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Attenuated androgen discontinuation in patients with hereditary angioedema: a commented case series.Allergy, Asthma, and Clinical... Jan 2022Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including...
BACKGROUND
Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including attenuated androgens. Efficacy of attenuated androgens has not been assessed in large, randomized, placebo-controlled trials and can be associated with frequent, and sometimes severe, side effects. As better tolerated targeted therapies become available, attenuated androgen withdrawal is increasingly considered by physicians and their patients with HAE. Attenuated androgens withdrawal has not been systematically studied in HAE, although examination of other disorders indicates that attenuated androgen withdrawal may result in mood disturbances and flu-like symptoms. Standardized protocols for attenuated androgen discontinuation that continue to provide control of attacks while limiting potential attenuated androgen withdrawal symptoms are not established as the outcomes of different withdrawal strategies have not been compared. We aim to describe the challenges of attenuated androgen discontinuation in patients with HAE and how these may continue into the post-androgen period.
CASE PRESENTATION
We present a retrospective case series of 10 patients with confirmed type I HAE who have discontinued prophylactic treatment with attenuated androgens. The most common reason for attenuated androgen discontinuation was side effects. Attenuated androgens were either immediately withdrawn, tapered and/or overlapped with another treatment. The major challenge of discontinuation was the management of an increased frequency and severity of HAE attacks in some patients.
CONCLUSIONS
Healthcare teams need to undertake careful planning and monitoring after attenuated androgens discontinuation, and modify treatment strategies if HAE control is destabilized with an increased number of attacks. Discontinuation of attenuated androgens is definitively an option in an evolving HAE treatment landscape, and outcomes can be favourable with additional patient support and education.
PubMed: 35027083
DOI: 10.1186/s13223-021-00644-0 -
Plants (Basel, Switzerland) Dec 2021and have historically been used for the treatment of precocious puberty (PP) in oriental medicine. Our study aimed to evaluate the effect of APE, a mixture of the...
and have historically been used for the treatment of precocious puberty (PP) in oriental medicine. Our study aimed to evaluate the effect of APE, a mixture of the extracts from these herbs, against danazol-induced PP in female rats. The offspring were injected danazol to establish the PP model, and then treated with APE daily, and observed for vaginal opening. At the end of the study, the levels of gonadotropic hormones, such as estradiol, follicle-stimulating hormone, and luteinizing hormone, were determined by ELISA. Moreover, the mRNA expression of GnRH, netrin-1, and UNC5C in hypothalamic tissues was determined by real-time PCR. Network pharmacological analysis was performed to predict the active compounds of APE and their potential actions. APE treatment delayed vaginal opening in rats with PP. In addition, APE treatment reduced LH levels and suppressed UNC5C expression. Gene set enrichment analysis revealed that the targets of APE were significantly associated with GnRH signaling and ovarian steroidogenesis pathways. In conclusion, APE may be used as a therapeutic remedy to inhibit the activation of the hypothalamic-pituitary-gonadal axis.
PubMed: 35009026
DOI: 10.3390/plants11010023 -
Anesthesia and Pain Medicine Apr 2022Hereditary angioedema (HAE) is an autosomal dominant disorder. The characteristic of HAE is recurrent angioedema episodes due to low C1 esterase inhibitor (C1-INH)...
BACKGROUND
Hereditary angioedema (HAE) is an autosomal dominant disorder. The characteristic of HAE is recurrent angioedema episodes due to low C1 esterase inhibitor (C1-INH) level. HAE symptoms, especially those affecting oropharynx or larynx may develop respiratory distress syndrome due to impaired airway, which can be potentially fatal.
CASE
We report a clinical case of a 57 year-old woman, with type I HAE, scheduled for total laparoscopic hysterectomy under general endotracheal anesthesia, which was done successfully without inducing airway edema. Danazol, which increases liver synthesis of C1-INH, was administered and fresh frozen plasma (FFP), which contained C1-INH, was transfused after induction.
CONCLUSIONS
For HAE patients, the greatest concern is that general anesthesia can induces upper airway edema by direct mucosal irritation by the endotracheal tube. The perioperative management should include both prophylactic increase of C1-INH production and on-demand administration of C1-INH or FFP.
PubMed: 34991189
DOI: 10.17085/apm.21088 -
Cureus Nov 2021Hereditary angioedema is an autosomal dominant genetic disease that causes tissue edema mediated by bradykinin. The angioedema attacks have several triggers including...
Hereditary angioedema is an autosomal dominant genetic disease that causes tissue edema mediated by bradykinin. The angioedema attacks have several triggers including stress, trauma, infection, and increased estrogens levels. This explains the greater incidence and clinical severity in women, which are usually asymptomatic until puberty, when the attacks begin to occur. It may involve multiple locations on the body, leading to complications, such as surgical intervention prompt by severe acute abdominal pain, and laryngeal edema that can culminate in death from asphyxia. This is of particular concern as this angioedema does not respond to life-saving medications commonly used in its treatment, namely, high doses of second-generation antihistamines, corticosteroids, and epinephrine. Hereditary angioedema attacks are treated with specific medication that includes icatibant, ecallantide, and C1 inhibitor, the latter being also used in short-term and long-term prophylaxis. There are other pharmacological strategies for long-term prophylaxis like lanadelumab, danazol, stanozolol, aminocaproic acid, and tranexamic acid. During pregnancy and lactation, the preferred treatment and prophylaxis is C1 inhibitor. We report a case of hereditary angioedema describing its chronological evolution over a period of a woman's life, and highlighting some of the specificities of this pathology that intersect with the specialty of Obstetrics and Gynecology. Our aim is to draw attention to these particularities, namely the triggering factors of crisis, the need for high suspicion of the diagnosis, and the treatment and prophylaxis options for pregnant and non-pregnant women that can make the difference between life and death. To achieve a favorable outcome, the multidisciplinary teamwork between the specialties of Immunoallergology and Obstetrics and Gynecology was crucial.
PubMed: 34976488
DOI: 10.7759/cureus.19861 -
Evidence-based Complementary and... 2021The management of adenomyosis is challenging and limiting. Qiu's Neiyi recipe (Qiu) is a traditional Chinese medicine (TCM) prescription clinically used for...
BACKGROUND
The management of adenomyosis is challenging and limiting. Qiu's Neiyi recipe (Qiu) is a traditional Chinese medicine (TCM) prescription clinically used for endometriosis treatment in China, but the effect and mechanism of Qiu on adenomyosis are undefined.
METHODS
An experimental adenomyosis model was induced in female neonatal ICR mice administrated with tamoxifen. The adenomyosis mice were divided into five groups: high-, middle-, and low-Qiu's group, danazol group, and model group. The mice just administrated with the solvent only (no tamoxifen or drugs) were served as the control group. After 28 days of administration, the body, uterine, spleen, and thymus weights of all mice were examined. Then, the myometrial infiltration and the expression of inflammatory factors were detected by histology examination, ELISA, and qRT-PCR in the uterus. In addition, the MAPK/ERK signaling pathway-related protein expression in adenomyosis mice was detected by immunohistochemical (IHC) staining, qRT-PCR, and western blotting.
RESULTS
In experimental adenomyosis mice, Qiu treatment improved the symptoms of adenomyosis by reducing the myometrial infiltration and increasing the index of spleen and thymus. The elevated levels of IL-1, IL-6, and TNF- in serum and uterus tissues of adenomyosis model mice were also decreased after Qiu treatment. The improvement of Qiu on the adenomyosis was achieved by inhibiting the activated MAPK/ERK signaling pathway, including reducing the mRNA and protein expressions of p-ERK/ERK, p-JNK/JNK, and p-p38/38 in the uterus tissues.
CONCLUSION
Qiu alleviated the inflammatory reaction and uterus histological changes in mice with adenomyosis, and the potential mechanism is through the inhibition of the MAPK/ERK signaling pathway. Qiu may be a promising treatment for adenomyosis.
PubMed: 34931128
DOI: 10.1155/2021/9791498 -
Oxford Medical Case Reports Nov 2021Dyskeratosis congenita (DC) is an inherited disease characterized by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Non-cutaneous...
Dyskeratosis congenita (DC) is an inherited disease characterized by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Non-cutaneous abnormalities (dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal) have also been reported. Bone marrow failure (BMF) is the main cause of early mortality, with an additional predisposition to malignancy. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. Men are more affected than women are and X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. There are no targeted therapies for DC. Patients treated with androgens had a hematological response. We herein describe case of a 32-year-old man, presented with several characteristic systemic features of this condition, including the classic triad of lesions, dysplastic bone marrow, epiphora and liver cirrhosis with grade I esophageal varices. Therefore, a prophylactic propranolol was started in additional to danazol. Three-week later, the patient had subsequent increases in his platelet, red cell and white cell counts.
PubMed: 34858620
DOI: 10.1093/omcr/omab041 -
BMJ Open Respiratory Research Dec 2021Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening.
METHODS AND ANALYSIS
A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population.
ETHICS AND DISSEMINATION
Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences.
TRIAL REGISTRATION NUMBERS
NCT04638517; Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).
Topics: Australia; COVID-19; Child; Danazol; Humans; Pulmonary Fibrosis; Telomere; Treatment Outcome
PubMed: 34857525
DOI: 10.1136/bmjresp-2021-001127 -
Pharmaceutics Oct 2021Gene therapy is a powerful tool for the development of new treatment strategies for various conditions, by aiming to transport biologically active nucleic acids into...
Gene therapy is a powerful tool for the development of new treatment strategies for various conditions, by aiming to transport biologically active nucleic acids into diseased cells. To achieve that goal, we used highly potential delivery vectors, cell-penetrating peptides (CPPs), as oligonucleotide carriers for the development of a therapeutic approach for endometriosis and cancer. Despite marked differences, both of these conditions still exhibit similarities, like excessive, uncoordinated, and autonomous cellular proliferation and invasion, accompanied by overlapping gene expression patterns. Thus, in the current study, we investigated the therapeutic effects of CPP and siRNA nanoparticles using in vitro models of benign endometriosis and malignant glioblastoma. We demonstrated that CPPs PepFect6 and NickFect70 are highly effective in transfecting cell lines, primary cell cultures, and three-dimensional spheroids. CPP nanoparticles are capable of inducing siRNA-specific knockdown of therapeutic genes, ribonucleotide reductase subunit M2 (RRM2), and vascular endothelial growth factor (VEGF), which results in the reduction of in vitro cellular proliferation, invasion, and migration. In addition, we proved that it is possible to achieve synergistic suppression of endometriosis cellular proliferation and invasion by combining gene therapy and hormonal treatment approaches by co-administering CPP/siRNA nanoparticles together with the endometriosis-drug danazol. We suggest a novel target, RRM2, for endometriosis therapy and as a proof-of-concept, we propose a CPP-mediated gene therapy approach for endometriosis and cancer.
PubMed: 34683911
DOI: 10.3390/pharmaceutics13101618 -
Clinical and Experimental Immunology Dec 2021Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be...
Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is rare and is associated with underlying lymphoproliferative diseases. C1-INH deficiency may be due to neoplastic over-consumption of C1-INH and the generation of anti-C1-INH autoantibodies. Uncovering an occult malignancy can lead to earlier oncology referral and improvement of angioedema after treatment of the underlying lymphoproliferative disorder. We characterized seven patients with C1-INH-AAE that highlights the importance of recognizing the association between C1-INH-AAE and underlying malignancy. In acute attacks, patients may be resistant to C1-INH therapy due to the presence of anti-C1-INH autoantibodies or rapid complement consumption, and may respond better to icatibant or ecallantide, which directly affect bradykinin. Treatment of the underlying malignancy also improves AAE-C1-INH symptoms and supports the role of lymphoproliferative B cells in AAE-C1-INH pathophysiology. Monitoring levels of C4, C1-INH function and level, and C1q may be predictive of AAE-C1-INH control and be used as surrogates for treatment efficacy. With close monitoring, low-dose danazol can be effective for long-term prophylaxis. Annual evaluation in AAE-C1-INH is recommended if an underlying malignancy is not found, as angioedema may precede the development of malignancy by several years. Our single-center study has aided in standardization of comprehensive AAE-C1-INH diagnosis, treatment, and monitoring strategies towards future therapeutic clinical trials.
Topics: Aged; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Autoantibodies; Bradykinin; Bradykinin B2 Receptor Antagonists; Complement C1 Inhibitor Protein; Complement C1q; Female; Hereditary Angioedema Types I and II; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Peptides; Retrospective Studies
PubMed: 34586637
DOI: 10.1111/cei.13667 -
BMC Pulmonary Medicine Sep 2021Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported.
BACKGROUND
Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported.
CASE PRESENTATION
A 23-year-old student presented with a four-year history of progressive cough and exertional dyspnea. Physical examination was remarkable for typical mucocutaneous abnormalities. Chest computerized tomography scan revealed interstitial fibrosis. Testing of peripheral blood leukocytes confirmed that his telomeres were 30th percentile of age-matched controls. A heterozygous missense mutation located in exon 22 of PARN gene was identified in the patient by whole exome sequencing. The patient refused danazol therapy and lung transplantation, and died of respiratory failure 2 years later. In addition, this case and 26 reported cases of DC-related PF identified through the comprehensive search of PubMed, Web of Science, WANFANG and CNKI were reviewed. Later-onset PF was observed in 11 patients (40.7%). Radiological usual interstitial pneumonia (UIP) pattern or possible UIP pattern was noted only in half of patients. However, histopathological UIP or probable UIP patterns were found in 63.6% of patients. Age at bone marrow failure (BMF) and the frequency of normal to mild thrombocytopenia in later-onset patients was significantly higher than in early-onset patients (p = 0.017 and p = 0.021, respectively). Age at PF and age at BMF in DC patients with TERC/TERT variants was significantly higher than in those with TINF2 variants or DKC1/NHP2 variants (p = 0.004 and p = 0.003, respectively). The patients with TERT/TERC/RTEL1/PARN variants had a significantly better transplant-free survival than those with TINF2 variants or DKC1/NHP2 variants (p < 0.05). Patients who underwent surgical lung biopsy had significantly worse transplant-free survival than those without lung biopsy (p = 0.042). Worse survival was found in patients with immunosuppression therapy than in those without (p = 0.012).
CONCLUSIONS
It is common for DC-associated PF to occur later in life without significant hematological manifestations. Mutations in the genes encoding different components of the telomere maintenance pathway were associated with clinical phenotypes and prognosis. PF caused by DC should be kept in mind by clinicians in the differential diagnosis of patients with unexplained PF and should be excluded before diagnostic surgical lung biopsy is undertaken or empirical immunosuppression therapy is prescribed.
Topics: Cell Cycle Proteins; DNA Helicases; Dyskeratosis Congenita; Fatal Outcome; Humans; Idiopathic Pulmonary Fibrosis; Male; Nuclear Proteins; Telomere-Binding Proteins; Young Adult
PubMed: 34479523
DOI: 10.1186/s12890-021-01645-w