Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects

Article

作者: Cadegiani, Flavio A ; Baldi, Fernando ; Chamie, Juan J ; Kory, Pierre ; Proença, Fernando Carlos ; Kerr, Lucy ; Lobo, Raysildo ; Hibberd, Jennifer A ; Assagra, Washington Luiz

Background We have previously demonstrated that ivermectin used as prophylaxis for coronavirus disease 2019 (COVID-19), irrespective of the regularity, in a strictly controlled citywide program in Southern Brazil (Itajaí, Brazil), was associated with reductions in COVID-19 infection, hospitalization, and mortality rates. In this study, our objective was to determine if the regular use of ivermectin impacted the level of protection from COVID-19 and related outcomes, reinforcing the efficacy of ivermectin through the demonstration of a dose-response effect. Methods This exploratory analysis of a prospective observational study involved a program that used ivermectin at a dose of 0.2 mg/kg/day for two consecutive days, every 15 days, for 150 days. Regularity definitions were as follows: regular users had 180 mg or more of ivermectin and irregular users had up to 60 mg, in total, throughout the program. Comparisons were made between non-users (subjects who did not use ivermectin), and regular and irregular users after multivariate adjustments. The full city database was used to calculate and compare COVID-19 infection and the risk of dying from COVID-19. The COVID-19 database was used and propensity score matching (PSM) was employed for hospitalization and mortality rates. Results Among 223,128 subjects from the city of Itajaí, 159,560 were 18 years old or up and were not infected by COVID-19 until July 7, 2020, from which 45,716 (28.7%) did not use and 113,844 (71.3%) used ivermectin. Among ivermectin users, 33,971 (29.8%) used irregularly (up to 60 mg) and 8,325 (7.3%) used regularly (more than 180 mg). The remaining 71,548 participants were not included in the analysis. COVID-19 infection rate was 49% lower for regular users (3.40%) than non-users (6.64%) (risk rate (RR): 0.51; 95% CI: 0.45-0.58; p < 0.0001), and 25% lower than irregular users (4.54%) (RR: 0.75; 95% CI: 0.66-0.85; p < 0.0001). The infection rate was 32% lower for irregular users than non-users (RR: 0.68; 95% CI: 0.64-0.73; p < 0.0001). Among COVID-19 participants, regularusers were older and had a higher prevalence of type 2 diabetes and hypertension than irregular and non-users. After PSM, the matched analysis contained 283 subjects in each group of non-users and regular users, between regular users and irregular users, and 1,542 subjects between non-users and irregular users. The hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p < 0.0001), and by 29% among irregular users compared to non-users (RR: 0.781; 95% CI: 0.49-1.05; p = 0.099). Mortality rate was 92% lower in regular users than non-users (RR: 0.08; 95% CI: 0.02-0.35; p = 0.0008) and 84% lower than irregular users (RR: 0.16; 95% CI: 0.04-0.71; p = 0.016), while irregular users had a 37% lower mortality rate reduction than non-users (RR: 0.67; 95% CI: 0.40-0.99; p = 0.049). Risk of dying from COVID-19 was 86% lower among regular users than non-users (RR: 0.14; 95% CI: 0.03-0.57; p = 0.006), and 72% lower than irregular users (RR: 0.28; 95% CI: 0.07-1.18; p = 0.083), while irregular users had a 51% reduction compared to non-users (RR: 0.49; 95% CI: 0.32-0.76; p = 0.001). Conclusion Non-use of ivermectin was associated with a 12.5-fold increase in mortality rate and a seven-fold increased risk of dying from COVID-19 compared to the regular use of ivermectin. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.

2022-08-11·Cureus

Catecholamines Are the Key Trigger of COVID-19 mRNA Vaccine-Induced Myocarditis: A Compelling Hypothesis Supported by Epidemiological, Anatomopathological, Molecular, and Physiological Findings

Review

作者: Cadegiani, Flavio A

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced myocarditis is a rare but well-documented complication in young males. The increased incidence of sudden death among athletes following vaccination has been reported and requires further investigation. Whether the risk of myocarditis, a known major cause of sudden death in young male athletes, also increases after coronavirus disease 2019 (COVID-19) infection is unknown. The severity and implications of these critical adverse effects require a thorough analysis to elucidate their key triggering mechanisms. The present review aimed to evaluate whether there is a justification to hypothesize that catecholamines in a "hypercatecholaminergic" state are the key trigger of SARS-CoV-2 mRNA vaccine-induced myocarditis and related outcomes and whether similar risks are also present following COVID-19 infection. A thorough, structured scoping review of the literature was performed to build the hypothesis through three pillars: detection of myocarditis risk, potential alterations and abnormalities identified after SARS-CoV-2 mRNA vaccination or COVID-19 infection and consequent events, and physiological characteristics of the most affected population. The following terms were searched in indexed and non-indexed peer review articles and recent preprints (<12 months): agent, "SARS-CoV-2" or "COVID-19"; event, "myocarditis" or "sudden death(s)" or "myocarditis+sudden death(s)" or "cardiac event(s)"; underlying cause, "mRNA" or "spike protein" or "infection" or "vaccine"; proposed trigger, "catecholamine(s)" or "adrenaline" or "epinephrine" or "noradrenaline" or "norepinephrine" or "testosterone"; and affected population, "young male(s)" or "athlete(s)." The rationale and data that supported the hypothesis were as follows: SARS-CoV-2 mRNA vaccine-induced myocarditis primarily affected young males, while the risk was not observed following COVID-19 infection; independent autopsies or biopsies of patients who presented post-SARS-CoV-2 mRNA vaccine myocarditis in different geographical regions enabled the conclusion that a primary hypercatecholaminergic state was the key trigger of these events; SARS-CoV-2 mRNA was densely present, and SARS-CoV-2 spike protein was progressively produced in adrenal medulla chromaffin cells, which are responsible for catecholamine production; the dihydroxyphenylalanine decarboxylase enzyme that converts dopamine into noradrenaline was overexpressed in the presence of SARS-CoV-2 mRNA, leading to enhanced noradrenaline activity; catecholamine responses were physiologically higher in young adults and males than in other populations; catecholamine responses and resting catecholamine production were higher in male athletes than in non-athletes; catecholamine responses to stress and its sensitivity were enhanced in the presence of androgens; and catecholamine expressions in young male athletes were already high at baseline, were higher following vaccination, and were higher than those in non-vaccinated athletes. The epidemiological, autopsy, molecular, and physiological findings unanimously and strongly suggest that a hypercatecholaminergic state is the critical trigger of the rare cases of myocarditis due to components from SARS-CoV-2, potentially increasing sudden deaths among elite male athletes.

2022-08-01·Clinical Therapeutics

Nonpharmacological Interventions for the Management of Testosterone and Sperm Parameters: A Scoping Review

Review

作者: Forbes, Scott C ; Santos, Heitor O ; Cadegiani, Flávio A

PURPOSETestosterone replacement and associated pharmacologic agents are effective strategies to treat male hypogonadism; however, nutraceutical agents and lifestyle modification approaches have gained medical interest. The purpose of this scoping review is to highlight the evidence (or lack thereof) of nutraceuticals and lifestyle modification approaches in the management of testosterone levels and sperm parameters.METHODSA scoping review of nonpharmacologic interventions (supplements, herbal medicines, diets, sleep, and exercise) with the potential to improve male health was undertaken to elucidate changes in testosterone levels and sperm parameters in men with hypogonadism or infertility compared with healthy patients.FINDINGSA multitude of nutraceuticals and functional nutrients are purported to stimulate testosterone production; however, only a select few have had promising results, such as zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha, based on well-controlled randomized clinical trials of men with low testosterone levels and related problems. Except for l-arginine, these natural agents, as well as tribulus and ω3 fatty acids, can improve some degree of sperm parameters in infertile men. Before implementing these nutraceutical agents, adequate sleep, exercise, and weight loss in patients with obesity are imperative. The effects of nonpharmacologic interventions on testosterone levels are modest and hence do not directly translate into clinical benefits. Correspondingly, androgen receptor content, but not endogenous androgens, has been regarded as the principal factor in muscle hypertrophy.IMPLICATIONSA limited number of supplements and herbal medicines can be considered as adjunctive approaches in the management of testosterone levels and sperm parameters, primarily in men with low testosterone levels and infertility, whereas most nonpharmacologic supplements appear to lack evidence. Although proper physical exercise, sleep, and diet are indisputable approaches because of the general benefits to health, the use of nutraceuticals, if considered, must be personalized by physicians and/or registered dietitians.

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