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"A comparative study on Ivermectin- Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients".
Abstract
Coronavirus disease 2019 (COVID19) is a WHO declared a global pandemic. From the time of origin to till many antiviral and other drugs are on desperate use to find a cure. We decided to investigate the efficacy of Ivermectin-Doxycycline combination therapy and compare it to the standard HCQ-Azithromycin therapy among the mild to moderate cases of COVID19 patients in Bangladesh.
Patients were divided into two groups. Ivermectin 200µgm/kg single dose + Doxycycline 100mg BID for 10d and Hydroxychloroquine 400mg 1st day then 200mg BID for 9days + Azithromycin 500mg daily for 5Days was given to the Group-A and group-B respectively. Treatment outcomes were evaluated on the 5th day in case of asymptomatic patients and the 2nd non-symptomatic day onward from the first day of the drug intake by PCR study.
According to this study both the Ivermectin-Doxycycline and HCQ-Azithromycin treatment regimens were found to be effective against SARS-CoV-2 infection. But concerning the treatment outcome, adverse effect, and safety Ivermectin-Doxycycline combination is superior to HCQ-Azithromycin therapy for mild to moderate degree of COVID19 patients in Bangladesh. We strongly believe by rescheduling and increasing the duration of Ivermectin to 3days will certainly decrease the recovery period further than that of our study. This will also prevent disease progression and morbidity to COVID19 patients.
... Initially, it was considered an anthelmintic drug. The drug has been used effectively to treat lymphatic filariasis, head lice, strongyloidiasis, and river blindness [6,7]. Many studies have shown its effectiveness against various RNA viruses [8]. ...
... Patients in group A were treated with ivermectin and doxycycline, while the Group B patients were treated with hydroxychloroquine and azithromycin. After comparing the above groups with two different combinations, it was found that the results were better in group A. Furthermore, the adverse events were 31.67% in group A as compared to 46.43% in group B [6]. Reports of various studies involving the use of ivermectin against viral infections are presented in Table 1. ...
... Ivermectin + doxycycline produced a better recovery rate as compared to hydroxychloroquine + azithromycin. The former combination also shortened the duration of recovery [6]. A matched controlled study (AIIMS Bhubaneshwar) ...
An unprecedented global health crisis has developed due to the emergence of the mysterious coronavirus-2 of the severe acute respiratory syndrome, which has resulted in millions of deaths around the globe, as no therapy could control the ‘cytokine storm’. Consequently, many vaccines have been developed and several others are being developed for this infection. Although most of the approved vaccines have been highly effective, many developing, and economically poor countries are still deprived of vaccination against SARS-CoV-2 due to the unequal distribution of vaccines worldwide. Furthermore, the uncertainty about the effectiveness of the available vaccines against the emerging mutants and variants also remains a matter of concern. Due to the multistep pathogenesis and unique features, combination therapy using safe immunomodulatory and antiviral drugs should be considered as the most effective and acceptable therapeutic regimen for this infection. Based on a thorough assessment of the literature, it was determined that it would be interesting to study the therapeutic potential of ivermectin and doxycycline, given their roles in several biological pathways involved in SARS CoV-2 pathogenesis. Following that, a comprehensive literature search was undertaken using Scopus, Web of Science, and Pubmed, depending on the inclusion and exclusion criteria. The present study provides a mechanism and comprehensive report, highlighting the role of combined therapy with ivermectin and doxycycline in alleviating the ‘cytokine storm’ of COVID-19 infection.
... В первой группе пациентов наблюдались следующие НР: вялость -у 14 (23,3%), тошнота -у 11 (18,3%) и головокружение -у 7 (11,66%). Во второй группе у 13 пациентов (23,21%) развилось помутнение зрения и головная боль, у 22 (39,2%) -вялость и головокружение, у 10 (17,85%) -брадикардия и у 9 (16,07%) -тошнота и рвота [43]. ...
... Ивермектин характеризуется достаточно благоприятным профилем безопасности при исполь зовании по утвержденным показаниям в стандартных дозах (150-200 мг/кг). Наиболее распространенными НР при его применении являются слабость, диарея, тошнота, рвота, кожная сыпь, головокружение 21 [40][41][42][43]45]. Большинство НР -легкие, имеют преходящий характер, и их возникновение, как правило, связано с гибелью паразита, а не с действием препарата. ...
The search for an effective and safe COVID-19 therapy involves, among other things, assessment of efficacy of medicines already used for the treatment of other diseases, and having potential antiviral activity against SARS-CoV-2. The relevance of the presented study stems from ambiguous data on the off-label use of the antiparasitic medicine ivermectin for the treatment of COVID-19 patients. The aim of the study was to analyse ivermectin efficacy and safety for COVID-19 treatment, as reflected in the scientific literature. Ivermectin, an antiparasitic medicine from the group of macrocyclic lactones produced by Streptomyces avermitilis , stimulates release of the inhibitory neurotransmitter gamma-aminobutyric acid, which leads to impaired transmission of nerve impulses, paralysis and death of parasites. The results of preclinical studies show ivermectin’s inhibitory activity against a number of RNA and DNA viruses, including SARS-CoV-2. The results of ivermectin clinical studies are ambiguous: a number of studies demonstrated a positive effect on the condition of COVID-19 patients, however, there is currently no convincing evidence of the validity and efficacy of ivermectin use for the prevention and treatment of COVID-19 patients. The safety profile of ivermectin is relatively favourable. Large randomised controlled trials are needed to fully assess the feasibility of using ivermectin in COVID-19.
... Ivermectin is a macrocyclic lactone derivative with broad antiparasitic (Chhaiya et al., 2012), antiviral (Momekov & Momekova, 2020), and anti-cancer therapeutic bioactivities (Juarez et al., 2020). Ivermectin was determined to be an effective option for managing individuals with mild-to-moderate COVID-19 infection since it is effective in in vitro studies against several RNA viruses (Mohiuddin Chowdhury et al., 2020). Caly et al. approved ivermectin to inhibit the replication of SARS-CoV-2 in vitro by around 5000-fold at 48 h (Caly et al., 2020). ...
Post-COVID-19 conditions encompass a wide range of health problems, including enteritis, but their association with parasitic infections has not yet been investigated. This study analyzed gastrointestinal symptoms, medical histories, fecal Cryptosporidium oocysts, and the history of COVID-19 infection in patients who attended the Faculty of Medicine, Cairo University, from January to July 2021. Fecal biomarkers, including H. pylori, occult blood, fecal calprotectin (FCAL), and TNF-a, were measured, and Cryptosporidium spp. genotypes were molecularly characterized among post-COVID-19 patients using RFLP. Preliminary results from 210 post-COVID-19 patients revealed that group 1 (Cryptosporidiumpositive) (n = 49) and group 2 (Cryptosporidium-negative) (n = 161) showed no significant difference in the prevalence rate of diabetes mellitus (DM). While group 2 was linked to diarrhea, only infections with Cryptosporidium post-COVID-19 were related to chronic diarrhea, vomiting, and weight loss. A total of 220 healthy subjects served as negative controls. Administering azithromycin, hydroxychloroquine, and ivermectin was significantly related to an increased risk of Cryptosporidium infection in group 1, whereas only azithromycin was more frequently recorded in group 2. Antioxidant supplementation insignificantly affected the incidence of cryptosporidiosis. Cryptosporidiosis with a history of COVID-19 was linked to H. pylori infections, increased inflammatory biomarkers (FCAL and TNF-a), and occult blood when compared with group 2. Cryptosporidium genotype 1 was the most commonly occurring subset in individuals with post-COVID-19. The findings demonstrated that aggravating gastrointestinal manifestations, increased fecal biomarkers and anti-COVID-19 therapeutic interventions are significantly related to the existence of Cryptosporidium oocysts in patients with post-COVID-19, indicating the predominance of.
... They were found to be effective in reducing viral load in COVID-19 patients. Some other examples of the repurposed drugs against COVID-19 include sofosbuvir, ribavirin, streptomycin, teicoplanin, and other antibiotics [47][48][49][50][51][52][53]. Drug repurposing is an innovative approach to defining a second medical use of the shelved therapeutic compounds, but its flip side could be challenging, such as drug resistance, etc. [54]. ...
Background: P7 viroporin in HCV is a cation-selective ion channel-forming protein, functional in the oligomeric form. It is considered to be a potential target for anti-HCV compounds due to its crucial role in viral entry, assembly and release.
Method
Conserved crucial residues present in HCV p7 protein were delineated with a specific focus on the genotypes 3a &1b prevalent in India from the available literature. Using the Flex-X docking tool, a library of FDA-approved drugs was docked on the receptor sites prepared around crucial residues. In the present study, we propose drug repurposing to target viroporin p7, which may help in the rapid development of effective anti-HCV therapies.
Results
With our approach of poly-pharmacology, a variety of drugs currently identified classified as antibiotics, anti-parasitic, antiemetic, anti-retroviral, and anti-neoplastic were found to dock successfully with the p7 viroporin. Noteworthy among these are general-purpose cephalosporin antibiotics, leucal, phthalylsulfathiazole, and granisetron, which may be useful in acute HCV infection and anti-neoplastic sorafenib and nilotinib, which may be valuable in advanced HCV-HCC cases.
Conclusion
This study could pave the way for quick repurposing of these compounds as anti-HCV therapeutics.
The management of coronavirus disease-2019 (COVID-19) is witnessing a change as we learn more about the pathophysiology and the severity of the disease. Several randomized controlled trials (RCTs) and meta-analysis have been published over the last few months. Several interventions and therapies which showed promise in the initial days of the pandemic have subsequently failed to show benefit in well-designed trials. Understanding of the methods of oxygen delivery and ventilation have also evolved over the past few months. The Indian Society of Critical Care Medicine (ISCCM) has reviewed the evidence that has emerged since the publication of its position statement in May and has put together an addendum of updated evidence.
How to cite this article: Mehta Y, Chaudhry D, Abraham OC, Chacko J, Divatia J, Jagiasi B, et al. Critical Care for COVID-19 Affected Patients: Position Statement of the Indian Society of Critical Care Medicine. Indian J Crit Care Med 2020;24(Suppl 5):S225–S230.
Background: A definitive treatment of SARS CoV-2 is yet to arrive and the human death toll rises exponentially globally. In this health emergency, it might be useful to look into the old therapies which could be effective against the virus. In vitro research showed Ivermectin could decrease the concentration of coronavirus 4000 to 5000 folds in living lung tissue.
Aim: In this prospective study a combination of Ivermectin and Doxycycline will be evaluated therapeutically to treat COVID-19 patients.
Methods: 100 COVID-19 patients were enrolled in this study with a predefined inclusion and exclusion criteria. RT- PCR of the SERS-CoV-2 will be done at designated government hospitals. The clinical features and response to treatment were noted according to a dedicated protocol.
Results: In this study male and female were 64 and 36 respectively, the age ranged between 8 to 84 years. Retesting was done between 4 and 18 days of starting medication. All patients tested negative and their symptoms improved within 72 hours. There were no noticeable side effects.
Conclusion: Combination of Ivermectin and doxycycline was found to be very effective in viral clearance in mild and moderately sick COVID-19 patients. Medical societies and institutions should undertake larger multi center studies to validate and recommend this combination therapy to include in national guidelines
Importance:
No therapy to date has been shown to improve survival for patients infected with SARS-CoV-2. Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in vitro but clinical response has not been previously evaluated.
Objective:
To determine whether Ivermectin is associated with lower mortality rate in patients hospitalized with COVID-19.
Design and Setting:
Retrospective cohort study of consecutive patients hospitalized at four Broward Health hospitals in South Florida with confirmed SARS-CoV-2. Enrollment dates were March 15, 2020 through May 11, 2020. Follow up data for all outcomes was May 19, 2020.
Participants:
280 patients with confirmed SARS-CoV-2 infection (mean age 59.6 years [standard deviation 17.9], 45.4% female), of whom 173 were treated with ivermectin and 107 were usual care were reviewed. 27 identified patients were not reviewed due to multiple admissions, lack of confirmed COVID results during hospitalization, age less than 18, pregnancy, or incarceration.
Exposure:
Patients were categorized into two treatment groups based on whether they received at least one dose of ivermectin at any time during the hospitalization. Treatment decisions were at the discretion of the treating physicians. Severe pulmonary involvement at study entry was characterized as need for either FiO2 ≥50%, or noninvasive or invasive mechanical ventilation.
Main Outcomes and Measures:
The primary outcome was all-cause in-hospital mortality. Secondary outcomes included subgroup mortality in patients with severe pulmonary involvement and extubation rates for patients requiring invasive ventilation.
Results:
Univariate analysis showed lower mortality in the ivermectin group (25.2% versus 15.0%, OR 0.52, 95% CI 0.29-0.96, P=.03). Mortality was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%, OR 0.15, CI 0.05-0.47, P=.001), but there was no significant difference in successful extubation rates (36.1% vs 15.4%, OR 3.11 (0.88-11.00), p=.07). After adjustment for between-group differences and mortality risks, the mortality difference remained significant for the entire cohort (OR 0.27, CI 0.09-0.85, p=.03; HR 0.37, CI 0.19-0.71, p=.03).
Conclusions and Relevance:
Ivermectin was associated with lower mortality during treatment of COVID-19, especially in patients who required higher inspired oxygen or ventilatory support. These findings require randomized controlled trials for confirmation.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Since its first report in December 2019, despite great efforts made in almost every country worldwide, this disease continues to spread globally, especially in most parts of Europe, Iran, and the United States. Here, we update the recent understanding in clinical characteristics, diagnosis strategies, as well as clinical management of COVID-19 in China as compared to Italy, with the purpose to integrate the China experience with the global efforts to outline references for prevention, basic research, treatment as well as final control of the disease. Being the first two countries we feel appropriate to evaluate the evolution of the disease as well as the early result of the treatment, in order to offer a different baseline to other countries. It is also interesting to compare two countries, with a very significant difference in population, where the morbidity and mortality has been so different, and unrelated to the size of the country.
The broad-spectrum antiparasitic agent ivermectin has been very recently found to inhibit SARS-CoV-2 in vitro and proposed as a candidate for drug repurposing in COVID-19. In the present report the in vitro antiviral activity end-points are analyzed from the pharmacokinetic perspective. The available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations are not likely to be attainable in humans.
There are currently no proven or approved treatments for coronavirus disease 2019 (COVID‐19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID‐19 are treated with these agents and more evidence accumulates, there continues to be no high‐quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto‐immune conditions, and provided a component in the original rationale for their use in patients with COVID‐19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID‐19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID‐19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID‐19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case‐by‐case basis after rigorous consideration of the risks and benefits of this therapeutic approach.
Introduction: Caly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5 uM. The concentration resulting in 50% inhibition (IC50, 2 uM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted.
Method: Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 ug/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose.
Results: Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 uM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 uM).
Conclusions: The likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.
The broad-spectrum antiparasitic agent ivermectin has been very recently found to inhibit SARS-CoV-2 in vitro and proposed as a candidate for drug repurposing in COVID-19. In the present report the in vitro antiviral activity end-points are analyzed from the pharmacokinetic perspective. The available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations are not likely to be attainable in humans.
Currently, there is not any specific effective anti-viral treatment for COVID-19. Although most of the COVID-19 patients have mild or moderate courses, up to 5-10% can have severe, potentially life-threatening course and there is an urgent need for effective drugs. Optimized supportive care remains the mainstay of therapy. There have been more than 300 clinical trials going on, various antiviral and immunomodulating agents are in various stages of evaluation for COVID-19 in those trials and some of them will be published in the next couple of months. Despite the urgent need to find an effective antiviral treatment for COVID-19 through randomized controlled studies, certain agents are being used all over the world based on either in-vitro or extrapolated evidence or observational studies. The most frequently used agents both in Turkey and all over the world including chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir and remdesivir will be reviewed here .Nitazoxanide and ivermectin were also included in this review as they have recently been reported to have an activity against SARS-CoV-2 in-vitro and are licensed for the treatment of some other human infections.
Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.
Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
Background:
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection.
Methods:
The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile.
Results:
Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.
Conclusions:
Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
Background:
An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date.
Methods:
In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done.
Findings:
From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats.
Interpretation:
Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.
Funding:
The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).
Background:
A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients.
Methods:
All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not.
Findings:
By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
Interpretation:
The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies.
Funding:
Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
Ivermectin is one of the most important drugs in veterinary and human medicine for the control of parasitic infection and was the joint focus of the 2015 Nobel Prize in Physiology or Medicine, some 35 years after its remarkable discovery. Although best described for its activity on glutamate-gated chloride channels in parasitic nematodes, understanding of its mode of action remains incomplete. In the field of veterinary medicine, resistance to ivermectin is now widespread, but the mechanisms underlying resistance are unresolved. Here we discuss the history of this versatile drug and its use in global health. Based on recent studies in a variety of systems, we question whether ivermectin could have additional modes of action on parasitic nematodes.
Doxycycline is a member of the tetracycline class of antibiotics and has been used clinically for more than 40 years. It is a well-tolerated drug that is bacteriostatic and acts via the inhibition of bacterial ribosomes. It is generally given at a dose of 100-mg daily or twice daily. It is well absorbed and has generally good tissue penetration. The serum half-life is 18–22 hours and dosage does not need to be adjusted in the presence of renal or hepatic impairment. Major side effects are gastro-intestinal and dermatological and it is generally contra-indicated in pregnancy or childhood because of concerns about discolouration of developing teeth and potential effects on growing bones. Drug interactions are not common although can occur with the concomitant use of methotrexate and the oral contraceptive pill, and its absorption can be reduced by the co-administration with some antacids and iron preparations. It has activity against many organisms, including Gram-positives, Gram-negatives and atypical bacteria. In addition, it appears to have some potentially clinically useful anti-inflammatory properties.
The presentation of exogenous protein antigens in a major histocompatibility complex class I-restricted fashion to CD8+ T cells is called cross-presentation. We demonstrate that cross-presentation of soluble viral antigens (derived from hepatitis C virus [HCV], hepatitis B virus [HBV], or human immunodeficiency virus) to specific CD8+ T cell clones is dramatically improved when antigen-presenting dendritic cells (DCs) are pulsed with the antigen in the presence of chloroquine or ammonium chloride, which reduce acidification of the endocytic system. The export of soluble antigen into the cytosol is considerably higher in chloroquine-treated than in untreated DCs, as detected by confocal microscopy of cultured cells and Western blot analysis comparing endocytic and cytosolic fractions. To pursue our findings in an in vivo setting, we boosted groups of HBV vaccine responder individuals with a further dose of hepatitis B envelope protein vaccine with or without a single dose of chloroquine. Although all individuals showed a boost in antibody titers to HBV, six of nine individuals who were administered chloroquine showed a substantial CD8+ T cell response to HBV antigen, whereas zero of eight without chloroquine lacked a CD8 response. Our results suggest that chloroquine treatment improves CD8 immunity during vaccination.
An epidemic caused by SARS-Coronavirus-2 (SARS-CoV-2) infection has appeared in Wuhan City in December 2019 and subsequently spread in China. The disease has shown a "clustering epidemic" pattern, and family-clustered onset has been the main characteristic. We collected data from 130 cases from 35 cluster-onset families (COFs) and 41 cases from 16 solitary-onset families (SOFs). The incidence 2019 coronavirus disease (COVID-19) in COFs was significantly higher than that of SOFs. Our study also showed that patients with exposure to high-risk factors (respiratory droplets and close contact), advanced age, and comorbidities were more likely to develop COVID-19 in the COFs. In addition, advanced age and elevated neutrophil/lymphocyte ratio (NLR) were risk factors for death in patients with SARS-CoV-2 infection in the COFs.
Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
Hydroxychloroquine and azithromycin have clinical promise to treat COVID-19, although its mechanism of action to inhibit the replication of coronavirus is unclear. Using molecular modeling and recent discoveries made by this lab on the structure of nucleic acids, a mechanism of action is developed for hydroxychloroquine (HCQ) and azithromycin (AZR) to inhibit the replication of the coronavirus disease COVID-19. The mechanism involves: (1) binding the Cl end-element of HCQ through ionic means to adjacent phosphate groups of the uracil nucleotide; (2) forming an intermolecular hydrogen bond of an NH group of HCQ to an open oxygen element of uracil; (3) binding OH end group of HCQ through ionic means with adjacent phosphate groups of the adenine nucleotide. The mechanism of action is extended to AZR as a drug delivery vector that collects HCQ and two ions of positive two charge, such as Mg2+, Zn2+ or Ca2+, and delivers the assembly to a secondary structure of single-strand RNA. As with HCQ, the structural biology of AZR is compatible for use as a collection and delivery vesicle including: (1) open access for the Cl end element and the NH group of HCQ to align and bind with Uracil, and (2) the ability to deliver and bind through ionic coupling of the OH end group of HCQ to the adenine nucleotide. The molecular ionic attachment of HCQ to RNA nucleotides enabled by AZR results in the inhibition of the replication capability of the coronavirus disease COVID-19.
Background
We need an effective treatment to cure COVID-19 patients and to decrease virus carriage duration.
Methods
We conducted an uncontrolled non-comparative observational study in a cohort of 80 relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin over a period of at least three days, with three main measurements: clinical outcome, contagiousness as assessed by PCR and culture, and length of stay in infectious disease unit (IDU).
Results
All patients improved clinically except one 86 year-old patient who died, and one 74 year-old patient still in intensive care. A rapid fall of nasopharyngeal viral load was noted, with 83% negative at Day7, and 93% at Day8. Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day5. Consequently patients were able to be rapidly discharged from IDU with a mean length of stay of five days.
Conclusion
We believe there is urgency to evaluate the effectiveness of this potentially-life saving therapeutic strategy at a larger scale, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold and to decrease duration of carriage and avoid the spread of the disease. Furthermore, the cost of treatment is negligible.
Currently there is a race against time to identify prophylactic and therapeutic treatments against COVID‐19. Until these treatments are developed, tested and mass produced, it might be prudent to look into existing therapies that could be effective against this virus. Based on the available evidence we believe that tetracyclines may be effective agents in the treatment of COVID‐19. Tetracyclines (e.g. tetracycline, doxycycline, and minocycline) are highly lipophilic antibiotics that are known to chelate zinc compounds on matrix metalloproteinases (MMPs)1. Coronaviruses are also known to heavily rely on host MMPs for survival, cell infiltration, cell to cell adhesion, and replication, many of which have zinc as part of their MMP complex2,3. It is possible that the zinc chelating properties of tetracyclines may also aid in inhibiting COVID‐19 infection in humans limiting their ability to replicate within the host.
Background
Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads.
Patients and methods
French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point.
Results
Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms.
Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.
Conclusion
Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
Background:
Onchocerciasis, also known as "river blindness," is a parasitic disease that is caused by infection from the filarial nematode (roundworm), Onchocerca volvulus. Nematodes are transmitted from person to person by blackflies of the Simulium genus, which usually breed in fast flowing streams and rivers. The disease is the second leading infectious cause of blindness in endemic areas.Ivermectin (a microfilaricide) is widely distributed to endemic populations for prevention and treatment of onchocerciasis. Doxycycline, an antibiotic, targets Wolbachia organisms that are crucial to the survival of adult onchocerca (macrofilaricide). Combined treatment with both drugs is believed to cause direct microfilarial death by ivermectin and indirect macrofilarial death by doxycycline. Long-term reduction in the numbers of microfilaria in the skin and eyes and in the numbers of adult worms in the body has the potential to reduce the transmission and occurrence of onchocercal eye disease.
Objectives:
The primary aim of this review was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocerciasis. The secondary aim was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal ocular lesions in communities co-endemic for onchocerciasis and Loa loa (loiasis) infection.
Search methods:
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 7, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), PubMed (1948 to July 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to July 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 1 July 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 July 2015.
Selection criteria:
We included randomized controlled trials (RCTs) that had compared doxycycline plus ivermectin versus ivermectin alone. Participants with or without one or more characteristic signs of ocular onchocerciasis resided in communities where onchocerciasis was endemic.
Data collection and analysis:
Two review authors independently assessed trial eligibility and extracted data. We used standard methodological procedures as expected by Cochrane.
Main results:
We identified three RCTs including a total of 466 participants with a diagnosis of onchocerciasis. All trials compared doxycycline plus ivermectin versus ivermectin alone. One study investigated improvement in visual impairment at six-month follow-up; the other two studies measured microfilarial loads in skin snips to assess sustained effects of treatment at follow-up of 21 months or longer. The studies were conducted at various centers across three countries (Cameroon, Ghana, and Liberia). We judged all studies to be at overall high risk of bias because of inadequate randomization and lack of masking (one study), missing data (two studies), and selective outcome reporting (three studies).Only one study measured visual outcomes. This study reported uncertainty about the difference in the proportion of participants with improvement in visual impairment at six-month follow-up for doxycycline plus ivermectin compared with ivermectin alone (risk ratio (RR) 1.06, 95% confidence interval (95% CI) 0.80 to 1.39; 240 participants; very low-quality evidence). No participant in either group showed improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at six-month follow-up. More participants in the doxycycline plus ivermectin group than in the ivermectin alone group showed improvement in iridocyclitis (RR 1.24, 95% CI 0.69 to 2.22) and punctate keratitis (RR 1.43, 95% CI 1.02 to 2.00) at six-month follow-up; however, we graded these results as very low quality.Two studies reported that a six-week course of doxycycline may result in Wolbachia depletion and macrofilaricidal and sterilizing activities in female Onchocerca worms; however, no analysis was possible because data were missing and incomplete (graded evidence as very low quality). Adverse events were reported in 16 of 135 (12%) participants in one of these studies and included itching, headaches, body pains, and vertigo; no difference between treatment groups was reported for any adverse event. The second study reported that one (1.3%) participant in the doxycycline plus ivermectin group had bloody diarrhea after treatment was initiated.
Authors' conclusions:
Available evidence on the effectiveness of doxycycline plus ivermectin compared with ivermectin alone in preventing and treating onchocerciasis is unclear. Limited evidence of very low quality from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, effects on vision-related outcomes are uncertain. Future studies should consider the effectiveness of treatments in preventing visual acuity and visual field loss and their effects on anterior and posterior segment lesions, particularly chorioretinitis. These studies should report outcomes in a uniform and consistent manner at follow-up of three years or longer to allow detection of meaningful changes in vision-related outcomes.
Organization WH Review of side effects and toxicity of chloroquine
- H Weniger
Weniger H, Organization WH Review of side effects and
toxicity of chloroquine. 1979.https://apps.who.int/iris/handle/10665/65773. Accessed March thirty-first, 2020.
Clinical findings in a group of patients infected with the 2019 novel Coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series
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novel Coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series." BMJ, 2020, p. m792. [CrossRef ]
Pharmacokinetic bases of the hydroxychloroquine response in COVID-19: implications for therapy and prevention
- Andrea Savarino
- Mohammad Tarek
Savarino, Andrea, and Mohammad Tarek. "Pharmacokinetic
bases of the hydroxychloroquine response in COVID-19: implications for therapy and prevention." 2020.
ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19
- Juliana C Rajter
Rajter, Juliana C., et al. "ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin
is Associated with Lower Mortality in Hospitalized Patients with COVID19." 2020.
The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19
- Virginia D Schmith
Schmith, Virginia D., et al. "The Approved Dose of Ivermectin Alone is not the Ideal
Dose for the Treatment of COVID-19." 2020.