence networks included in the study were drawn and publication bias was assessed. The drugs most likely to be the best postoperative treatment were explored through mixed comparison of different drugs and efficacy ranking. RESULT: Effective rate: dienogest, leprerelin, gestrinone and LNG-IUS were better than placebo after EMT fertility preservation surgery; dienogest was superior to mifepristone and danazol. LNG-IUS is superior to danazol. LNG-IUS has the highest potential for improving the effectiveness of EMT symptoms. Recurrence rate: the application of dienogest, leuprolide, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was lower than that of placebo; dienogest and LNG-IUS were lower than danazol. The recurrence rate of dinorgestrel was the last place with the highest performance. Pregnancy rate: in the cases with fertility requirements, dienogest and,leuprolide were better than placebo after EMT fertility preservation surgery; dienogest was superior to danazol, gestrinone and mifepristone. Leuprolide is superior to danazol and gestrinone. The first rank of dienogest pregnancy rate was the highest. Adverse reaction rate: the application of dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was higher than that of placebo. After placebo, LNG-IUS had the highest adverse reaction rate. CONCLUSION: For patients after fertility preserving surgery for EMT, the recurrence rate of dienogest was the last place with highest preference. The first rank of dienogest pregnancy was the highest.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study.

BACKGROUND: The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48. METHODS: MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1-4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib. The primary endpoint, which has already been reported, was Myelofibrosis Symptom Assessment Form TSS response rate at week 24. Predefined secondary endpoints were duration of week 24 TSS and transfusion independence responses, safety, and survival, which are summarised post hoc at the week 48 data cutoff (May 17, 2022). TSS, transfusion independence, and splenic responses at week 48 were defined post hoc and assessed in all evaluable patients who entered the open-label period and provided sufficient data. The timing of this updated analysis was defined post hoc after all patients had the opportunity to complete their week 48 assessments, as most patients entered an extended access study (NCT03441113) after week 48. This study is registered with ClinicalTrials.gov, number NCT04173494, and is now complete. FINDINGS: Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6-55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3-4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia). INTERPRETATION: Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia. FUNDING: Sierra Oncology, a GSK company.

Gonadotropin-releasing hormone analogues for endometriosis.

BACKGROUND: Endometriosis is a common gynaecological condition affecting 6 to 11% of reproductive-age women and may cause dyspareunia, dysmenorrhoea, and infertility. One treatment strategy is medical therapy with gonadotrophin-releasing hormone analogues (GnRHas) to reduce pain due to endometriosis. One of the adverse effects of GnRHas is a decreased bone mineral density. In addition to assessing the effect on pain, quality of life, most troublesome symptom and patients' satisfaction, the current review also evaluated the effect on bone mineral density and risk of adverse effects in women with endometriosis who use GnRHas versus other treatment options. OBJECTIVES: To assess the effectiveness and safety of GnRH analogues (GnRHas) in the treatment of painful symptoms associated with endometriosis and to determine the effects of GnRHas on bone mineral density of women with endometriosis. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and the trial registries in May 2022 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) which compared GnRHas with other hormonal treatment options, including analgesics, danazol, intra-uterine progestogens, oral or injectable progestogens, gestrinone and also GnRHas compared with no treatment or placebo. Trials comparing GnRHas versus GnRHas in conjunction with add-back therapy (hormonal or non-hormonal) or calcium-regulation agents were also included in this review.  DATA COLLECTION AND ANALYSIS: We used standard methodology as recommended by Cochrane. Primary outcomes are relief of overall pain and the objective measurement of bone mineral density. Secondary outcomes include adverse effects, quality of life, improvement in the most troublesome symptoms and patient satisfaction.  Due to high risk of bias associated with some of the studies, primary analyses of all review outcomes were restricted to studies at low risk of selection bias. Sensitivity analysis including all studies was then performed. MAIN RESULTS: Seventy-two studies involving 7355 patients were included. The evidence was very low to low quality: the main limitations of all studies were serious risk of bias due to poor reporting of study methods, and serious imprecision.  Trials comparing GnRHas versus no treatment  We did not identify any studies. Trials comparing GnRHas versus placebo There may be a decrease in overall pain, reported as pelvic pain scores (RR 2.14; 95% CI 1.41 to 3.24, 1 RCT, n = 87, low-certainty evidence), dysmenorrhoea scores (RR 2.25; 95% CI 1.59 to 3.16, 1 RCT, n = 85, low-certainty evidence), dyspareunia scores (RR 2.21; 95% CI 1.39 to 3.54, 1 RCT, n = 59, low-certainty evidence), and pelvic tenderness scores (RR 2.28; 95% CI 1.48 to 3.50, 1 RCT, n = 85, low-certainty evidence) after three months of treatment. We are uncertain of the effect for pelvic induration, based on the results found after three months of treatment (RR 1.07; 95% CI 0.64 to 1.79, 1 RCT, n = 81, low-certainty evidence). Besides, treatment with GnRHas may be associated with a greater incidence of hot flushes at three months of treatment (RR 3.08; 95% CI 1.89 to 5.01, 1 RCT, n = 100, low-certainty evidence). Trials comparing GnRHas versus danazol For overall pain, for women treated with either GnRHas or danazol, a subdivision was made between pelvic tenderness, partly resolved and completely resolved. We are uncertain about the effect on relief of overall pain, when a subdivision was made for overall pain (MD -0.30; 95% CI -1.66 to 1.06, 1 RCT, n = 41, very low-certainty evidence), pelvic pain (MD 0.20; 95% CI -0.26 to 0.66, 1 RCT, n = 41, very low-certainty evidence), dysmenorrhoea (MD 0.10; 95% CI -0.49 to 0.69, 1 RCT, n = 41, very low-certainty evidence), dyspareunia (MD -0.20; 95% CI -0.77 to 0.37, 1 RCT, n = 41, very low-certainty evidence), pelvic induration (MD -0.10; 95% CI -0.59 to 0.39, 1 RCT, n = 41, very low-certainty evidence), and pelvic tenderness (MD -0.20; 95% CI -0.78 to 0.38, 1 RCT, n = 41, very low-certainty evidence) after three months of treatment. For pelvic pain (MD 0.50; 95% CI 0.10 to 0.90, 1 RCT, n = 41, very low-certainty evidence) and pelvic induration (MD 0.70; 95% CI 0.21 to 1.19, 1 RCT, n = 41, very low-certainty evidence), the complaints may decrease slightly after treatment with GnRHas, compared to danazol, for six months of treatment. Trials comparing GnRHas versus analgesics  We did not identify any studies. Trials comparing GnRHas versus intra-uterine progestogens We did not identify any low risk of bias studies. Trials comparing GnRHas versus GnRHas in conjunction with calcium-regulating agents There may be a slight decrease in bone mineral density (BMD) after 12 months treatment with GnRHas, compared to GnRHas in conjunction with calcium-regulating agents for anterior-posterior spine (MD -7.00; 95% CI -7.53 to -6.47, 1 RCT, n = 41, very low-certainty evidence) and lateral spine (MD -12.40; 95% CI -13.31 to -11.49, 1 RCT, n = 41, very low-certainty evidence).  AUTHORS' CONCLUSIONS: For relief of overall pain, there may be a slight decrease in favour of treatment with GnRHas compared to placebo or oral or injectable progestogens. We are uncertain about the effect when comparing GnRHas with danazol, intra-uterine progestogens or gestrinone. For BMD, there may be a slight decrease when women are treated with GnRHas, compared to gestrinone. There was a bigger decrease of BMD in favour of GnRHas, compared to GnRHas in conjunction with calcium-regulating agents. However, there may be a slight increase in adverse effects when women are treated with GnRHas, compared to placebo or gestrinone. Due to a very low to low certainty of the evidence, a wide range of outcome measures and a wide range of outcome measurement instruments, the results should be interpreted with caution.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

[Hereditary angioedema and its new treatments: An update]. / Mise au point sur les angiœdèmes héréditaires et leurs nouvelles thérapeutiques.

Hereditary angioedema, with or without deficient C1 inhibitor level or function, is a rare disease characterized by recurrent attacks of noninflammatory subcutaneous and/or submucosal edema. It may be life-threatening and substantially affects quality of life. Attacks may be spontaneous or induced, in a setting of emotional stress, by infections or physical trauma, in particular. As the key mediator is bradykinin, this angioedema does not respond to the usual treatments of mast cell-mediated angioedema (antihistamines, corticosteroids, adrenaline), which is much more frequent. Therapeutic management of hereditary angioedema first consists in treating severe attacks with a selective B2 bradykinin receptor antagonist or a C1 inhibitor concentrate. The latter or an attenuated androgen (danazol) can be used for short-term prophylaxis. Therapeutic solutions conventionally proposed for long-term prophylaxis (danazol, antifibrinolytics [tranexamic acid], C1 inhibitor concentrate) vary in efficacy and/or pose problems of safety or ease of use. Kallikrein inhibitors (subcutaneous lanadelumab, oral berotralstat) recently made available as disease-modifying treatment constitute an important advance in long-term prophylaxis of hereditary angioedema attacks. The advent of these new drugs is accompanied by a new ambition for patients: optimize control of the disease and thereby minimize its impact on quality of life.

Rare Pattern of Myelodysplastic Syndrome (MDS) with Serum Monoclonal Immunoglobulin: Case Report.

Background: Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by bone marrow dysplasia, ineffective hematopoiesis, and cytopenias. Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients have a high risk of secondary MDS or acute myeloid leukemia (AML) compared to healthy persons, and chemotherapy or transplantation may result in secondary treatment-related MDS. Methods: A patient was diagnosed with both MDS and MGUS, which was treated using thalidomide, dexamethasone, and danazol. A follow-up blood test was conducted to determine leukocyte and hemoglobin levels. Results: Immunoprotein electrophoresis showed M protein peak with IgA+ κ components. Nuclear cells proliferated actively in bone marrow aspirates. Bone marrow analysis suggested a myelodysplastic syndrome with myeloblastoma (MDS-RS) and a new plasmacytoma. The immunophenotype was shown as follows: R5 cells (red) are about 15.5%. Among the CD38+CD45 cells, about 95.9% of cKappa cells and 1.7% of cLambda cells are considered as plasmacytoma. Gene detection showed that the patient carried 14 gene mutations, and karyotype analysis showed that they had normal male chromosome structure. The patient was diagnosed as MDS and MGUS, and finally discharged after treatment with thalidomide (75 mg daily), dexamethasone (3 mg daily), and danazol (200 mg twice daily). Within 1 year, the disease has stabilized. Conclusion: The combination of plasma cell disease and myeloid malignancy may increase mortality. This is uncommon and may be easily misdiagnosed if not detected early. When a myeloid neoplasm tests positive for MDS and serum M protein, clinicians should evaluate for other plasma cell disease.

Pharmacologic Interventions to Minimize Fluid Absorption at the Time of Hysteroscopy: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess which interventions are effective in reducing fluid absorption at the time of hysteroscopy. DATA SOURCE: Ovid MEDLINE, Ovid EMBASE, PubMed (non-MEDLINE records only), EBM Reviews-Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov , and Web of Science were searched from inception to February 2022 without restriction on language or geographic origin. METHODS OF STUDY SELECTION: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, all English-language, full-text articles reporting fluid balance, with an intervention and comparator arm, were included. Title and abstract screening and full-text review were completed independently by two authors. Conflicts were resolved through discussion and consensus. Studies' risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale for observational studies. TABULATION, INTEGRATION, AND RESULTS: The search identified 906 studies, 28 of which were eligible for inclusion, examining the following interventions: gonadotropin-releasing hormone (GnRH) agonist; ulipristal acetate; vasopressin; danazol; oxytocin; and local, general, and regional anesthesia. A significant reduction in mean fluid absorption was seen in patients preoperatively treated with danazol (-175.7 mL, 95% CI -325.4 to -26.0) and a GnRH agonist (-139.68 mL, 95% CI -203.2, -76.2) compared with patients in a control group. Ulipristal acetate and type of anesthesia showed no difference. Data on type of anesthesia and vasopressin use were not amenable to meta-analysis; however, four studies favored vasopressin over control regarding fluid absorption. Mean operative time was reduced after preoperative treatment with ulipristal acetate (-7.1 min, 95% CI -11.31 to -2.9), danazol (-7.5 min, 95% CI -8.7 to -6.3), and a GnRH agonist (-3.3 min, 95% CI -5.6 to -0.98). CONCLUSION: Preoperative treatment with a GnRH agonist and danazol were both found to be effective in reducing fluid absorption and operative time across a range of hysteroscopic procedures. High-quality research aimed at evaluating other interventions, such as combined hormonal contraception, progestin therapy, and vasopressin, are still lacking in the literature. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021233804.

A combined ligand and target-based virtual screening strategy to repurpose drugs as putrescine uptake inhibitors with trypanocidal activity.

Chagas disease, also known as American trypanosomiasis, is a neglected tropical disease caused by the protozoa Trypanosoma cruzi, affecting nearly 7 million people only in the Americas. Polyamines are essential compounds for parasite growth, survival, and differentiation. However, because trypanosomatids are auxotrophic for polyamines, they must be obtained from the host by specific transporters. In this investigation, an ensemble of QSAR classifiers able to identify polyamine analogs with trypanocidal activity was developed. Then, a multi-template homology model of the dimeric polyamine transporter of T. cruzi, TcPAT12, was created with Rosetta, and then refined by enhanced sampling molecular dynamics simulations. Using representative snapshots extracted from the trajectory, a docking model able to discriminate between active and inactive compounds was developed and validated. Both models were applied in a parallel virtual screening campaign to repurpose known drugs as anti-trypanosomal compounds inhibiting polyamine transport in T. cruzi. Montelukast, Quinestrol, Danazol, and Dutasteride were selected for in vitro testing, and all of them inhibited putrescine uptake in biochemical assays, confirming the predictive ability of the computational models. Furthermore, all the confirmed hits proved to inhibit epimastigote proliferation, and Quinestrol and Danazol were able to inhibit, in the low micromolar range, the viability of trypomastigotes and the intracellular growth of amastigotes.

Evaluation of safety and effectiveness of gestrinone in the treatment of endometriosis: a systematic review and meta-analysis.

PURPOSE: Endometriosis is a common chronic gynecological disease defined as the presence of endometrial glands and stroma tissue outside the uterus. Gestrinone is an effective antiestrogen that induces endometrial atrophy and/or amenorrhea. The purpose of this systematic review is to provide an evaluation of safety and effectiveness of gestrinone for the treatment of endometriosis. METHODS: We performed a search in six electronic databases: PubMed, MEDLINE (ovid), Embase, Cochrane CENTRAL (clinical trials), Web of Science and Scopus. Our selected primary outcomes were the changes in dysmenorrhea, pain relief including pelvic pain and dyspareunia. The secondary outcomes embrace hormones parameters, pregnancy rate and adverse events. RESULTS: Of 3269 references screened, 16 studies were included involving 1286 women. All studies compared gestrinone with other drugs treatments (placebo, Danazol, Mifepristone tablets, Leuprolide acetate, Quyu Jiedu Recipe) during 6 months. When compared with other drugs treatments, gestrinone relieved dysmenorrhea, pelvic pain, and morphologic response in the ovary. There was an increase on the pregnancy rate. Regarding the side effects observed, gestrinone showed the same adverse events and increased the risk of acne and seborrhea when compared to other treatments. Even if there was any difference in efficacy between gestrinone, danazol, leuprolide acetate, or Quyu Jiedu Recipe Chinese Medicine, it remains unclear due to insufficient data. CONCLUSION: Based limited evidence available suggests that gestrinone appeared to be safe and may have some efficacy advantages over danazol, as well as other therapeutic interventions for treating endometriosis. However, this conclusion should be interpreted with caution, due the quality of the evidence provided is generally very low or unclear. TRIAL REGISTRATION: CRD42021284148.

Interventions for the long-term prevention of hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE. OBJECTIVES: To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021. SELECTION CRITERIA: We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE. AUTHORS' CONCLUSIONS: The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs.

Endometriosis: Evaluation and Treatment.

Endometriosis is an inflammatory condition caused by the presence of endometrial tissue in extra-uterine locations and can involve bowel, bladder, and all peritoneal structures. It is one of the most common gynecologic disorders, affecting up to 10% of people of reproductive age. Presentation of endometriosis can vary widely, from infertility in asymptomatic people to debilitating pelvic pain, dysmenorrhea, and period-related gastrointestinal or urinary symptoms. Diagnosis of endometriosis in the primary care setting is clinical and often challenging, frequently resulting in delayed diagnosis and treatment. Although transvaginal ultrasonography is used to evaluate endometriosis of deep pelvic sites to rule out other causes of pelvic pain, magnetic resonance imaging is preferred if deep infiltrating endometriosis is suspected. Laparoscopy with biopsy remains the definitive method for diagnosis, although several gynecologic organizations recommend empiric therapy without immediate surgical diagnosis. Combined hormonal contraceptives with or without nonsteroidal anti-inflammatory drugs are first-line options in managing symptoms and have a tolerable adverse effect profile. Second-line treatments include gonadotropin-releasing hormone (GnRH) receptor agonists with add-back therapy, GnRH receptor antagonists, and danazol. Aromatase inhibitors are reserved for severe disease. All of these treatments are effective but may cause additional adverse effects. Referral to gynecology for surgical management is indicated if empiric therapy is ineffective, immediate diagnosis and treatment are necessary, or patients desire pregnancy. Alternative treatments have limited benefit in alleviating pain symptoms but may warrant further investigation.

Ruxolitinib combined with prednisone, thalidomide and danazol in patients with myelofibrosis: Results of a pilot study.

Ruxolitinib is a safe and effective therapy of myeloproliferative neoplasm-associated (MPN) myelofibrosis. However, often there are dose reductions and/or therapy interruptions because of therapy-related adverse events (AEs), especially anemia and thrombocytopenia. We previously reported combined therapy with prednisone, thalidomide and danazol (PTD) reversed anemia and thrombocytopenia in people with MPN-associated myelofibrosis. We wondered whether adding PTD to ruxolitinib might mitigate the hematologic AEs and thereby avoid the dose reduction of ruxolitinib and improve the efficacy. To test this hypothesis, we conducted a baseline hemoglobin and platelet concentration assignment prospective observational study in 72 patients comparing 3-month dose adjustment and efficacy of ruxolitinib with (N = 53, the study group) or without (N = 19, the control group) PTD. According to the platelet counts, the median daily ruxolitinib doses in the study group increased from 30 to 40 mg by week 12, whereas in the control group it remained at 30 mg (p = 0.019). In the study group 35 patients had a hemoglobin increase ≥10 g/L compared with no patient receiving ruxolitinib only (p < 0.001). Platelet increases >100 × 10E+9/L were seen in 56.6% and 5.3% of patients in the two groups, respectively (p < 0.001). In patients with anemia and thrombocytopenia, 18 patients in the study group had an anemia response at week 12 and 12 had a platelet increase of ≥50 × 10E+9/L. No patient in the control group achieved either response (p < 0.001 and p = 0.078). The study group had a more spleen response than the control group (p = 0.046). Peripheral edema and transaminase elevation were the main nonhematologic AEs of PTD. These AEs can be alleviated by adjusting the danazol dose. In conclusion, adding PTD to ruxolitinib improved ruxolitinib-associated anemia and thrombocytopenia, and resulted in a higher ruxolitinib dose.

Danazol.

A comprehensive profile of danazol describing the nomenclatures, formulae, elemental composition, appearance, uses and applications is presented. The profile contains the method which was utilized for the preparation of the drug substance and its respective scheme is outlined. The physical characteristics of the drug including the solubility, X-ray powder diffraction pattern, differential scanning calorimetry, thermal behavior and spectroscopic studies are described. The methods which were used for the analysis of the drug substance in bulk drug and/or in pharmaceutical formulations including the compendial, spectrophotometric, electrochemical and the chromatographic methods are reported. The stability, toxicity, pharmacokinetics, bioavailability, drug evaluation and monitoring, comparisons, pharmacology, in addition to several compiled reviews on the drug substance which were involved. Finally, two hundred and seventy-nine references are listed at the end of this profile.

Gut microbiome alterations in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease with wide intra- and interindividual clinical variation. There are no reliable indicators available in clinical practice to predict the onset and severity of HAE. Uncovering the changes in the gut microbiota in HAE patients may offer insight into a missing piece of the pathogenesis and help explain the clinical heterogeneity. OBJECTIVE: Explore whether dysbiosis exists in patients with HAE and whether there are biomarkers to indicate the episodes. METHODS: Fecal samples and clinical data were collected from patients with C1-inhibitor-related HAE and their healthy family members. Patients were grouped on the basis of the most recent conditions of HAE episodes and major clinical manifestations. The gut microbiota was evaluated by sequencing the 16S ribosomal RNA gene and analyzed for diversity. RESULTS: Microbial richness and diversity were significantly reduced among patients who had recent HAE attacks, especially for those presenting with abdominal symptoms (P = .003 and P = .048 compared with healthy controls and patients with no recent episodes, respectively). Decreased Firmicutes and increased Proteobacteria were found among the individuals with a recent episode, along with a marked increase of pathogenic bacteria on the basis of the predictive functional profiling. Dysbiosis was restored after regular use of danazol or tranexamic acid. A combined biomarker composed of Bifidobacterium, Lachnospira, Paraprevotella, Desulfovibrio, and Staphylococcus was proposed to detect the recent edema episodes. CONCLUSION: We reported alterations of the gut microbiome in patients with HAE and explored the possible role of bacteria in the etiology of edema episodes, which may provide new clues for the prediction of disease course, clinical treatment, and therapeutic evaluation.