Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vitro. Based on physiologically-based pharmacokinetic models, a dosing regimen of hydroxychloroquine sulfate 400 mg twice daily for one day, followed by 200 mg twice daily for four more days is recommended for treating SARS-CoV-2 infection. This dosing regimen achieved concentrations in lung fluid three times higher than a chloroquine regimen used in previous studies.
Remdesivir and chloroquine were found to be highly effective at inhibiting the novel coronavirus (2019-nCoV) in vitro. Remdesivir had an EC50 of 0.77 μM and chloroquine had an EC50 of 1.13 μM, both showing potent antiviral activity at low micromolar concentrations. Time-of-addition experiments demonstrated that remdesivir and chloroquine functioned at stages post viral entry. Given their proven safety profiles in humans and effectiveness against other viruses, the authors suggest that remdesivir and chloroquine should be assessed for treating patients infected with 2019-nCoV.
This document summarizes a study that evaluated the use of the Line Probe Assay (LPA) for rapid detection of Multi Drug Resistant Tuberculosis (MDR-TB) in Sudan. 300 smear-positive sputum samples were collected from TB patients and tested using LPA, culture-based drug susceptibility testing (DST), and conventional laboratory methods. Results found a high prevalence of MDR-TB in Sudan of 38% by DST and 37.3% by LPA. Comparison of LPA and DST results showed high accuracy of LPA for rapid detection of rifampin and isoniazid resistance with a sensitivity of 98.3% and specificity of 100%. LPA provided results within 2
Chloroquine has been shown to be effective against SARS-CoV-2 in vitro and has a well-established safety profile due to decades of use for malaria prevention and treatment. It is a cheap and widely available drug. Chinese researchers plan to promptly evaluate chloroquine's potential use for both preventing and treating the disease caused by the novel coronavirus, based on these promising in vitro results. If clinical trials confirm the biological effects, chloroquine could become one of the simplest and most affordable treatments available for this respiratory infection.
The study found that Ivermectin, an FDA-approved anti-parasitic drug, is able to inhibit the replication of SARS-CoV-2, the virus that causes COVID-19, in vitro. A single dose of Ivermectin resulted in a 5000-fold reduction in viral RNA at 48 hours in infected Vero-hSLAM cells. The authors hypothesize that Ivermectin acts by inhibiting the nuclear import of viral proteins through interaction with importin proteins. They conclude that Ivermectin warrants further investigation for potential benefits against COVID-19 in humans.
Limitations in the screening of potentially anti-cryptosporidial agents using...UniversitasGadjahMada
The emergence of cryptosporidiosis, a zoonotic disease of the gastrointestinal and respiratory tract caused by Cryptosporidium Tyzzer, 1907, triggered numerous screening studies of various compounds for potential anti-cryptosporidial activity, the majority of which proved ineffective. Extracts of Indonesian plants, Piper betle and Diospyros sumatrana, were tested for potential anticryptosporidial activity using Mastomys coucha (Smith), experimentally inoculated with Cryptosporidium proliferans Kváč, Havrdová, Hlásková, Daňková, Kanděra, Ježková, Vítovec, Sak, Ortega, Xiao, Modrý, Chelladurai, Prantlová et McEvoy, 2016. None of the plant extracts tested showed significant activity against cryptosporidia; however, the results indicate that the following issues should be addressed in similar experimental studies. The monitoring of oocyst shedding during the entire experimental trial, supplemented with histological examination of affected gastric tissue at the time of treatment termination, revealed that similar studies are generally unreliable if evaluations of drug efficacy are based exclusively on oocyst shedding. Moreover, the reduction of oocyst shedding did not guarantee the eradication of cryptosporidia in treated individuals. For treatment trials performed on experimentally inoculated laboratory rodents, only animals in the advanced phase of cryptosporidiosis should be used for the correct interpretation of pathological alterations observed in affected tissue. All the solvents used (methanol, methanol-tetrahydrofuran and dimethylsulfoxid) were shown to be suitable for these studies, i.e. they did not exhibit negative effects on the subjects. The halofuginone lactate, routinely administered in intestinal cryptosporidiosis in calves, was shown to be ineffective against gastric cryptosporidiosis in mice caused by C. proliferans. In contrast, the control application of extract Arabidopsis thaliana, from which we had expected a neutral effect, turned out to have some positive impact on affected gastric tissue.
- The document discusses three drugs - hydroxychloroquine, ivermectin, and azithromycin - that have shown potential therapeutic effects against COVID-19. Hydroxychloroquine and azithromycin are thought to act by increasing pH within cells, while ivermectin may inhibit import of viral proteins.
- However, more in vivo clinical studies are still needed to fully evaluate the efficacy and safety of these drugs individually and in combination for treating and preventing COVID-19. Precautions around dosage will also be important given past issues with hydroxychloroquine poisoning.
Protective Effect of Egyptian Propolis Against Rabbit PasteurellosisBee Healthy Farms
Propolis is known for its protective effects on humans and animals, including improving respiratory conditions. It's also documented to be a very complementary adjuvant with other treatment modalities.
Pasteurella multocida is a well known cause of morbidity and mortality in rabbits. The predominant syndrome is upper respiratory disease or "snuffles." P. multocida is often endemic in rabbit colonies and the acquisition of infection in young rabbits is correlated to the prevalence in adult rabbits.
The document discusses a study that evaluated the anti-viral activity and cytotoxicity of aqueous extracts of Sphaeranthus indicus and Coldenia procumbens against HIV-1 and HIV-2. The aqueous extract of Coldenia procumbens showed more potent anti-HIV activity than Sphaeranthus indicus, inhibiting both HIV-1 and HIV-2 replication with IC50 values of 32.10 and 41.60 μg/ml respectively. The aqueous extract of Sphaeranthus indicus inhibited HIV-1 replication with an IC50 of 52.35 μg/ml but did not inhibit HIV-2 replication. Neither extract showed cytotoxicity up to 125 μg/ml. The study demonstrates the
Remdesivir and chloroquine were found to be highly effective at inhibiting the novel coronavirus (2019-nCoV) in vitro. Remdesivir had an EC50 of 0.77 μM and chloroquine had an EC50 of 1.13 μM, both showing potent antiviral activity at low micromolar concentrations. Time-of-addition experiments demonstrated that remdesivir and chloroquine functioned at stages post viral entry. Given their proven safety profiles in humans and effectiveness against other viruses, the authors suggest that remdesivir and chloroquine should be assessed for treating patients infected with 2019-nCoV.
This document summarizes a study that evaluated the use of the Line Probe Assay (LPA) for rapid detection of Multi Drug Resistant Tuberculosis (MDR-TB) in Sudan. 300 smear-positive sputum samples were collected from TB patients and tested using LPA, culture-based drug susceptibility testing (DST), and conventional laboratory methods. Results found a high prevalence of MDR-TB in Sudan of 38% by DST and 37.3% by LPA. Comparison of LPA and DST results showed high accuracy of LPA for rapid detection of rifampin and isoniazid resistance with a sensitivity of 98.3% and specificity of 100%. LPA provided results within 2
Chloroquine has been shown to be effective against SARS-CoV-2 in vitro and has a well-established safety profile due to decades of use for malaria prevention and treatment. It is a cheap and widely available drug. Chinese researchers plan to promptly evaluate chloroquine's potential use for both preventing and treating the disease caused by the novel coronavirus, based on these promising in vitro results. If clinical trials confirm the biological effects, chloroquine could become one of the simplest and most affordable treatments available for this respiratory infection.
The study found that Ivermectin, an FDA-approved anti-parasitic drug, is able to inhibit the replication of SARS-CoV-2, the virus that causes COVID-19, in vitro. A single dose of Ivermectin resulted in a 5000-fold reduction in viral RNA at 48 hours in infected Vero-hSLAM cells. The authors hypothesize that Ivermectin acts by inhibiting the nuclear import of viral proteins through interaction with importin proteins. They conclude that Ivermectin warrants further investigation for potential benefits against COVID-19 in humans.
Limitations in the screening of potentially anti-cryptosporidial agents using...UniversitasGadjahMada
The emergence of cryptosporidiosis, a zoonotic disease of the gastrointestinal and respiratory tract caused by Cryptosporidium Tyzzer, 1907, triggered numerous screening studies of various compounds for potential anti-cryptosporidial activity, the majority of which proved ineffective. Extracts of Indonesian plants, Piper betle and Diospyros sumatrana, were tested for potential anticryptosporidial activity using Mastomys coucha (Smith), experimentally inoculated with Cryptosporidium proliferans Kváč, Havrdová, Hlásková, Daňková, Kanděra, Ježková, Vítovec, Sak, Ortega, Xiao, Modrý, Chelladurai, Prantlová et McEvoy, 2016. None of the plant extracts tested showed significant activity against cryptosporidia; however, the results indicate that the following issues should be addressed in similar experimental studies. The monitoring of oocyst shedding during the entire experimental trial, supplemented with histological examination of affected gastric tissue at the time of treatment termination, revealed that similar studies are generally unreliable if evaluations of drug efficacy are based exclusively on oocyst shedding. Moreover, the reduction of oocyst shedding did not guarantee the eradication of cryptosporidia in treated individuals. For treatment trials performed on experimentally inoculated laboratory rodents, only animals in the advanced phase of cryptosporidiosis should be used for the correct interpretation of pathological alterations observed in affected tissue. All the solvents used (methanol, methanol-tetrahydrofuran and dimethylsulfoxid) were shown to be suitable for these studies, i.e. they did not exhibit negative effects on the subjects. The halofuginone lactate, routinely administered in intestinal cryptosporidiosis in calves, was shown to be ineffective against gastric cryptosporidiosis in mice caused by C. proliferans. In contrast, the control application of extract Arabidopsis thaliana, from which we had expected a neutral effect, turned out to have some positive impact on affected gastric tissue.
- The document discusses three drugs - hydroxychloroquine, ivermectin, and azithromycin - that have shown potential therapeutic effects against COVID-19. Hydroxychloroquine and azithromycin are thought to act by increasing pH within cells, while ivermectin may inhibit import of viral proteins.
- However, more in vivo clinical studies are still needed to fully evaluate the efficacy and safety of these drugs individually and in combination for treating and preventing COVID-19. Precautions around dosage will also be important given past issues with hydroxychloroquine poisoning.
Protective Effect of Egyptian Propolis Against Rabbit PasteurellosisBee Healthy Farms
Propolis is known for its protective effects on humans and animals, including improving respiratory conditions. It's also documented to be a very complementary adjuvant with other treatment modalities.
Pasteurella multocida is a well known cause of morbidity and mortality in rabbits. The predominant syndrome is upper respiratory disease or "snuffles." P. multocida is often endemic in rabbit colonies and the acquisition of infection in young rabbits is correlated to the prevalence in adult rabbits.
The document discusses a study that evaluated the anti-viral activity and cytotoxicity of aqueous extracts of Sphaeranthus indicus and Coldenia procumbens against HIV-1 and HIV-2. The aqueous extract of Coldenia procumbens showed more potent anti-HIV activity than Sphaeranthus indicus, inhibiting both HIV-1 and HIV-2 replication with IC50 values of 32.10 and 41.60 μg/ml respectively. The aqueous extract of Sphaeranthus indicus inhibited HIV-1 replication with an IC50 of 52.35 μg/ml but did not inhibit HIV-2 replication. Neither extract showed cytotoxicity up to 125 μg/ml. The study demonstrates the
A novel coronavirus from patients with pneumonia in china, 2019MANUELPERALTA33
- In December 2019, a cluster of pneumonia cases of unknown cause emerged in Wuhan, China and was linked to a seafood market.
- Researchers isolated a novel coronavirus (2019-nCoV) from bronchoalveolar lavage fluid of patients with pneumonia.
- The virus was able to infect and replicate in human airway epithelial cells in vitro, causing cytopathic effects. Electron microscopy images showed spherical virus particles around 60-140nm in diameter with distinctive spikes.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
Treatment of COVID-19; old tricks for new challengesLuisaSarlat
Coronavirus disease (COVID-19), which appeared in December 2019, presents a global challenge, particularly in the rapid increase of critically ill patients with pneumonia and absence of definitive treatment. To date, over 81,000 cases have been confirmed, with over 2700 deaths. The mortality appears to be around 2%; early published data indicate 25.9% with SARS-CoV-2 pneumonia required ICU admission and 20.1% developed acute respiratory distress syndrome
This study analyzed urine samples collected from 2011-2013 at a hospital in Silchar, India to determine the antibiotic resistance patterns of bacteria causing urinary tract infections (UTIs). The main findings were:
1) Escherichia coli was the most common cause of UTIs, identified in 38.54% of samples. Resistance to oral antibiotics like fluoroquinolones and cephalosporins was high for E. coli isolates.
2) Extended spectrum beta-lactamase (ESBL) production was observed in 28.74% of E. coli and 40.74% of Klebsiella isolates.
3) Methicillin-resistant Staphylococcus aureus (
Insignt from nono medicine into chloroquine efficacy against COVID-19Valentina Corona
Chloroquine, an approved malaria drug, may have potential therapeutic effects against COVID-19 based on preliminary clinical trials and studies. Chloroquine is known to inhibit endocytosis and increase lysosomal pH, which could interfere with SARS-CoV-2 cellular entry and fusion. Specifically, chloroquine may suppress the protein PICALM, reducing clathrin-mediated endocytosis of SARS-CoV-2. However, more clinical trial data is still needed to verify chloroquine's efficacy against COVID-19, and further studies aim to better understand chloroquine's mechanisms of action and optimal dosing protocols.
O ptimization of hyrozycloroquine in mangement of covid 19Ahmed Ali
This document summarizes the potential use of hydroxychloroquine (HCQ) in treating COVID-19. It discusses HCQ's pharmacological properties including its immunomodulatory and antiviral effects. Based on its ability to increase lysosomal pH and disrupt viral fusion and replication, HCQ has demonstrated efficacy against SARS-CoV-1 in vitro and in animal models. The document proposes guidelines for optimizing HCQ's efficacy and safety in COVID-19 treatment, including early administration, loading doses, and continued maintenance doses under medical supervision. More clinical trials are needed to evaluate HCQ specifically for early COVID-19 treatment.
This document proposes using bromhexine as a prophylactic and treatment for SARS-CoV-2. Bromhexine is a mucolytic drug that selectively inhibits the protease TMPRSS2, which plays an important role in SARS-CoV-2 cell entry. The document argues that chloroquine alone may not be effective as a prophylactic. It proposes combining a less toxic derivative of chloroquine with bromhexine to block viral entry by inhibiting both the endosomal pathway and TMPRSS2. Bromhexine has safety and affordability advantages over other TMPRSS2 inhibitors and may effectively prevent SARS-CoV-2 transmission when used as a prophylactic by inhibiting viral entry
Sensitivity and specificity of 99mTc-UBI29-41 and 67Ga-Citrate scintigraphy i...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
This document summarizes a study identifying Parainfluenza virus 4 in humans in Najaf, Iraq between 2012-2013. Nasal swabs and blood samples were collected from 320 individuals and tested using rapid tests and RT-PCR. Thirty-three samples tested positive for Parainfluenza virus 4 using virus-specific primers in RT-PCR. The study concludes that RT-PCR is a rapid and sensitive method for identifying Parainfluenza virus 4 that could be used to diagnose infections.
Lo studio “Shock and kill” sugli effetti degli inibitori delle istone deaceti...mabasta
This document summarizes findings from a study investigating the use of histone deacetylase inhibitors (HDACIs) and the glutathione synthesis inhibitor buthionine sulfoximine (BSO) to activate HIV-1 from latency as part of "shock and kill" strategies for HIV eradication. The study tested various HDACIs for their ability to induce HIV-1 replication in cell line models. Class I-selective HDACIs were generally more potent activators with lower toxicity compared to non-selective HDACIs. However, toxicity remained a concern. Adding BSO increased the HIV-1 activating effects of class I HDACIs at lower, non-toxic concentrations by depleting glutathione and creating a pro-oxidant environment
The Role of Sauropus androgynus (L.) Merr. Leaf Powder in the Broiler Chicken...UniversitasGadjahMada
Aflatoxin (AF) is the secondary metabolite of Aspergillus flavus and commonly contaminates feed during storage.AF causes lowered growth rate, stress, and increased mortality in the poultry, especially for broiler industries.The aims of this study are to determine the effects of Sauropus androgynus (L.) Merr. leaf powder (SAP) in the chickens fed a diet naturally contaminated with AF. A total of 108 chickens are divided into 6 group: group I fed with basal diet (AF not detectable); group II fed with basal diet (AF not detectable) + 5%SAP; group III with AF (>1 ppb <50 ppb); group IVwithAF (>1 ppb <50ppb) + 5% SAP; groupVwithAF (>51 ppb <100 ppb) + 5%SAP; group VI with AF (>101 ppb <150 ppb) + 5% SAP.The data of the body weight, feed intake and efficiency, the relative weight of liver, kidney, spleen, bursa of Fabricius (BF), histopathology, haematological profile, haemagglutination inhibition (HI) titer, AF residue, and immunohistochemistry are collected on days 7, 14, and 21. All the data were analysed using SPSS 16. The supplementation of 5%SAPin the chickens fed a diet naturally contaminated withAFshowed the potential effects of the bodyweight performance, haematological profile protection, increase in the cellular and humoral immune responses, reduction of AF residue in the organ, protection of liver, kidney, spleen, and BF histopathology, and increase in the immune-expression of CD4+/CD8+ lymphocytes ratio (P < 0.05). It shows that 5% SAP can be used as the alternative herbal supplementation to depress the impacts of aflatoxicosis in the broiler chickens.
The emergence of the severe acute respiratory syndrome coronavirus-2, responsible for causing corona virus disease 2019 (COVID-19), marked the third time in the twenty-first century when a new, highly pathogenic human coronavirus outbreak has led to an epidemic. The COVID-19 epidemic has emerged in late December 2019 in Wuhan city of China and spread rapidly to other parts of the world. This quick spread of SARS-CoV-2 infection to many states across the globe affecting many people has led WHO to declare it a pandemic on March 11, 2020. In this presentation, we discuss recent updates regarding various therapeutic approaches to combat COVID-19 pandemic according to the biosynthetic source and enlist the major pipeline drugs and traditional medicines that are under trial for COVID-19. Altogether, the information provided in this project dissertation will work as an intellectual groundwork and provides an insight into the ongoing development of various therapeutic agents.
1) The study tested the ability of individual bacteriophages (DCMK-1, DCMK-2, DCMK-3, DCMK-4) and bacteriophage cocktails to reduce Burkholderia cenocepacia infection in a Lemna minor (duckweed) model.
2) All individual phages and cocktails significantly reduced infection compared to controls, but DCMK-4 and the DCMK-1,2,3,4 and DCMK-2,3,4 cocktails performed best with the highest duckweed survivorship.
3) DCMK-2 performed the worst of the individual phages. The DCMK
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
INTENDED LEARNING OUTCOMES
At the end of this class, students should be able to:
1. Define Medical Laboratory Science and explain its relevance as a discipline.
2. Define Medical Microbiology and list its sub- specialties.
3. Define micro-organism and highlight the differences between Prokaryotes and Eukaryotes.
4. Differentiate between infection and infectious disease.
5. List and explain the modes of transmission of infectious agents.
6. List and explain the different methods of diagnosis of infectious diseases
This document describes the isolation and characterization of a new giant virus called Cedratvirus. Key points:
- Cedratvirus was isolated from an environmental sample in Algeria using Acanthamoeba castellanii.
- It has an ovoid shape with a cork structure at each end, resembling Pithovirus sibericum but with a unique double cork feature.
- The 589kb genome is most closely related to the pithovirus genomes, sharing over 100 genes, but with only 21% of genes involved in best reciprocal hits, indicating genetic distance from known pithoviruses.
- The study analyzed data from over 96,000 patients hospitalized with COVID-19 across 671 hospitals on 6 continents to evaluate the effects of hydroxychloroquine or chloroquine, with or without macrolides.
- Patients receiving the drug regimens within 48 hours of diagnosis were compared to over 81,000 patients in a control group.
- After adjusting for factors like age, comorbidities, and severity, all four treatment regimens were associated with an increased risk of in-hospital death and new ventricular arrhythmias compared to the control group.
- The study found no evidence that hydroxychloroquine or chloroquine, either alone or with macrolides,
Monkeypox Drug and Vaccine Discovery - Creative BiolabsCreative-Biolabs
This document discusses drug and vaccine discovery efforts for monkeypox. It outlines the workflow for drug repurposing targeting monkeypox, identifying potential existing drugs that could be effective. These include tecovirimat, brincidofovir, and others. It also describes the process for vaccine development, noting existing smallpox vaccines may prevent monkeypox. Finally, it lists the services and products available from Creative Biolabs to support anti-monkeypox drug and vaccine discovery.
This document summarizes two reviews on the use of chloroquine and hydroxychloroquine to treat COVID-19. The first review identified 9 studies including 3 clinical trials of 150 patients that suggested chloroquine and hydroxychloroquine can successfully treat COVID-19. It also found COVID-19 is less common in areas where malaria is more common. The second review discussed ongoing clinical trials of various potential drugs and therapeutic approaches to treat and prevent COVID-19, including remdesivir, favipiravir, lopinavir/ritonavir, chloroquine, hydroxychloroquine and corticosteroids, though definitive results are still pending.
A novel coronavirus from patients with pneumonia in china, 2019MANUELPERALTA33
- In December 2019, a cluster of pneumonia cases of unknown cause emerged in Wuhan, China and was linked to a seafood market.
- Researchers isolated a novel coronavirus (2019-nCoV) from bronchoalveolar lavage fluid of patients with pneumonia.
- The virus was able to infect and replicate in human airway epithelial cells in vitro, causing cytopathic effects. Electron microscopy images showed spherical virus particles around 60-140nm in diameter with distinctive spikes.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
Treatment of COVID-19; old tricks for new challengesLuisaSarlat
Coronavirus disease (COVID-19), which appeared in December 2019, presents a global challenge, particularly in the rapid increase of critically ill patients with pneumonia and absence of definitive treatment. To date, over 81,000 cases have been confirmed, with over 2700 deaths. The mortality appears to be around 2%; early published data indicate 25.9% with SARS-CoV-2 pneumonia required ICU admission and 20.1% developed acute respiratory distress syndrome
This study analyzed urine samples collected from 2011-2013 at a hospital in Silchar, India to determine the antibiotic resistance patterns of bacteria causing urinary tract infections (UTIs). The main findings were:
1) Escherichia coli was the most common cause of UTIs, identified in 38.54% of samples. Resistance to oral antibiotics like fluoroquinolones and cephalosporins was high for E. coli isolates.
2) Extended spectrum beta-lactamase (ESBL) production was observed in 28.74% of E. coli and 40.74% of Klebsiella isolates.
3) Methicillin-resistant Staphylococcus aureus (
Insignt from nono medicine into chloroquine efficacy against COVID-19Valentina Corona
Chloroquine, an approved malaria drug, may have potential therapeutic effects against COVID-19 based on preliminary clinical trials and studies. Chloroquine is known to inhibit endocytosis and increase lysosomal pH, which could interfere with SARS-CoV-2 cellular entry and fusion. Specifically, chloroquine may suppress the protein PICALM, reducing clathrin-mediated endocytosis of SARS-CoV-2. However, more clinical trial data is still needed to verify chloroquine's efficacy against COVID-19, and further studies aim to better understand chloroquine's mechanisms of action and optimal dosing protocols.
O ptimization of hyrozycloroquine in mangement of covid 19Ahmed Ali
This document summarizes the potential use of hydroxychloroquine (HCQ) in treating COVID-19. It discusses HCQ's pharmacological properties including its immunomodulatory and antiviral effects. Based on its ability to increase lysosomal pH and disrupt viral fusion and replication, HCQ has demonstrated efficacy against SARS-CoV-1 in vitro and in animal models. The document proposes guidelines for optimizing HCQ's efficacy and safety in COVID-19 treatment, including early administration, loading doses, and continued maintenance doses under medical supervision. More clinical trials are needed to evaluate HCQ specifically for early COVID-19 treatment.
This document proposes using bromhexine as a prophylactic and treatment for SARS-CoV-2. Bromhexine is a mucolytic drug that selectively inhibits the protease TMPRSS2, which plays an important role in SARS-CoV-2 cell entry. The document argues that chloroquine alone may not be effective as a prophylactic. It proposes combining a less toxic derivative of chloroquine with bromhexine to block viral entry by inhibiting both the endosomal pathway and TMPRSS2. Bromhexine has safety and affordability advantages over other TMPRSS2 inhibitors and may effectively prevent SARS-CoV-2 transmission when used as a prophylactic by inhibiting viral entry
Sensitivity and specificity of 99mTc-UBI29-41 and 67Ga-Citrate scintigraphy i...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
This document summarizes a study identifying Parainfluenza virus 4 in humans in Najaf, Iraq between 2012-2013. Nasal swabs and blood samples were collected from 320 individuals and tested using rapid tests and RT-PCR. Thirty-three samples tested positive for Parainfluenza virus 4 using virus-specific primers in RT-PCR. The study concludes that RT-PCR is a rapid and sensitive method for identifying Parainfluenza virus 4 that could be used to diagnose infections.
Lo studio “Shock and kill” sugli effetti degli inibitori delle istone deaceti...mabasta
This document summarizes findings from a study investigating the use of histone deacetylase inhibitors (HDACIs) and the glutathione synthesis inhibitor buthionine sulfoximine (BSO) to activate HIV-1 from latency as part of "shock and kill" strategies for HIV eradication. The study tested various HDACIs for their ability to induce HIV-1 replication in cell line models. Class I-selective HDACIs were generally more potent activators with lower toxicity compared to non-selective HDACIs. However, toxicity remained a concern. Adding BSO increased the HIV-1 activating effects of class I HDACIs at lower, non-toxic concentrations by depleting glutathione and creating a pro-oxidant environment
The Role of Sauropus androgynus (L.) Merr. Leaf Powder in the Broiler Chicken...UniversitasGadjahMada
Aflatoxin (AF) is the secondary metabolite of Aspergillus flavus and commonly contaminates feed during storage.AF causes lowered growth rate, stress, and increased mortality in the poultry, especially for broiler industries.The aims of this study are to determine the effects of Sauropus androgynus (L.) Merr. leaf powder (SAP) in the chickens fed a diet naturally contaminated with AF. A total of 108 chickens are divided into 6 group: group I fed with basal diet (AF not detectable); group II fed with basal diet (AF not detectable) + 5%SAP; group III with AF (>1 ppb <50 ppb); group IVwithAF (>1 ppb <50ppb) + 5% SAP; groupVwithAF (>51 ppb <100 ppb) + 5%SAP; group VI with AF (>101 ppb <150 ppb) + 5% SAP.The data of the body weight, feed intake and efficiency, the relative weight of liver, kidney, spleen, bursa of Fabricius (BF), histopathology, haematological profile, haemagglutination inhibition (HI) titer, AF residue, and immunohistochemistry are collected on days 7, 14, and 21. All the data were analysed using SPSS 16. The supplementation of 5%SAPin the chickens fed a diet naturally contaminated withAFshowed the potential effects of the bodyweight performance, haematological profile protection, increase in the cellular and humoral immune responses, reduction of AF residue in the organ, protection of liver, kidney, spleen, and BF histopathology, and increase in the immune-expression of CD4+/CD8+ lymphocytes ratio (P < 0.05). It shows that 5% SAP can be used as the alternative herbal supplementation to depress the impacts of aflatoxicosis in the broiler chickens.
The emergence of the severe acute respiratory syndrome coronavirus-2, responsible for causing corona virus disease 2019 (COVID-19), marked the third time in the twenty-first century when a new, highly pathogenic human coronavirus outbreak has led to an epidemic. The COVID-19 epidemic has emerged in late December 2019 in Wuhan city of China and spread rapidly to other parts of the world. This quick spread of SARS-CoV-2 infection to many states across the globe affecting many people has led WHO to declare it a pandemic on March 11, 2020. In this presentation, we discuss recent updates regarding various therapeutic approaches to combat COVID-19 pandemic according to the biosynthetic source and enlist the major pipeline drugs and traditional medicines that are under trial for COVID-19. Altogether, the information provided in this project dissertation will work as an intellectual groundwork and provides an insight into the ongoing development of various therapeutic agents.
1) The study tested the ability of individual bacteriophages (DCMK-1, DCMK-2, DCMK-3, DCMK-4) and bacteriophage cocktails to reduce Burkholderia cenocepacia infection in a Lemna minor (duckweed) model.
2) All individual phages and cocktails significantly reduced infection compared to controls, but DCMK-4 and the DCMK-1,2,3,4 and DCMK-2,3,4 cocktails performed best with the highest duckweed survivorship.
3) DCMK-2 performed the worst of the individual phages. The DCMK
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
INTENDED LEARNING OUTCOMES
At the end of this class, students should be able to:
1. Define Medical Laboratory Science and explain its relevance as a discipline.
2. Define Medical Microbiology and list its sub- specialties.
3. Define micro-organism and highlight the differences between Prokaryotes and Eukaryotes.
4. Differentiate between infection and infectious disease.
5. List and explain the modes of transmission of infectious agents.
6. List and explain the different methods of diagnosis of infectious diseases
This document describes the isolation and characterization of a new giant virus called Cedratvirus. Key points:
- Cedratvirus was isolated from an environmental sample in Algeria using Acanthamoeba castellanii.
- It has an ovoid shape with a cork structure at each end, resembling Pithovirus sibericum but with a unique double cork feature.
- The 589kb genome is most closely related to the pithovirus genomes, sharing over 100 genes, but with only 21% of genes involved in best reciprocal hits, indicating genetic distance from known pithoviruses.
- The study analyzed data from over 96,000 patients hospitalized with COVID-19 across 671 hospitals on 6 continents to evaluate the effects of hydroxychloroquine or chloroquine, with or without macrolides.
- Patients receiving the drug regimens within 48 hours of diagnosis were compared to over 81,000 patients in a control group.
- After adjusting for factors like age, comorbidities, and severity, all four treatment regimens were associated with an increased risk of in-hospital death and new ventricular arrhythmias compared to the control group.
- The study found no evidence that hydroxychloroquine or chloroquine, either alone or with macrolides,
Monkeypox Drug and Vaccine Discovery - Creative BiolabsCreative-Biolabs
This document discusses drug and vaccine discovery efforts for monkeypox. It outlines the workflow for drug repurposing targeting monkeypox, identifying potential existing drugs that could be effective. These include tecovirimat, brincidofovir, and others. It also describes the process for vaccine development, noting existing smallpox vaccines may prevent monkeypox. Finally, it lists the services and products available from Creative Biolabs to support anti-monkeypox drug and vaccine discovery.
This document summarizes two reviews on the use of chloroquine and hydroxychloroquine to treat COVID-19. The first review identified 9 studies including 3 clinical trials of 150 patients that suggested chloroquine and hydroxychloroquine can successfully treat COVID-19. It also found COVID-19 is less common in areas where malaria is more common. The second review discussed ongoing clinical trials of various potential drugs and therapeutic approaches to treat and prevent COVID-19, including remdesivir, favipiravir, lopinavir/ritonavir, chloroquine, hydroxychloroquine and corticosteroids, though definitive results are still pending.
A novel coronavirus from patients with pneumonia in china, 2019Juan Rubio
- In late December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood market in Wuhan, China. Through testing samples from these patients, a novel coronavirus was discovered and named 2019-nCoV.
- Using samples from the pneumonia patients, researchers were able to isolate and culture the novel coronavirus (2019-nCoV) using human airway epithelial cells. Electron microscopy of the cultured cells showed coronavirus particles.
- Genomic sequencing of samples from the patients identified the virus as a new strain of coronavirus within the subgenus sarbecovirus, most closely related to SARS-CoV and MERS-CoV but distinct from them.
Five drug development strategies to combat SARS-CoV2Anton Yuryev
Slides were presented at webinar on “Opportunities & Challenges in Drug Discovery and Development” organised by Elsevier in collaboration with Dr Reddy’s Institute of Life Sciences, Hyderabad on July 16th,2020
Immunization with sars coronavirus vaccines leads to pulmonary immunopathologyLANStillH2O
1) A study evaluated four SARS-CoV vaccine candidates in mice to assess safety, immunogenicity, and efficacy.
2) All vaccines induced neutralizing antibodies and protected mice from SARS-CoV challenge as shown by reduced lung virus levels.
3) However, when mice were challenged after vaccination, all mice exhibited histopathologic lung changes, including eosinophil infiltration. This suggested the vaccines induced a Th2-type immunopathology rather than protection from disease.
4) The findings indicate SARS-CoV vaccines may protect against infection but could also cause immunopathology upon exposure to the live virus. More research is needed before applying these vaccines to humans.
Homeopathic Dilutions of Mercury Chloride as an Effective and Affordable Trea...semualkaira
A novel human coronavirus that is now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (formerly called
HCoV-19) emerged in Wuhan,China, in late 2019 and is now causing a pandemic [1]. The epidemic of SARS-CoV wassuccessfully
contained through public health interventions, including case detection and isolation. Transmission of SARS-CoV occurred mainly
after days of illness
This study evaluated the pharmacodynamic relationships between drug levels and HIV suppression in fresh and cryopreserved cervical tissue using an ex vivo challenge assay. Women used vaginal rings containing dapivirine and/or maraviroc for 28 days. Cervical biopsies were collected and either used fresh or cryopreserved and shipped for processing. HIV replication was greater in fresh tissue compared to cryopreserved tissue. Drug levels in fresh cervical tissue and cervicovaginal fluid negatively correlated with HIV levels, but cryopreserved tissue showed no such correlations. The ex vivo challenge assay using fresh tissue can help prioritize drugs for HIV prevention by defining pharmacodynamic relationships.
This study evaluated the pharmacodynamic relationships between drug levels and HIV suppression in fresh and cryopreserved cervical tissue using an ex vivo challenge assay. Women used vaginal rings containing dapivirine and/or maraviroc for 28 days. Cervical biopsies were collected and either used fresh or cryopreserved and shipped for processing. HIV replication was greater in fresh tissue compared to cryopreserved tissue. Drug levels in fresh cervical tissue and cervicovaginal fluid negatively correlated with HIV levels, but cryopreserved tissue showed no such correlations. The ex vivo challenge assay using fresh tissue defined pharmacokinetic/pharmacodynamic relationships and could help prioritize drug candidates for HIV prevention.
This randomized controlled trial evaluated the effect of daily bathing with chlorhexidine-impregnated washcloths versus non-antimicrobial washcloths on the acquisition of multidrug-resistant organisms (MDROs) and hospital-acquired bloodstream infections across nine intensive care and bone marrow transplant units. The study found that chlorhexidine bathing resulted in a 23% lower rate of MDRO acquisition and a 28% lower rate of hospital-acquired bloodstream infections compared to non-antimicrobial bathing. No serious skin reactions were reported with chlorhexidine use.
Effect of pH concentration on hydatid cyst protoscolices infectivity: In vitr...iosrjce
IOSR Journal of Nursing and health Science is ambitious to disseminate information and experience in education, practice and investigation between medicine, nursing and all the sciences involved in health care. Nursing & Health Sciences focuses on the international exchange of knowledge in nursing and health sciences. The journal publishes peer-reviewed papers on original research, education and clinical practice.
By encouraging scholars from around the world to share their knowledge and expertise, the journal aims to provide the reader with a deeper understanding of the lived experience of nursing and health sciences and the opportunity to enrich their own area of practice. The journal publishes original papers, reviews, special and general articles, case management etc.
This study examined the association between hydroxychloroquine use and intubation or death in 1376 patients hospitalized with COVID-19 at Columbia University Irving Medical Center in New York City. The primary outcome was a composite of intubation or death. 811 patients (58.9%) received hydroxychloroquine. There was no significant association between hydroxychloroquine use and intubation or death in the primary analysis or sensitivity analyses. Randomized controlled trials are still needed to determine if hydroxychloroquine is effective for treating COVID-19.
Resistance pattern of cephadroxil monohydrate and ceftrixone against differen...pharmaindexing
Resistance pattern of cephadroxil monohydrate and ceftrixone against different clinical isolates was the aim of the study and 90 clinical isolates comprising of Escherichia coli, Staphylococcus aureus, Klebsiella, Proteus and Pseudomonas aerogenosa were collected from different local pathological laboratories and their resistant pattern against cephadroxil monohydrate and ceftrixone were studied using disc diffusion method. Klebsiella, (86.6% against cephadroxil monohydrate and 53.33% against ceftrixone) and Proteus (66.67% against cephadroxil monohydrate and 33.33% against ceftrixone). In case of Staphylococcus aureus and Escherichia coli, resistance found was 41.18% and 48% against ceftrixone,82.35% and 97.62% against cephadroxil monohydrate respectively and in case of Pseudomonas aerogenosa resistance found was 40% against ceftrixone and 90% against cephadroxil monohydrate. It is concluded from these figures that microbial resistance against these cephalosporins are increasing in the population which is alarming and therefore it is recommended to physicians to prescribe these antibiotics only of no other alternate is available in clinical practices.
This document describes a computational screening study of 12 FDA-approved antiviral drugs against SARS-CoV-2 spike protein and main protease targets using molecular docking. Key findings include:
- Ganciclovir and zanamivir showed strong binding energies (below -9 kcal/mol) with both targets through hydrogen bonding interactions.
- Ribavirin and tenofovir also exhibited significant binding energies above -8 kcal/mol with multiple hydrogen bonds to the main protease and spike protein.
- The study identifies potential dual-target antiviral properties of existing drugs, providing a starting point for further pre-clinical and clinical tests against SARS-CoV-2.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Hiranandani Hospital in Powai, Mumbai, is a premier healthcare institution that has been serving the community with exceptional medical care since its establishment. As a part of the renowned Hiranandani Group, the hospital is committed to delivering world-class healthcare services across a wide range of specialties, including kidney transplantation. With its state-of-the-art facilities, advanced medical technology, and a team of highly skilled healthcare professionals, Hiranandani Hospital has earned a reputation as a trusted name in the healthcare industry. The hospital's patient-centric approach, coupled with its focus on innovation and excellence, ensures that patients receive the highest standard of care in a compassionate and supportive environment.
One health condition that is becoming more common day by day is diabetes.
According to research conducted by the National Family Health Survey of India, diabetic cases show a projection which might increase to 10.4% by 2030.
Travel vaccination in Manchester offers comprehensive immunization services for individuals planning international trips. Expert healthcare providers administer vaccines tailored to your destination, ensuring you stay protected against various diseases. Conveniently located clinics and flexible appointment options make it easy to get the necessary shots before your journey. Stay healthy and travel with confidence by getting vaccinated in Manchester. Visit us: www.nxhealthcare.co.uk
2. 2 / 25
Hospital, Beijing, China. (liudongyang@sina.vip.com)
Main point: Hydroxychloroquine was found to be more potent than chloroquine at
inhibiting SARS-CoV-2 in vitro. Hydroxychloroquine sulfate 400 mg given twice
daily for 1 day, followed by 200 mg twice daily for 4 more days is recommended to
treat SARS-CoV-2 infection.
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Abstract
Background. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine
has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine
shares the same mechanism of action as chloroquine, but its more tolerable safety
profile makes it the preferred drug to treat malaria and autoimmune conditions. We
propose that the immunomodulatory effect of hydroxychloroquine also may be useful
in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2
infected patients. Currently, there is no evidence to support the use of
hydroxychloroquine in SARS-CoV-2 infection.
Methods. The pharmacological activity of chloroquine and hydroxychloroquine was
tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic
models (PBPK) were implemented for both drugs separately by integrating their in
vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid
were simulated under 5 different dosing regimens to explore the most effective
regimen whilst considering the drug’s safety profile.
Results. Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than
chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose
of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a
maintenance dose of 200 mg given twice daily for 4 days is recommended for
SARS-CoV-2 infection, as it reached three times the potency of chloroquine
phosphate when given 500 mg twice daily 5 days in advance.
Conclusions. Hydroxychloroquine was found to be more potent than chloroquine to
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INTRODUCTION
In December 2019 the outbreak of a novel coronavirus, Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2 or COVID-2019), was first reported in
Wuhan, China. The outbreak has since rapidly spread to other provinces in mainland
China, as well as other countries around the world. Currently the number of people
diagnosed with SARS-CoV-2 infection is increasing by approximately 1000 cases a
day. Unfortunately, to date, no drugs have approved by regulatory agencies for the
treatment of SARS-CoV-2 infection.
Chloroquine is a widely used anti-malarial with immunomodulatory effects [1-5]. In a
recent in vitro study chloroquine was found to inhibit the growth of SARS-CoV-2 in
vitro [6]. This finding has been supported by clinical studies conducted in
approximately one-hundred SARS-CoV-2 infected patients [7, 8].
Hydroxychloroquine is an analog of chloroquine that has fewer concerns about
drug-drug interactions. In the previous SARS outbreak, hydroxychloroquine was
reported to have anti-SARS-CoV activity in vitro [9]. This suggests that
hydroxychloroquine may be a potential pharmacological agent for the treatment of
COVID-19 infection. However, to date, there is no clinical evidence to support the
use of hydroxychloroquine as a treatment for SARS-CoV-2 infection.
The molecular mechanism of action of chloroquine and hydroxychloroquine has not
been fully elucidated. Findings from previous studies have suggested that chloroquine
and hydroxychloroquine may inhibit the coronavirus through a series of steps. Firstly,
the drugs can change the pH at the surface of the cell membrane and thus, inhibit the
fusion of the virus to the cell membrane. It can also inhibit nucleic acid replication,
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glycosylation of viral proteins, virus assembly, new virus particle transport, virus
release and other processes to achieve its antiviral effects [10].
A reliable estimation of hydroxychloroquine and chloroquine concentrations in the
lung, the target tissue, may be used for guiding dose recommendations.
Physiologically-based pharmacokinetic (PBPK) models are a mathematical modelling
technique that can predict drug concentrations in human tissues in silico by
integrating physiological and drug disposition parameters. PBPK models are widely
used in drug development to help identify whether a clinical trial is warranted as well
as help guide the use of drugs based on predictions from well-validated models [11,
12].
In this study we aimed to: (i) investigate the antiviral and prophylactic activity of
hydroxychloroquine and chloroquine in vitro, (ii) build a PBPK model for
hydroxychloroquine and chloroquine using data from literature, and, (iii) predict drug
concentrations under different dosing regimens using the developed PBPK models.
METHODS
In Vitro Antiviral Activity Experiment
Experiment Materials
Chloroquine phosphate and hydroxychloroquine sulfate were purchased from Beijing
Innochem Science & Technology Co, Ltd. The lyophilized powder was diluted in
double distilled water to 10 mM. Hydroxychloroquine sulfate was readily soluble in
water. Chloroquine phosphate was dissolved by shaking the solution at room
temperature for 2 hours. The chloroquine and hydroxychloroquine solutions were
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filtered through a 0.22 μm membrane and were then stored at −80°C. The clinically
isolated SARS-CoV-2 virus strain, C-Tan-nCoV Wuhan strain 01, was propagated in
Vero cells.
Cell Culture
The Vero cells were derived from the African green monkey kidney and were grown
in Dulbecco's Modified Eagle Medium (DMEM) (Sigma Aldrich, Boston, MA, USA)
supplemented with 5% fetal bovine serum (Logan, UT, USA). The cells were
maintained in a humidified atmosphere with 5% CO2 at 37°C. The culture medium
was replaced each day.
Antiviral Activity Assay
The anti-SARS-CoV-2 activity of chloroquine and hydroxychloroquine was
investigated in vitro. Cells were seeded into 96-well plates at a density of 1×104
cells/well and were grown for 24 hours. The in vitro experiment was divided into two
sections, named: (i) the treatment study and (ii) the prophylactic study.
Treatment study: In the treatment study Vero cells were infected at a multiplicity of
infection (MOI) of 0.01 (100 PFU/well) for 2 hours at a temperature of 37°C .Virus
input was washed with DMEM and the cells were then treated with medium
containing either chloroquine or hydroxychloroquine at 0.032, 0.16, 0.80, 4, 20, 100
μM for 24 or 48 hours.
Drug pretreatment study: Vero cells were pretreated with chloroquine or
hydroxychloroquine for 2 hours and then, were removed from the drug-containing
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medium. The virus-containing medium was then added to the infected Vero cells (as
described for the treatment study) for 2 hours. Following this, the virus-containing
medium was removed and replaced with fresh medium that did not contain drugs or
viruses.
The supernatant was collected, and, the RNA was extracted and analyzed by relative
quantification using RT-PCR (methods described in a previously published study) [13,
14].
Viral RNA Extraction and RT-PCR
Viral RNA was extracted from 100 μL of supernatant of infected cells using the
automated nucleic acid extraction system (TIANLONG, China) and the
manufacturer’s instructions. Detection of the SARS-CoV-2 virus was performed using
the One Step Prime Script RT-PCR kit (TaKaRa, Japan) on the Light Cycler 480
Real-Time PCR system (Roche, Rotkreuz, Switzerland) with primers. The following
sequences were used:
forward primer: 5ʹ-AGAAGATTGGTTAGATGATGATAGT-3ʹ;
reverse primer:5ʹ-TTCCATCTCTAATTGAGGTTGAACC-3ʹ;
and probe:5ʹ-FAM-TCCTCACTGCCGTCTTGTTG ACCA-BHQ1-3ʹ.
All experiments were conducted in triplicates. The relative expression was estimated
using the 2-△△Ct
method.
Statistical Analysis
A sigmoidal concentration-response function, Y=Bottom + (Top-Bottom)/
(1+10^((LogEC50-X)*HillSlope)), was fit to the data using nonlinear regression. The
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EC50 values were calculated using PRISM (GraphPad software, San Diego, CA,
USA).
PBPK Model Development, Validation and Simulation
The PBPK models for chloroquine and hydroxychloroquine were developed using
Simcyp simulator (version 18). The chloroquine compound file was provided by
Simcyp Limited (a Certara company, Blades Enterprise Centre, Sheffield, UK) and
the hydroxychloroquine compound file was self-built. Physical and chemical
parameters were obtained from the literature [15]. Pharmacokinetic parameters, such
as liver intrinsic clearance, fa and ka, were determined from clinical data [16]. These
data are summarized in supplement 1. The lung to blood concentration ratio for
chloroquine and hydroxychloroquine (obtained from animal studies) was used to
predict the drug concentration in the lungs [17, 18].
Validation Data
Published chloroquine and hydroxychloroquine clinical trial data were used to
validate the developed PBPK models (details summarized in supplement 2) [16,
19-23]. Data obtained from the literature in graphical form were extracted using Plot
Digitizer (version 2.26, GetData). Pharmacokinetic parameters that could not be
sourced from the literature were estimated using extracted data in Phoenix (version
8.6, Certara company).
Validation Method
Concentration-time profiles were simulated under different published clinical trial
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protocols using the developed PBPK models for hydroxychloroquine and chloroquine
[16, 19-23]. The Simcyp “Healthy volunteer”, “Chinese healthy volunteer” and
“Pediatric” virtual populations were used in the simulations as the clinical trials were
conducted in Caucasian, Chinese and children populations, respectively.
Simulated exposure data was compared to observed data. The criterion to determine
model accuracy was based on whether the observed data fell within the 90%
confidence interval of the predicted values. The ratio of predicted pharmacokinetic
(PK) parameters (e.g. Cmax and AUC) to observed values was used to evaluate model
performance. The predicted values were considered reasonable if the ratio of
predicted to observed data was within a 2-fold range (0.5≤ratio≤2.0).
Simulation Method
The exposure of chloroquine and hydroxychloroquine in the lungs, plasma and blood
were simulated under different dosing regimens (shown in Table 1) using the
validated PBPK models. A correction factor for chloroquine base and
hydroxychloroquine base was input into the model simulations. Chloroquine
phosphate 500 mg is equivalent to 300 mg of chloroquine base and 200 mg of
hydroxychloroquine sulfate is equivalent to 155 mg of hydroxychloroquine base. The
“Chinese Healthy Volunteers” virtual population provided in Simcyp was used for the
simulations. All simulations were performed with 10 trials and 10 subjects per trial.
Virtual subjects were aged between 20 to 50 years of age, and, 50% of the subjects
were male and 50% female.
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Dose regimen optimization
The PBPK models were used to predict the lung tissue concentrations of chloroquine
and hydroxychloroquine under different dosing regimens (Table 1). The lung trough
concentration on days 1, 3, 5 and 10 were adjusted by the plasma unbound fraction
(fu,plasma) to obtain the free lung trough concentration. The ratio of the free lung trough
concentration to the in vitro EC50 values (RLTEC) was calculated and the results
tabulated. In a recent clinical trial 500 mg of chloroquine phosphate given twice daily
was shown to be effective on study day 5 (RLTEC, day5). This dosing regimen for
chloroquine was used as the target for dose optimization for hydroxychloroquine (i.e.,
the RLTEC of hydroxychloroquine should not be lower than the RLTEC, day5 of
chloroquine at any time).
RESULTS
Antiviral Activity in vitro
Results from the in vitro study showed that both chloroquine and hydroxychloroquine
have good antiviral activity. Chloroquine and hydroxychloroquine were found to
decrease the viral replication in a concentration-dependent manner. The EC50 values
for chloroquine were 23.90 and 5.47 μM at 24 and 48 hours, respectively (Figure 1a).
EC50 values for hydroxychloroquine were 6.14 and 0.72 μM at 24 and 48 hours,
respectively (Figure 1b).
Antiviral Pre-treatment Activity in vitro
Hydroxychloroquine exhibited a superior in vitro antiviral effect in comparison to
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chloroquine when drug was added prior to the viral challenge. The EC50 values for
chloroquine were >100 and 18.01 μM at 24 and 48 hours, respectively. EC50 values
for hydroxychloroquine were 6.25 and 5.85 μM at 24 and 48 hours, respectively. It
was noted that with longer incubation times the EC50 values for chloroquine and
hydroxychloroquine tended to decrease. The inhibitory effect of chloroquine was poor.
This was particularly evident at 24 hours, whereby, even at the highest concentration
of chloroquine used in the study, the inhibition rate did not exceed 50% (Figure 1c
and 1d).
PBPK model development, validation and simulation
Validation results
The predicted and observed plasma/blood concentration time profiles for chloroquine
and hydroxychloroquine is shown in Figure 2. Intravenous data was used to
understand the distribution and elimination phase of the two drugs, and, oral
administration data was used to understand the intracorporal absorption process. Most
of the observed data fell within the 90% prediction interval. The ratio of predicted to
observed PK parameters (Cmax and AUC) were within the range of 0.5 to 2.0 (details
summarized in supplement 2), indicating that the prediction accuracy of the developed
PBPK models was acceptable and could be used to simulate the different dosing
scenarios.
Simulation results
The simulated lung, blood and plasma concentration time profiles for chloroquine and
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hydroxychloroquine under the different dosing regimens is shown in Figure 3. It can
be seen that the lung, blood and plasma concentrations of chloroquine increased
slowly after the first dose was given and was yet to reach steady state on day 10. The
simulated chloroquine concentration in lung tissue was much higher than in plasma,
where the lung to plasma ratio increased with time and reached a ratio of
approximately 400. The projected lung, blood and plasma concentrations of
hydroxychloroquine rapidly increased and reached steady state following the initial
loading dose and subsequent maintenance doses (Figure 3b to 3f).
Suggested dosing regimens for hydroxychloroquine to treat SARS-CoV-2
infection
The free lung trough concentrations were also projected from the simulations. The
ratio of free lung trough concentration to EC50 (RLTEC) under the different dosing
regimens is shown in Table 1. The RLTEC values of hydroxychloroquine were found to
be higher than the RLTEC values of chloroquine on days 1, 3, 5 and 10. This suggests
that hydroxychloroquine may achieve ideal clinical efficacy under the simulated
dosing regimens.
The RLTEC on day 1 was notably higher for hydroxychloroquine than for chloroquine.
This is likely to be due to the loading dose of hydroxychloroquine given, thus
enabling a faster clinical effect. There was no significant difference between the once
and twice daily maintenance dosing regimens (Regimen C and D, respectively) when
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used from day 2 to day 10; hence, the once daily dosing regimen may be preferred to
improve patient compliance. Despite Regimen F being a 5 day treatment regimen, the
lung trough concentrations were still above the target concentration on day 10.
However, if the treatment duration of Regimen F was extended to 10 days (i.e.
Regimen E) it resulted in a higher drug concentration on day 10. Overall, Regimen F
may be the best regimen whilst considering both efficacy, safety and patient
compliance.
DISCUSSION
In this study, hydroxychloroquine exhibited better in vitro anti-SARS-CoV-2 activity
than chloroquine. This was demonstrated by the EC50 values for hydroxychloroquine
always being smaller than the EC50 values for chloroquine, indicating that
hydroxychloroquine has a more potent antiviral activity (shown in Figure 1). In the
study by Wang et al [6], chloroquine was shown to have an inhibitory effect on
SARS-CoV-2 with an EC50 value of 1.13 μM after a 48 hour incubation time. These
findings are comparable with our in vitro chloroquine results of an EC50 value of 5.47
μM. In addition, an unpublished clinical trial has demonstrated the therapeutic effect
of chloroquine in SARS-CoV-2 infected patients. On the basis of
hydroxychloroquine’s superior antiviral and prophylactic activity, as well as its more
tolerable safety profile in comparison to chloroquine, we believe that
hydroxychloroquine may be a promising drug for the treatment of SARS-CoV-2
infection [24].
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In our study we noted that the EC50 values for hydroxychloroquine and chloroquine
decreased with longer incubation times. This suggests that incubation time may
influence the drug’s antiviral activity. Both hydroxychloroquine and chloroquine have
been reported to accumulate in cells [25]. It is possible that a longer incubation time
may provide more time for the drug to accumulate to higher intracellular
concentrations and ultimately exhibit a better antiviral effect [26]. Another possible
explanation is that the drug-induced cytotoxicity may take time to develop, and hence,
the drug effect may increase with time [27].
The PBPK model for hydroxychloroquine and chloroquine was validated with in vivo
PK data from humans, rats and mice. The model was able to reasonably predict drug
concentrations in human lung tissue. A permeability rate limiting model was
implemented in the PBPK model to mimic the characteristics of both drugs. In
addition, a high lung to plasma partition coefficient ratio (Kp ratio) was used to
imitate the drugs’ high accumulation in lung tissue. The Kp ratio for humans was
assumed to be same as the ratio for rats because there was no human data available.
This assumption may be reasonable as the transportation of both drugs is completely
via passive diffusion (i.e. no transporters are involved).
In some patients it has been reported that their immune response to the SARS-CoV-2
virus results in the increase of cytokines IL-6 and IL-10 [13, 28]. This may progress
to a cytokine storm, followed by multi-organ failure and potentially death. Both
hydroxychloroquine and chloroquine have immunomodulatory effects and can
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suppress the increase of immune factors [29, 30]. Bearing this in mind, it is possible
that early treatment with either of the drugs may help prevent the progression of the
disease to a critical, life-threatening state. In critically ill SARS-CoV-2 infected
patients the use of corticosteroids may be harmful [31]. Whilst, the use of
immunosuppressants (e.g. tocilizumab) are not ideal either as it can suppress the
immune system and lead to an increased risk of infection [32]. In this setting,
hydroxychloroquine may be an ideal drug to treat SARS-CoV-2 infection as it can
inhibit the virus via its antiviral effects and help mediate the cytokine storm via its
immunomodulatory effects. Based on work conducted in our lab, we recommend the
concomitant use of low dose hydroxychloroquine with an anti-inflammatory drug to
help mitigate the cytokine storm in critically ill SARS-CoV-2 patients.
Several clinical trials are currently investigating the use of hydroxychloroquine to
treat SARS-CoV-2 infection. However, it is worth noting that the dosing regimens
used in these trials are mainly based on previous clinical experience, raising the
concern that adverse effects may occur in study participants (supplement 3). In this
study, an optimized dosing regimen was designed for hydroxychloroquine to have a
high loading dose and low maintenance dose based on it’s unique pharmacokinetics
(i.e. high accumulation in cells and long elimination half-life). Using PBPK modelling
and simulation techniques the optimal dosing regimen for hydroxychloroquine was
evaluated in in silico. The simulation results demonstrated that Regimen F was able to
achieve treatment efficacy as well as have a good safety profile, even considering
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possible underestimation of drug efficacy to some extent. However, future clinical
trials evaluating this regimen are required before it can be readily used in the clinic.
The combination of the in vitro antiviral activity data and predicted drug
concentrations in this study are being used to support the design of dosing regimens
used in a future clinical trial.
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Acknowledgements
We want to thank Dr. Lisa Almond and Luke Guilliatt from Simcyp Limited for
providing the chloroquine compound file.
Funding
This work was supported by the “13th Five-Year” National Major New Drug Projects
of China, Ministry of Science and Technology of the People’s Republic of China,
[grant number No.2017ZX09101001-002-001] and Bill & Melinda Gates Foundation
[OPP1204780].
Conflict of Interest
C.S., H.L., and D.L. have patents pending for Anti-microbial infection pharmoceutical
composition and its application. All other authors have no potential conflicts.
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Figures
Figure 1. The antiviral activities of chloroquine and hydroxychloroquine for treatment
or prophylactic treatment against SARS-CoV-2 in vitro. The antiviral activities of
chloroquine and hydroxychloroquine for therapeutic and prophylactic use were tested
on the Vero cells infected with SARS-CoV-2 clinically isolate strain. (a) and (b): For
treatment group, chloroquine and hydroxychloroquine were added medium after the
Vero cells infected and cells were incubated with medium contained drugs for 24 or
48 hours. (c) and (d): For prophylactic treatment group, the Vero cells were
pre-treated with chloroquine and hydroxychloroquine for 2 hours, and then viruses
were added to medium to infect cells. After that, the medium was removed and
replaced with fresh medium without drugs or viruses and cells were incubated for 24
or 48 hours. The viral yield in the cell supernatant was quantified by RT-PCR.
Figure 2. Predicted and observed mean arithmetic concentration profiles. (a) and (b):
validation for hydroxychloroquine (HCQ) PBPK model by blood data after
intravenous administration; (c): validation for HCQ PBPK model by blood data after
oral administration; (d): validation for HCQ PBPK model by plasma data after oral
administration; (e): validation for chloroquine (CQ) PBPK model by blood data after
oral administration; (f): validation for CQ PBPK model by blood data after
intravenous administration; (g): validation for CQ PBPK model by plasma data after
oral administration; (h): validation for CQ PBPK model by plasma data after oral
administration. Details were summarized in supplement 2.
Figure 3. Predicted plasma (a), blood (b), and lung (c) concentration-time profiles of
chloroquine (CQ) under the dose regimen A, and hydroxychloroquine (HCQ) under
dose regimen B, regimen C, regimen D, regimen E, and regimen F.
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Tables
Table 1: Ratios of free lung tissue trough concentration/EC50 (RLTEC) under different dosage
regimens
Drug
NO
.
Dosing Regimen
RLTEC
Day1 Day3 Day5 Day10
Chloroquine
phosphate
A. D1-D10 500 mg BID 2.38 5.92 18.9 40.7
Hydroxychloroquine
sulfate
B.
D1 800 mg+400 mg;
D2-D10 400 mg QD
33.3 55.1 103 168
C.
D1 600 mg BID;
D2-D10 400 mg QD
31.7 54.7 103 169
D.
D1 600 mg BID;
D2-D10 200 mg BID
31.7 53.1 101 167
E.
D1 400 mg BID;
D2-D10 200 mg BID
21.0 38.9 85.4 154
F.
D1 400 mg BID;
D2-D5 200 mg BID
21.0 38.9 85.4 83.3
RLTEC: ratio of free lung tissue trough concentration/EC50.
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