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Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

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... 100) revealed a reduction in fever, boost computerized tomography scan of lung, and limiting the convalescent time. A clinical trial from France also used CQ in some of infected patients with COVID-19 claimed to have positive clinical outcomes (68). Manli and his team work 2020 (66) and Wang et al., 2020 (20) also observed that remdesivir and CQ are highly effective in the control of SARS-CoV-2 infection in vitro, promising the potentially effective use of these two drugs as combination for treatment and management of COVID 19 in future. ...
... Manli and his team work 2020 (66) and Wang et al., 2020 (20) also observed that remdesivir and CQ are highly effective in the control of SARS-CoV-2 infection in vitro, promising the potentially effective use of these two drugs as combination for treatment and management of COVID 19 in future. Thus an antimalarial drug, CQ believed to be one of the drug candidates that show to have good supporting effects on SARS-CoV-2 at the cellular level (68). ...
Article
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Unusual pneumonia result from unknown pathogen was emerged in December 2019 in a seafood market of Wuhan city in China. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV) which has taken the world to the edge of health emergency. On 11 th March 2020, COVID-19 was declared a pandemic by the World Health Organization. SARS-CoV-2 belongs to the family of Coronaviridae. Corona virus has been reported to cause similar morbific impacts on the lower respiratory system. Transmits occurs when people breathe in air contaminated by droplets and small airborne particles. Transmission can also occur if sprayed with contaminated fluids, in the eyes, nose or mouth. People remain contagious for up to 20 days, and can spread the virus even if they do not develop any symptoms. Although this disease primarily targets lungs, damages in other organs, such as heart, kidney, liver, and testis, may occur.
... Although the main symptoms are confined to the respiratory system, non-respiratory complications such as the intestinal tract, renal, hepatic, cardiovascular system, central and peripheral nervous system, and lymphocytopenia have been reported 8,9 . Additionally, the main para-clinical features include leukocytosis, lymphopenia, elevated C-reactive protein (CRP), and evidence of ground-glass opacity on chest computed tomography (CT) 10 . In clinical management, several investigational therapeutics such as hydroxychloroquine, azithromycin, ribavirin, interferon, lopinavir-ritonavir remdesivir, favipiravir, and corticosteroids have been used. ...
... The laboratory results of patients are also summarized in Table 3. Laboratory parameters including LDH, Creatinine, AST, ALT, and neutrophil to lymphocyte ratio were statistically different between surviving and non-survived groups. The results of hospitalization also showed that the median time of hospitalization in survived patients was 7 (5-11) days and in on-survived patients was 9 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) days (P= 0.129). Using linear regression and stepwise approach, all variables were entered to find a model to predict mortality. ...
Article
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Background: Coronavirus disease 2019 (COVID-19) is a concern in the medical community as the virus spreads around the world. It has a heavy global burden, particularly in low-income countries. This virus has its specific outcomes in each population. Hence, it is necessary to design studies to find the epidemiological behaviour of this virus. Materials and Methods: This cross-sectional study was conducted in the Labbafinezhad hospital, Tehran, Iran. Demographic features include age, sex, past medical history, drug history, habitual file, influenza vaccination history, recent exposure history, clinical symptoms or signs, and the recorded symptoms. The clinical examination and para-clinical assessment, including chest computed tomography (CT) and laboratory testing on admission, were recorded. Results: It was found that patients with a history of kidney transplantation, high level of LDH, high level of AST, and increased neutrophil to lymphocyte ratio are most at risk of death. Conclusion: Parameters mentioned could help practitioners predict patient outcomes, and necessary interventions could be considered in this regard.
... In vitro studies and smaller clinical trials held in China and France have suggested that chloroquine and hydroxychloroquine are effective in reducing viral replication and consequently decreasing viral load in numerous infections including those caused by SARS-associated coronavirus (CoV) and MERS-CoV. [7][8][9] Chloroquine has been widely used for over half a century for the treatment of malaria in different regions of the world and figures in the World Health Organization (WHO) list of essential medications. ...
... Systematic analysis Italy Chloroquine is widely used, safe, cheap, and shown to be effective in viral infections in preclinical studies Specific preclinical evidence and expert opinions suggest potential use against SARS-CoV-2 A search in trial registries shows that 23 clinical trials are on-going in China There is an urgent need of high-quality clinical data from different geographic areas Chloroquine and Hydroxychloroquine as available weapons to fight COVID-19 [8] March 14,2020 A review of evidence from in vitro studies systematic review and recommendations ...
Article
Background: The coronavirus disease-2019 (COVID-19) pandemic is coming to the fore and has surfaced as a public health emergency of international concern. The lack of vaccines or an effective treatment has led to the global hunt for potential pharmaceuticals in adequately managing this disease. This systematic review highlights the efficacy of chloroquine and its derivative hydroxychloroquine in the treatment of COVID-19 and also explores the safety profile of these drugs. Methods: EMBASE, COCHRANE, and PubMed databases were searched for studies on the use of hydroxychloroquine or chloroquine in the treatment of COVID-19. Results: Twenty articles were selected including expert opinions, National Guidelines, three small randomized controlled trials, and one prospective study. Both hydroxychloroquine and chloroquine have shown promising results including reduction in hospital length of stay and overall mortality. Moreover, concomitant use with azithromycin seems to reduce viral load to a greater extent. Conclusions: Considering the known safety profile of these drugs in the treatment of other diseases, their availability and affordability, chloroquine and hydroxychloroquine are potential antiviral agents in the treatment of COVID-19. However, reported side effects of these drugs when used in conjunction with azithromycin in patients with comorbidities have raised significant safety concerns. High-quality randomized clinical trials are warranted to provide more comprehensive evidence of the safety of these drugs in patients infected with COVID-19.
... Absent an antiviral medication, the virus enters the cell and travels to the lysosome, where the combination of enzymatic activity and low pH causes the virus to be cleaved, releasing replication enzymes and viral RNA. In addition to the rapid increase in endosomal pH, the inhibition of endocytosis and the disruption of endosome-virus fusion have all been hypothesized to be the mechanisms of chloroquine's antiviral effect (Colson et al., 2020). These medications have been associated with the side effects of nausea, vomiting, anorexia, uncontrolled itching, epigastric discomfort, unease, trouble adjusting to new surroundings, and headaches. ...
Chapter
COVID-19 (or Coronavirus Disease) originated in China (Hubei provenance, Wuhan city). The first recorded illness occurred in December 2019. It has affected all parts of the world, and the WHO designated the COVID-19 disease, caused by the new Coronavirus SARS-CoV-2, a pandemic on March 11, 2020. Some debatable speculations indicate that it is a man-made virus, intentionally synthesized in the laboratory but was unintentionally emancipated from a laboratory of Wuhan, China. The primitive theory suggested the spread from the Hunan seafood market of China probably from an animal source. However, this theory is not fully supported. COVID-19 infection has a varying range of signs and symptoms from low fever, dry cough to lower respiratory tract infection, breathing difficulties, pulmonary edema, acute respiratory distress syndrome (ARDS), metabolic acidosis, sepsis, coagulation, lymphopenia, hypoxemia, multiorgan failure, and eventually, mortality. In patients with comorbidity such as diabetes, cardiovascular disease, high blood pressure, stroke, and kidney disease, fatality rate is higher. Young and elderly people are more likely to experience unfavorable outcomes due to poor immunity. There have been several treatment methods explored to tackle the COVID-19 pandemic, including medications, interferon, vaccines, oligonucleotides, peptides, and monoclonal and immunomodulatory antibodies, among other things. The World Health Organization has recommended preventive measures like washing hands, using face masks, sanitizers, and maintaining a safe distance to prevent the spread of the pandemic. One of the promising alternatives is the vaccine. One must take all preventive measures in the pandemic until it becomes feeble.
... CQ/HCQ has been used for COVID-19 treatment in many circumstances, showing promise, especially if used together with Azithromycin (AZM) [27][28][29][30][31][32][33][34][35][36][37][38][39]. ...
Article
Treatments do not replace vaccinations or restrictions, but are practical, effective, and safe means to help to reduce the fatality associated with COVID-19 infection. While no treatment is available and effective for all the current and future variants of COVID-19, treatments reduce the risk of COVID-19 becoming endemic and reduce mortality and collateral damages. The use of Zinc (Zn) for COVID-19 infection is here reviewed. Zn supplementation may help in prevention as well as during the administration of therapies. Zn supplementation reduces the risks of serious outcomes from Covid19 infection. Evidence also suggests that Zn helps in treatments of COVID-19 infection if taken in conjunction with antiviral drugs. The literature supports the use of Zn, with improvements towards a lower risk ranging from 37% in late treatment, RR 0.63 CI [0.53-0.74], to 78% in sufficiency, RR 0.22 CI [0.05-0.96].
... In recent days, different nations have shown interest in the possibility of developing vaccines for the virus. More recently, Chloroquine phosphate, Chloroquine, and Hydroxychloroquine, and Remdesivir [11][12][13][14][15] have been suggested as possible means to treat infected persons. However, this option is subject to clinical trials and approval by the relevant health and food agencies across the world. ...
Article
Full-text available
The outbreak of the coronavirus in Wuhan city, China in December 2019 has taken a different dimension that the World Health Organization declared it PANDEMIC in January 2020. The virus was later code named Covid-19. Covid-19 is now a global concern ravaging the world. Different suggestions on possibilities to control the spread of the virus have been advanced in recent times. Nonpharmaceutical approaches such as partial lockdown, total lockdown, and social distancing have been adopted to reduce the spread of the Covid-19. This study focused on how effective social distancing is to curtail the spread of Covid-19. The objective of this study is to determine the social distancing value measured in meters that could help reduce the spread of the virus. In this study, we proposed a prediction model based on social distancing value and height to investigate whether social distancing will help curtail the spread of the virus. The model is classified as detection and prediction phases. The prediction phase utilizes information from the detection phase to analyse the effect of social distancing value on the spread of Covid-19. The study revealed that as the social distancing value increases, the probability of spread decreases. The result also showed that as the social distancing values increases, the probability of safety from been infected increases. The study concludes that increasing the social distancing value up to three or four meters could reduce the probability of spread and increase the probability of safety from been infected by the virus.
... In vitro based evidence of suppression of activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronavirus strains provoked increased interest in the use of hydroxychloroquine (HCQ) and chloroquine for the treatment of COVID-19 [4][5][6][7][8]. A search of the clinicaltrials.gov ...
Article
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Introduction: COVID-19, caused by the coronavirus SARS-CoV-2 has quickly spread around the world. Currently there is an active search for vaccines and therapeutics, including repurposing of well-known drugs. COVID-19 continues to be a challenge with only a few therapeutic and no chemoprophylactic interventions to combat the virus.
... Hydroxychloroquine 400 mg b.i.d. p.o. on first day and 200 mg b.i.d. after for 7 d: Hydroxychloroquine blocks viral internalization into host cells and it is also effective in terms of modulating the immune response to COVID-19 infection [5][6][7][8][9] (Table 1). ...
Article
Full-text available
... 11,15 Based on these mechanisms of action and clinical experience early in the pandemic, hydroxychloroquine was used as a treatment for COVID-19 in some settings and discussion regarding its efficacy is still in course. 16 Treatment of COVID-19 with hydroxychloroquine has been recommended in many treatment guidelines, including in China, France, Italy, Netherlands, South Korea, United States and in Brazil, where national regulatory agencies have authorized the use of hydroxychloroquine in hospitalized patients. [17][18][19] Our primary aim was to assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for mild to moderate ARDS. ...
Article
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Some studies have shown that secondary infections during the COVID-19 pandemic may have contributed to the high mortality. Our objective was to identify the frequency, types and etiology of bacterial infections in patients with COVID-19 admitted to an intensive care unit (ICU) and to evaluate the results of ICU stay, duration of mechanical ventilation (MV) and in-hospital mortality. It was a single-center study with a retrospective cohort of patients admitted consecutively to the ICU for more than 48 h between March and May 2020. Comparisons of groups with and without ICU- acquired infection were performed. A total of 191 patients with laboratory-confirmed COVID-19 were included and 57 patients had 97 secondary infectious events. The most frequent agents were Acinetobacter baumannii (28.9%), Pseudomonas aeruginosa (22.7%) and Klebsiella pneumoniae (14.4%); multi-drug resistance was present in 96% of A. baumannii and in 57% of K. pneumoniae. The most prevalent infection was ventilator-associated pneumonia in 57.9% of patients with bacterial infections, or 17.3% of all COVID-19 patients admitted to the ICU, followed by tracheobronchitis (26.3%). Patients with secondary infections had a longer ICU stay (40.0 vs. 17 days; p < 0.001), as well as a longer duration of MV (24.0 vs 9.0 days; p= 0.003). There were 68 (35.6%) deaths overall, of which 27 (39.7%) patients had bacterial infections. Among the 123 survivors, 30 (24.4%) had a secondary infections (OR 2.041; 95% CI 1.080 - 3.859). A high incidence of secondary infections, mainly caused by gram-negative bacteria has been observed. Secondary infections were associated with longer ICU stay, MV use and higher mortality.
... The interferon protein alerts/signals other cells to the danger, while the virus is knocked out by the interferon protein. Suppressor of cytokine signaling 1 (SOCS1) is a protein that is encoded by the SOCS1 gene in humans and is used to inhibit this process to avoid cytokine storms [12]. ...
Article
Full-text available
The advent of SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) respectively, eventually ushered in the impactful SARS-COV2 (Severe Acute Respiratory Syndrome Coronavirus 2 which led to the disease described as COVID-19. The LiveWell Initiative LWI drew up Study Protocols for the COVID-19 Response in Africa, using repurposed 4-Aminoquinolines in the treatment of PCR Positively Tested COVID-19 Patients under treatment at the Oyo State Isolation Center. After an initial hypothesis testing and debate of the hypothesis by physicians, pharmacists, virologists and other key scientists...the Study Protocols were put to test. The Principal Investigator at the Oyo State Isolation Center, a well respected Professor of Medicine and former Chief Medical Director of the University College Hospital in Ibadan Oyo State, in collaboration with the LWI Team, Chrisland University and other Key Researchers, arrived at very positive and impactful study outcomes.
... However, the patients' outcome treated with this combination suggested that the curative effect of these drugs is minimal with potentially toxic side effects that might be harmful to the patients 12 . Some other repurposed drugs are also currently used, taking the advantage of drug safety, to treat the COVID-19 patients as a short-term and non-specific solution [13][14][15][16] . Identifying bioactive compounds from the natural sources, which could inhibit SARS-CoV-2 main protease, has been considered as an alternative approach to combat COVID-19. ...
Article
Full-text available
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is highly pathogenic to humans and has created health care threats worldwide. This urgent situation has focused the researchers worldwide towards the development of novel vaccine or small molecule therapeutics for SARS-CoV-2. Although several vaccines have already been discovered and are in use for the masses, no therapeutic medication has yet been approved by FDA for the treatment of COVID-19. Keeping this in view, in the present study, we have identified promising hits against the main protease (M pro ) of SARS-CoV-2 from edible mushrooms. Structure-based virtual screening (VS) of 2433 compounds derived from mushrooms was performed with M pro protein (6LU7). Four promising hits, namely, Kynapcin-12 (M_78), Kynapcin-28 (M_82), Kynapcin-24 (M_83), and Neonambiterphenyls-A (M_366) were identified based on the result of docking, Lipinski’s rule, 100 ns molecular dynamics (MD) simulation and MM/PBSA binding free energy calculations. Finally, the inhibitory properties of these hits were compared with three known inhibitors, baicalein ( 1 ), baicalin ( 2 ), and biflavonoid ( 3 ). Data indicated that M_78, M_82 and M_83 compounds present in edible mushroom Polyozellus multiplex were potent inhibitors of M pro protein (6LU7). It could be concluded that edible mushroom Polyozellus multiplex has potential activity against SARS-CoV-2 infection and identified molecules could be further explored as therapeutic inhibitors against SARS-CoV-2.
... Within the rapid mutability and tremendous appearance of new variants of the SARS-CoV-2 virus, vaccines might lose their specificities and performance [6,7]. In our opinion, classical treatments, like the antimalarial hydroxychloroquine that has been efficaciously used by several infectious centers and has been approved in treating the disease by many authors [8][9][10], are sought as ideal for relieving the infection and saving lives. Alternative medicine also showed great potential in fighting COVID-19 [11,12]. ...
Article
Full-text available
Fighting against the emergent coronavirus disease (COVID-19) remains a big challenge at the front of the world communities. Recent research has outlined the potential of various medicinal herbs to counteract the infection. This study aimed to evaluate the interaction of artemisinin, a sesquiterpene lactone extracted from the Artemisia genus, and its derivatives with the SARS-CoV-2 main protease. To assess their potential use against COVID-19, the interactions of the main active principle of Artemisia with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) was investigated through in silico probing. Our results showed that artemesinin and its derivatives manifested good oral absorption and bioavailability scores (0.55). They potently bound to the Mpro site of action—specifically, to its Cys145 residue. The selected compounds established two to three conventional hydrogen bonds with binding affinities ranging between −5.2 and −8.1 kcal/mol. Furthermore, artemisinin interactions with angiotensin converting enzyme 2 (ACE2) were dependent on the ACE2 allelic variants. The best score was recorded with rs961360700. A molecular dynamic simulation showed sufficient stability of the artemisinin–Mpro complex on the trajectory of 100 ns simulation frame. These binding interactions, together with drug-likeness and pharmacokinetic findings, confirmed that artemisinin might inhibit Mpro activity and explain the ethnopharmacological use of the herb and its possible antiviral activity against SARS-CoV-2 infection inducing COVID-19. Nevertheless, it interacted differently with the various ACE2 allelic variants reported to bind with the SARS-CoV-2 spike protein.
... HCQ is utmost commonly consumed as a first-line medication for auto immune based diseases in patients like systemic lupus erythematosus and rheumatoid arthritis and has increased wide media attention as a promising antiviral drug for usage versus severe acute respiratory syndrome (which causes COVID-19) [1][2][3][4][5][6][7]. Unfortunately, the origination of research on HCQ has preceded to misperception in the rheumatological community concerning the protection consequences of HCQ in its conventional customs. ...
Article
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Selective, sensitive, easy, and fast voltammetric techniques were developed for the analysis of Hydroxychloroquine (HCQ). These analysis were carried out at sodium dodecyl sulphate modified carbon nanotube paste electrode (SDSMCNTPE) using an aqueous 0.2 M phosphate buffer solution as supporting electrolyte. The field emission-scanning electron microscopy, cyclic voltammetry (CV), and electrochemical impedance spectroscopy were used for material characterization. A minute quantity of the SDS surfactant was sufficient to convey an outstanding electrocatalytic action to the electrochemical oxidation nature of HCQ. The HCQ molecule parades only electrochemical oxidation (irreversible) with the transfer of two electrons. The detection of HCQ was carried out through CV method at SDSMCNTPE and bare carbon nanotube paste electrode (BCNTPE). The corresponding analytical curve offered a decent linear nature in the considered HCQ concentration range (10–40 µM) and the detection limit was found to be 0.85 µM. The significant peak to peak split-up was observed between HCQ and interferents with a decent sensitivity and stability. The SDSMCNTPE to be an approachable electrode for the usage in the examination of HCQ independently and in the presence of paracetamol (PC) and ascorbic acid (AA). Thus, they were used to determine HCQ in pharmaceutical formulations and the results that showed good agreement with comparative methods. Furthermore, a mechanism for HCQ electro-oxidation was proposed.
... Many studies have been conducted to identify effective treatment in order to cure symptomatic patients and limit the transmission to the community. Different medications were proposed to be candidates for the treatment of COVID-19; some of these options focused on the use of old antiviral medications and testing their effectiveness against COVID-19 [8,9]. There are contradictory findings against the effectiveness of antimalarial agents such as hydroxychloroquine (HCQ) and chloroquine on Many studies have demonstrated their effectiveness in inhibiting SARS-CoV-2 [10][11][12]. ...
Article
Background The current management practices for patients with COVID-19 consist of infection prevention and supportive care. We aimed to explore the association between negative nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) clearance and different therapeutic interventions. Methods This study is a retrospective cohort study of 93 patients who were admitted to a tertiary hospital in Saudi Arabia with a PCR confirmed diagnosis of COVID-19. There were three intervention subgroups (group A) (n = 45), which included those who received chloroquine or hydroxychloroquine (HCQ) only (A1), those who received chloroquine or HCQ in combination with azithromycin (A2), and those who received chloroquine or HCQ in combination with antiviral drugs with or without azithromycin (A3), as well as one supportive care group (group B) (n = 48). The primary and secondary endpoints were achieving negative SARS-CoV-2 nasopharyngeal PCR samples within five and 12 days from the start of the intervention, respectively. Results A median time of three days (interquartile range (IQR): 2.00-6.50) is needed from the time of starting the intervention/supportive care to the first negative PCR sample. There was no statistically significant difference neither between the percentage of patients in the intervention group and the supportive care group who achieved the primary or secondary endpoint nor in the median time needed to achieve the first negative PCR sample (p > 0.05). Conclusion Prescribing antimalarial medications was not shown to shorten the disease course nor to accelerate the negative PCR conversion rate.
... The majority of the deceased victims are older adults or those who were pre-diagnosed with diabetes, hypertension, rheumatic, cardiac and kidney diseases Palmieri et al., 2020;Silva et al., 2020;Wang et al., 2020;Xiang et al., 2020;Zhou et al., 2020). An effective therapy is still needed; athough some antiviral drugs such as chloroquine (blocking the binding of virion to cell receptor), lopinavir-ritonavir (a HIV protease / CYP450 inhibitor) and remdesivir (an adenosine analogue blocking viral RNA replication) have been repurposed and intensively tested, their efficacy remains to be confirmed in clinical treatment Colson et al., 2020;C. J. Gordon et al., 2020;Ko et al., 2020). ...
Preprint
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Network pharmacology analysis can act as a strategy to identify the pharmacological effect of plant-based bioactive compounds against coronavirus diseases. This study aimed to investigate the potential pharmacological mechanism of a local ethnomedicine (Costus speciosus, Hibiscus rosa-sinensis and Phyllanthus niruri) of Northern Borneo against coronaviruses known as CHP. Compounds in CHP were extracted from databases and screened for their oral bioavailability and drug-likeness before a compound-target network was built. Furthermore, the protein-protein interaction network and pathway enrichment were constructed and analyzed. A compound-target network consisting of 48 putative bioactive compounds targeting 587 candidate genes was identified. A total of 186 coronavirus-related genes were extracted and TP53, STAT3, HSP90AA1, STAT1, and EP300 were predicted to be the key targets. Notably, mapping of these target genes into the target-pathway network illustrated that functional enrichment was on viral infection and regulation of inflammation pathways. Urinatetralin is predicted, for the first time, as a bioactive compound that solely targets STAT3. The results from this study indicate that compounds present in CHP employ STAT3 and its connected pathways as the mechanism of action against coronaviruses. In conclusion, urinatetralin should be further investigated for its potential application against coronavirus infections.
... Chloroquine and Hydroxychloroquine, anti-malarial medications, have been shown to protect against infections caused by various DNA and RNA viruses, including human coronaviruses 45 . CQ and HCQ are indicated to shorten the span of COVID-19 infection 46 . CQ is the primary drug suggested to have efficacy COVID-19 47 . ...
Article
Full-text available
The SARS-CoV-2 virus, accountable for the COVID-19 pandemic, is now sweeping the globe. As a result, as this disease resists testing and adoption of new treatments, repositioning existing medications may provide a quick and appealing method with established safety, features, and dose used. They are not, however, specific or focused. However, numerous medications have been studied for their efficacy and safety in treatment of COVID-19, with the majority currently undergoing clinical trials. The goal is to rapidly expand novel preventative and therapeutic medications, as well as to apply preventive methods such as early patient identification, isolation, and treatment. Moreover, reducing transmission through physical contact is also important. In the fight against this dangerous disease, finding the proper treatment is crucial. This article summarizes several anti-malarial, anti-parasitic, monoclonal antibodies, immunosuppressant, and immunomodulating agents in clinical trials for COVID-19. The purpose of this article is to evaluate and explore the potential roles of several medications now utilized in COVID-19.
... However, several clinical trials are underway; and most of them are focused on relieving the symptoms [15]. Besides, the antiviral efficiency of several already existing drugs has been testified in several studies [16,17]. However, repurposed drugs have proven effective, but their efficacy and safety are still ambiguous [18][19][20]. ...
Article
Full-text available
SARS-CoV-2, a new and fast circulating coronavirus strain, infected over 214 countries and territories worldwide and caused global health emergencies. The absence of appropriate medicines and vaccinations has further complicated the condition. SARS-CoV-2 main protease (M pro) is crucial for its propagation, and it is considered a striking target. This study used several computational approaches to determine the probable antagonist of SARS-CoV-2 M pro from bioactive phytochemicals of Syzygium aromaticum. A total of 20 compounds were screened through in silico approach. The molecular dynamics simulation studies were then carried out for further insights. We found crategolic acid, oleanolic acid, and kaempferol have considerable binding affinity and important molecular contacts with catalytic pocket residues, His41-Cys145. The pharmacological properties through ADMET analysis also showed that these compounds could be used as safe drug candidates. The molecular dynamics simulation study further confirmed these compound's stability with M pro. However, further detailed in-vitro and in-vivo analyses are compulsory to evaluate the real potentiality of identified compounds.
... On the other hand, empirical evidence for HCQ effectiveness in COVID-19 is limited. Currently, a few studies reported the antiviral activity of HCQ against SARS-CoV-2 (144,216). Following the promising results, the usage of HCQ for certain COVID-19 patients improve. However, HCQ is well known to have severe complications and side effects in some cases. ...
Article
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Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.
... Furthermore, HCQ has potential for COVID-19. 16 A method for easily detecting HCQ in patients' urine can aid clinical diagnosis and treatment. ...
Article
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In this study, we developed a facile method for synthesizing dual-emission carbon nanodots (CDs) through trimesic acid and o-phenylenediamine through electrolysis for 2 h. The synthesized CDs were mainly 3-7 nm in size, with an average size of 5.17 nm. The dual-emission fluorescent property of these CDs could be observed under two different excitation wavelengths. The green emission of the CDs could be quenched after the addition of mercury ions or copper ions, and the blue emission of the CDs could be inhibited using hydroxychloroquine (HCQ). Furthermore, the quenched fluorescence of CDs/Cu2+ could be recovered through the addition of glyphosate. We developed a multifunctional chemical sensor by using these special fluorescence materials. Under optimal conditions, the detection limits of mercury ions, glyphosate, and HCQ were 0.42 μM, 1.1 mg L-1, and 0.14 μM, respectively. Moreover, this method can be used to detect mercury ions, glyphosate, and HCQ in environmental water, cereals, and urine samples, respectively.
... Such an emergency throws a challenge to the entire scientific community to work together and come up with an effective antidote against this deadly virus (SARS-CoV-2). Numerous attempts have been made to find useful drugs or vaccines to combat this virus [1][2][3][4]. But till date, no specific drug has been found. ...
Article
Using molecular docking and other studies, 20 compounds extracted from Monochoria hastata (L.) Solms were screened, and their inhibitory efficiency examined against main protease (3CLpro) of SARS CoV-2. All the compounds were found to binding with 3CLpro through van der Waals and electrostatic forces of attractions. Among them, Azelaic dihydrazide (ADZ) was found to have the highest docking score. 3CLpro-ADZ complex was studied by MD simulation. ADZ was found to disrupt the structure of 3CLpro after 2 ns. RMSD and RMSF analysis along with sequence and binding energy analysis suggest that ADZ can be a potential drug against SARS CoV-2.
... Within the rapid mutability and tremendous appearance of new variants of the SARS-CoV-2 virus, vaccines might lose their specificities and performance [6,7]. In our opinion, classical treatments, like the antimalarial hydroxychloroquine that has been efficaciously used by several infectious centers and has been approved in treating the disease by many authors [8][9][10], are sought as ideal for relieving the infection and saving lives. Alternative medicine also showed great potential in fighting COVID-19 [11,12]. ...
Article
Citation: Badraoui, R.; Saoudi, M.; Hamadou, W.S.; Elkahoui, S.; Siddiqui, A.J.; Alam, J.M.; Jamal, A.; Adnan, M.; Suliemen, A.M.E.; Alreshidi, M.M.; et al. Antiviral Effects of Artemisinin and Its Derivatives against SARS-CoV-2 Main Protease: Computational Evidences and Interactions with ACE2 Allelic Variants. Pharmaceuticals 2022, 15, 129.
... The pandemic has affected millions and shows no signs of abating. Multiple treatment options have been evaluated, including chloroquine, lopinavir/ritonavir, azithromycin, remdesivir, monoclonal antibodies to IL-6, and others [1][2][3]. In a short time period, we have expanded our knowledge base on SARS-CoV-2 (the pathogen), host-virus interactions including the receptor molecules that empower the virus to enter cells, key genes that are modulated during the course of COVID-19, and therapies to manage the disease per se. ...
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The role for circulating miRNAs as biomarkers of the COVID-19 disease remains uncertain. We analysed the circulating miRNA profile in twelve COVID-19 patients with moderate-severe disease. This analysis was conducted by performing next generation sequencing (NGS) followed by real-time polymerase chain reaction (RT-qPCR). Compared with healthy controls, we detected significant changes in the circulating miRNA profile of COVID-19 patients. The miRNAs that were significantly altered in all the COVID-19 patients were miR-150-5p, miR-375, miR-122-5p, miR-494-3p, miR-3197, miR-4690-5p, miR-1915-3p, and miR-3652. Infection assays performed using miRNA mimics in HEK-293 T cells determined miR-150-5p to have a crucial role in SARS-CoV-2 infection and this was based on the following data: (i) miR-150-5p mimic lowered in vitro SARS-CoV-2 infection; (ii) miR-150-5p inhibitor reversed the effects of miR-150-5p mimic on SARS-CoV-2 infection of cells; and (iii) a novel miRNA recognition element (MRE) was identified in the coding strand of SARS-CoV-2 nsp10, the expression of which could be inhibited by miR-150-5p mimic. Our findings identified crucial miRNA footprints in COVID-19 patients with moderate-severe disease. A combination of co-transfection and Western blotting experiments also determined the ability of miR-150-5p to inhibit SARS-CoV-2 infection via directly interacting with MRE in the coding strand of nsp10. Our investigation showed that a sharp decline in the miR-150-5p plasma levels in COVID-19 patients may support enhanced SARS-CoV-2 infection. Furthermore, this study provides insight into one possible mechanism by which COVID-19-induced changes to miR-150-5p levels may promote SARS-CoV-2 infection via modulating nsp10 expression.
... Recently, it has been shown that omicron enters cells mainly by TMPRSS2-independent fusion following endocytosis after processing by cathepsin B or L, while the other variants enter by fusion following proteolytic processing by TMPPRSS2 [68]. Chloroquine is a weak base compound, referred to as lysosomotropic drug, which accumulates in endosomes and lysosomes, and increased lysosomal pH leading to a decrease in lysosomal protease activities and, finally, prevents viral entry into host cells [69,70]. Chloroquine also inhibits viral replication due to the lack of enzyme functional activities at a high pH [71]. ...
Article
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Over the past two years, several variants of SARS-CoV-2 have emerged and spread all over the world. However, infectivity, clinical severity, re-infection, virulence, transmissibility, vaccine responses and escape, and epidemiological aspects have differed between SARS-CoV-2 variants. Currently, very few treatments are recommended against SARS-CoV-2. Identification of effective drugs among repurposing FDA-approved drugs is a rapid, efficient and low-cost strategy against SARS-CoV-2. One of those drugs is ivermectin. Ivermectin is an antihelminthic agent that previously showed in vitro effects against a SARS-CoV-2 isolate (Australia/VI01/2020 isolate) with an IC50 of around 2 µM. We evaluated the in vitro activity of ivermectin on Vero E6 cells infected with 30 clinically isolated SARS-CoV-2 strains belonging to 14 different variants, and particularly 17 strains belonging to six variants of concern (VOC) (variants related to Wuhan, alpha, beta, gamma, delta and omicron). The in vitro activity of ivermectin was compared to those of chloroquine and remdesivir. Unlike chloroquine (EC50 from 4.3 ± 2.5 to 29.3 ± 5.2 µM) or remdesivir (EC50 from 0.4 ± 0.3 to 25.2 ± 9.4 µM), ivermectin showed a relatively homogeneous in vitro activity against SARS-CoV-2 regardless of the strains or variants (EC50 from 5.1 ± 0.5 to 6.7 ± 0.4 µM), except for one omicron strain (EC50 = 1.3 ± 0.5 µM). Ivermectin (No. EC50 = 219, mean EC50 = 5.7 ± 1.0 µM) was, overall, more potent in vitro than chloroquine (No. EC50 = 214, mean EC50 = 16.1 ± 9.0 µM) (p = 1.3 × 10−34) and remdesivir (No. EC50 = 201, mean EC50 = 11.9 ± 10.0 µM) (p = 1.6 × 10−13). These results should be interpreted with caution regarding the potential use of ivermectin in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results into actual clinical treatment in patients.
... Reduces pneumonia with least toxic effects [42,43]. ...
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Coronavirus disease 2019 (COVID-19) is rapidly expanding in U.S.A, Spain and Europe and to respond to it, countries are using national lockdown strategies and restrictions on international travels. While in India, strategies implemented proves to be more efficient in controlling the community spread of the disease. Our statistical analysis was based on the publicly available data of the new daily confirmed cases reported from various countries and about the ongoing trials of several diagnostic and treatment methods. Real time RT-PCR proved its inefficiency as a diagnostic tool, thus the country focused on the ELISA based humoral response assay and included Convalescent Plasma therapy as a core treatment protocol and this helped India to ensure higher recovery rate (22.5%) in a short duration. Complete lockdown till 3rd and imposition of stringent measures helped the country to limit the death toll (3%). Union Ministry of Health and Family Welfare is monitoring around 9.45 lakh suspected cases. From our statistical analysis, it is clear that India is in a better position than many other countries in case of survival rates but immediate actions have to be taken so as to avoid disease spread in the states with higher population density. Convalescent Plasma therapy should be implemented and developing effective diagnostic tools and anti-viral drugs should be of major concern.
... La hidroxicloroquina es más potente que la cloroquina y tiene mejor perfil de seguridad. 25 La posibilidad de prolongación del QTc y otros efectos adversos debe alertar al clínico. 26 Un pequeño estudio francés sin distribución al azar (disponible como impresión previa) concluyó que la hidroxicloroquina más azitromicina se asoció con carga viral del 100% indetectable. ...
Article
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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the rapid spread of a disease, affecting thousands of people worldwide. On March 11, 2020, the World Health Organization declared the COVID-19 outbreak as a pandemic. The virus has been identified as the cause of an outbreak of pneumonia of unknown cause in Wuhan city, China, in December 2019. The clinical presentation is that of a respiratory infection with a severity of symptoms ranging from mild illness similar to the common cold up to severe viral pneumonia causing life-threatening acute respiratory distress syndrome. There is no specific treatment available that has been clinically proven, other than supportive treatment.
... These results made hydroxychloroquine one of the first antivirals to be tested in the most severe cases of Covid-19. A famous (and peculiar) French microbiologist, Didier Raoult, advisor to the French government in the fight against the pandemic, quickly published that this compound was effective in humans against the coronavirus (Colson et al. 2020). ...
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Following the declaration, in March 2020, of the Covid-19 pandemic , there was an escalation of disinformation, involving multiple actors and reaching global dimensions. In this article, we analyze the possible causes and characteristics of the spread of disinformation on this issue. Disinformation about science can be explained by the distance that separates scientific knowledge from common knowledge and the difficult relationship between science and the media. The pandemic has multiplied the number of scientific publications and has accelerated publication rates, which has contributed to the dissemination of provisional, erroneous , or totally false information. A process of politicization has also developed, which has led to misinformation. In addition, the need to confront this health crisis has led society to demand accurate information from science, despite the fact that in many cases there is only uncertainty. The experience of this pandemic highlights the importance of providing citizens with accessible and rigorous knowledge that creates confidence in science. To achieve this, it is necessary to have specialized professionals capable of providing rigorous information, not only on the results but also on the research processes. ARTICLE HISTORY
... In cell cultures, chloroquine was effective even when viral particles had already entered cells by trapping the endosomes via pH increase, disturbing fusion of the viral envelope with the endosomal membrane [54]. Based on the findings of 1 study, a 500-mg oral dose of chloroquine given once or twice a day was recommended for COVID-19 treatment [57]. ...
Article
The coronavirus disease 2019 (COVID-19) pandemic rapidly spread globally. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, is a positive-sense single-stranded RNA virus with a reported fatality rate ranging from 1% to 7%, and people with immune-compromised conditions, children, and older adults are particularly vulnerable. Respiratory failure and cytokine storm-induced multiple organ failure are the major causes of death. This article highlights the innate and adaptive immune mechanisms of host cells activated in response to SARS-CoV-2 infection and possible therapeutic approaches against COVID-19. Some potential drugs proven to be effective for other viral diseases are under clinical trials now for use against COVID-19. Examples include inhibitors of RNA-dependent RNA polymerase (remdesivir, favipiravir, ribavirin), viral protein synthesis (ivermectin, lopinavir/ritonavir), and fusion of the viral membrane with host cells (chloroquine, hydroxychloroquine, nitazoxanide, and umifenovir). This article also presents the intellectual groundwork for the ongoing development of vaccines in preclinical and clinical trials, explaining potential candidates (live attenuated-whole virus vaccines, inactivated vaccines, subunit vaccines, DNA-based vaccines, protein-based vaccines, nanoparticle-based vaccines, virus-like particles and mRNA-based vaccines). Designing and developing an effective vaccine (both prophylactic and therapeutic) would be a long-term solution and the most effective way to eliminate the COVID-19 pandemic.
... For the post-exposure prophylaxis against SARS-CoV-2 infection, hydroxychloroquine is currently under analysis in clinical trials for the treatment of patients with COVID- 19 [45]. Hydroxy-chloroquine has been used for long periods; thus, it would be one of the suitable choices for the treatment of this virus [46]. Hydroxychloroquine has been used for intracellular bacterial infections for 30 years, particularly to treat the bacterium Coxiella burnetiid [47,48]. ...
Article
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COVID-19 is an infectious pandemic disease which is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Up to date, scientists are trying to identify a new specific antiviral drug to overcome this disease. Different methods are under study and evaluation in the entire world to control the virus, including blood plasma, blood purification, and antimicrobial and antiviral agents; however, there are no approved drugs yet. This review is focused on the conducted clinical trials worldwide, including the Iraq-Kurdistan region, China, USA, and Europe, to find relevant data on the agents with potential efficacy to treat the COVID-19 infection. The utmost commonly assessed therapies for this disease were chloroquine phosphate, hydroxyl-chloroquine, azithromycin, lopinavir/ritonavir, favipiravir, remdesivir, and alternatively, blood plasma, ivermectin in combination with doxycycline, and dexamethazone. This review suggests that blood plasma transfusion, the combination of hydroxyl-chloroquine with azithromycin, and remdesivir were the most abundant and efficient therapies. Thus, more light could be shed on these particular drugs on the road of drug investigation against COVID-19 pneumonia.
... The number of early SARS-CoV-2 infections in Daegu increased rapidly, but numerous hospitals in South Korea were not well prepared to deal with this unexpected catastrophic event. Accordingly, hospitals in South Korea had to treat SARS-CoV-2 patients with management methods such as standard supportive care alone or repositioning of old drugs which include antibiotics such as 3 rd cephalosporin, azithromycin, etc, or antiviral agents such as hydroxychloroquine (HQ), lopinavir/ ritonavir (LoP/R), etc [3][4][5]. Also, these repositioned drugs were recommended by some nonrandomized studies, and Emergency Use Authorization of FDA suggested using antibacterial, antiviral, antiinflammatory drugs to treat SARS-CoV-2 [5][6][7]. ...
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Objectives To assess efficacy and safety of the combined treatment of antibiotics (3rd-generation cephalosporin and azithromycin) and antiviral agents (lopinavir/ritonavir or hydroxychloroquine) on moderate COVID-19 patients in South Korea. Methods A retrospective cohort study of the 358 laboratory-confirmed SARS-CoV-2 (COVID-19) patients was conducted. 299 patients met inclusion criteria for analysis. Propensity score matching (PSM) and Cox regression method were used to control and adjust for confounding factors. Mild to moderate COVID-19 patients were managed with either CA/LoP (cephalosporin, azithromycin, and lopinavir/ritonavir) (n = 57), CA/HQ (cephalosporin, azithromycin, and hydroxychloroquine) (n = 25) or standard supportive care (n = 217). We analyzed the association between treatment group and standard supportive group in terms of three endpoints: time to symptom resolution, time to viral clearance, and hospital stay duration. Using propensity-score matching analysis, three rounds of propensity-matching analysis were performed to balance baseline characteristics among three cohorts. Results Kaplan-Meier curves fitted using propensity score-matched data revealed no significant differences on time to symptom resolution, time to viral clearance, hospital stay duration among the three treatment arms (CA/LoP vs Standard, log-rank p-value = 0.2, 0.58, and 0.74 respectively for the three endpoints) (CA/HQ vs Standard, log-rank p-value = 0.46, 0.99, and 0.75 respectively). Similarly, Cox regression analysis on matched cohorts of CA/LoP and standard supportive group showed that hazard ratios of time to symptom resolution (HR: 1.447 [95%-CI: 0.813–2.577]), time to viral clearance(HR: 0.861, [95%-CI: 0.485–1.527]), and hospital stay duration (HR: 0.902, [95%-CI: 0.510–1.595]) were not significant. For CA/HQ and standard supportive group, hazard ratios of the three endpoints all showed no statistical significance (HR: 1.331 [95%-CI:0.631–2.809], 1.005 [95%-CI:0.480–2.105], and 0.887, [95%-CI:0.422–1.862] respectively). No severe adverse event or death was observed in all groups. Conclusions Combined treatment of 3rd cephalosporin, azithromycin and either low-dose lopinavir/ritonavir or hydroxychloroquine was not associated with better clinical outcomes in terms of time to symptom resolution, time to viral clearance, and hospital stay duration compared to standard supportive treatment alone. Microbiological evidence should be closely monitored when treating SARS-CoV-2 patients with antibiotics to prevent indiscreet administration of empirical antimicrobial treatments.
... Preclinical studies showed that chloroquine has antiviral activity against SARS-CoV-2 (Keyaerts et al., 2004), which could contribute to the blockade of coronavirus infection . Similarly, studies in cell cultures showed that the combination of remdesivir/chloroquine or hydroxychloroquine was highly effective in controlling SARS-CoV-2 infection (Colson et al., 2020). ...
Chapter
The specific contribution of this chapter will be to provide information about the potential therapeutic effects of antidepressant drugs in COVID-19 disease as well as their potential mechanism of action.
... In addition, changes in endosomal pH can inhibit cathepsin L-mediated priming, thereby preventing viral entry through this pathway [29]. Due to the similarities between SARS-CoV and SARS-CoV-2, CQ was investigated as a potential antiviral against the novel coronavirus [30][31][32]. HCQ, a derivative of CQ, is thought to behave similarly as CQ but with much reduced toxicities in animals [33]. The additional anti-inflammatory properties of HCQ were also touted to be useful for mitigating cytokine storms that may occur with COVID-19 infection (Fig. 2B), thus making this proposed dual action drug highly desirable for treating both the symptoms and the infection itself [34]. ...
Article
The coronavirus disease 2019 (COVID-19) pandemic had grounded the world to a standstill. As the disease continues to rage two years on, it is apparent that effective therapeutics are critical for a successful endemic living with COVID-19. A dearth in suitable antivirals has prompted researchers and healthcare professionals to investigate existing and developmental drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although some of these drugs initially appeared to be promising for the treatment of COVID-19, they were ultimately found to be ineffective. In this review, we provide a retrospective analysis on the merits and limitations of some of these drugs that were tested against SARS-CoV-2 as well as those used for adjuvant therapy. While many of these drugs are no longer part of our arsenal for the treatment of COVID-19, important lessons can be learnt. The recent inclusion of molnupiravir and PaxlovidTM as treatment options for COVID-19 represent our best hope to date for endemic living with COVID-19. Our viewpoints on these two drugs and their prospects as current and future antiviral agents will also be provided.
... These agents were proposed as a potential treatment for the novel coronavirus. CQ and HCQ share very similar structures and mechanisms of action, so both drugs may be useful to treat SARS-CoV-2 infection based on several in vitro studies [62,63]. Several modes of action were proposed to explain the therapeutic effects of CQ/HCQ, however, a precise underlying mechanism remains unknown. ...
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Novel COVID-19 is a public health emergency that poses a serious threat to people worldwide. Given the virus spreading so quickly, novel antiviral medications are desperately needed. Repurposing existing drugs is the first strategy. Anti-parasitic drugs were among the first to be considered as a potential treatment option for this disease. Even though many papers have discussed the efficacy of various anti-parasitic drugs in treating COVID-19 separately, so far, no single study comprehensively discussed these drugs. This study reviews some anti-parasitic recommended drugs to treat COVID-19, in terms of function and in vitro as well as clinical results. Finally, we briefly review the advanced techniques, such as artificial intelligence, that have been used to find effective drugs for the treatment of COVID-19.
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This review contains an early update on the Covid-19 outbreak. From epidemic status to pandemic status. We reviewed the pattern of spread of Covid-19 across the globe for the first one hundred and twelve days leading to it been described as public health emergency of international concern (PHEIC) and its eventual proclamation as Pandemic. The pneumonia of unknown etiology was initially reported to have occurred in Wuhan city, Hubei province in China. Since its proclamation as a pandemic, the human race, and the global economy had been reconfigured. Every sector of human existence has gotten its share of the outbreak. Within the first fifty days of the outbreak, the major economic powers outside China had confirmed cases of Covid-19 leading to several deaths and shutting down economic activities. During the early days of the virus, Wuhan city, China was the epicenter in the Western Pacific Region (WPR), Italy and Spain the epicenter in the European region with the highest number of deaths recorded in Italy. In the southeast Asian region, India has the highest number of confirmed cases while Iran has the highest in the Eastern Mediterranean corridor, South Africa has the highest confirmed cases in the Africa corridor and the United State of America is the global epicenter with over seven hundred thousand confirmed cases. Globalization fast-tracked the spread of the virus. This review revealed that countries with strong economic powers and natural resources confirmed Covid-19 in the first fifty days and earlier while countries without strong economic identities and natural resources confirmed Covid-19 after eighty days of the outbreak. For the first one hundred and twelve days, over two million confirmed cases and over one hundred and fifty thousand deaths have been recorded globally. The case fatality ratio (CFR) for Covid-19 globally is 6.82% up to 21st April 2020 and this is expected to change in the coming days. In general, over two hundred and ten countries have confirmed cases of Covid-19 for the period under review.
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As a behavioral neuroscientist focused on psychopathology, the happenings pertaining to the measures taken to address COVID-19 and their consequences are as much of interest as anything other work that I do. This document is a collation of quotes and some comments pertaining to every aspect of COVID-19 and its impact on the brain and behavior, on the individual and on society as a whole. The same document is updated weekly (generally) and also available on the web at: https://sammutlab.com/covid-19-resources/
Article
Giriş ve Amaç: Bu çalışmada Eğitim Aile Sağlığı Merkezlerine (EASM) kayıtlı ve COVID-19 nedeniyle evde hidroksiklorokin (HCQ) tedavisi alan hastaların ilaç uyumlarını ve geri bildirimlerinin değerlendirilmesi amaçlandı. Gereç ve Yöntem: Hastanemize bağlı Eğitim Aile Sağlığı Merkezlerinde kayıtlı COVID-19 nedeniyle evde tedavi gören ve HCQ tedavisi gören hastalar dahil edildi. Evde takip edilen bu hastalara ev takiplerinin 6. ve 14. günleri arasında bir kez ulaşıldı. Hastalara HCQ tedavisine uyumları, ilaç yan etkileri, geri bildirimler, ateş ve öksürük gibi semptomların süreleri, hastaneye yeniden sevklerle ilgili bilgileri içeren 31 maddeden oluşan anket soruları yöneltildi. Anket yoluyla toplanan veriler istatistiksel analiz ile değerlendirildi. İstatistiksel analizler SPSS 17.0 programı ile yapıldı. Bulgular: Çalışmaya 37'si erkek 30'u kadın toplam 67 hasta katıldı. Ortalama yaş 45.34 ± 19.01 yıldır. Orta derecede semptomları olan 7 hasta ve hafif semptomları olan 60 hasta vardı. Bir hasta ilaca bağlı cilt döküntüsü nedeniyle tedaviyi bıraktı. 63 hastanın semptomlarında azalma oldu. Hastaneye yatan 23 hastanın ortalama yatış süresi 12.96 ± 5.92 gündü. Tekrar hastaneye sevk edilen 5 hasta vardı. Azitromisin kullanımı olanlarda tekrar hastaneye sevk oranı daha düşük bulundu. Sonuç: HCQ kullanan evdeki takip edilen COVİD-19 hastalarının çoğunluğunun semptomlarında hafifleme olmuştur. HCQ ile kombine azitromisin tedavisi alanlarda tekrar hastaneye yatma oranları daha düşük gözlenmiştir.
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ABSTRACT Introduction: During the initial weeks of the COVID-19 pandemic, there was limited information and evidence about therapeutic interventions for management of COVID-19 infections. Consequently, fever clinics were established in Saudi Arabia to provide supportive treatment for all COVID-19 patients as specialised clinics. During the early months of 2020, Hydroxychloroquine (HCQ) was being used as part of the Saudi Ministry of Health (MoH) protocol for management of COVID-19 infections. Aim: To report the experience with implementing fever clinic utilising the HCQ-based protocol for adults with mild and moderate symptoms of COVID-19, and provide further evidence regarding the efficacy and safety of HCQ. Materials and Methods: A prospective observational study was conducted in one of the primary healthcare centres in Saudi Arabia. All patients with suspected or confirmed COVID-19 who visited the fever clinic and met the eligibility criteria of starting HCQ based protocol were included in the study. Beside supportive treatment, the intervention dose of HCQ was 400 mg twice a day for one day followed by 200 mg twice a day for another four days. Statistical Package for Social Sciences (SPSS) version 22 was used for data analyses. Results: A total of 108 patients with mean age of 36 years with Standard Deviation (SD) of 9.3 were included in the study. The mean Body Mass Index (BMI) was 27.1 (SD 4.9). In addition, 73.1% of the patients were males and 25% were smokers. The study findings showed that the fever clinic was effective in managing the symptoms of COVID-19 and treating the patients regardless of the use of or completion of HCQ. In particular, on day 6, cough improved in >85% of the patients and fever was resolved in >83% of patients. However, there were no statistically significant differences among the patients who received/completed HCQ and those who did not start or complete the protocol in terms of negative conversion based on the Nasopharyngeal (NP) swab real-time Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) by day 14, and resolution/improvement of symptoms on day 6 (p>0.05). Conclusion: This study documented the experience of implementing a fever clinic to manage the suspected and confirmed COVID-19 patients with mild to moderate symptoms during the initial phase of the pandemic in Saudi Arabia. The study findings revealed that the concept of fever clinics was useful for managing suspected and confirmed cases. At the same time, there were no additional benefits of HCQ compared to the supportive treatment in this study.
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SARS-Cov-2 (severe acute respiratory syndrome coronavirus) that initially came to notice in December 2019 is the agent responsible for COVID-19 is still spreading rapidly worldwide and it is presently a potent danger to the world and also to the economy. Patients with COVID-19 are still at risk of Acute Respiratory Distress Syndrome (ARDS), respiratory failure, and death. Those patients whose aged more than sixty years with comorbidities, children, and healthcare workers are highly vulnerable to this virus patient shows various symptoms most commonly cough, fever, difficulty in breathing, fatigue, sore throat. The infection could be categorized into three stages: mild infection, the pulmonary stage, and the inflammatory stage. As the COVID-19 pandemic continues, it has been clear that infection caused due to SARS-Cov-2 might be responsible for the unpredicted long-term health consequences. In addition to this, it has acute respiratory manifestations, adversely SARS-Cov-2 also affects the other organ systems. However, there is limited to the management of COVID-19 related conditions of the extrapulmonary systems. After recovery, patients remain at risk for lung disease, heart disease, and mental ailment. There may be long-term consequences of adverse effects they observed in the course of COVID-19 and during its treatment. This review provided information about the extrapulmonary manifestations of COVID-19 that may impair the urinary, cardiovascular, gastrointestinal, hematological, hematopoietic, neurological, or reproductive systems. Also, the main purpose of this article is to describe the current concern of the extra pulmonary complications that were caused due to COVID-19 and also to improve the management and diagnosis of these patients.
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Background In the beginning of the COVID-19 pandemic, many hospitalized patients received empiric hydroxychloroquine/chloroquine (HC/CQ). Although some retrospective-observational trials suggested potential benefit, all subsequent randomized clinical trials (RCTs) failed to show benefit and use generally ceased. Herein, we summarize key studies that clinicians advising patients on HC/CQ efficacy:safety calculus in hospitalized COVID-19 patients would want to know about in a practical one-stop-shopping source. Methods Pubmed and Google were searched on November 4, 2021. Search words included: COVID-19, hydroxychloroquine, chloroquine, in vitro, animal studies, clinical trials, and meta-analyses. Studies were assessed for import and included if considered impactful for benefit:risk assessment. Results These searches led to inclusion of 12 in vitro and animal reports; 12 retrospective-observational trials, 19 interventional clinical trials (17 RCTs, 1 single-arm, 1 controlled but unblinded), and 51 meta-analyses in hospitalized patients. Inconsistent efficacy was seen in vitro and in animal studies for coronaviruses and nil in SARS-CoV-2 animal models specifically. Most retrospective-observational studies in hospitalized COVID-19 patients found no efficacy; QT prolongation and increased adverse events and mortality were reported in some. All RCTs and almost all meta-analyses provided robust data showing no benefit in overall populations and subgroups, yet concerning safety issues in many. Conclusions HC/CQ have inconsistent anti-coronavirus efficacy in vitro and in animal models, and no convincing efficacy yet substantial safety issues in the overwhelming majority of retrospective-observational trials, RCTs, and meta-analyses in hospitalized COVID-19 patients. HC/CQ should not be prescribed for hospitalized COVID-19 patients outside of clinical trials.
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Malaria is a severe parasite infectious disease with high fatality. As one of the approved treatments of this disease, hydroxychloroquine (HCQ) lacks clinical administration guidelines for patients with special health conditions and co-morbidities. This may result in improper dosing for different populations and lead them to suffer from severe side effects. One of the most important toxicities of HCQ overdose is cardiotoxicity. In this study, we built and validated a physiologically based pharmacokinetic modeling (PBPK) model for HCQ. With the full-PBPK model, we predicted the pharmacokinetic (PK) profile for malaria patients without other co-morbidities under the HCQ dosing regimen suggested by Food and Drug Administration (FDA) guidance. The PK profiles for different special populations were also predicted and compared to the normal population. Moreover, we proposed a series of adjusted dosing regimens for different populations with special health conditions and predicted the concentration-time (C-T) curve of the drug plasma concentration in these populations which include the pregnant population, elderly population, RA patients, and renal impairment populations. The recommended special population-dependent dosage regimens can maintain the similar drug levels observed in the virtual healthy population under the original dosing regimen provided by FDA. Last, we developed mathematic formulas for predicting dosage based on a patient’s body measurements and two indexes of renal function (glomerular filtration rate and serum creatine level) for the pediatric and morbidly obese populations. Those formulas can facilitate personalized treatment of this disease. We hope to provide some advice to clinical practice when taking HCQ as a treatment for malaria patients with special health conditions or co-morbidities so that they will not suffer from severe side effects due to higher drug plasma concentration, especially cardiotoxicity.
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An efficient method of producing quinine derivatives via reaction of acylation with 4,5-dichloroisothiazole-3-, 5-arylisoxazole-3-, adamantane- and hydrochlorides of pyridine-3- and pyridine-4-carbonyl chlorides was developed. All synthesized compounds were tested for antiviral, antimicrobial and analgesic activity. The most pronounced antibacterial activity was shown by the compounds 2e, 3b, 3c and 3e with isoxazole and pyridine fragments. It was found that most of the tested compounds showed significant analgesic activity reducing the pain response of animals to the irritating effect of acetic acid.
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The world is foreseeing an ever-increasing human health crisis by virtue of threats from viral disease outbreaks recently showcased by COVID-19 and also those in the previous two decades by other coronaviruses. Many lives have been lost and various world economies have been constrained with the effect from the current pandemic. Corona-warriors, as the name is floating in the air, have also emerged in the shape of the medical and healthcare practitioners, fundraising charity trusts, and sanitation workforces, who are variously catering to the cause. On this mission, most scientific communities and pharmaceutical giants are also investing their best efforts toward studying the molecular biology of these pathogens and discovering and/or designing potential vaccine candidates against the notorious killers. The scenarios, however, have been felt graver with new mutant SARS-2 CoV strains hitting with sporadic emergence, complicating development and contradicting efficacies of these putative vaccines and standard therapies up close to dissemination into the public. Many viral and other pathogenic entities have been found to correlate their bases of pathogenesis and disease severity to, besides other factors, the development of pronounced oxidative stress. Abnormally generated and ill-regulated oxidative stress profiles are reported to effectuate severity, as seen in COVID-19 cases that may trigger cytokine/chemokine storms, ill-orchestrated NETosis, pyroptosis, and others that culminate into symptoms like colitis, ARD/DIC, endothelial dysfunction, coagulopathies, and graver chances of sepsis. Here, we narrate important studies with some of the potent antioxidant molecules which have surfaced with their promises at directly and/or indirectly evading the chances of COVID-19 and possibly other viral diseases. We present a compelling view of the various mechanistic networks within which CoV-led oxidative stress could detriment the homeostatic harmony within the cell/tissue systems by interfering with inflammatory and immunological stimuli and how the antioxidants emerge as a highly sought therapy.
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Background The etiological agent for the coronavirus illness outbreak in 2019–2020 is a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19), whereas coronavirus disease pandemic of 2019 (COVID-19) has compelled the implementation of novel therapeutic options. Main body of the abstract There are currently no targeted therapeutic medicines for this condition, and effective treatment options are quite restricted; however, new therapeutic candidates targeting the viral replication cycle are being investigated. The primary protease of the severe acute respiratory syndrome coronavirus 2 virus is a major target for therapeutic development (M Pro ). Severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus (MERS-CoV) all seem to have a structurally conserved substrate-binding domain that can be used to develop novel protease inhibitors. Short conclusion With the recent publication of the X-ray crystal structure of the severe acute respiratory syndrome coronavirus 2 Mm, virtual and in vitro screening investigations to find M Pro inhibitors are fast progressing. The focus of this review is on recent advancements in the quest for small-molecule inhibitors of the severe acute respiratory syndrome coronavirus 2 main protease.
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Covid-19 (coronavirus disease 2019) is a global public health crisis." There is no successful accepted prescription until recently, but researchers are rushing to find a cure for patients, particularly those who have other underlying disorders or develop a severe form of the disease. The purpose of this study is to establish the facts regarding COVID-19 as much as it is a practical treatment. In this study, we talk about some of the drugs that were used to treat patients infected with the Coronavirus. Some of these drugs had effective results in reducing serious symptoms, such as dexamethasone, and some of them were banned after several trials.
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Background: The emergence of Zika virus (ZIKV) is associated to dramatic complications in fetuses and neonates. As there is no vaccine and no drug to prevent and treat ZIKV infections, there is an urgent need to have active drugs against ZIKV that can be used during pregnancy. Large screening strategies suggested that azithromycin (AZ) has an in vitro activity against ZIKV, we provide additional data supporting this hypothesis. Methods: We tested the efficacy of AZ on ZIKV-infected Vero cells at a concentration that can be reached in vivo in amniotic fluid. We conducted two experiments with addition to infected cells of a single dose or multi doses of 50 mg/L of AZ, and analyzed ZIKV replication by immunofluorescence assay (IFA) and by measuring viral RNA loads at different times up to 96 h post-infection (hpi). Results: Addition of a single dose of 50 mg/L of AZ prevented replication of ZIKV during 48 hpi; after 48 hpi, ZIKV replication was detected by IFA but viral RNA loads remained lower than in untreated infected cells. ZIKV replication was inhibited by addition of multi doses of 50 mg/L of AZ. Conclusions: Our data confirm the in vitro activity of AZ against ZIKV. Since there will be no active specific drugs and vaccine available soon against ZIKV, AZ might be the first compound that could prevent and treat ZIKV infections, with the advantages of being an approved and safe drug usable during pregnancy.
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Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of similar to 30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC(50)s], 3 to 8 mu M). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.
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Patients with classic Whipple's disease have a lifetime defect in immunity to Tropheryma whipplei and frequently develop treatment failures, relapses or reinfections. Empirical treatments were tested before culture was possible, but the only in vitro bactericidal treatment consists of a combination of doxycycline and hydroxychloroquine. Our laboratory has been a reference centre since the first culturing of Tropheryma whipplei, and we have tested 27 000 samples by PCR and diagnosed 250 cases of classic Whipple's disease. We report here the clinical course of patients who were followed by one of our group. Of 29 patients, 22 (76%) were previously treated with immunosuppressive drugs, 26 (90%) suffered from arthralgias and 22 (76%) exhibited weight loss. Intravenous initial treatment was paradoxically associated with an increased risk of failure (P = 0.0282). Treatment with doxycycline and hydroxychloroquine (±sulfadiazine or trimethoprim/sulfamethoxazole) was associated with a better outcome (0/13 failures), whereas all 14 patients who were first treated with trimethoprim/sulfamethoxazole and referred to us (P < 0.0001) experienced failure. Among the patients treated with doxycycline and hydroxychloroquine after previous antibiotic treatments, two presented with a reinfection caused by different T. whipplei strains. Finally, serum therapeutic drug monitoring allowed us to detect a lack of compliance in the only patient with failure among the 22 patients treated with lifetime doxycycline. In vitro results were confirmed by clinical outcomes and trimethoprim/sulfamethoxazole was associated with failures. The recommended management is a combination of doxycycline and hydroxychloroquine for 1 year, followed by doxycycline for the patient's lifetime along with stringent therapeutic drug monitoring.
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Until recently, human coronaviruses (HCoVs), such as HCoV strain OC43 (HCoV-OC43), were mainly known to cause 15 to 30% of mild upper respiratory tract infections. In recent years, the identification of new HCoVs, including severe acute respiratory syndrome coronavirus, revealed that HCoVs can be highly pathogenic and can cause more severe upper and lower respiratory tract infections, including bronchiolitis and pneumonia. To date, no specific antiviral drugs to prevent or treat HCoV infections are available. We demonstrate that chloroquine, a widely used drug with well-known antimalarial effects, inhibits HCoV-OC43 replication in HRT-18 cells, with a 50% effective concentration (+/- standard deviation) of 0.306 +/- 0.0091 microM and a 50% cytotoxic concentration (+/- standard deviation) of 419 +/- 192.5 microM, resulting in a selectivity index of 1,369. Further, we investigated whether chloroquine could prevent HCoV-OC43-induced death in newborn mice. Our results show that a lethal HCoV-OC43 infection in newborn C57BL/6 mice can be treated with chloroquine acquired transplacentally or via maternal milk. The highest survival rate (98.6%) of the pups was found when mother mice were treated daily with a concentration of 15 mg of chloroquine per kg of body weight. Survival rates declined in a dose-dependent manner, with 88% survival when treated with 5 mg/kg chloroquine and 13% survival when treated with 1 mg/kg chloroquine. Our results show that chloroquine can be highly effective against HCoV-OC43 infection in newborn mice and may be considered as a future drug against HCoVs.
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Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available. We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations. Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.
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In a paper published 2 years ago in this journal some of us described the potentially therapeutic benefits of the quinoline antimalarial chloroquine in viral diseases such as HIV-1/AIDS and severe acute respiratory syndrome (SARS). Chloroquine/hydroxychloroquine has since been adopted to treat HIV-1-infected patients in clinical trials and new insights into its antiviral activity have been obtained from in-vitro studies. On the HIV/AIDS front chloroquine (250 mg twice daily) has been administered to HIV-1-infected patients with baseline viral loads over 50 000 copies per mL in combination with lamivudine (150 mg twice daily) and hydroxyurea (500 mg twice daily) in an ongoing clinical trial in India. Ten out of 18 volunteers had an undetectable viral load at week 24.2 The median drop in viral load was more than 2.0 log more than the median 1.5 log drop seen with a nucleoside reverse transcriptase inhibitor (NRTI) and hydroxyurea alone. (excerpt)
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Compounds approved for therapeutic use and in vitro inhibitors of severe acute respiratory syndrome coronavirus (SARS-CoV) were evaluated for inhibition in the mouse SARS-CoV replication model. A hybrid interferon, interferon alpha (IFN-alpha) B/D, and a mismatched double-stranded (ds) RNA interferon (IFN) inducer, Ampligen (poly I:poly C124), were the only compounds that potently inhibited virus titres in the lungs of infected mice as assessed by CPE titration assays. When mice were dosed intraperitoneally (i.p.) with IFN-alpha B/D once daily for 3 days beginning 4 h after virus exposure, SARS-CoV replication in the lungs of infected mice was reduced by 1 log10 at 10,000 and 32,000 IU; at the highest dose of 100,000 IU, virus lung titres were below detectable limits. Ampligen used i.p. at 10 mg/kg 4 h prior to virus exposure also reduced virus lung titres to below detectable limits. Nelfinavir, beta-D-N4-hydroxycytidine, calpain inhibitor VI, 3-deazaneplanocin A and Alferon (human leukocyte IFN-alpha-n3) did not significantly reduce lung virus titres in mice. Anti-inflammatory agents, chloroquine, amodiaquin and pentoxifylline, were also inactive in vivo, suggesting that although they may be useful in ameliorating the hyperinflammatory response induced by the virus infection, they will not significantly reduce the replication of the virus, the inducer of inflammatory response. Thus, anti-inflammatory agents may only be useful in treating virus lung infections if used in combination with agents that inhibit virus replication. In summary, the data suggest that induction of IFN by mismatched dsRNA or actual treatment with exogenous IFN-alpha can inhibit SARS-CoV replication in the lungs of mice.
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The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
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Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents.
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There is no consistently reliable treatment for endocarditis resulting from chronic Coxiella burnetii infection, the causative agent of Q fever. Although certain antibiotics are recommended on the basis of their in vitro bactericidal activities, results of therapy with these antibiotics are often disappointing. To evaluate whether the currently recommended antibiotic susceptibility tests for C. burnetii give misleading results because of continued division of uninfected cells, thereby resulting in the dilution of infected cells and, hence, a false picture of antibiotic efficacy, we blocked cell division during antibiotic susceptibility testing with cycloheximide. Using this new method, we found that the currently recommended antibiotics for the treatment of Q fever, doxycycline, pefloxacin, and rifampin, did not reduce the ratio of infected to noninfected cells (either L929 or P388D1) by 9 days postinfection. To test the hypothesis that this lack of antibacterial activity is due to antibiotic inactivation by the low pH of the phagolysosomes in which C. burnetii is found, we used alkalinizing lysosomotropic agents (chloroquine or amantadine) concurrently with doxycycline. This resulted in the sterilization of C. burnetii infection in P388D1 cells. This finding seems to confirm our suspicion that the acidic conditions of the phagolysosomes in which C. burnetii is located inhibit antibiotic activity. This inhibition can be reversed in vitro when lysosomotropic alkalinizing agents are used.
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Q fever endocarditis, caused by Coxiella burnetii, is fatal in 25% to 60% of patients. Currently, treatment with a long-term tetracycline and quinolone regimen for at least 4 years is recommended, although relapses are frequent. Between January 1987 and December 1997, the reference treatment of Q fever endocarditis was compared with one of doxycycline and hydroxychloroquine sulfate. Patients were treated by conventional therapy until May 1991 and then by the new regimen. Microimmunofluorescence was used for antibody-level determination for diagnosis and follow-up. Thirty-five patients were included in the study, 26 males and 9 females. Of 14 patients treated with a doxycycline and quinolone combination, 1 died, 7 relapsed (3 were re-treated and 4 switched to the new regimen), 1 is still being treated, and 5 were considered cured using this regimen only. The mean duration of therapy for cure in this group was 55 months (median, 60 months). Twenty-one patients received the doxycycline and hydroxychloroquine regimen: 1 patient died of a surgical complication, 2 are still being treated, 17 were cured, and 1 is currently being evaluated. Two patients treated for 12 months but none of the patients treated for longer than 18 months relapsed. The mean duration of treatment in this group was 31 months (median, 26 months). No significant differences were observed between the 2 regimens in terms of death, valve surgery, or tolerance. The mortality rate for both regimens in this study was 5%. Prescription of the doxycycline and hydroxychloroquine combination for at least 18 months allows shortening of the duration of therapy and reduction in the number of relapses.
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We report on chloroquine, a 4-amino-quinoline, as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. Chloroquine is a clinically approved drug effective against malaria. We tested chloroquine phosphate for its antiviral potential against SARS-CoV-induced cytopathicity in Vero E6 cell culture. Results indicate that the IC50 of chloroquine for antiviral activity (8.8 +/- 1.2 microM) was significantly lower than its cytostatic activity; CC50 (261.3 +/- 14.5 microM), yielding a selectivity index of 30. The IC50 of chloroquine for inhibition of SARS-CoV in vitro approximates the plasma concentrations of chloroquine reached during treatment of acute malaria. Addition of chloroquine to infected cultures could be delayed for up to 5h postinfection, without an important drop in antiviral activity. Chloroquine, an old antimalarial drug, may be considered for immediate use in the prevention and treatment of SARS-CoV infections.
Article
Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ), have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some selectivity toward SARS-CoV infection. These new drugs may offer an interesting alternative for Asia where SARS originated and malaria has remained endemic.
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In 2000, Tropheryma whipplei was finally identified as the cause of Whipple's disease, a chronic condition with protean manifestations that was first described in 1907. This review discusses the epidemiology, pathogenesis, diagnosis, and treatment of this rare and elusive chronic disease.
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Whipple's disease is considered a rare chronic disease with a broad spectrum of clinical manifestations. Several antibiotics have been used for the treatment of this disease, and the current reference treatment was determined empirically on the basis of only a few clinical observations. Patients should be treated for months, and many relapse after antibiotic withdrawal. We report here the first extensive study on the susceptibilities of three reference strains of Tropheryma whipplei to antibiotic in cell culture by using a real-time PCR assay as previously described. We found that doxycycline, macrolides, ketolides, aminoglygosides, penicillin, rifampin, teicoplanin, chloramphenicol, and trimethoprim-sulfamethoxazole were active, with MICs ranging from 0.25 to 2 μg/ml. Vancomycin was somewhat active at an MIC of 10 μg/ml. We found heterogeneity in the susceptibility to imipenem, with one strain being susceptible and the two other strains being resistant. Cephalosporins, colimycine, aztreonam, and fluoroquinolones were not active. We also demonstrated that a combination of doxycycline and hydroxychloroquine was bactericidal. This combination has been shown to be active in the treatment of patients suffering from chronic infections with Coxiella burnetii, a bacterium that is also found intracellularly in acidic vacuoles. We believe, then, that this combination therapy should be further evaluated in clinical trials for the treatment of Whipple's disease.
Article
Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide.
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The antiviral effects of chloroquine (CQ) on human coronavirus 229E (HCoV-229E) infection of human fetal lung cell line, L132 are reported. CQ significantly decreased the viral replication at concentrations lower than in clinical usage. We demonstrated that CQ affects the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). Furthermore, p38 MAPK inhibitor, SB203580, inhibits CPE induced by HCoV-229E infection and viral replication. Our findings suggest that CQ affects the activation of MAPKs, involved in the replication of HCoV-229E.
Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia
Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia [in Chinese].