Treatment of Serious COVID-19 with Testosterone Suppression and High-dose Estrogen Therapy.
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ABSTRACT:
SUBMITTER: Coelingh Bennink HJT
PROVIDER: S-EPMC8257425 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:At present, there are no proven agents for treatment of coronavirus disease (COVID-19). The available evidence has not allowed guidelines to clearly recommend any drugs outside the context of clinical trials. The novel coronavirus SARS-CoV-2 that causes COVID-19 invokes a hyperinflammatory state driven by multiple cells and mediators like interleukin (IL)-1, IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNFα), etc. Considering the proven role of cytokine dysregulation in causing this hyperinflammation in the lungs with IL-6 being a key driver, particularly in seriously ill COVID-19 patients, it is crucial to further explore selective cytokine blockade with drugs like the IL-6 inhibitors tocilizumab, sarilumab, and siltuximab. These targeted monoclonal antibodies can dampen the downstream IL-6 signaling pathways, which can lead to decreased cell proliferation, differentiation, oxidative stress, exudation, and improve clinical outcomes in patients with evident features of cytokine-driven inflammation like persistent fever, dyspnea and elevated markers. Preliminary evidence has come for tocilizumab from some small studies, and interim analysis of a randomized controlled trial; the latter also being available for sarilumab. International guidelines do include IL-6 inhibitors as one of the options available for severe or critically ill patients. There has been increased interest in evaluating these drugs with a series of clinical trials being registered and conducted in different countries. The level of investigation though perhaps needs to be further intensified as there is a need to focus on therapeutic options that can prove to be 'life-saving' as the number of COVID-19 fatalities worldwide keeps increasing alarmingly. IL-6 inhibitors could be one such treatment option, with generation of more evidence and completion of a larger number of systematic studies.
| S-EPMC7292936 | biostudies-literature
Project description:BackgroundWomen are two times more likely to be diagnosed with depression than men. Sex hormones modulating serotonergic transmission are proposed to partly underlie these epidemiologic findings. Here, we used the cross-sex steroid hormone treatment of transsexuals seeking sex reassignment as a model to investigate acute and chronic effects of testosterone and estradiol on serotonin reuptake transporter (SERT) binding in female-to-male and male-to-female transsexuals.MethodsThirty-three transsexuals underwent [(11)C]DASB positron emission tomography before start of treatment, a subset of which underwent a second scan 4 weeks and a third scan 4 months after treatment start. SERT nondisplaceable binding potential was quantified in 12 regions of interest. Treatment effects were analyzed using linear mixed models. Changes of hormone plasma levels were correlated with changes in regional SERT nondisplaceable binding potential.ResultsOne and 4 months of androgen treatment in female-to-male transsexuals increased SERT binding in amygdala, caudate, putamen, and median raphe nucleus. SERT binding increases correlated with treatment-induced increases in testosterone levels, suggesting that testosterone increases SERT expression on the cell surface. Conversely, 4 months of antiandrogen and estrogen treatment in male-to-female transsexuals led to decreases in SERT binding in insula, anterior, and mid-cingulate cortex. Increases in estradiol levels correlated negatively with decreases in regional SERT binding, indicating a protective effect of estradiol against SERT loss.ConclusionsGiven the central role of the SERT in the treatment of depression and anxiety disorders, these findings may lead to new treatment modalities and expand our understanding of the mechanism of action of antidepressant treatment properties.
| S-EPMC4585531 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19), has caused more than 179 million infections and 3.8 million deaths worldwide. Global health authorities working on the COVID-19 outbreak continue to explore methods to reduce the rate of its transmission to healthy individuals. Treatment protocols thus far have focused on social distancing and masking, treatment with antivirals early in infection, and steroids to reduce the inflammatory response. An alternative approach is therapy with low dose radiation (LDR), which has several advantages compared to the current drugs and medicines. To date more than 10 case reports and pilot clinical trial preliminary outcome are available from different countries. These reports cover a wide range of patient conditions and LDR treatment strategies. Although one report showed the failure to observe the improvement of COVID-19 patients after LDR therapy, the majority showed some clinical improvement, and demonstrated the safety of LDR for COVID-19 patients, particularly with 0.5 Gy. This review aims to summarize the potential rationales and mechanisms of LDR therapy for COVID-19 patients, and its current clinical status and potential use.
| S-EPMC8429076 | biostudies-literature
Project description:Low-dose dexamethasone reduces mortality in patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). We retrospectively analyzed the efficacy of high-dose dexamethasone in patients with COVID-19-related ARDS and evaluated factors affecting the composite outcome (death or invasive mechanical ventilation). From March 4th to April 1st 2020, 98 patients with COVID-19 pneumonia were included. Those who after at least 7 days from symptom onset presented a worsening of the respiratory function or of inflammatory biomarkers were started on intravenous high-dose dexamethasone (20 mg daily for 5 days, followed by 10 mg daily for 5 days). Most patients were males (62%) with a mean age of 69 years. Hypertension and cardiovascular disease (CVD) were prevalent. Following dexamethasone treatment, a significant improvement in PaO2/FiO2 (277.41 [178.5-374.8] mmHg vs. 146.75 [93.62-231.16] mmHg, p < 0.001), PaO2 (88.15 [76.62-112.0] mmHg vs. 65.65 [57.07-81.22] mmHg, p < 0.001), and SpO2 (96 [95-98]% vs. 94 [90-96]%, p < 0.001) was observed. A concomitant decrease in C-reactive protein and ferritin levels was found (132.25 [82.27-186.5] mg/L vs. 7.3 [3.3-24.2] mg/L and 1169 [665-2056] ng/mL vs. 874.0 [569.5-1434] ng/mL, respectively; p < 0.001 for both vs. baseline). CVD was found to increase the risk of the composite outcome (RR 7.64, 95% CI 1.24-47.06, p = 0.028). In hospitalized patients with COVID-19-related ARDS, high-dose dexamethasone rapidly improves the clinical status and decreases inflammatory biomarkers. CVD was found to increase the risk of the composite outcome. These data support the importance of randomized clinical trials with high-dose dexamethasone in COVID-19 patients.
| S-EPMC8286167 | biostudies-literature
Project description:BackgroundThere is no effective therapy for the severe acute respiratory syndrome by coronavirus 2 (SARS-CoV2) responsible for the Coronavirus disease 2019 (Covid-19). To date, dexamethasone has shown a decrease in mortality in patients who require oxygen, especially those with invasive mechanical ventilation. However, it is unknown if another corticosteroid can be used, the optimal dose and its duration, to achieve a better clinical outcome. The objective of the study was to compare the differences in clinical outcome and laboratory results in hospitalized patients with severe SARS-CoV2 Pneumonia treated with dexamethasone at 6 mg doses versus patients treated with high-dose methylprednisolone.Materials and methodsAmbispective cohort study with survival analysis of 216 patients diagnosed with severe Covid-19 pneumonia confirmed by polymerase chain reaction for SARS-CoV2 by Berlin protocol, who were hospitalized in a high-complexity clinic in Medellín, Colombia. The patients should also have supplementary oxygen and radiological confirmation of Pneumonia by chest tomography. Sample size was not calculated since the total population that met the inclusion criteria was evaluated. 111 patients were treated with the institutional protocol with intravenous dexamethasone 6 mg QD for seven to 10 days if they required oxygen. Since September 15, 2020, the hospitalization protocol of the clinic was modified by the Infectious Diseases and Pulmonology service, recommending a high dose of methylprednisolone of 250 to 500 mg every day for three days with a subsequent change to oral prednisone 50 mg every day for 14 days. The protocol was not applied in the intensive care unit, where dexamethasone continued to be administered. The clinical outcome and differences in laboratory results of the patients who received dexamethasone vs. the prospective cohort that received methylprednisolone from September 15 to October 31, 2020, were evaluated. Follow-up was carried out by outpatient consultation one month after discharge or by telephone, inquiring about readmission or living-dead status.Results216 patients had Covid-19 pneumonia documented by ground-glass imaging and alveolar pressure / inspired oxygen fraction (PaFi) less than 300. 111 patients received dexamethasone (DXM) and 105 received methylprednisolone (MTP). Patients in the DXM group evolved to severe ARDS in a higher proportion (26.1% vs 17.1% than the MTP group). Upon completion 4 days of treatment with parenteral corticosteroid, laboratory markers of severity decreased significantly in the group that received MTP, CRP 2.85 (2.3-3.8) vs 7.2 (5.4-9.8), (p-value < 0.0001), D-dimer 691 (612-847) vs 1083 (740-1565) (p-value = 0.04) and DHL 273 (244-289) vs 355 (270.6-422) (p-value = 0.01). After starting the corticosteroid, transfer to the intensive care unit (4.8% vs. 14.4%) and mortality (9,5% vs. 17.1%) was lower in the group that received MTP. Recovery time was shorter in patients treated with MTP, three days (3-4) vs. DXM 6 days (5-8) (p-value < 0.0001). At 30-day follow-up, 88 (92.6%) were alive in MTP vs 58 (63.1%) of those who received dexamethasone.ConclusionsIn this study, the treatment of severe Covid-19 Pneumonia with high-dose methylprednisolone for three days followed by oral prednisone for 14 days, compared with 6 mg dexamethasone for 7 to 10 days, statistically significantly decreased the recovery time, the need for transfer to intensive care and the severity markers C-reactive protein (CRP), D-dimer and LDH. Randomized controlled studies with methylprednisolone are required to corroborate its effect, and studies in a population hospitalized in intensive care wards.
| S-EPMC8148307 | biostudies-literature
Project description:Abstract The coronavirus disease-2019 (COVID-19) pandemic caused by SARS-CoV-2 has exacted an enormous toll on healthcare systems worldwide. The cytokine storm that follows pulmonary infection is causally linked to respiratory compromise and mortality in the majority of patients. The sparsity of viable treatment options for this viral infection and the sequelae of pulmonary complications have fueled the quest for new therapeutic considerations. One such option, the long-forgotten idea of using low-dose radiation therapy, has recently found renewed interest in many academic centers. We outline the scientific and logistical rationale for consideration of this option and the mechanistic underpinnings of any potential therapeutic value, particularly as viewed from an immunological perspective. We also discuss the preliminary and/or published results of prospective trials examining low-dose radiation therapy for COVID-19.
| S-EPMC7717342 | biostudies-literature
Project description: Not available
| S-EPMC8261810 | biostudies-literature
Project description:Background and purposeThe objective of this work is to evaluate the risk of carcinogenesis of low dose ionizing radiation therapy (LDRT), for treatment of immune-related pneumonia following COVID-19 infection, through the estimation of effective dose and the lifetime attributable risk of cancer (LAR).Material and methodsLDRT treatment was planned in male and female computational phantoms. Equivalent doses in organs were estimated using both treatment planning system calculations and a peripheral dose model (based on ionization chamber measurements). Skin dose was estimated using radiochromic films. Later, effective dose and LAR were calculated following radiation protection procedures.ResultsEquivalent doses to organs per unit of prescription dose range from 10 mSv/cGy to 0.0051 mSv/cGy. Effective doses range from 204 mSv to 426 mSv, for prescription doses ranging from 50 cGy to 100 cGy. Total LAR for a prescription dose of 50 cGy ranges from 1.7 to 0.29% for male and from 4.9 to 0.54% for female, for ages ranging from 20 to 80 years old.ConclusionsThe organs that mainly contribute to risk are lung and breast. Risk for out-of-field organs is low, less than 0.06 cases per 10000. Female LAR is on average 2.2 times that of a male of the same age. Effective doses are of the same order of magnitude as the higher-dose interventional radiology techniques. For a 60 year-old male, LAR is 8 times that from a cardiac CT, when prescription dose is 50 cGy.
| S-EPMC7553901 | biostudies-literature
Project description:The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.
| S-EPMC8009137 | biostudies-literature
Project description: Not available
| S-BSST563 | biostudies-other