COVID-19: When Something is Better Than Nothing
July 02, 2021
Multidrug therapy for early COVID-19
(Accepted paper. In press.)
THERAPY WITH AZITHROMYCIN PLUS NITAZOXANIDE, IVERMECTIN OR HYDROXYCHLOROQUINE IN OUTPATIENT SETTINGS SIGNIFICANTLY REDUCED SYMPTOMS COMPARED TO KNOWN OUTCOMES IN UNTREATED PATIENTS.
The pathophysiology of COVID-19 is highly complex due to the inherent actions of SARS-CoV-2, and has multiple mechanisms of action that should be blocked. With HIV and hepatitis B and C only cocktail of drugs work, why this would be different here?
It is expected that targeting only one mechanism will unlikely provide sufficient protection to become effective. However, studies insist on testing a single molecule.
Unlike when using a sole drug, for which the discussion regarding the efficacy remains, combination between two to four drugs, almost regardless of which combination when certain drugs are considered, demonstrated to be much superior to placebo – and we’re not talking about 10 patients, but more than 700 patients instead. To us, the difference in terms of efficacy is sufficient to raise ethical questions about the use of full placebo in future trials on COVID-19. Our data and rationale were accepted and is about to be published in a high impact journal.
Link in New Microbes New Infections soon.
Flavio A. Cadegiani, Andy Goren, Carlos G. Wambier, John McCoyEarly COVID-19 Therapy with Azithromycin Plus Nitazoxanide, Ivermectin or Hydroxychloroquine in Outpatient Settings Significantly Reduced Symptoms Compared to Known Outcomes in Untreated Patients. medRxiv 2020.10.31.20223883; doi:https://doi.org/10.1101/2020.10.31.20223883
In a prospective observational study (pre-AndroCoV Trial), the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated unexpected improvements in COVID-19 outcomes, when compared to untreated patients. The apparent yet likely positive results raised ethical concerns on the employment of further full placebo84 controlled studies in early stage COVID-19. The present analysis aimed to elucidate whether full placebo-control randomized clinical trials (RCTs) on early-stage COVID-19 are still ethically acceptable, through a comparative analysis with two control87 groups. Active group (AG) consisted of patients enrolled in the Pre AndroCoV-Trial (n= 585). Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients of the same population (n = 137), and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes based on a thorough and structured review of indexed articles and official statements. Patients were matched for sex, age, comorbidities and disease severity at baseline. Compared to CG1 and CG2, AG showed reduction of 31.5-36.5% in viral shedding (p < 0.0001), 70-85% in disease duration (p < 0.0001), and 100% in respiratory complications, hospitalization, mechanical ventilations, and deaths (p < 0.0001 for all). For every 1,000 confirmed cases for COVID-19, at least 70 hospitalizations, 50 mechanical ventilations and five deaths were prevented. Benefits from the combination of early COVID-19 detection and early pharmacological approaches were consistent and overwhelming when compared to untreated groups, which, together with and well-established safety profile of the drug combinations tested in the Pre-AndroCoV Trial, precluded our study to continue employing full placebo in early COVID-19.
A Prostate Cancer Drug that can Prevent COVID-19 Hospitalization
July 02, 2021
Proxalutamide and early COVID-19
PROXALUTAMIDE, A NON-STEROIDAL ANTIANDROGEN TESTED FOR PROSTATE AND BREAST CANCER, REDUCED HOSPITALIZATIONS IN MALE COVID-19 PATIENTS
In the study with proxalutamide in outpatients, we observed that the drug was able to reduce inflammatory and thromboembolic markers without the need of glucocorticoids and anticoagulants, respectively. This fact called our attention to the possibility that proxalutamide could also work in later stages of COVID-19, particularly in hospitalized patients.
Goren A, Cadegiani FA, et al. Proxalutamide Reduces the Rate of Hospitalization for COVID-19 Male Outpatients: A Randomized Double-Blind Placebo-Controlled Trial. Front Med. 2021 Jun 11. doi: 10.3389/fmed.2021.668698
Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (ClinicalTrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale <3) were administered proxalutamide 200 mg/day or placebo for up to 7 days. The primary endpoint was hospitalization rate at 30 days post-randomization.
A total of 268 men were randomized in a 1:1 ratio. 134 patients receiving proxalutamide and 134 receiving placebo were included in the intention-to-treat analysis. The 30-day hospitalization rate was 2.2% in men taking proxalutamide compared to 26% in placebo, P<0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03 to 0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost during follow-up, and 2 patients died from acute respiratory distress syndrome. Here we demonstrate the hospitalization rate in proxalutamide treated men was reduced
A Prostate Cancer Drug for Early COVID-19
July 02, 2021
A strong antiandrogen to clear the COVID-19 virus (SARS-CoV-2)
PROXALUTAMIDE WAS ABLE TO ACCELERATE THE VIRAL CLEARANCE AND TIME-TO-RECOVERY IN COVID-19.
The paper published in Cureus by our research team is a preliminary report of the randomized clinical trial (RCT) we conducted with patients infected by COVID-19 during the first 07 days of symptoms, still mild, aiming to prevent the progression of the disease, deaths, and long-term COVID-19 consequences.
The present paper is a sub-analysis of the RCT containing only those that were able to perform rtPCRs (exams to detect the SARS-CoV-2 virus directly, or its fragments) before the treatment and after 07 days of treatment, and to correlate with clinical improvement.
Subjects that took proxalutamide presented a faster clinical recovery and more than double the chance of presenting a negative rtPCR test on day 07, compared to placebo.
Cadegiani FA, McCoy J, Gustavo Wambier C, Vaño-Galván S, Shapiro J, Tosti A, Zimerman RA, Goren A. Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial. Cureus. 2021 Feb 22;13(2):e13492. doi: 10.7759/cureus.13492. PMID: 33633920; PMCID: PMC7899267.
The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into type II pneumocytes is dependent on a modification of viral spike proteins by transmembrane protease serine 2 (TMPRSS2) expressed on the surface of human cells. TMPRSS2 is regulated by the androgen receptor, hence, SARS-CoV-2 infectivity is indirectly dependent on androgenic status and phenotype. Previously, we have reported that men affected by androgenetic alopecia (AGA) are overrepresented in severe coronavirus disease 2019 (COVID-19). Additionally, we have reported that men taking antiandrogenic drugs, e.g., 5-alpha-reductase inhibitors (5ARis), are less likely to have severe COVID-19. Here we aimed to test whether the androgen receptor antagonist, Proxalutamide, would be a beneficial treatment for subjects with SARS-CoV-2 infection.
Male and female subjects were recruited to a double-blinded, randomized, prospective, investigational study of Proxalutamide for the treatment of COVID-19. Mild to moderate, non-hospitalized subjects, who were confirmed positive for SARS-CoV-2, were treated with either Proxalutamide 200 mg/day or placebo. Endpoints for the study were remission time (days) and the percentage of subjects confirmed negative for SARS-CoV-2 on Day 7 after treatment. A negative SARS-CoV-2 test was defined by concentration-time (Ct)>40 determined by real-time reverse transcription-polymerase chain reaction (rtPCR).
Two-hundred thirty-six (2360 subjects were included in the study (108 female, 128 male); 171 were randomized to the Proxalutamide arm and 65 were in the placebo group. On Day 7, SARS-CoV-2 became non-detectable with rtPCR (cT>40) in 82% of the subjects in the Proxalutamide group versus 31% in the placebo group (p < 0.001). The average clinical remission time for patients treated with Proxalutamide was 4.2 ±5.4 days versus 21.8 ±13.0 days in the placebo arm (p < 0.001).
Proxalutamide significantly accelerated viral clearance on Day 7 in mild to moderate COVID-19 patients versus placebo. Further, the time to clinical remission was significantly reduced in patients treated with Proxalutamide versus placebo.
Repurposing an old Drug For COVID-19
July 02, 2021
Prostatic and hair drug for early COVID-19
DUTASTERIDE, A BROAD 5ALPHA-REDUCTASE INHIBITOR, USED FOR BEINIGN PROSTATE HYPERPLASIA AND FOR ANDROGENETIC HAIR LOSS, DEMONSTRATED TO INCREASE THE SPEED OF VIRAL VANISHING, SPEED UP CLINICAL IMPROVEMENT, AND IMPROVE INFLAMMATORY MARKERS IN COVID-19.
The paper also published in Cureus by us is a also preliminary report of another randomized clinical trial (RCT) we conducted, also in non-hospitalized patients with COVID-19 with the molecular diagnosis until up to 07 days, to evaluate the use of dutasteride. The two-thirds of patients that underwent a more comprehensive biochemical panel (as planned before the RCT started) were included in the present analysis. Patients that took dutasteride demonstrated to become negative for SARS-CoV-2 at higher rates than those that took placebo, had faster clinical recovery, and quicker improvement of inflammatory markers, D-dimer, and oxygen saturation than placebo group.
Cadegiani FA, McCoy J, Gustavo Wambier C, Goren A. Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial - Biochemical). Cureus. 2021 Feb 1;13(2):e13047. doi: 10.7759/cureus.13047. PMID: 33643746; PMCID: PMC7885746.
Background and objective
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and subsequent infectivity are mediated by androgens and the androgen receptors through the regulation of transmembrane protease, serine 2 (TMPRSS2). Androgenetic alopecia (AGA) predisposes males to severe coronavirus disease 2019 (COVID-19) disease, while the use of 5-alpha-reductase inhibitors (5ARis) and androgen receptor antagonists reduce COVID-19 disease severity. In this study, we aimed to determine the potential benefit of dutasteride, a commonly used broad and potent 5ARi, as a treatment for COVID-19.
Design, setting, and participants
The study was conducted at outpatient clinics. Subjects presented to the clinics with a positive reverse transcription-polymerase chain reaction (RT-PCR) test taken within 24 hours of recruitment. All subjects presented with mild to moderate symptoms.
Subjects were given either dutasteride 0.5 mg/day or placebo for 30 days or until full COVID-19 remission. All subjects received standard therapy with nitazoxanide 500 mg twice a day for six days and azithromycin 500 mg/day for five days.
Main outcome(s) and measure(s)
The main outcome(s) and measure(s) were as follows: time to remission, oxygen saturation (%), positivity rates of RT-PCR-SARS-CoV-2, and biochemical analysis [ultrasensitive C-reactive protein (usCRP), D-dimer, lactate, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), ultrasensitive troponin, and ferritin].
Subjects taking dutasteride (n=43) demonstrated reduced fatigue, anosmia, and overall disease duration compared to subjects taking a placebo (n=44) (p<.0001 for all). Compared to the placebo group, on Day seven, subjects taking dutasteride had a higher virologic remission rate (64.3% versus 11.8%; p=.0094), higher clinical recovery rate (84.7% versus 57.5%; p=.03), higher mean [standard deviation: SD] oxygen saturation (97.0% [1.4%] versus 95.7% [2.0%]; p=.02), lower median [Interquartile range: IQR] usCRP (0.34 mg/L [0.23 mg/L-0.66 mg/L] versus 1.47 mg/L [0.70 mg/L-3.37 mg/L]; p<.0001), lower median [IQR] lactate (2.01 mmol/L [1.12 mmol/L-2.43 mmol/L] versus 2.66 mmol/L [2.05 mmol/L-3.55 mmol/L]; p=.0049), lower median [IQR] ESR (5.0 mm/1h [3.0 mm/1h-11.0 mm/1h] versus 14.0 mm/1h [7.25 mm/1h-18.5 mm/1h]; p=.0007), lower median [IQR] LDH (165 U/L [144 U/L-198 U/L] versus 210 U/L [179 U/L-249 U/L]; p=.0013) and lower median [IQR] troponin levels (0.005 ng/mL [0.003 ng/mL-0.009 ng/mL] versus 0.007 ng/mL [0.006 ng/mL-0.010 ng/mL]; p=.048).
Conclusions and relevance
The findings from this study suggest that in males with mild COVID-19 symptoms undergoing early therapy with nitazoxanide and azithromycin, treatment with dutasteride reduces viral shedding and inflammatory markers compared to males treated with a placebo.
It’s Not Time to Build Up Muscles With Hormones
July 02, 2021
Exogenous steroid hormones and COVID-19
USERS OF SYNTHETIC ANABOLIC STEROIDS DERIVED FROM DIHYDROTESTOSTERONE (DHT) MAY HAVE THE RISK OF SEVERE COVID-19 ENHANCED
We published a case report of a young male without any risk factor that quickly progressed to a severe inflammatory stage right after he was diagnosed with COVID-19. Besides potential genetic factors, which were unlikely the cause in this case, the only reason why he could have quickly developed a more severe stage of COVID-19 was the use of high doses of oxandrolone, which is an anabolic steroid derived from dihydrotestosterone (DHT). We administered a highly potent non-steroidal antiandrogen (NSAA), proxalutamide, at a dose of 200mg daily for 07 days. After 01 single doses, his inflammatory levels reduced by more than 90%, without the use of glucocorticoids or other medications that may have influenced this reduction.
This case report reinforced the theory that high androgenic activity could enhance SARS-CoV-2 infectivity and severity.
Cadegiani F, Lin EM, Goren A, Wambier CG. Potential risk for developing severe COVID-19 disease among anabolic steroid users. BMJ Case Rep. 2021 Feb 26;14(2):e241572. doi: 10.1136/bcr-2021-241572. PMID: 33637513; PMCID: PMC7919571.
A severe case of COVID-19 was observed in an otherwise healthy 28-year-old man who had taken oxandrolone 40 mg/day as an anabolic steroid. The patient had been taking oxandrolone for enhanced bodybuilding 30 days prior to presenting to an outpatient clinic with COVID-19 symptoms. The patient reported that his symptoms have rapidly worsened over the course of 4 days prior to presenting at the clinic. As part of an experimental antiandrogen treatment for hyperandrogenic men suffering from COVID-19, he was administered a single 600 mg dose of the novel antiandrogen proxalutamide. Twenty-four hours after administration of this dose, marked improvement of symptoms and markers of disease severity were observed. To our knowledge, this is the first case that potentially links anabolic steroid use to COVID-19 disease severity.
This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
Polycystic Ovary Syndrome: A Risk Factor For COVID-19
July 02, 2021
Women and COVID-19
WOMEN AFFECTED BY POLYCYSTIC OVARY SYNDROME OR OTHER STATES THAT CAUSES EXCESS OF MASCULINE HORMONES ARE MORE SEVERLY AFFECTED BY COVID-19
This paper is a result of a prospective analysis of 112 women, including 56 affected by hyperandrogenism and 56 without. Women with any hyperandrogenic state had more symptoms, and more severe and prolonged duration of symptoms, and were less likely to be asymptomatic than women without hyperandrogenism.
This analysis provides additional evidence to the androgen theory on COVID-19, that increased androgenic activity is an independent predictor of severe COVID-19.
Cadegiani FA, Lim RK, Goren A, McCoy J, Situm M, Kovacevic M, Vañó Galván S, Sinclair R, Tosti A, Wambier CG. Clinical symptoms of hyperandrogenic women diagnosed with COVID-19. J Eur Acad Dermatol Venereol. 2021 Feb;35(2):e101-e104. doi: 10.1111/jdv.17004. Epub 2020 Nov 8. PMID: 33089570.
Bald Men And Vaccines for COVID-19
July 02, 2021
Vaccine for COVID-19 in bald men
BALD MEN MAY HAVE WEAKER RESPONSE TO VACCINES FOR COVID-19 (AND HOW THIS CAN BE ADDRESSED)
In this paper, we hypothesized that men affected by androgenetic alopecia could present a weaker immunological response to COVID-19. We provided a thorough molecular explanation for this, and why the concurrent use of an antiandrogen agent when vaccinating for COVID-19 could enhance the response in this population of males.
Goren A, Cadegiani FA, Wambier CG, Vano-Galvan S, Tosti A, Shapiro J, Mesinkovska NA, Ramos PM, Sinclair R, Lupi O, Hercogova J, McCoy J. Androgenetic alopecia may be associated with weaker COVID-19 T-cell immune response: An insight into a potential COVID-19 vaccine booster. Med Hypotheses. 2021 Jan;146:110439. doi: 10.1016/j.mehy.2020.110439. Epub 2020 Nov 28. PMID: 33308937; PMCID: PMC7695567.
A Clinical Diagnosis of COVID-19 is Possible
July 02, 2021
Clinical diagnosis of COVID-19
A CLINICAL DIAGNOSIS OF COVID-19 WAS SHOWN TO BE FEASIBLE AND ACCURATE, AND COULD REDUCE HEALTH COSTS RELATED TO COVID-19
We analysed the data of 1,557 patients regarding their symptoms and likelihood of being positive for COVID-19 through molecular diagnosis using rtPCR for SARS-CoV-2. We found out that the number and specificity of symptoms could be a highly accurate method for the diagnosis of COVID-19. This has been internally validated by a prospective follow-up of 200 patients. An accuracy above 80% was made possible, close to the accuracy of rtPCR, and has been shown to be a great, costless alternative, which may allow better access to COVID-19 management in places where rtPCRs are not available. Of course, symptoms may not be attributed to other diagnoses, those with chronic or recurrent symptoms should present changes in the symptom patterns, and is valid while the circulation of SARS-CoV-2 is highly present.
Cadegiani FA, Zimerman RA, Campello de Souza B, McCoy J, Pereira E Costa RA, Gustavo Wambier C, Goren A. The AndroCoV Clinical Scoring for COVID-19 Diagnosis: A Prompt, Feasible, Costless, and Highly Sensitive Diagnostic Tool for COVID-19 Based on a 1757-Patient Cohort. Cureus. 2021 Jan 7;13(1):e12565. doi: 10.7759/cureus.12565. PMID: 33437562; PMCID: PMC7793341.
A major barrier for successful therapeutic approaches for COVID-19 is the inability to diagnose COVID-19 during the viral replication stage, when drugs with potential antiviral activity could demonstrate efficacy and preclude progression to more severe stages. Reasons that hamper an earlier diagnosis of COVID-19 include the unspecific and mild symptoms during the first stage, the delay in the diagnosis and specific management caused by the requirement of a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 for the diagnosis of COVID-19, and the insufficient sensitivity of the RT-PCR-SARS-CoV-2, converse to what is recommended for a screening test during an outbreak. More sensitive and earlier diagnostic tools for COVID-19 should be unraveled as a key strategy for a breakthrough change in the disease course and response to specific therapies, particularly those that target the blockage of viral shedding. We aimed to create an accurate, sensitive, easy-to-perform, and intuitive clinical scoring for the diagnosis of COVID-19 without the need for an RT-PCR-SARS-CoV-2 (termed The AndroCoV Clinical Scoring for COVID-19 Diagnosis), resulting from a 1,757 population cohort, to eventually encourage the management of patients with a high pre-clinical likelihood of presenting COVID-19, independent of an RT-PCR-SARS-COV-2 test, to avoid delays and loss of appropriate timing for potential therapies.
This is a post-hoc analysis of clinical data prospectively collected of the Pre-AndroCoV and AndroCov Trials, which resulted in scorings for the clinical diagnosis of COVID-19 based on the likelihood of presenting with actual COVID-19 according to the number of symptoms, presence of anosmia, and known positive household contact. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and accuracy were calculated for subjects screened in two different periods and both periods together, for females, males, and both, in a total of nine different scenarios, according to combinations of one, two, or three or more symptoms or the presence of anosmia in subjects without known positive household contacts, and no symptoms, one, two, or three or more symptoms, or presence of anosmia or ageusia in subjects with known positive household contacts. Scorings that yielded the highest pre-test probability, sensitivity, and accuracy were selected.
Of the 1,757 patients screened, 1,284 were diagnosed with COVID-19. The scoring that required: (1) two or more symptoms, or anosmia or ageusia alone, for subjects without known contact; or (2) one or more symptoms, including anosmia or ageusia alone, when with known positive contacts presented the highest accuracy (80.4%) among all combinations attempted, and higher sensitivity (85.7%) than RT-PCR-SARS-CoV-2 commercially available kit tests.
The AndroCoV clinical scoring for COVID-19 diagnosis was demonstrated to be a feasible, easy, costless, and sensitive diagnostic tool for the clinical diagnosis of COVID-19. Because the clinical diagnosis of COVID-19 avoids delays in specific treatments, particularly for high-risk populations, prevents false-negative diagnosis, and reduces diagnostic costs, this diagnostic tool should be considered as an option for COVID-19 diagnosis, at least while SARS-CoV-2 is the prevailing circulating virus and vaccination rate is below the required for herd immunity.
When That Drug For Hair Loss May Benefit You From COVID-19
July 02, 2021
Chronic use of dutasteride and protection against COVID-19
CHRONIC USE OF DUTASTERIDE REDUCES COVID-19 SYMPTOMS IN MALES WITH ANDROGENETIC ALOPECIA
In a similar analysis that we did in women, we discovered that males with androgenetic alopecia (AGA) had more, more severe, and prolonged symptoms compared to men without AGA. However, the chronic use of dutasteride reduced symptoms to levels below those found in non-AGA males.
Both facts that males with enhanced androgen expression phenotypically observed through AGA had more severe COVID-19, and that the chronic use of a broad 5alpha-reductase antiandrogen reduced severity and symptoms substantially, adds further evidence for the role of androgens on the regulation of SARS-CoV-2 infectivity and pathogenesis.
McCoy J, Cadegiani FA, Wambier CG, Herrera S, Vaño-Galván S, Mesinkovska NA, Ramos PM, Shapiro J, Sinclair R, Tosti A, Goren A. 5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia. J Eur Acad Dermatol Venereol. 2021 Apr;35(4):e243-e246. doi: 10.1111/jdv.17021. Epub 2020 Nov 22. PMID: 33135263.
Another Benefit From Dutasteride For COVID-19
July 02, 2021
When used for prostate, dutasteride may protect older men against severe COVID-19
DUTASTERIDE NOT ONLY REDUCES SYMPTOMS IN COVID-19, BUT ALSO PREVENTS PROGRESSION OF THE DISEASE AMONG HOSPITALIZED OLD MALES
We were able to detect the benefits not only in non-hospitalized men with COVID-19, but also in hospitalized ones. In this analysis, conducted in Madrid, Spain, hospitalized males with a median age above 80 years old using dutasteride for benign prostate hyperplasia were less likely to get worse to the point that required an Intensive Care Unit (ICU), compared to males with an average age below 70 years old that were not using dutasteride. We would expect the opposite since above 60 years old the chances of getting severe increase exponentially with the increase of age. It means that dutasteride not only evened the risk with younger men, but also protected even when compared to more than 10 years younger males. This benefit was found irrespective of baldness.
This is one more demonstration of the veracity of the androgen theory on COVID-19.
Goren A, Wambier CG, Herrera S, McCoy J, Vaño-Galván S, Gioia F, Comeche B, Ron R, Serrano-Villar S, Ramos PM, Cadegiani FA, Kovacevic M, Tosti A, Shapiro J, Sinclair R. Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men. J Eur Acad Dermatol Venereol. 2021 Jan;35(1):e13-e15. doi: 10.1111/jdv.16953. Epub 2020 Oct 21. PMID: 32977363; PMCID: PMC7536996.
Your Sensitivity to Masculine Hormones Matters in COVID-19
July 02, 2021
Sensitivity to masculine hormones and COVID-19
DIFFERENT LENGTH AND SENSITIVITY OF ANDROGEN RECEPTORS MAY PREDICT COVID-19 SEVERITY
The androgen theory on COVID-19 is about the direct correlation between androgen activity and COVID-19 severity. However, the androgen activity is not only determined by levels of androgens – which by the way tend to be the result of the balance between dihydrotestoterone (DHT), an androgen five times more potent than testosterone, and testosterone – but also by the sensitivity of the androgen receptor (AR). For two men with same levels of testosterone and DHT, the one with more sensitive AR will present more androgen activity. It is like that the testosterone and DHT circulating in the man with more sensitive AR has a more efficient action of these hormones by the enhanced ability of the AR to trigger biological functions once coupled with androgens.
In this paper, we demonstrated through the analysis of 77 males that the genetics of the AR is an independent predictor of COVID-19, it means, regardless of testosterone or DHT levels, age, comorbidities, and other factors.
This is another piece of evidence to show the relevance of androgens for SARS-CoV-2 pathogenicity.
McCoy J, Wambier CG, Herrera S, Vaño-Galván S, Gioia F, Comeche B, Ron R, Serrano-Villar S, Iwasiow RM, Tayeb MA, Cadegiani FA, Mesinkovska NA, Shapiro J, Sinclair R, Goren A. Androgen receptor genetic variant predicts COVID-19 disease severity: a prospective longitudinal study of hospitalized COVID-19 male patients. J Eur Acad Dermatol Venereol. 2021 Jan;35(1):e15-e17. doi: 10.1111/jdv.16956. Epub 2020 Oct 21. PMID: 32977355; PMCID: PMC7536899.
When The Lack of Thyroid Function May Protect Against COVID-19
July 02, 2021
Hypothyroidism and COVID-19
PATIENTS WITH HYPOTHYROIDISM ARE LESS LIKELY TO GET INFECTED BY SARS-COV-2
The COVID-19 virus, SARS-CoV-2, entries in the cells through an enzyme called Angiotensin-converting enzyme-2 (ACE-2). For the cell entry, though, the SARS-CoV-2 needs to be “prepared” to couple with ACE-2 adequately through modifications in its spike protein. The two major proteins that prime the spike protein of SARS-CoV-2 are the TMPRSS-2 and furin.
While androgens are the only known modulators of TMPRSS-2 expression (camostat, nafamostat, and bromexhine are direct inhibitors of TMPRSS-2, but do not reduce its expression), a major cleaver of furin is the bioactive isoform of the thyroid hormone, the triiodothyronine (T3).
What happens is that patients with hypothyroidism are only treated with (levo)thyroxine (T4), which is a pro-hormone that requires convertion into T3 by a groups of enzymes called deionidase.
The problem is that because thyroid also produces between 10% and 20% of direct T3, when patients with hypothyroidism are treated with T4, not all tissues will normalize in-tissue T3 levels, since this may be the reason why the thyroid gland produces a little bit of T3 directly.
And the lungs are among the organs that has the weakest ability to convert T4 into T3.
To achieve normal T3 levels in the lung, patients would need supraphysiological doses of T4.
Since patients with hypothyroidism have lower in-tissue T3 levels in the lungs, and T3 is key for SARS-CoV-2 entry, we hypothesized that this group of patients would be less likely to get infected by SARS-CoV-2.
Indeed, in our cross-sectional study with more than 12,000 patients, those affected by hypothyroidism had approximately 50% less chance to get infected.
On the other hand, T3 is almost mandatory for the regulation of immunologic response in the lungs. The use of T3 has been proposed for Acute Respiratory Distress Syndrome (ARDS) and other acute pulmonary conditions. Besides, during acute diseases, T3 is reduced due to the conversion of T4 into the bio-inactive isoform called reverse T3 (rT3), leading to a condition called euthyroid sick syndrome.
We would expect that although patients with hypothyroidism would be harder to get infected, once infected with COVID-19, these patients would be at higher risk to develop acute pulmonary conditions due to lack of T3.
However, increase of hospitalization rates was not observed among those with hypothyroidism that were infected.
In summary, it seems that it is harder to get infected by SARS-CoV-2 if you have hypothyroidism, even when treated and TSH levels normalized, but it does not seem to increase the risk of being hospitalized when infected.
Nguyen C, Yale K, Ghigi A, Zheng K, Mesinkovska NA, Wambier CG, Cadegiani FA, Goren A. SARS-CoV-2 infection in patients with thyroid disease: a cross-sectional study. Ann Thyroid. 2022 Mar;6:7. doi: 10.21037/aot-21-8. Epub 2021 Mar 30. PMID: 34151187; PMCID: PMC8211102.
Should We Work as One-Size-Fits-All For Stay-At-Home Policies in COVID-19?
July 02, 2021
Stay-at-home policy and COVID-19 new variants
IN-HOME PROLONGED EXPOSITION OF HOUSEHOLDS TO THE VIRUS MAY LEAD TO THE EMERGENCE OF NOVEL SARS-COV-2 VARIANTS
In this paper, we demonstrated that although stay-at-home orders have been successfully associated with further reductions in novel cases and deaths, in particular places it can propitiate the development of new SARS-CoV-2 mutants. In the country where data was analyzed (Brazil), this correlation has not been found, except for the state of Amazonas. In this state, isolation rates above 40% were exponentially correlated with occurrence of new SARS-CoV-2 variants. Speculatively, the reasons that could justify this particularity in the state of Amazonas include the large number of households per home and peculiarities of the immunologic systems of indigens, which are ethnicities highly prevalent in the state, and that tend to present poorer responses to viral infections, possibly due to lack of historical contact with viruses and other infections.
Zimerman RA, Cadegiani FA, Pereira E Costa RA, Goren A, Campello de Souza B. Stay-At-Home Orders Are Associated With Emergence of Novel SARS-CoV-2 Variants. Cureus. 2021 Mar 11;13(3):e13819. doi: 10.7759/cureus.13819. PMID: 33728228; PMCID: PMC7949745.
While public health strategies to contain the current coronavirus disease 2019 (COVID-19) pandemic are primarily focused on social distancing and isolation, emerging evidence suggest that in some regions social isolation failed to lead to further decrease in the number of COVID-19 deaths in the long run. This apparent paradox was particularly observed in the northern region of Brazil, in the state of Amazonas. We hypothesized that the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations, leading to more transmissible and pathogenic variants, could explain the lack of further reductions in COVID-19 new cases and related deaths in some regions. Our objective is to determine if social isolation is associated with the emergence of new SARS-CoV-2 variants, particularly the P.1 lineage and E484K mutants, in Brazil and in the state of Amazonas.
Materials and methods
We assessed the prevailing SARS-CoV-2 genomes present in Brazil available on the GISAID (Global Initiative on Sharing All Influenza Data) database collected between June 1, 2020, and January 31, 2021. Data regarding demographics, lineage, and prevalence of P.1 lineage and E484K mutations were obtained. Social isolation was measured using the Social Isolation Index (SII), which quantifies the percentage of individuals that stayed within a distance of 450 meters from their homes on a given day, between February 1, 2020, and January 24, 2021. The number of daily COVID-19 deaths was obtained from the Brazilian Ministry of Health (OpenDataSUS, 2021) between March 12, 2020, and January 10, 2021. SII was correlated with the prevalence P.1 lineage and E484K mutations in the eight following weeks. All univariate associations were estimated using the Spearman Correlation Index. 3D surfaces were employed to reflect the relationship between time, social isolation, and prevalence of genomic variants simultaneously.
A total of 773 and 77 samples were obtained in Brazil and in the Amazonas state, respectively. In the state of Amazonas, SII on a given week was positively, significantly, and moderately or strongly (r > 0.6) correlated with the prevalence of both P.1 lineage and other E484K variants in the six following weeks after the SII on a given week. Conversely, in overall Brazil, correlations between SII and P.1 lineage and E484K variants were weaker and shorter, or negative, respectively. When SII was below 40%, P.1 lineage or E484K variants were not detected in the following weeks. When SII was above 40%, apparently exponential positive correlations between SII and prevalence of both P.1 lineage and E484K variants were observed.
The results of this study indicate that SII above 40% is associated with the emergence of SARS-CoV-2 E484K variants and P.1 lineage in the state of Amazonas, which was not observed in overall Brazil.
That Old Drug For Hypertension That Has Always Been Underappreciated
July 02, 2021
Spionolactone and COVID-19 (1)
SPIRONOLACTONE COULD BE A CANDIDATE AGAINST COVID-19
Spironolactone is an antihypertensive agent with multiple properties including regulation of the renin-angiotensin-aldosterone system (RAAS), which is typically abnormal not only in hypertension, but also in diabetes and obesity, downregulation of the androgen activity by blocking the androgen receptors (AR), and may protection to the heart, kidneys, and lungs.
Altogether, the regulation of the RAAS and AR, which correspond to the two major determinants of SARS-CoV-2 infectivity, and the protection to the organs most affected by COVID-19 allowed us hypothesize spironolactone as a promising drug for COVID-19. In this brief article, we summarize the potential benefits of spironolactone if used against COVID-19.
Cadegiani FA, Wambier CG, Goren A. Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19. Front Med (Lausanne). 2020 Jul 28;7:453. doi: 10.3389/fmed.2020.00453. PMID: 32850920; PMCID: PMC7399048.
How Does Spironolactone, a Drug For Hypertension, May Protect Against COVID-19?
July 02, 2021
Spironolactone and COVID-19 (2)
THE MECHANISMS THAT EXPLAIN WHY SPIRONOLACTONE MAY PROTECT AGAINST COVID-19
This manuscript is a more thorough description of the cellular environment of the renin-angiotensin-aldosterone system (RAAS), specifically the balances between angiotensin II and angiotensin-1-7, and between membrane-attached and plasma circulating angiotensin-converting enzyme-2 (ACE-2), in healthy subjects, in untreated hypertension, in hypertension using specific antihypertensive drug classes, and other metabolic diseases. We describe how spironolactone could positively modulate these aspects of the RAAS, ACE-2, and the androgens as well, and for which stages of COVID-19 spironolactone could be more effective.
Cadegiani FA, Goren A, Wambier CG. Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS). Med Hypotheses. 2020 Oct;143:110112. doi: 10.1016/j.mehy.2020.110112. Epub 2020 Jul 16. PMID: 32721806; PMCID: PMC7363620.
Understanding The Roles Of The Masculine Hormones In COVID-19
July 02, 2021
Androgens and COVID-19
WHY ARE ANDROGENS, ANDROGEN RECEPTOR, AND ANDROGENETIC ALOPECIA SO INVOLVED IN COVID-19?
This is a comprehensive review in which we provide the full rationale of the role of androgens in the pathogenesis of COVID-19, by the regulation of the expression of TMPRSS-2, which is a key protein for SARS-CoV-2 infectivity, as it primes the virus, allowing its cell entry through ACE-2. We bring all the observational, epidemiological and therapeutical data that support the androgen hypothesis in COVID-19. We provide potential therapeutical options for all the steps of the pathway from testosterone until the SARS-CoV-2 spike protein primed by TMPRSS-2 coupling with ACE-2, including inhibitors of 5alpha reductase, that inhibits the conversion of testosterone into dihydrotestosterone (DHT), antagonists of the androgen receptor (AR) that ultimately inhibits TMPRSS-2 expression, direct blockers of TMPRSS-2, and blockers of the SARS-CoV-2 spike protein to ACE-2.
Wambier CG, Mehta N, Goren A, Cadegiani FA. COVID-19, androgens, and androgenetic alopecia. Derm Rev. 2020;1-8. First published: 23 December 2020/ DOI: https://doi.org/10.1002/der2.50
The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in males may be due to the higher androgen expression. It is also known that androgen sensitivity is correlated with androgenic alopecia. The “Gabrin sign” identifies those with severe androgen alopecia (Hamilton Norwood scale = 3–7) who are at a higher risk for developing severe coronavirus disease 2019 (COVID-19) symptoms. The aim of this review article is to examine the current scientific evidence of the link between androgenic alopecia, androgens, and the severity of COVID-19 and also, to review possible therapeutic targets to impact COVID-19 outcomes.
The activation of the androgen receptor results in an increase in tissular expression of TMPRSS2 a protease that primes the spikes of SARS-CoV-2 for infectivity, resulting in the potential increase of viral load and dissemination through organs.
Therapies directed at suppressing the androgen expression have demonstrated clinical applicability to modify the host's vulnerability to COVID-19. This brings new insight to interventional virology research, particularly in respiratory viruses, such as coronavirus and influenza, which depend on TMPRSS2 surface antigen priming for infectivity.
COVID-19 as an Endocrine Disease
July 02, 2021
Drugs for endocrine diseases and COVID-19
REPURPOSING ENDOCRINE DRUGS FOR COVID-19 HAS SEVERAL ADVANTAGES AND MAY BE PROMISING OPTIONS
In this review, I explain that in a scenario of pandemic, repurposing currently existing drugs may be a great alternative, due to several reasons: 1. Well-established safety profile, which is inherent to old drugs, and allows their use without the need of extensively proven, 1A level of evidence, once it is known that it is very unlikely that these drugs would cause harm, in the lack of therapeutical options; 2. Whenever there are side effects or risks and they are acceptable in the context of the potential benefits, we know the side effects and risks so we can have a risk-driven surveillance, a more directed and efficient monitoring; 3. Health providers are more familiar with the management of the drugs and are able to manage it in primary, non-specialized, outpatient settings, not requiring highly-specialized centers for its administration; and 4. In the paved paths for drug approval, due to the investments needed from the conception of a new molecule until the performance of multicentric, highly-monitored placebo-controlled, double-blind randomized clinical trials (RCTs) with all the structure necessary for approval and registration purposes, non-patented drugs will unlikely follow the whole pathway due to the high, non-profitable investments. This becomes eventually a pitfall, since drugs that are approved tend to be patented and with high cost. This means that although approved, these drugs unlikely have favorable cost-effectiveness, precluding from a large-scale use. Oppositely, repurposed drugs, although they will not have RCTs with the same level of structure, will have the necessary cost-effectiveness for the use in public settings.
Due to all the reasons described above, repurposing drugs is a brave battle that finds big pharma and large health organizations and regulatory agencies as major barriers, but deserves to be thoroughly described as feasible and plausible alternatives.
In this paper, I describe for each drug or drug class the theoretical mechanisms of action that could protect from COVID-19 – direct- or host-mediated antiviral properties, control of the effects of the virus, or control of the damage caused by the effects of the virus; 2. How and when each drug or drug class could be better used; and 3. The current data at the time of the review that supported their use.
Multiple drugs and drug classes have been proposed, from specific hormones and hormone blockers until medications for diabetes, hypertension, dyslipidemia, and thrombosis.
A lot of options to be explored for COVID-19. Not having one is what kills patients already sick. They cannot wait for undisputable evidence.
Cadegiani FA. Repurposing existing drugs for COVID-19: an endocrinology perspective. BMC Endocr Disord. 2020 Sep 29;20(1):149. doi: 10.1186/s12902-020-00626-0. PMID: 32993622; PMCID: PMC7523486.
Background: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2.
Main text: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed.
Conclusion: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
Spironolactone: Among The First Drugs to be Hypothesized as Being Protective Against COVID-19
July 02, 2021
Spironolactone and COVID-19 (3)
SPIRONOLACTONE: A SOLUTION FOR HYPERTENSIVE PATIENTS WITH COVID-19?
This was the very first paper that I published on COVID-19. By the time of its publications, concerns were raised regarding the use of specific antihypertensive drug classes as being independent risk factors for COVID-19 due to their actions to raise cell-attached angiotensin converting enzyme-2 (ACE-2), the door through which SARS-CoV-2, the COVID-19 virus, enters into the cells.
By that time, since spironolactone is an antagonist of aldosterone, the end-product of the renin-angiotensin-aldosterone system (RAAS), leading to a distinct vessel and lung environment states in terms of proportion between cell-attached and free circulating ACE-2, and between angiotensin-2 and angiotensin-1-7, compared to ACE inhibitors (ACEis) and angiotensin-2 receptor blockers (ARBs), the two most used drug classes for hypertension.
To solve this possible yet controversial question, I proposed in this letter that spironolactone could be a good substitution to ACEis and ARBs in case these were really confirmed as risk factors.
Actually, there is a dual correlation between membrane-attached ACE-2 availability and COVID-19 severity. While higher attached ACE-2 concentrations may enhance SARS-CoV-2 infectivity, its presence modulates the inflammatory response and the so called ‘cytokine storm’, playing a sequential harmful followed by beneficial hole in COVID-19. For this reason, interestingly, the use of ACEi or ARBs during COVID-19 in previously non-users of these two drug classes may bring benefits by increasing attached ACE-2 when this is desirable, for the inflammatory stage, to protect against over- and dysfunctional inflammatory responses.
Noteworthy, this paper has been accepted within 24 hours since it was submitted, in a highly regarded journal, and hasn’t been questioned or retracted. This means that fast speed review and acceptance process is not necessarily something bad.
Cadegiani FA. Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension?. Am J Physiol Endocrinol Metab. 2020;318(5):E587‐E588. doi:10.1152/ajpendo.00136.2020.