Pooled results from phase 3 clinical trials demonstrate that roxadustat is efficacious and may be comparable to placebo in studies done to date for treating anemia in patients with chronic kidney disease who do not require dialysis.
Many individuals with kidney dysfunction develop anemia, or a shortage of healthy red blood cells that carry oxygen to the body’s tissues. Some treatments for anemia are linked with serious cardiovascular side effects, but a new class of oral drugs called hypoxia inducible factor-prolyl hydroxylase inhibitors may be comparable to placebo in these trials. These drugs act on the pathway involved in the production of erythropoietin that stimulates red blood cell formation.
To evaluate the efficacy and cardiovascular safety of one such inhibitor — called roxadustat — Robert Provenzano, MD (Wayne State University School of Medicine) and his colleagues analyzed data pooled from three phase 3 studies of roxadustat in patients with chronic kidney disease and anemia.
In total, 2,391 patients received roxadustat and 1,886 received a placebo. Roxadustat treatment boosted levels of hemoglobin (the protein in red blood cells responsible for transporting oxygen): roxadustat- vs. placebo-treated patients showed an average change in hemoglobin averaged over weeks 28 to 52 of 1.9 vs. 0.1 g/dL. Roxadustat also reduced the need for red blood cell transfusions in the first 52 weeks, and there were no increased risks of mortality, heart attacks, strokes linked to the drug.
“Roxadustat was shown to be effective, with an acceptable safety profile,” said Dr. Provenzano. “As an oral agent, roxadustat addresses the significant unmet need in treating anemia in patients with kidney disease.”
Study co-authors include Lynda Szczech, MD, Robert Leong, MD, Khalil Saikali, MD, Ming Zhong, PhD, Tyson T. Lee, PhD, Dustin J. Little, MD, Mark T, Houser, MD, Lars Frison, PhD, John Houghton, and Thomas B. Neff, MD.
Disclosures: RP serves as a consultant for AstraZeneca, DaVita, and FibroGen. LS, RL, KGS, MZ, TTL are employees of FibroGen and hold stock and/or stock options in FibroGen. MTH, LF, DJL, and JH are employees of AstraZeneca and hold stock and/or stock options in AstraZeneca.
FeaturedImage Credit: Kateryna Kon / Shutterstock
Reference: Robert Provenzano, Lynda Szczech, Robert Leong, Khalil G. Saikali, Ming Zhong, Tyson T. Lee, Dustin J. Little, Mark T. Houser, Lars Frison, John Houghton, Thomas B. Neff. Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non–Dialysis-Dependent CKD. Clinical Journal of the American Society of Nephrology, 2021; 16 (8): 1190 DOI: 10.2215/CJN.16191020
A licensed drug normally used to treat abnormal levels of fatty substances in the blood could reduce infection caused by the SARS-CoV-2 virus by up to 70 per cent, reveals a study in the laboratory by an international collaboration of researchers.
The research team, led by the University of Birmingham and Keele University in the UK and the San Raffaele Scientific Institute in Italy, has demonstrated that fenofibrate and its active form (fenofibric acid) can significantly reduce SARS-COV-2 infection in human cells in the laboratory. Importantly, reduction of infection was obtained using concentrations of the drug which are safe and achievable using the standard clinical dose of fenofibrate. Fenofibrate, which is approved for use by most countries in the world including the US Food and Drug Administration (FDA) and the UK’s National Institute for Health and Care Excellence (NICE), is an oral drug currently used to treat conditions such as high levels of cholesterol and lipids (fatty substances) in the blood.
The team is now calling for clinical trials to test the drug in hospitalised COVID-19 patients, to be carried out in addition to two clinical trials also currently underway in such patients in research being led by the Hospital of the University of Pennsylvania in the US and Hebrew University of Jerusalem in Israel.
SARS-CoV-2, the virus that causes COVID-19, infects the host through an interaction between the Spike protein on the surface of the virus and the ACE2 receptor protein on host cells. In this study, responding to the global COVID-19 pandemic, the team tested a panel of already licensed drugs – including fenofibrate – to identify candidates that disrupt ACE2 and Spike interactions. Having identified fenofibrate as a candidate, they then tested the efficacy of the drug in reducing infection in cells in the laboratory using the original strains of the SARS-CoV-2 virus isolated in 2020. They found fenofibrate reduced infection by up to 70%. Additional unpublished data also indicates that fenofibrate is equally effective against the newer variants of SARS-CoV-2 including the alpha and beta variants and research is ongoing into its efficacy in the delta variant.
Corresponding author Dr Farhat Khanim, of the University of Birmingham in the UK, explained: “The development of new more infectious SARS-CoV-2 variants has resulted in a rapid expansion in infection rates and deaths in several countries around the world, especially the UK, US and Europe. Whilst vaccine programmes will hopefully reduce infection rates and virus spread in the longer term, there is still an urgent need to expand our arsenal of drugs to treat SARS-CoV-2-positive patients.”
Co-corresponding author Dr Alan Richardson, of Keele University in the UK, added: “Whilst in some countries vaccination programmes are progressing at speed, vaccine uptake rates are variable and for most low middle income countries, significant proportions of the population are unlikely to be vaccinated until 2022. Furthermore, whilst vaccination has been shown to reduce infection rates and severity of disease, we are as yet unsure of the strength and duration of the response. Therapies are still urgently needed to manage COVID-19 patients who develop symptoms or require hospitalisation.”
Co-author Dr Elisa Vicenzi, of the San Raffaele Scientific Institute in Milan, Italy, said: “Our data indicates that fenofibrate may have the potential to reduce the severity of COVID-19 symptoms and also virus spread. Given that fenofibrate is an oral drug which is very cheap and available worldwide, together with its extensive history of clinical use and its good safety profile, our data has global implications – especially in low-middle income countries and in those individuals for whom vaccines are not recommended or suitable such as children, those with hyper-immune disorders and those using immune-suppressants.”
First author Dr Scott Davies, also of the University of Birmingham, concluded: “We now urgently need further clinical studies to establish whether fenofibrate is a potential therapeutic agent to treat SARS-CoV-2 infection.”
The research, published today in Frontiers in Pharmacology, was also carried out in collaboration with the University of Copenhagen in Denmark and the University of Liverpool in the UK.
Reference: Davies et al. ‘The hyperlipidaemic drug fenofibrate significantly reduces infection by SARS-1 CoV-2 in cell culture models’. Frontiers in Pharmacology. Preprint
Ju and colleagues identified that the combination of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir effectively inhibit SARS-CoV-2 polymerase and exonuclease. Their study recently appeared in BioRxiv.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for COVID-19, is a positive-sense single-stranded RNA virus. Thus, it requires an RNA-dependent RNA polymerase (RdRp) to replicate and transcribe its genome. Because of its large genome (~30 kb) and error-prone RdRp, SARS-CoV-2 also possesses a 3’-5’ exonuclease for proofreading to maintain the integrity of the genome. The replication complex of coronaviruses consists of several viral proteins, including the RdRp itself (nonstructural protein 12; nsp12) and its two accessory proteins (nsp7 and nsp8), and the exonuclease (nsp14) with its accessory protein (nsp10).
Upto date, variety of drugs have been proposed with an aim to target various SARS-CoV-2 proteins, which are essential for its infectious cycle but, no drugs including Remdesivir, found effective in reducing viral activity of Covid-19. Why? The reason I already mentioned above. SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. However, we could overcome this deficiency if we use the combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease.
Ju and colleagues previously demonstrated that the FDA approved HCV NS5A inhibitors, Daclatasvir and Velpatasvir, and to a lesser extent the NS5A inhibitors Elbasvir and Ledipasvir, can inhibit the SARS-CoV-2 exonuclease. Of particular interest, Daclatasvir and Velpatasvir inhibit both the SARS-CoV-2 polymerase and exonuclease. Now, they showed that two additional hepatitis C virus NS5A inhibitors, Pibrentasvir and Ombitasvir, also inhibit the exonuclease, and have the highest inhibitory activity based on their molecular assay. These compounds are predicted to interfere with the binding of the Mg++ ion with the 3’ terminus of the RNA in the active site of the exonuclease (nsp14).
“The Mg++ ion coordinates amino acid residues Asp-90, Glu-92, Glu-191 and Asp-273 and the 3’ terminus of the RNA. Because the NS5A inhibitors interfere with this coordination, they are likely to prevent nucleotide excision from the RNA.”
They also showed that, in the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir, Temofovir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision.
Additionally, in a recent in silico modeling study it has been suggested that Ritonavir also binds to the active site of nsp14, which led the authors to the prediction that Ritonavir may inhibit exonuclease activity. Now, Ju and colleagues have experimentally shown that Ritonavir and Lopinavir, HIV protease inhibitors that make up the combination drug Kaletra, inhibit the SARS-CoV-2 exonuclease in a concentration-dependent manner, but with less potency than Pibrentasvir and Ombitasvir.
Finally, they showed that by combining Pibrentasvir or Ombitasvir with Remdesivir, Sofosbuvir, Tenofovir or Favipiravir, higher inhibitory activity for SARS-CoV-2 was achievable at lower doses, bringing the nucleotides’ pharmacological parameters more in line with their pharmacokinetic exposures.
Summing up the results, their study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.
All images credit except featured: Authors
Reference: Xuanting Wang, Carolina Q. Sacramento, Steffen Jockusch, Otávio Augusto Chaves, Chuanjuan Tao, Natalia Fintelman-Rodrigues, Minchen Chien, Jairo R Temerozo, Xiaoxu Li, Shiv Kumar, Wei Xie, Dinshaw J Patel, Cindy Meyer, Aitor Garzia, Thomas Tuschl, Patricia T Bozza, James J Russo, Thiago Moreno L Souza, Jingyue Ju, “Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics”, bioRxiv 2021.07.21.453274; doi: https://doi.org/10.1101/2021.07.21.453274
Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article
Researchers discovered a small molecule, ErSO, that eradicates breast cancers in mice by targeting a pathway that protects cancer cells.
A new approach to treating breast cancer kills 95-100% of cancer cells in mouse models of human estrogen-receptor-positive breast cancers and their metastases in bone, brain, liver and lungs. The newly developed drug, called ErSO, quickly shrinks even large tumors to undetectable levels.
Led by scientists at the University of Illinois Urbana-Champaign, the research team reports the findings in the journal Science Translational Medicine.
“Even when a few breast cancer cells do survive, enabling tumors to regrow over several months, the tumors that regrow remain completely sensitive to retreatment with ErSO,” said U. of I. biochemistry professor David Shapiro, who led the research with Illinois chemistry professor Paul Hergenrother. “It is striking that ErSO caused the rapid destruction of most lung, bone and liver metastases and dramatic shrinkage of brain metastases, since tumors that have spread to other sites in the body are responsible for most breast cancer deaths,” Shapiro said.
The activity of ErSO depends on a protein called the estrogen receptor, which is present in a high percentage of breast tumors. When ErSO binds to the estrogen receptor, it upregulates a cellular pathway that prepares cancer cells for rapid growth and protects them from stress. This pathway, called the anticipatory Unfolded Protein Response, or a-UPR, spurs the production of proteins that protect the cell from harm.
“The a-UPR is already on, but running at a low level, in many breast cancer cells,” Shapiro said. “It turns out that this pathway shields cancer cells from being killed off by anti-cancer drugs.”
Shapiro and former U. of I. medical scholar Neal Andruska first identified the a-UPR pathway in 2014 and reported the development of a compound that pushed the a-UPR pathway into overdrive to selectively kill estrogen-receptor-containing breast cancer cells.
“Because this pathway is already on in cancer cells, it’s easy for us to overactivate it, to switch the breast cancer cells into lethal mode,” said graduate student Darjan Duraki, who shares first-author status on the new report with graduate student Matthew Boudreau.
While the original compound prevented breast cancer cells from growing, it did not rapidly kill them, and it had undesirable side effects. For the new research, Shapiro and Hergenrother worked together on a search for a much more potent small molecule that would target the a-UPR. Their analysis led to the discovery of ErSO, a small molecule that had powerful anticancer properties without detectable side effects in mice, further tests revealed.
“This anticipatory UPR is estrogen-receptor dependent,” Hergenrother said. “The unique thing about this compound is that it doesn’t touch cells that lack the estrogen receptor, and it doesn’t affect healthy cells – whether or not they have an estrogen receptor. But it’s super-potent against estrogen-receptor-positive cancer cells.”
ErSO is nothing like the drugs that are commonly used to treat estrogen-receptor-positive cancers, Shapiro said.
“This is not another version of tamoxifen or fulvestrant, which are therapeutically used to block estrogen signaling in breast cancer,” he said. Even though it binds to the same receptor that estrogen binds, it targets a different site on the estrogen receptor and attacks a protective cellular pathway that is already turned on in cancer cells, he said.
“Since about 75% of breast cancers are estrogen-receptor positive, ErSO has potential against the most common form of breast cancer,” Boudreau said. “The amount of estrogen receptor needed for ErSO to target a breast cancer is very low, so ErSO may also work against some breast cancers not traditionally considered to be ER-positive.”
Further studies in mice showed that exposure to the drug had no effect on their reproductive development. And the compound was well tolerated in mice, rats and dogs given doses much higher than required for therapeutic efficacy, the researchers found.
ErSO also worked quickly, even against advanced, human-derived breast cancer tumors in mice, the researchers report. Often within a week of exposure to ErSO, advanced human-derived breast cancers in mice shrank to undetectable levels.
“Many of these breast cancers shrink by more than 99% in just three days,” Shapiro said. “ErSO is fast-acting and its effects on breast cancers in mice are large and dramatic.”
The pharmaceutical company Bayer AG has licensed the new drug and will explore its potential for further study in human clinical trials targeting estrogen-receptor-positive breast cancers, the researchers said. The researchers will next explore whether ErSO is effective against other types of cancers that contain estrogen receptor.
Study co-authors at the U. of I. also include veterinary clinical medicine professor Timothy Fan, molecular and integrative physiology professor Erik Nelson, and professor emeritus of pathology Edward Roy. Fan, Hergenrother, Nelson, Shapiro and Roy are affiliates of the Cancer Center at Illinois. Fan, Hergenrother and Nelson also are affiliated with the Carl R. Woese Institute for Genomic Biology at Illinois and Hergenrother and Fan are faculty in the Carle Illinois College of Medicine at the U. of I.
Funders of this work include the University of Illinois, the U.S. Department of Defense, the National Institutes of Health, and Systems Oncology. The U. of I. has filed patents on some compounds described in the study.
The paper “A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice” is available online and from the U. of I. News Bureau. DOI: 10.1126/scitranslmed.abf1383
A study found that the drug masitinib inhibited the replication of SARS-CoV-2 in human cell cultures, and could be effective against many types of coronaviruses and picornaviruses.
A new University of Chicago study has found that the drug masitinib may be effective in treating COVID-19.
The drug, which has undergone several clinical trials for human conditions but has not yet received approval to treat humans, inhibited the replication of SARS-CoV-2 in human cell cultures and in a mouse model, leading to much lower viral loads.
Researchers at UChicago’s Pritzker School of Molecular Engineering (PME), working with collaborators at Argonne National Laboratory and around the world, also found that the drug could be effective against many types of coronaviruses and picornaviruses. Because of the way it inhibits replication, it has also been shown to remain effective in the face of COVID-19 variants.
Prof. Savas Tay
“Inhibitors of the main protease of SARS-CoV-2, like masitinib, could be a new potential way to treat COVID patients, especially in early stages of the disease,” said Prof. Savas Tay, who led the research. “COVID-19 will likely be with us for many years, and novel coronaviruses will continue to arise. Finding existing drugs that have antiviral properties can be an essential part of treating these diseases.”
When COVID-19 lockdowns began in March 2020, Tay and Nir Drayman, a postdoctoral fellow who specializes in virology, began to think about how they could help. To search for a better treatment for the disease, they began by screening a library of 1,900 clinically safe drugs against OC43, a coronavirus that causes the common cold and can be studied under regular biosafety conditions. They used cell cultures to determine the drugs’ effect on infection.
They then gave the top 30 drug candidates to microbiology professor Glenn Randall, who tested them in cell cultures against the SARS-CoV-2 virus at the Howard Taylor Ricketts Laboratory, a BSL-3 facility at Argonne National Laboratory. Measurements in the high-containment lab revealed nearly 20 drugs that inhibit SARS-CoV-2.
They also sent the drug candidates to other collaborators to test against the 3CL protease, the enzyme within coronaviruses that allows them to replicate inside a cell. They found that of the drug candidates, masitinib completely inhibited the 3CL viral enzyme inside the cell, a fact that was confirmed by X-ray crystallography by Prof. Andrzej Joachimiak’s group at Argonne. The drug specifically binds to the 3CL protease active site and inhibits further viral replication.
“That gave us a strong indication of how this drug works, and we became confident that it has a chance to work in humans,” Drayman said.
“Novel coronaviruses will continue to arise…finding existing drugs that have antiviral properties can be an essential part of treating these diseases.”
Though masitinib is currently only approved to treat mast cell tumors in dogs, it has undergone human clinical trials for several diseases, including melanoma, Alzheimer’s disease, multiple sclerosis, and asthma. It has been shown to be safe in humans but does cause side effects, including gastrointestinal disorders and edema, and could potentially raise a patient’s risk for heart disease.
Drug effective against variants, other viruses
Next, the researchers worked with peers at the University of Louisville to test the drug in a mouse model. They found that it reduced the SARS-CoV-2 viral load by more than 99 percent and reduced inflammatory cytokine levels in mice.
In parallel, the researchers also began to test the drug in cell cultures against other viruses and found that it was also effective against picornaviruses, which include Hepatitis A, polio, and rhinoviruses that cause the common cold.
They also tested it in cell cultures against three SARS-CoV-2 variants, Alpha, Beta, and Gamma, and found that it worked equally well against them, since it binds to the protease and not to the surface of the virus.
Now, the team is working with the pharmaceutical company that developed the drug (AB Science) to tweak the drug to make it an even more effective antiviral. Meanwhile, masitinib itself could be taken to human clinical trials in the future to test it as a COVID-19 treatment.
“Masitinib has the potential to be an effective antiviral now, especially when someone is first infected and the antiviral properties of the drug will have the biggest effect,” Drayman said. “This isn’t the first novel coronavirus outbreak, and it’s not going to be the last. In addition to vaccines, we need to have new treatments available to help those who have been infected.”
Other authors on the paper include Jennifer K. DeMarco, Krysten A. Jones, Saara-Anne Azizi, Heather M. Froggatt, Kemin Tan, Natalia Ivanovna Maltseva, Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S. Kathayat, Mason R. Firpo, Vincent Mastrodomenico, Emily A. Bruce, Madaline M. Schmidt, Robert Jedrzejczak, Miguel Á. Muñoz-Alía, Brooke Schuster, Vishnu Nair, Kyu-yeon Han, Amornrat O’Brien, Anastasia Tomatsidou, Bjoern Meyer, Marco Vignuzzi, Dominique Missiakas, Jason W. Botten, Christopher B. Brooke, Hyun Lee, Susan C. Baker, Bryan C. Mounce, Nicholas S. Heaton, William E Severson, Kenneth E Palmer, Bryan C. Dickinson, and Andrzej Joachimiak.
Citation: “Masitinib is a broad coronavirus 3CL inhibitor that effectively blocks replication of SARS-CoV-2,” Drayman et. al., July 20, 2021, Science. DOI: 10.1126/science.abg5827
Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Energy, National Institute of General Medical Sciences, Pritzker School of Molecular Engineering.
Mayo Clinic researchers and collaborators used computer simulation and artificial intelligence (AI) to select 30 million potential drugs that block the SARS-CoV-2 virus, which causes COVID-19. In the work published in Biomolecules , researchers accelerated drug discovery to better identify and study the most promising targets, as they are interested in discovering new treatments for COVID-19 .
“A multi-drug platform was used to select the ones that might work. The analysis was done with drugs clinically tested and licensed by the US Food and Drug Administration, as well as other novel compounds. Thanks to the computational power of advanced technology, it was possible to determine the best drug from a composite library for further investigation, ”says Dr. Thomas Caulfield , a molecular neuroscientist at Mayo Clinic and an expert author on the paper.
The studies were carried out using a computer simulation called silicon detection (which means on the computer) and validated through biological experiments with live viruses. This type of research uses digital databases and mathematical concepts to identify potentially useful drug compounds. Other types of research are carried out in cell lines, which is known as in vitro , or they are carried out in living organisms such as mice or humans and is known as in vivo.
The researchers started with 30 million drug compounds. Virtual assessment tools predicted the behavior of various drug compounds and showed the pattern of how they would interact with particulate biological targets of SARS-CoV-2. Selection with silicon reduced the compounds to 25. Then, for further analysis and laboratory testing, the researchers conducted a pilot study of all 25 compounds against infectious SARS-CoV-2 in human cell cultures, and then they tested for a common problem with drugs, which is toxicity.
Because one of the liver’s tasks is to clean the blood, including the drug components, the team created a model of the human liver on a honeycomb-shaped surface that was no larger than the size of a pencil eraser. The researchers were able to predict that all of those 25 compounds would be safe for the human liver.
‘The goal is to deactivate the infection and restore the cells to health. What we want is to aggressively target the SARS-CoV-2 duplication cycle from several fronts to inhibit entry and spread of the virus, ”says Dr. Caulfield.
The researchers hope that a combination of drugs, similar to a drug cocktail used in the treatment of HIV, will complement the vaccination against COVID-19. Dr. Caufield says the next step is to move forward on the basis of the new discoveries. The researchers plan to test the combination of drugs to obtain pairs that act in synergy and are more powerful against the virus than a single compound.
“This discovery opens the way for the future creation of drugs and clinical trials to accelerate the administration of possible drugs,” concludes the doctor.
Dr. Caulfield led the drug selection team, which included colleagues from Mayo Clinic in Florida and Mayo Clinic in Rochester, as well as researchers from Brigham and Women’s Hospital (affiliated with Harvard Medical School) and the University of California at Riverside. Funding for this study came from the National Institutes of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Center for Personalized Medicine at Mayo Clinic. For a full list of authors, funding information, and conflict of interest statements, see the article in Biomolecules .
This article and others regarding more studies are in the Mayo Clinic research publication Discovery’s Edge .
Tests of a drug known to stimulate brain activity have shown early success in reducing symptoms of sluggish cognitive tempo in 38 men and women with attention deficit hyperactivity disorder (ADHD).
A collection of symptoms including persistent dreaminess, fatigue, and slow-working speed, sluggish cognitive tempo has been a subject of debate over whether it is part of, or separate from, ADHD.
Researchers at NYU Grossman School of Medicine and Icahn School of Medicine at Mount Sinai who led the study say the stimulant lisdexamfetamine (Vyvanse®) reduced by 30 percent self-reported symptoms of sluggish cognitive tempo. It also lowered by more than 40 percent symptoms of ADHD and significantly corrected deficits in executive brain function, which included fewer episodes of procrastination, improvements in keeping things in mind, and strengthened prioritization skills.
Published online in the Journal of Clinical Psychiatry on June 29, the study also showed that one-quarter of the overall improvements in sluggish cognitive tempo, such as feelings of boredom, trouble staying alert, and signs of confusion, were due to improvements in symptoms of ADHD.
The team interpreted that outcome to mean that decreases in ADHD-related incidents of physical restlessness, behaving impulsively, and/or moments of not paying attention were linked to some but not all of the improvements in sluggish cognitive tempo.
“Our study provides further evidence that sluggish cognitive tempo may be distinct from attention deficit hyperactivity disorder and that the stimulant lisdexamfetamine treats both conditions in adults, and when they occur together,” says lead study investigator and psychiatrist Lenard A. Adler, MD.
Dr. Adler, who directs the Adult ADHD Program at NYU Langone Health, says until now stimulants have only been shown to improve sluggish cognitive tempo symptoms in children with ADHD. The NYU Langone–Mount Sinai team’s findings, he adds, are the first to show that such treatments also work in adults.
A professor in the Department of Psychiatry and the Department of Child and Adolescent Psychiatry at NYU Langone, Dr. Adler says sluggish cognitive tempo is likely a subset of symptoms commonly seen in some patients with ADHD and other psychiatric disorders. However, it remains unclear if sluggish cognitive tempo is a distinct psychiatric condition on its own and if stimulant medications will improve sluggish cognitive tempo in patients without ADHD.
Some specialists have been seeking to qualify sluggish cognitive tempo as distinct, but critics say more research is needed to settle the question. “These findings highlight the importance of assessing symptoms of sluggish cognitive tempo and executive brain function in patients when they are initially diagnosed with ADHD,” says Dr. Adler.
For the study, funded by the drug manufacturer, Takeda Pharmaceuticals of Cambridge, Massachusetts, several dozen volunteer participants received daily doses of either lisdexamfetamine or a placebo sugar pill for one month. Researchers then carefully tracked their psychiatric health on a weekly basis through standardized tests for signs and symptoms of sluggish cognitive tempo, ADHD, as well as other measures of brain function. Study participants then switched roles: the one-half who had been taking the placebo started taking daily doses of lisdexamfetamine, while the other half, who had been on the drug during the study’s first phase, started taking the placebo.
Dr. Adler has received grant and/or research support from Sunovion Pharmaceuticals, Enymotec, Shire Pharmaceuticals (now part of Takeda), Otsuka, and Lundbeck. He has also served as a paid consultant to these companies, in addition to Bracket, SUNY, the National Football League, and Major League Baseball. He has also received royalty payments since 2004 from NYU for adult ADHD diagnostic and training materials. All of these relationships are being managed in accordance with the policies and procedures of NYU Langone.
Besides Dr. Adler, other NYU Langone researchers involved in the study are Terry Leon, MS, RN; Taylor Sardoff, BA; and Michael Silverstein, MS. Other investigators include Beth Krone, PhD, and Jeffrey Newcorn, MD, at Icahn School of Medicine at Mount Sinai in New York City; and Stephen Faraone, PhD, at SUNY Upstate Medical University in Syracuse, New York.
Featured image: The stimulant lisdexamfetamine reduced self-reported symptoms of sluggish cognitive tempo in adults with attention deficit hyperactivity disorder. PHOTO: HAILSHADOW/GETTY
Effective therapeutics which can inhibit the replication of SARS-CoV-2 in infected individuals are still under development. Several studies suggested the use of drug combinations which can inhibit or prevent SARS-CoV-2 infection. Weeks before, we wrote an article on the study which showed that, the use of combination of Pegasys (IFNa) and nafamostat can effectively prevent SARS-CoV-2 infection in cell culture and hamsters. Now, Dr. Kim Stegmann and colleagues showed that the combination of NHC and DHODH inhibitors such as teriflunomide, IMU-838/vidofludimus, and BAY2402234, strongly synergizes to inhibit SARS-CoV-2 replication. Their study recently appeared in BioRxiv.
The nucleoside analogue N4-hydroxycytidine (NHC), also known as EIDD-1931, interferes with SARS-CoV-2 replication in cell culture. It is the active metabolite of the prodrug Molnupiravir (MK-4482), which is currently being evaluated for the treatment of COVID-19 in advanced clinical studies. Meanwhile, inhibitors of dihydroorotate dehydrogenase (DHODH), by reducing the cellular synthesis of pyrimidines, counteract virus replication and are also being clinically evaluated for COVID-19 therapy.
Now, Kim Stegmann and colleagues carried out study to determine the effectiveness of single and combination of NHC and DHODH inhibitors, in preventing SARS-CoV-2 infection.
They showed that the combination of NHC and DHODH inhibitors such as teriflunomide, IMU-838/vidofludimus, and BAY2402234, strongly synergizes to inhibit SARS-CoV-2 replication. While single drug treatment only mildly impaired virus replication, combination treatments reduced virus yields by at least two orders of magnitude.
They determined this by RT-PCR, TCID50, immunoblot and immunofluorescence assays in Vero E6 and Calu-3 cells infected with wildtype and the Alpha and Beta variants of SARS-CoV-2.
They proposed that the lack of available pyrimidine nucleotides upon DHODH inhibition increases the incorporation of NHC in nascent viral RNA, thus precluding the correct synthesis of the viral genome in subsequent rounds of replication, thereby inhibiting the production of replication competent virus particles. This concept was further supported by the rescue of replicating virus after addition of pyrimidine nucleosides to the media.
“Since both classes of compounds are undergoing advanced clinical evaluation for the treatment of COVID-19, our observations at least raise the prespective of using both drugs as antiviral combination therapy.”
— concluded authors of the study
Reference: Kim M. Stegmann, Antje Dickmanns, Natalie Heinen, Uwe Groß, Dirk Görlich, Stephanie Pfaender, Matthias Dobbelstein, “N4-hydroxycytidine and inhibitors of dihydroorotate dehydrogenase synergistically suppress SARS-CoV-2 replication”, bioRxiv 2021.06.28.450163; doi: https://doi.org/10.1101/2021.06.28.450163
Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is the virus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. More than 166,000,000 confirmed infections and 3,400,000 deaths worldwide as of 23 May 2021. Currently there are no therapies which can completely eliminate this infectious virus and prevent transmission. So there is an urgent need for oral antiviral therapies that can, not only easily distributes on a scale that meets global demand but also reduce transmission and infection.
Molnupiravir is an experimental antiviral drug which is orally active and was developed for the treatment of influenza. Results of first-in-human Phase 1 trail in healthy volunteers showed that the molnupiravir is safe and well tolerated. Now, Dr. William Fischer and colleagues reported the results of a Phase 2 randomized, clinical trail evaluating the safety, tolerability and antiviral efficacy of molnupiravir in treatment of covid 19.
In this randomized clinical trail, 202 eligible participants who have SARS-CoV-2 infection and symptom onset, have given 1:1 to 200 mg molnupiravir or placebo, or 3:1 to molnupiravir (400 or 800 mg) or placebo, twice daily for 5 days.
They found that, in just 4 days after treatment initiation, there was no infectious virus isolated from any participants who received 400 or 800 mg molnupiravir. Participants treated with 800 mg molnupiravir compared to placebo showed significant decrease in infectious virus isolation. They also showed that time to viral RNA clearance was also decreased. Moreover, there are very less number of grade 3+ adverse events. (You can check it out in Table 1 given above.)
“This trail provides strong biological evidence that supports development of molnupiravir as an oral agent to reduce infectious viral replication and interrupt progression of COVID-19 in early stages of disease.”
Another important fact is that, molnupiravir can be produced at large scale and it does not require cold transportation or infection control infrastructure for administration.
“The results of this trail demonstrate safety, tolerability and antiviral efficacy of molnupiravir to reduce replication if SARS-CoV-2 and accelerate clearance of infectious virus and support ongoing trails if molnupiravir to prevent progression of COVID-19 and eliminate onward transmission of SARS-CoV-2”
— concluded authors of the study
Reference: William A Fischer II, Joseph J Eron Jr., Wayne Holman, Myron S Cohen, Lei Fang, Laura J Szewczyk, Timothy P Sheahan, Ralph S Baric, Katie R Mollan, Cameron R Wolfe, Elizabeth R Duke, Masoud M Azizad, Katyna BorrotoiEsoda, David A Wohl, Amy James Loftis, Paul Alabanza, Felicia Lipansky, Wendy P Painter, “Molnupiravir, an Oral Antiviral Treatment for COVID-19”, medRxiv 2021.06.17.21258639; doi: https://doi.org/10.1101/2021.06.17.21258639
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