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A Retrospective Observational Study of Chlorine Dioxide Effectiveness to Covid19-like Symptoms Prophylaxis in Relatives Living with COVID19 Patients
Abstract
To date, there is no effective prophylactic agent to prevent COVID-19. However, the development of symptoms similar to covid19 could be prevented with an aqueous solution of chlorine dioxide (ClO2). This retrospective study evaluated the effectiveness of an aqueous solution of ClO2 (CDS) as a prophylactic agent in 1,163 family members living with positive/suspected COVID19 patients. Prophylactic treatment consisted of 0.0003% chlorine dioxide solution (CDS) orally for at least fourteen days. Family members in whom no reports of the development of covid19-like symptoms were found in the medical history were considered successful cases. The efficacy of CDS in preventing covid19-like symptoms was 90.4% (1,051 of 1,163 relatives did not report any symptoms). The comorbidities, sex and severity of the illness of the sick patient did not contribute to the development of symptoms similar to covid19 (P = 0.092, P = 0.351 and P = 0.574, respectively). However, older relatives were more likely to develop covid19-like symptoms (ORa = 4.22, P = 0.002). There was no evidence of alterations in blood parameters or in the QTc interval in relatives who consumed CDS. The recent findings regarding Chlorine Dioxide justify designing clinical trials to assess its efficacy for preventing SARS-CoV-2 infection.
... 49 This should not be done conversely, without scaling to design or justify dosage regimens directly in humans, such as the presented cases in which ClO 2 promoters justify its use in humans (specifically for COVID-19 treatment) by arguing that a NOAEL (after oral ingestion) reported in a reproduction toxicity study in rats can be extrapolated to a "safe" human consumption dose in adults. 50,51 Additionally, the authors of this review believe that information on routes of administration in animals is still incomplete, as only a few studies of oral and intravenous administration were identified. Besides, knowledge of potential target organs and systems is needed, which can be complemented with a more comprehensive panel of animal tests for this substance (in different species), such as carcinogenicity studies, specific genetic toxicology assays, and immunotoxicity studies, which were absent in the reviewed literature. ...
... Despite denying any conflicts of interest, the authors, at the end of the article, thank Andreas Kalcker, the leading promoter of CDS consumption, with whom they have published other works directly. 65 Out of the time scope of our review, but worth mentioning in 2021, Aparicio et al. 51 published a retrospective observational study in which ClO 2 is administered as prophylaxis treatment to family members of individuals with COVID-19 (confirmed by PCR). ...
Background. Chlorine dioxide (ClO2) and its related compounds have been proposed as a treatment for several diseases; their popularity increased during the COVID-19 pandemic. This study aimed to identify, characterize, and synthesize the existing publications regarding ClO2 and its related compounds' toxicity and efficacy as a treatment. Material and Methods. A scoping systematic review of animal and human studies was carried out in PubMed and EMBASE from their origin 1946 to October 20, 2020. Outcomes of interest were toxicity and efficacy of ClO2 and related compounds. After title, abstract, and full-text peered-review screening, data was extracted and synthesized. Methodological and reporting bias was analyzed in order to identify low-quality studies. Results. We identified 15 animal and 19 human studies out of 752 articles found in academic literature. The latter selection included 13 toxicity case reports and 6 clinical studies reporting on the topical and systemic administration of ClO2. Animal studies hinted at the possibility of reproductive, developmental, thyroid, hematological, and nephrotic damage in different species. Most studies displayed methodological bias and low quality in reporting. On the human side, several case reports described mild and severe intoxications with ClO2 and related compounds at different doses in healthy and comorbid individuals. Clinical studies revealed no conclusive evidence on ClO2 as an effective systemic treatment. Conclusions. The principle of precaution should be called upon until quality evidence is provided; new and more comprehensive pre-clinical studies are needed before carrying out human trials. Meanwhile, tighter regulations on this substance could prevent adverse toxicological events.
Citation: Castro-Pastrana LI, Rico Cuevas JI, Martínez Hernández L, Lozano Jiménez I, Dreser-Mansilla A, Hegewisch-Taylor J. A Pseudoscience Tale: Insufficient Evidence Regarding Chlorine Dioxide’s Toxicity and Efficacy. Lat Am J Clin Sci Med Technol.2023 Feb; 5:64-93
... Thus, CDS has the potential to prevent tissue invasion and cell transformation [5][6][7][8][9] .The cytotoxic effect of CDS was demonstrated by inhibiting the proliferation of human cancer cell lines and pancreatic adenocarcinoma 6,7,10 CDS does not appear to be toxic to normal cells, it was shown that CDS does not have an apoptotic effect on human gingival fibroblasts and does not decrease the viability of periodontal ligament stem cells 11,12 . Also, in the public health context, the oral use of CDS has been reported as a safe and effective therapy to treat COVID-19 [13][14][15][16][17] . ...
Chlorine dioxide is a potent oxidant with in vitro anticancer activity. Its precise mechanism of action has not been thoroughly explored, but it is proposed that it acts through the redox imbalance of cancer cells. Three patients were treated for metastatic cancer (kidney, prostate and lymphoma), on a compassionate basis. We report lasting tumor response with a combination of oral, enema and/or intravenous chlorine dioxide, without side effects. The patients had refused conventional chemotherapy, radiation therapy or immunotherapy. This preliminary work suggest that chlorine dioxide and his free radicals might be the mediators. Chlorine dioxide is both a promising and unexpensive anticancer agent. Rigorous clinical trials are needed to confirm these preliminary results.
Keywords : Chlorine dioxide solution, cancer, reactive oxygen species, intermittent fasting, ketogenic diet
... Thus, CDS has the potential to prevent tissue invasion and cell transformation [5][6][7][8][9] .The cytotoxic effect of CDS was demonstrated by inhibiting the proliferation of human cancer cell lines and pancreatic adenocarcinoma 6,7,10 CDS does not appear to be toxic to normal cells, it was shown that CDS does not have an apoptotic effect on human gingival fibroblasts and does not decrease the viability of periodontal ligament stem cells 11,12 . Also, in the public health context, the oral use of CDS has been reported as a safe and effective therapy to treat COVID-19 [13][14][15][16][17] . ...
Chlorine dioxide is a potent oxidant with in vitro anticancer activity. Its precise mechanism of action has not been thoroughly explored, but it is proposed that it acts through the redox imbalance of cancer cells. Three patients were treated for metastatic cancer (kidney, prostate, lymphoma, uterus and melanoma), on a compassionate basis. We report lasting tumor response with a combination of oral, enema and/or intravenous chlorine dioxide, without side effects. The patients had refused conventional chemotherapy, radiation therapy or immunotherapy. This preliminary work suggest that chlorine dioxide and his free radicals might be the mediators. Chlorine dioxide is both a promising and unexpensive anticancer agent. Rigorous clinical trials are needed to confirm these preliminary results.
Keywords : Chlorine dioxide solution, cancer, reactive oxygen species, intermittent fasting, ketogenic diet
... CDS does not appear to be toxic to normal cells, it was shown that CDS does not have an apoptotic effect on human gingival fibroblasts and does not decrease the viability of periodontal ligament stem cells (Nishikiori et al., 2008;Láng et al., 2021). Also, in the public health context, the oral use of CDS has been reported as a safe and effective therapy to treat COVID-19 (Aparicio-Alonso et al., 2021b, 2021a, 2021cInsignares-Carrione et al., 2021;Mitchell, 2021). ...
Immunotherapy has recently yielded tremendous progress in the fight against malignancies. Its precise mechanism of action remains controversial. Activated leukocytes release reactive oxygen species which kill cancer cells. In the body, chlorine dioxide, orally ingested degrades into free radicals such as found in neutrophils.
Chlorine dioxide is a potent oxidant with in vitro anticancer activity. Its precise mechanism of action has not been thoroughly explored, but it is proposed that it acts through the redox imbalance of cancer cells. Six patients were treated for metastatic cancer (breast, kidney, prostate, lymphoma, uterus and melanoma), on a compassionate basis. We report lasting tumor response with a combination of oral, enema and/or intravenous chlorine dioxide, without any side effects. This preliminary work suggest that chlorine dioxide and free radicals might be the mediators for immunotherapies. Chlorine dioxide is both a promising and unexpensive anticancer agent. Rigorous clinical trials are needed to confirm these preliminary results.
Keywords : Chlorine dioxide , cancer, immunotherapy, Warburg effect, reactive oxygen species, intermittent fasting, ketogenic diet.
... Dr. Aparicio-Alonso practices at this medical center. He specializes in traumatology and orthopedics (Conoce al Dr. Manuel Aparicio Alonso n.d.), and has published three peer-reviewed articles demonstrating the effectiveness of CDS for COVID-19 (Aparicio-Alonso et al. 2021a, 2021b, 2021c. However, the evidence for the effectiveness of chlorine dioxide is contested in other scientific works (Baracaldo-Santamaría et al. 2022;de los Milagros Farfán-Castillo et al. 2022). ...
The COVID-19 pandemic has given rise to all types of beliefs, theories and explanations, whether scientific, religious or conspiratorial. At the beginning of the pandemic, science did not yet have a medicinal product for this new disease, and alternative medicines offering “miracle cures” were acclaimed by some citizens looking for an effective treatment for COVID-19. This article aims to study a specific “miracle cure,” namely, chlorine dioxide, a bleaching agent for textiles or paper that also has disinfectant properties (water, surfaces). The dissemination of information about chlorine dioxide to French-speaking people on the social network Twitter from December 1, 2019, to November 30, 2021, is analyzed using a graph network. The results show that messages pro-moting misinformation, even if they are likely to be quantitatively less numerous, spread more widely than those based on more reliable information. In addition, this article shows that chlorine dioxide was promoted as an effective cure by medical doctors and peer-reviewed articles, which consequently increased the dissemination of this belief in the social space. Consequently, the process of misinformation entered the sphere of scientific controversy. The boundary between science and misinformation is becoming blurred to the point that it is no longer possible until proven otherwise to call chlorine dioxide a “false miracle cure” but a controversial treatment against COVID-19
... Aunque se ha considerado el impacto de este nuevo hábito desde el punto de vista dermatológico (9), la exposición a través de otras vías, ocular o inhalatoria, resulta más importante si se atiende a la naturaleza química del compuesto. Es el caso del dióxido de cloro, presentado como una alternativa en el uso como desinfectante, debido a que no produce los problemas de sabor y olor que resultan del tratamiento con cloruros y que ha sido sugerido como terapia alternativa no aprobada, ante la ausencia de un tratamiento específico y efectivo para COVID-19 (10,11). ...
The COVID-19 pandemic has provided fertile ground for an ever-growing number of
controversies—and an expanding list of cases of suppression of dissent. Fueling scientific
and medical disputes are institutional, political, cultural, and economic factors that employ a
wide range of methodologies to create their own narratives for the purpose of influencing
public opinion and behaviors. Some of the more prominent controversies during the
pandemic include the safety and efficacy of COVID-19 vaccines, the justification for vaccine
mandates, and the use of treatments for COVID-19. The dominant narrative is that
COVID-19 vaccines are safe and effective, vaccine mandates are justified to reduce the
morbidity and mortality associated with COVID-19, and non-FDA approved treatments for
COVID-19 are ineffective or unsafe whereas FDA approved treatments are effective and
safe against COVID-19. Individuals who challenge the dominant narrative, a process known
as dissent, face wide ranging consequences. Although dissent may be viewed as unacceptable or even threatening to those who support the dominant view, dissent can also be useful as it can produce divergent thinking, improve decision making, and increase innovation.
Dissent is a double-edged sword. When suppressed or viewed as unacceptable, dissent can
lead to increased conflict which, if not resolved, can produce struggle and even violence. On
the other hand, when embraced and viewed as constructive, dissent can enhance scientific
discovery and produce novel therapeutic interventions.
During the COVID-19 pandemic, there have been numerous instances of suppression of
dissenting opinions. This review explores the suppression of dissent during the COVID-19
pandemic and the consequences of this suppression.
Background:
Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.
Areas of uncertainty:
We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.
Data sources:
We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.
Therapeutic advances:
Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
Background:
After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials.
Areas of uncertainty:
The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses.
Data sources:
Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns.
Therapeutic advances:
A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.
Conclusions:
Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.
Misinformation about coronavirus disease 2019 (COVID-19) is a significant threat to global public health because it can inadvertently exacerbate public health challenges by promoting spread of the disease. This study used a convenience sampling technique to examine factors associated with misinformation about COVID-19 in sub-Saharan Africa using an online cross-sectional survey. A link to the online self-administered questionnaire was distributed to 1,969 participants through social media platforms and the authors' email networks. Four false statements-informed by results from a pilot study-were included in the survey. The participants' responses were classified as "Agree," "Neutral," and "Disagree." A multinomial logistic regression was used to examine associated factors. Among those who responded to the survey, 19.3% believed that COVID-19 was designed to reduce world population, 22.2% thought the ability to hold your breath for 10 seconds meant that you do not have COVID-19, 27.8% believed drinking hot water flushes down the virus, and 13.9% thought that COVID-19 had little effect on Blacks compared with Whites. An average of 33.7% were unsure whether the 4 false statements were true. Multivariate analysis revealed that those who thought COVID-19 was unlikely to continue in their countries reported higher odds of believing in these 4 false statements. Other significant factors associated with belief in misinformation were age (older adults), employment status (unemployed), gender (female), education (bachelor's degree), and knowledge about the main clinical symptoms of COVID-19. Strategies to reduce the spread of false information about COVID-19 and other future pandemics should target these subpopulations, especially those with limited education. This will also enhance compliance with public health measures to reduce spread of further outbreaks.
Importance
Crowded indoor environments, such as households, are high-risk settings for the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Objectives
To examine evidence for household transmission of SARS-CoV-2, disaggregated by several covariates, and to compare it with other coronaviruses.
Data Source
PubMed, searched through October 19, 2020. Search terms included SARS-CoV-2 or COVID-19 with secondary attack rate, household, close contacts, contact transmission, contact attack rate, or family transmission.
Study Selection
All articles with original data for estimating household secondary attack rate were included. Case reports focusing on individual households and studies of close contacts that did not report secondary attack rates for household members were excluded.
Data Extraction and Synthesis
Meta-analyses were done using a restricted maximum-likelihood estimator model to yield a point estimate and 95% CI for secondary attack rate for each subgroup analyzed, with a random effect for each study. To make comparisons across exposure types, study was treated as a random effect, and exposure type was a fixed moderator. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.
Main Outcomes and Measures
Secondary attack rate for SARS-CoV-2, disaggregated by covariates (ie, household or family contact, index case symptom status, adult or child contacts, contact sex, relationship to index case, adult or child index cases, index case sex, number of contacts in household) and for other coronaviruses.
Results
A total of 54 relevant studies with 77 758 participants reporting household secondary transmission were identified. Estimated household secondary attack rate was 16.6% (95% CI, 14.0%-19.3%), higher than secondary attack rates for SARS-CoV (7.5%; 95% CI, 4.8%-10.7%) and MERS-CoV (4.7%; 95% CI, 0.9%-10.7%). Household secondary attack rates were increased from symptomatic index cases (18.0%; 95% CI, 14.2%-22.1%) than from asymptomatic index cases (0.7%; 95% CI, 0%-4.9%), to adult contacts (28.3%; 95% CI, 20.2%-37.1%) than to child contacts (16.8%; 95% CI, 12.3%-21.7%), to spouses (37.8%; 95% CI, 25.8%-50.5%) than to other family contacts (17.8%; 95% CI, 11.7%-24.8%), and in households with 1 contact (41.5%; 95% CI, 31.7%-51.7%) than in households with 3 or more contacts (22.8%; 95% CI, 13.6%-33.5%).
Conclusions and Relevance
The findings of this study suggest that given that individuals with suspected or confirmed infections are being referred to isolate at home, households will continue to be a significant venue for transmission of SARS-CoV-2.
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure.
Methods
We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations.
Results
We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18), and for twice-weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19-compatible illness (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08).
Conclusions
Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.
Background
The heart rate (HR) corrected QT interval (QTc) is crucial for diagnosis and risk stratification in the long QT syndrome (LQTS). Although its use has been questioned in some contexts, Bazett's formula has been applied in most diagnostic and prognostic studies in LQTS patients. However, studies on which formula eliminates the inverse relation between QT and HR are lacking in LQTS patients.
We therefore determined which QT correction formula is most appropriate in LQTS patients including the effect of beta blocker therapy and an evaluation of the agreement of the formulae when applying specific QTc limits for diagnostic and prognostic purposes.
Methods
Automated measurements from routine 12‐lead ECGs from 200 genetically confirmed LQTS patients from two Swedish regions were included (167 LQT1, 33 LQT2). QT correction was performed using the Bazett, Framingham, Fridericia, and Hodges formulae. Linear regression was used to compare the formulae in all patients, and before and after the initiation of beta blocking therapy in a subgroup (n = 44). Concordance analysis was performed for QTc ≥ 480 ms (diagnosis) and ≥500 ms (prognosis).
Results
The median age was 32 years (range 0.1–78), 123 (62%) were female and 52 (26%) were children ≤16 years. Bazett's formula was the only method resulting in a QTc without relation with HR. Initiation of beta blocking therapy did not alter the result. Concordance analyses showed clinically significant differences (Cohen's kappa 0.629–0.469) for diagnosis and prognosis in individual patients.
Conclusion
Bazett's formula remains preferable for diagnosis and prognosis in LQT1 and 2 patients.
Purpose:
To determine the utility of chest radiography in aiding clinical diagnosis of coronavirus disease 2019 (COVID-19) utilizing reverse-transcription polymerase chain reaction (RT-PCR) as the standard of comparison.
Materials and methods:
A retrospective study was performed of persons under investigation for COVID-19 presenting to this institution during the exponential growth phase of the COVID-19 outbreak in New Orleans (March 13-25, 2020). Three hundred seventy-six in-hospital chest radiographic examinations for 366 individual patients were reviewed along with concurrent RT-PCR tests. Two experienced radiologists categorized each chest radiograph as characteristic, nonspecific, or negative in appearance for COVID-19, utilizing well-documented COVID-19 imaging patterns. Chest radiograph categorization was compared against RT-PCR results to determine the utility of chest radiography in diagnosing COVID-19.
Results:
Of the 366 patients, the study consisted of 178 male (49%) and 188 female (51%) patients with a mean age of 52.7 years (range, 17 to 98 years). Of the 376 chest radiographic examinations, 37 (10%) exhibited the characteristic COVID-19 appearance; 215 (57%) exhibited the nonspecific appearance; and 124 (33%) were considered negative for a pulmonary abnormality. Of the 376 RT-PCR tests evaluated, 200 (53%) were positive and 176 (47%) were negative. RT-PCR tests took an average of 2.5 days ± 0.7 to provide results. Sensitivity and specificity for correctly identifying COVID-19 with a characteristic chest radiographic pattern was 15.5% (31/200) and 96.6% (170/176), with a positive predictive value and negative predictive value of 83.8% (31/37) and 50.1% (170/339), respectively.
Conclusion:
The presence of patchy and/or confluent, bandlike ground-glass opacity or consolidation in a peripheral and mid to lower lung zone distribution on a chest radiograph obtained in the setting of pandemic COVID-19 was highly suggestive of severe acute respiratory syndrome coronavirus 2 infection and should be used in conjunction with clinical judgment to make a diagnosis.© RSNA, 2020.
At the moment, there are no U.S. Food and Drug Administration (U.S. FDA)-approved drugs for the treatment of COVID-19, although several antiviral drugs are available for repurposing. Many of these drugs suffer from polymorphic transformations with changes in the drug’s safety and efficacy; many are poorly soluble, poorly bioavailable drugs. Current tools to reformulate antiviral APIs into safer and more bioavailable forms include pharmaceutical salts and cocrystals, even though it is difficult to classify solid forms into these regulatory-wise mutually exclusive categories. Pure liquid salt forms of APIs, ionic liquids that incorporate APIs into their structures (API-ILs) present all the advantages that salt forms provide from a pharmaceutical standpoint, without being subject to solid-state matter problems. In this perspective article, the myths and the most voiced concerns holding back implementation of API-ILs are examined, and two case studies of API-ILs antivirals (the amphoteric acyclovir and GSK2838232) are presented in detail, with a focus on drug property improvement. We advocate that the industry should consider the advantages of API-ILs which could be the genesis of disruptive innovation and believe that in order for the industry to grow and develop, the industry should be comfortable with a certain element of risk because progress often only comes from trying something different.
Objectives To estimate the attack rates, and identify the risk factors of COVID-19 infection.
Methods Based on a retrospective cohort study, we investigated 11,580 contacts of COVID-19 cases in Guangdong Province from January 10 to March 15, 2020. All contacts were tested by RT-PCR to detect their infection of SARS-COV-2. Attack rates by characteristics were calculated, and logistic regression was used to estimate the risk factors of infection for COVID-19.
Results A total of 515 of 11,580 contacts were identified to be infected with SARS-COV-2. Compared to young adults aged 20-29 years, the infected risk was higher in children (RR: 2.59, 95%CI: 1.79-3.76), and old people aged 60-69 years (RR: 5.29, 95%CI: 3.76-7.46). Females also had higher infected risk (RR: 1.66, 95%CI: 1.39-2.00). People having close relationship with index cases encountered higher risk to be infected (RR for spouse: 20.68, 95%CI: 14.28-29.95; RR for non-spouse family members: 9.55, 95%CI: 6.73-13.55; RR for close relatives: 5.90, 95%CI: 4.06-8.59; RR for other relatives: 3.37, 95%CI: 2.15-5.28). Moreover, contacts exposed to index case in symptomatic period (RR: 2.15, 95%CI: 1.67-2.79), with critically severe symptoms (RR: 1.61, 95%CI: 1.00-2.57), with symptoms of dizzy (RR: 1.58, 95%CI: 1.08-2.30), myalgia (RR: 1.49, 95%CI: 1.15-1.94), and chill (RR: 1.42, 95%CI: 1.05-1.92) had higher infected risks.
Conclusion Children, old people, females and family members are susceptible to be infected with COVID-19, while index cases in incubation period had lower contagiousness. Our findings will be helpful for developing targeted prevention and control strategies to combat the worldwide pandemic.
Since the first report of the coronavirus disease (COVID-19) in late December 2019, the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now widely spread to more than 187 countries and regions. However, it is unclear whether there has been cryptic transmission before these early officially confirmed cases, we therefore retrospectively screened for the SARS-CoV-2 RNA in 1271 nasopharyngeal swab samples, as well as the prevalence of IgM, IgG, and total antibodies against SARS-CoV-2 in 357 matched serum samples collected from hospitalized patients with influenza-like illness between December 1, 2018 and March 31, 2020 in Shanghai Ruijin Hospital. The onset date of the earliest COVID-19 case in this study was January 25, 2020. Before this time point, the presence of SARS-CoV-2 was not observed, which limited the possibility that SARS-CoV-2 has already spread among the population before the large-scale outbreak. Additionally, among 6662 patients with influenza-like illness from December 1, 2017 to March 31, 2020, the overall number of patients positive for influenza and other respiratory viruses during the COVID-19 period decreased significantly when compared with that in the same period of the last two years, reflecting that public health interventions can effectively control the spread of common respiratory viruses.
SARS-CoV-2 is very contagious and has rapidly spread globally. Due to various symptomatic and asymptomatic cases and the possibility of asymptomatic transmission, there is a pressing need for a fast and sensitive detection protocol to diagnose asymptomatic people. Various SARS-CoV-2 diagnostic kits are already available from many companies and national health agencies. However, publicly available information on these diagnostic kits is lacking. In response to the growing need and the lack of information, we developed and made available a low-cost, easy-access, real-time PCR-based protocol for the early detection of the virus in a previous study. During the development of the detection protocol, we found that unoptimized primer sets could inadvertently show false-positive results, raising the possibility that commercially available diagnostic kits might also contain primer sets that produce false-positive results. Here, we provide three-step guidelines for the design and optimization of specific primer sets. The three steps include (1) the selection of primer sets for target genes (RdRP, N, E, and S) in the genome of interest (SARS-CoV-2), (2) the in silico validation of primer and amplicon sequences, and (3) the optimization of PCR conditions (i.e., primer concentrations and annealing temperatures) for specific hybridization between the primers and target genes, and the elimination of spurious primer dimers. Furthermore, we have expanded the previously developed real-time PCR-based protocol to more conventional PCR-based protocols and applied a multiplex PCR-based protocol that allows the simultaneous testing of primer sets for RdRP, N, E, and S all in one reaction. Our newly optimized protocol should be helpful for the large-scale, high-fidelity screening of asymptomatic people, even without any high-specification equipment, for the further prevention of transmission, and to achieve early intervention and treatment for the rapidly propagating virus.
Background
Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected COVID‐19. Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation.
Methods and Results
We performed a case series of COVID‐19 positive/suspected patients admitted between 2/1/2020 and 4/4/2020 who were treated with azithromycin, hydroxychloroquine, or a combination. We evaluated baseline and post‐medication QT interval (QTc, Bazett's) using 12‐lead ECGs. Critical QTc prolongation was defined as: a) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and b) increased QTc of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID‐19 positive/suspected patients, 314 (64%) received either/both drugs, and 98 (73 COVID‐19 positive, 25 suspected) met study criteria (age 62±17 yrs, 61% male). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36 ms (p=0.005) with medications. Significant prolongation was observed only in men (18±43 ms vs ‐0.2±28 ms in women, p=0.02). 12% of patients reached critical QTc prolongation. Changes in QTc were highest with the combination compared to either drug, with much greater prolongation with combination vs. azithromycin (17±39 vs. 0.5±40 ms, p=0.07). No patients manifested torsades de pointes.
Conclusions
Overall 12% of patients manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone. The balance between uncertain benefit and potential risk when treating COVID‐19 patients should be carefully assessed.
Objective:
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also called COVID-19, has caused a pandemic which has swiftly involved the entire world and raised great public health concerns. The scientific community is actively exploring treatments that would potentially be effective in combating COVID-19. Hydroxychloroquine has been demonstrated to limit the replication of SARS-CoV-2 virus in vitro. In malarial pandemic countries, chloroquine is widely used to treat malaria. In malarial non-pandemic nations, chloroquine is not widely used. Chloroquine and hydroxychloroquine share similar chemical structures and mechanisms of action. The aim of this study was to indirectly investigate the efficacy of chloroquine and hydroxychloroquine for the treatment of COVID-19 by determining the prevalence of COVID-19 in malaria pandemic and non-pandemic nations. We sought evidence to support or refute the hypothesis that these drugs could show efficacy in the treatment of COVID-19.
Materials and methods:
We reviewed in vitro studies, in vivo studies, original studies, clinical trials, and consensus reports, that were conducted to evaluate the antiviral activities of chloroquine and hydroxychloroquine. The studies on "COVID-19 and its allied treatment were found from World Health Organization (WHO), ISI-Web of Science, PubMed, EMBASE, Scopus, Google Scholar, and clinical trial registries. The search was based on keywords: antiviral drugs, chloroquine, hydroxychloroquine, COVID-19, COVID-19 treatment modalities, and coronavirus. In addition, we analyzed the prevalence of COVID-19 in malaria pandemic and non-pandemic countries. The review and analyses were performed on March 28, 2020.
Results:
For this study, we identified a total of 09 published articles: 03 clinical trials with sample size 150; 03 in vitro studies and 03 expert consensus reports. These studies were all suggestive that chloroquine and hydroxychloroquine can successfully treat COVID-19 infections. We found that COVID-19 infections are highly pandemic in countries where malaria is least pandemic and are least pandemic in nations where malaria is highly pandemic.
Conclusions:
Chloroquine and hydroxychloroquine have antiviral characteristics in vitro. The findings support the hypothesis that these drugs have efficacy in the treatment of COVID-19. People are currently using these drugs for malaria. It is reasonable, given the hypothetical benefit of these two drugs, that they are now being tested in clinical trials to assess their effectiveness to combat this global health crisis.
Introduction:
The World Health Organization (WHO) declared COVID-19 outbreak as a world pandemic on 12th March 2020. Diagnosis of suspected cases is confirmed by nucleic acid assays with real-time PCR, using respiratory samples. Serology tests are comparatively easier to perform, but their utility may be limited by the performance and the fact that antibodies appear later during the disease course. We aimed to describe the performance data on serological assays for COVID-19.
Materials and methods:
A review of multiple reports and kit inserts on the diagnostic performance of rapid tests from various manufacturers that are commercially available were performed. Only preliminary data are available currently.
Results:
From a total of nine rapid detection test (RDT) kits, three kits offer total antibody detection, while six kits offer combination SARS-CoV-2 IgM and IgG detection in two separate test lines. All kits are based on colloidal gold-labeled immunochromatography principle and one-step method with results obtained within 15 minutes, using whole blood, serum or plasma samples. The sensitivity for both IgM and IgG tests ranges between 72.7% and 100%, while specificity ranges between 98.7% to 100%. Two immunochromatography using nasopharyngeal or throat swab for detection of COVID-19 specific antigen are also reviewed.
Conclusions:
There is much to determine regarding the value of serological testing in COVID-19 diagnosis and monitoring. More comprehensive evaluations of their performance are rapidly underway. The use of serology methods requires appropriate interpretations of the results and understanding the strengths and limitations of such tests.
The Novel corona virus 2019 which started as an outbreak in
China in December 2019 has rapidly spread all over the world,
such that on 11th March 2020 WHO declared this disease as pandemic
[1,2]. The emergency that the world faces today demands
that we develop urgent and effective measures to protect people at
high risk of transmission.
Motivation:
Viruses have caused many epidemics throughout human history. The novel coronavirus [10] is just the latest example. A new viral outbreak can be unpredictable, and development of specific defense tools and countermeasures against the new virus remains time-consuming even in today's era of modern medical science and technology. In the lack of effective and specific medication or vaccination, it would be desirable to have a nonspecific protocol or substance to render the virus inactive, a substance/protocol, which could be applied whenever a new viral outbreak occurs. This is especially important in cases when the emerging new virus is as infectious as SARS-CoV-2 [4].
Aims and structure of the present communication:
In this editorial, we propose to consider the possibility of developing and implementing antiviral protocols by applying high purity aqueous chlorine dioxide (ClO2) solutions. The aim of this proposal is to initiate research that could lead to the introduction of practical and effective antiviral protocols. To this end, we first discuss some important properties of the ClO2 molecule, which make it an advantageous antiviral agent, then some earlier results of ClO2 gas application against viruses will be reviewed. Finally, we hypothesize on methods to control the spread of viral infections using aqueous ClO2 solutions.
La interpretación médica de los resultados clínicos es una práctica fundamental en las decisiones clínicas sobre el paciente y, para ello, es necesario comparar los resultados obtenidos frente al intervalo de referencia calculado para la población del paciente. El objetivo de este estudio fue determinar los intervalos de referencia de diferentes analitos de química clínica en la población mexicana. Se analizaron 653,467 resultados de individuos de uno y otro género. Se utilizó el método no para-métrico de Tukey para la detección de valores extremos y se determinaron los intervalos de referencia a través del método no paramétrico recomendado por el CLSI en su guía C28-A3. Se observaron variaciones entre los intervalos de referencia calculados y los referidos en el inserto de diferentes analitos: los metabolitos como nitrógeno ureico y urea; las enzimas como alanina aminotransferasa, gamma glutamil transpeptidasa y lactato deshidrogenasa; y electrólitos como cloro, fósforo y magnesio mostraron intervalos con mayor concentración. Los intervalos de referencia de las pruebas clínicas analizadas, en algunos casos, muestran diferencias respecto a los intervalos sugeridos por el inserto, e incluso pueden diferir de los valores sugeridos por asociaciones internacionales. Por lo anterior, es recomendable determinar los intervalos de referencia en cada laboratorio clínico.
ClO2, the so-called "ideal biocide", could also be applied as an antiseptic if it was understood why the solution killing microbes rapidly does not cause any harm to humans or to animals. Our aim was to find the source of that selectivity by studying its reaction-diffusion mechanism both theoretically and experimentally.
ClO2 permeation measurements through protein membranes were performed and the time delay of ClO2 transport due to reaction and diffusion was determined. To calculate ClO2 penetration depths and estimate bacterial killing times, approximate solutions of the reaction-diffusion equation were derived. In these calculations evaporation rates of ClO2 were also measured and taken into account.
The rate law of the reaction-diffusion model predicts that the killing time is proportional to the square of the characteristic size (e.g. diameter) of a body, thus, small ones will be killed extremely fast. For example, the killing time for a bacterium is on the order of milliseconds in a 300 ppm ClO2 solution. Thus, a few minutes of contact time (limited by the volatility of ClO2) is quite enough to kill all bacteria, but short enough to keep ClO2 penetration into the living tissues of a greater organism safely below 0.1 mm, minimizing cytotoxic effects when applying it as an antiseptic. Additional properties of ClO2, advantageous for an antiseptic, are also discussed. Most importantly, that bacteria are not able to develop resistance against ClO2 as it reacts with biological thiols which play a vital role in all living organisms.
Selectivity of ClO2 between humans and bacteria is based not on their different biochemistry, but on their different size. We hope initiating clinical applications of this promising local antiseptic.
Airborne influenza virus infection of mice can be prevented by gaseous chlorine dioxide (ClO2). Here, I demonstrate that ClO2 abolishes the function of hemagglutinin (HA) of influenza A virus (H1N1) in a concentration-, time- and temperature-dependent manner. The half-inhibitory concentration (IC50) during a 2-min reaction with ClO2 at 25°C was 13.7 μM, and the. half-inactivation time (t1/2) with 100 μM ClO2 at 25°C was 19.5 s. Peptides generated from a tryptic digest of ClO2-treated virus were analyzed by mass spectrometry. A HA fragment, H2N-NLLWLTGK-COOH (residues 150 - 157) was identified in which the tryptophan 153 residue (W153) was 32 mass units greater than expected. This peptide, which is derived from the central region of the receptor binding site of HA, includes a highly conserved W153. It is shown that W153 was oxidized to N-formylkynurenine in the ClO2-treated virus. It is concluded that the inactivation of influenza virus by ClO2 is caused by oxidation of W153 in HA, thereby abolishing its receptor-binding ability.
Vitamin D deficiency is a pandemic disorder affecting over 1 billion of subjects worldwide and displaying a broad spectrum of implications on cardiovascular and inflammatory disorders. Since the initial reports of the association between hypovitaminosis D and COVID-19, Vitamin D has been pointed as a potentially interesting treatment for SARS-Cov-2 infection We provide an overview on the current status of vitamin D deficiency, the mechanisms of action of vitamin D and the current literature on the topic, with a special focus on the potential implications for COVID-19 pandemic.
Background
There is no known effective therapy for patients with COVID-19. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP).
Objective
to assess the change in QTc interval and arrhythmic events in patients with COVID-19 treated with HY/AZ
Methods
This is a retrospective study of 251 patients from two centers, diagnosed with COVID-19 and treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality.
Results
QTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia (VT) suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting extreme QTc prolongation was normal.
Conclusion
The combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.
Background:
The corona virus disease 2019 (COVID-19) caused by the corona virus 2 (SARS-CoV-2) has been rapidly spreading nationwide and abroad. A serologic test to identify antibody dynamics and response to SARS-CoV-2 was developed.
Methods:
The antibodies against SARS-CoV-2 were detected by an enzyme-linked immunosorbent assay (ELISA) based on the recombinant nucleocapsid protein of SARS-CoV-2 in patients with confirmed or suspected COVID-19 at 3-40 days after symptom onset. The gold standard for COVID-19 diagnosis was nucleic acid testing for SARS-CoV-2 by RT-PCR. The serodiagnostic power of the specific IgM and IgG antibodies against SARS-CoV-2 was investigated in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and consistency rate.
Results:
The seroconversion of specific IgM and IgG antibodies were observed as early as the 4th day after symptom onset. In the confirmed patients with COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 77.3% (51/66), 100%, 100%, 80.0%, and 88.1%, and those of IgG were 83.3.3% (55/66), 95.0%, 94.8%, 83.8%, and 88.9 %. In patients with suspected COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 87.5% (21/24), 100%, 100%, 95.2%, and 96.4%, and those of IgG were 70.8% (17/24), 96.6%, 85.0%, 89.1%, and 88.1%. Both antibodies performed well in serodiagnosis for COVID-19 rely on great specificity.
Conclusions:
The antibodies against SARS-CoV-2 can be detected in the middle and later stage of the illness. Antibody detection may play an important role in the diagnosis of COVID-19 as complement approach for viral nucleid acid assays.
Purpose
To evaluate the diagnostic value of computed tomography (CT) and real-time reverse-transcriptase-polymerase chain reaction (rRT-PCR) for COVID-19 pneumonia.
Methods
This retrospective study included all patients with COVID-19 pneumonia suspicion, who were examined by both CT and rRT-PCR at initial presentation. The sensitivities of both tests were then compared. For patients with a final confirmed diagnosis, clinical and laboratory data, in addition to CT imaging findings were evaluated.
Results
A total of 36 patients were finally diagnosed with COVID-19 pneumonia. Thirty-five patients had abnormal CT findings at presentation, whereas one patient had a normal CT. Using rRT-PCR, 30 patients were tested positive, with 6 cases initially missed. Amongst these 6 patients, 3 became positive in the second rRT-PCR assay(after 2 days, 2 days and 3 days respectively), and the other 3 became positive only in the third round of rRT-PCR tests(after 5 days, 6 days and 8 days respectively). At presentation, CT sensitivity was therefore 97.2%, whereas the sensitivity of initial rRT-PCR was only 83.3%.
Conclusion
rRT-PCR may produce initial false negative results. We suggest that patients with typical CT findings but negative rRT-PCR results should be isolated, and rRT-PCR should be repeated to avoid misdiagnosis.
QT prolongation constitutes one of the most frequently encountered electrical disorders of the myocardium. This is due not only to the presence of several associated congenital syndrome but also, and mainly, due to the QT-prolonging effects of several acquired conditions, such as ischaemia and heart failure, as well as multiple medications from widely different categories. Propensity of repolarization disturbances to arrhythmia appears to be inherent in the function of and electrophysiology of the myocardium. In the present review the issue of QT prolongation will be addressed in terms of pathophysiology, arrhythmogenesis, treatment and risk stratification approaches. Although already discussed in literature, it is hoped that the mechanistic approach of the present review will assist in improved understanding of the underlying changes in electrophysiology, as well as the rationale for current diagnostic and therapeutic approaches.
In the United States chlorination of potable water supplies has been the standard method of disinfection for about 75 years. In recent times concern has been raised about the propensity of chlorination to introduce potentially carcinogenic trihalomethanes (THM) such as chloroform into finished water. The levels of THM introduced depend on many factors including the quality of the raw water. Numerous community water treatment facilities are experiencing difficulty in meeting current U.S. Environmental Protection Agency standards, and it is likely that the permissible levels may be lowered in the future. An alternative to chlorination which does not generate THM during disinfection is chlorine dioxide, but there are concerns about the acute and chronic toxicity of ClO2 and its disinfection by-products, chlorite and chlorate. Deleterious effects of moderately high levels of these oxychlorines have been demonstrated experimentally on red blood cells, thyroid function, and development in laboratory animals. Adverse effects in controlled prospective studies in humans and in actual use situations in community water supplies have as yet failed to reveal clear evidence of adverse health effects. Among groups who may be at special risk from this suggested alternative are patients who must undergo chronic extracorporeal hemodialysis. The special needs, precautions, and experience to date in regard to finished water are reviewed. Again, very limited human experience has failed to reveal adverse health effects. Further study, caution, and extreme vigilance are indicated, but dialysis patients in carefully controlled facilities may be at no greater risk than the general population.
Chlorine dioxide is under consideration for use as a water disinfectant alternative to chlorination in the United States. A rising dose tolerance study was undertaken to assess the relative safety and tolerance of acute administration of chlorine dioxide and its byproducts, chlorite and chlorate, to normal healthy adult male volunteers. In evaluation of an extensive battery of laboratory tests and vital signs, no adverse physiological effects were identified. This provided a data base upon which a controlled 5-month study trial of these substances in normal healthy volunteer subjects was designed.
Antimalarial drugs are used for the control of mild manifestations of autoimmune diseases due to their low toxicity. Hydroxychloroquine (HCQ), a alpha-hydroxylated derivative of chloroquine, is usually preferred because of its higher tolerability. Mild and unspecific gastrointestinal symptoms are the main secondary effects related to HCQ use. Less than 1% of subjects show liver enzyme increase, although the percentage can be as high as 50% in subjects with chronic liver disease. A woman with mixed connective tissue disease who developed a reversible acute hepatitis shortly after the initiation of low-dose HCQ is presented. Two previous cases of patients with acute liver failure have previously been published. All three cases have been reported in the absence of previous liver disease. It seems to be a dose-dependent, idiosyncratic, and molecule-specific toxic effect and must be considered, taking into account the potential bad prognosis.
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