[Hereditary bradykinin angioedema. Case report]. / Angioedema hereditario por bradicinina. Reporte de Caso.

INTRODUCTION: Hereditary angioedema is an autosomal dominant genetic disease, associated with increased levels of bradykinin. It is classified into 3 types according to the C1-INH enzyme. The diagnosis is clinical and laboratory. Its treatment is divided into short- and long-term and crisis prophylaxis. CASE REPORT: 40-year-old female patient who came to the emergency service for labial edema without resolution with corticosteroids. The tests for IgE, C4 and C1 esterase inhibitors had a low result. She currently uses danazol prophylactically and fresh frozen plasma in crises. CONCLUSIONS: Since it is a disease that considerably affects the quality of life, hereditary angioedema must be diagnosed and an effective treatment plan made to prevent or reduce its complications.

INTRODUCCIÓN: El angioedema hereditario es una enfermedad genética autosómica dominante, asociada con aumento de las concentraciones de bradicinina. Se clasifica en tres tipos, de acuerdo con la enzima C1-INH. El diagnóstico se establece por las manifestaciones clínicas y los estudios de laboratorio. El tratamiento consiste profilaxis a corto y largo plazo, y protocolo para el control de las crisis. REPORTE DEL CASO: Paciente femenina de 40 años, que acudió al servicio de Urgencias por edema labial, sin reacción al tratamiento con corticosteroides. Se detectaron concentraciones bajas de IgE, C4 e inhibidores de la esterasa C1. Se estableció el diagnóstico de angioedema hereditario. Actualmente se mantiene en tratamiento profiláctico con danazol y plasma fresco congelado para el control de las crisis. CONCLUSIONES: El angioedema hereditario es una enfermedad que afecta considerablemente la calidad de vida; por tanto, debe diagnosticarse de forma oportuna y establecer un plan de tratamiento eficaz, con la intención de prevenir o reducir las complicaciones.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. FUNDING: Sierra Oncology.

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.

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.

A scalable platform to discover antimicrobials of ribosomal origin.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new antimicrobials in the face of rising antibiotic resistance. Here, we report a scalable platform that combines high-throughput bioinformatics with automated biosynthetic gene cluster refactoring for rapid evaluation of uncharacterized gene clusters. As a proof of concept, 96 RiPP gene clusters that originate from diverse bacterial phyla involving 383 biosynthetic genes are refactored in a high-throughput manner using a biological foundry with a success rate of 86%. Heterologous expression of all successfully refactored gene clusters in Escherichia coli enables the discovery of 30 compounds covering six RiPP classes: lanthipeptides, lasso peptides, graspetides, glycocins, linear azol(in)e-containing peptides, and thioamitides. A subset of the discovered lanthipeptides exhibit antibiotic activity, with one class II lanthipeptide showing low µM activity against Klebsiella pneumoniae, an ESKAPE pathogen. Overall, this work provides a robust platform for rapidly discovering RiPPs.

MPN-291 Management of PMF-Associated Anemia in Armenia. Data for the 10-Year Period Between 2010-2020.

BACKGROUND: Primary myelofibrosis (PMF) is Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, cytopenias, constitutional symptoms, hepatosplenomegaly, and extramedullary hematopoiesis. PMF-associated anemia is usually treated with androgens, danazol, erythropoiesis-stimulating agents (ESAs), immunomodulatory drugs (such as thalidomide, lenalidomide, pomalidomide), corticosteroids, and red blood cell (RBC) transfusions. AIMS: The aim of our retrospective study was to evaluate the management of PMF-associated anemia in Armenia. METHODS: The medical records of all patients diagnosed with PMF in Hematology Center in Armenia were analyzed retrospectively from 01/01/2010 to 12/31/2020. RESULTS: Between 2010-2020 the total number of patients was 238, 112 (47.1%) of which were alive by the time of data collection. Median age was 60 (28-88). Female patients were 102 (42.86%). At the time of diagnosis, 48 (42.86%) patients had anemia (Hb<12g/dL) of which 12 (10.71%) mild anemia (Hb 11-11.9g/dL); 20 (17.86%) moderate anemia (Hb 8-10.9g/dL); 16 (14.28%) severe anemia (Hb<8g/dL). Erythropoietin level was estimated only in one patient. In the majority of patients, anemia has correlated with chronic transfusions. At different stages of treatment, 23 (20.53%) patients were transfusion-dependent, 4 (3.57%) received androgens, 14 (12.5%) prednisone and 1 patient lenalidomide. Among all transfusion-dependent patients, no one has received iron chelation therapy. None of the patients underwent an allogeneic hematopoietic stem cell transplantation (HSCT) because it is not available in the Republic of Armenia. Treatment restrictions are due to financial reasons. CONCLUSIONS: Our work showed that due the significant diagnostic and therapeutic limitations in our country led to Inferior outcomes. The method of correlation of anemia in PMF patients is chronic transfusions, which also impairs the quality of life of patients.

MPN-478 MOMENTUM: Phase 3 Randomized Study of Momelotinib (MMB) versus Danazol (DAN) in Symptomatic and Anemic Myelofibrosis (MF) Patients Previously Treated With a JAK Inhibitor.

BACKGROUND: MMB, a JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity in the MF SIMPLIFY trials. The pivotal phase 3 MOMENTUM study of MF patients previously treated with a JAK inhibitor (JAKi) tested MMB vs DAN on key symptom, anemia, and splenic endpoints. METHODS: Eligibility: Primary or post- essential thrombocythemia (ET)/polycythemia vera (PV) MF; DIPSS High/Int-2/Int-1; MF symptom assessment form total symptom score (TSS) ≥10; hemoglobin <10 g/dL; prior JAKi ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 weeks or grade 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm. Stratification: TSS, palpable spleen, and RBC units transfused. JAKi taper/washout ≥21 days. RANDOMIZATION: 2:1 MMB 200 mg QD+DAN placebo or DAN 600 mg QD+MMB placebo for 24 weeks. PRIMARY ENDPOINT: TSS response (≥50% reduction from baseline) rate at week 24. Secondary endpoints, assessed sequentially at week 24: transfusion independence (TI) rate, splenic response rate (SRR; ≥25% volume reduction from baseline), TSS change from baseline, SRR (≥35% reduction) and rate of zero transfusions since baseline. RESULTS: 94/130 (72%) MMB and 38/65 (58%) DAN patients completed randomized treatment (RT). Mean baseline TSS were 28 (MMB) and 26 (DAN), hemoglobin levels were 8.1 (MMB) and 7.9 (DAN) g/dL, and median platelets were 97 (MMB) and 94 (DAN) x109/L. Baseline TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 (100%) and fedratinib in 9 (5%) patients. All primary and key secondary endpoints were met: TSS response (24.6% vs 9.2%), TI (30.8% vs 20.0%), SRR25 (40.0% vs 6.2%), TSS change (-9.36 vs -3.13), SRR35 (23.1% vs 3.1%), and zero transfusions (35.4% vs 16.9%). Most common grade ≥3 TEAEs in RT were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN patients in RT. Trend toward improved survival up to week 24 was seen with MMB vs DAN (HR=0.506, p=0.0719). CONCLUSIONS: In symptomatic and anemic MF patients, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF patients with anemia.

MPN-483 Thrombocytopenic Myelofibrosis (MF) Patients Previously Treated With a JAK Inhibitor in a Phase 3 Randomized Study of Momelotinib (MMB) versus Danazol (DAN) [MOMENTUM].

BACKGROUND: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, was evaluated (vs DAN) in a pivotal phase 3 study of MF patients previously treated with a JAK inhibitor (JAKi). This subgroup analysis evaluated MOMENTUM patients with baseline platelet counts ≤150 × 109/L. METHODS: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; total symptom score (TSS) ≥10; hemoglobin <10 g/dL; prior JAKi ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 weeks or Grade 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm; platelets ≥25 × 109/L. JAKi taper/washout ≥21 days. Randomization 2:1 to MMB 200 mg or DAN 600 mg QD (+ placebo) for 24 weeks. PRIMARY ENDPOINT: TSS response (≥50% reduction from baseline) rate at week 24. Secondary endpoints at week 24: transfusion independence (TI) rate, splenic response rate (SRR; ≥25% volume reduction from baseline), TSS change from baseline, SRR (≥35% reduction), and rate of zero transfusions since baseline. RESULTS: Mean baseline TSS: 29 MMB, 26 DAN, hemoglobin: 8.1 MMB, 7.8 DAN g/dL, and platelets: 74 × 109/L MMB, 73 × 109/L DAN. Efficacy results are consistent with the ITT analysis set for MMB vs DAN, respectively: TSS response rate (29.6% vs 11.6%), TI rate (32.1% vs 18.6%), SRR ≥25% (39.5% vs 7.0%), TSS change (-10.7 vs -3.8), SRR ≥35% (22.2% vs 4.7%), and rate of zero transfusions (30.9% vs 11.6%). Most common grade ≥3 TEAEs were thrombocytopenia (MMB, 31%; DAN, 16%) and anemia (MMB, 7%; DAN, 14%); grade ≥3 bleeding events: 9% MMB, 5% DAN. TEAEs leading to study drug discontinuation: 15% MMB, 19% DAN. A trend toward improved overall survival up to week 24 was seen with MMB vs DAN [HR (95% CI)=0.490 (0.195, 1.235)]. Analyses of patients with baseline platelets <100 × 109/L (N=100) and baseline platelets <50 × 109/L (N=31) show similar efficacy, safety, and survival profiles for MMB vs DAN. CONCLUSIONS: In symptomatic, anemic, and thrombocytopenic MF patients, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need in thrombocytopenic MF patients. NCT04173494.

The biology and management of dyskeratosis congenita and related disorders of telomeres.

BACKGROUND: Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders. WHAT IS COVERED: Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future. EXPERT VIEW: As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.

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.

Retrospective review of secondary prevention strategies for gastrointestinal bleeding and associated clinical outcomes in left ventricular assist device patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is one of the most common bleeding complications associated with left ventricular assist devices (LVAD). Currently, there is no strong evidence or clear guidance for which secondary GIB prophylaxis strategy should be implemented after the discontinuation of aspirin. METHODS: Our single-center study describes the outcomes of 26 LVAD patients who experienced a total of 49 GIB events: these individuals were either in Group-1 (lower INR target range) or Group-2 (lower INR target plus a hemostatic agent) as the secondary prophylaxis strategy. Each GIB event was considered an independent event. Outcomes assessed were bleeding reoccurrence rates, time to next GIB, acute GIB strategies, GIB-free days, thromboembolic events, survival, coagulation, and hematologic parameters. RESULTS: GIB reoccurrence rates were not statistically different: Group-1, 9 (40.9%), versus Group-2, 15 (55.6%); p = 0.308. Danazol was utilized 81.5% of the time as the designated hemostatic agent. Additionally, no significant differences were observed with all of our secondary outcome measures for bleeding, ischemic events, or survival. CONCLUSION: While our study was not powered to assess the clinical outcomes related to survival and thromboembolic events, no discernable increased risk for ischemic events including pump thrombosis were observed. Our data suggest that a lower INR target range plus danazol does not confer any additional benefit over a lower INR target range only approach. The results of this report are hypothesis-generating and additional studies are warranted to elucidate the optimal antithrombotic strategy and role of hemostatic agents in reducing the risk of recurrent GIB events.

3D-QSAR and scaffold hopping based designing of benzo[d]ox-azol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2(3H)-one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation.

Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)-approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations to form an active metabolite, aldophosphamide, which further biotransforms to its putative cytotoxic metabolite, phosphoramide mustard. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite, carboxyphosphamide, via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of benzo[d]oxazol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2(3H)-one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D-quantitative structure activity relationship (3D-QSAR) model coupled with scaffold hopping. The 3D-QSAR model was developed using reported indole-2,3-diones based ALDH1A1 inhibitors, which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The most selective indole-2,3-diones-based compound, that is, cmp 3, was further considered for scaffold hopping. Two top-ranked bioisosteres, that is, benzo[d]oxazol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2(3H)-one, were selected for designing new inhibitors by considering the field pattern of 3D-QSAR. All designed molecules were mapped perfectly on the 3D-QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5-6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D-QSAR result. The top five inhibitor-ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective toward ALDH1A1 over the other two isoforms, that is, ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective toward ALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02-0.80 µM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

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.

Effects of ranibizumab and zoledronic acid on endometriosis in a rat model.

PURPOSE: To investigate the histological efficacy of ranibizumab and zoledronic acid in an experimentally induced endometriosis model as compared with danazol, buserelin acetate and dienogest. METHODS: Endometrial implants were introduced in 52 female Wistar albino rats, which were then randomly divided into six groups. The animals were, respectively, given dienogest, danazol, buserelin acetate, zoledronic acid, ranibizumab and 0.9% NaCl. After 4 weeks, the volumes and histopathological properties of the implants were evaluated and the implants were excised completely at the third laparotomy. A histopathological scoring system was used to evaluate the preservation of epithelia. Endometrial explants were evaluated immunohistochemically. RESULTS: Among the groups, the histological score was significantly lower in the zoledronic acid and ranibizumab groups compared with the controls (p < 0.001). There were no significant differences regarding ellipsoidal volume levels between groups (p > 0.05). However, there was a statistically significant difference regarding cell numbers according to the degree of Bcl-2, NF-κB, and CD31 staining (p < 0.001). There was no statistically significant difference in Bcl-2, CD31, or NF-κB staining in the binary comparisons between the other groups (p > 0.05). For Bcl-2 staining, the staining rate of the group treated with zoledronic acid was significantly lower compared with the dienogest and danazol groups (p < 0.05). The staining rates of CD31 and NF-κB were significantly lower in the zoledronic acid and ranibizumab groups compared with the controls (p < 0.05). CONCLUSION: According to these results, zoledronic acid and ranibizumab may be putative candidates for the treatment of endometriosis.