Could some arthritis drugs reduce Alzheimer and related dementias risk in those with heart disease?
| Post date: 2022/05/16 |
Some rheumatoid arthritis drugs may help reduce the incidence of Alzheimer disease and related dementias in individuals with cardiovascular disease, according to new findings from the ongoing Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study.
The findings do not advocate the widespread use of these drugs for treating dementias, but the results may indicate a possible use of precision medicine in certain groups of at-risk people.
The study assessed data in Medicare claims from more than 22,000 people to see if those with rheumatoid arthritis who took one of three different classes of arthritis drugs were protected from dementia.
There were no statistically significant associations with lowered dementia risk except among those with cardiovascular disease who were treated with one class of arthritis drugs called tumor necrosis factor (TNF) inhibitors. TNF is a substance that can cause inflammation in the body and lead to immune-system diseases such as rheumatoid arthritis. The National Institute on Aging (NIA) DREAM study previously identified several FDA-approved drugs that are being tested as candidate treatments for Alzheimer disease and related dementias.
The research was published in JAMA Network Open and led by researchers at NIH’s NIA in collaboration with teams at Johns Hopkins University School of Medicine, Rutgers University, and Harvard Medical School.
Cardiac Issues After COVID Infection and Vaccination: New Data
| Post date: 2022/04/24 |
New data from two different sources on cardiac complications linked to COVID-19 have shown that such issues are low overall, but are higher after infection than after vaccination.
The new information comes from the Centers for Disease Control and Prevention's (CDC's) National Patient-Centered Clinical Research Network (PCORnet), and from a separate large international clinical study published online in Circulation on April 11.
CDC Data
The CDC study analyzed electronic health record data from 40 US healthcare systems from January 1, 2021, to January 31, 2022, on more than 15 million people aged 5 years or older.
It reports a rate of myocarditis or pericarditis after mRNA COVID-19 vaccination of 0-35.9 per 100,000 for males and 0-10.9 per 100,000 for females across different age groups and vaccine cohorts.
Rates of myocarditis or pericarditis after SARS-CoV-2 infection ranged from 12.6-114 per 100,000 for males and 5.4-61.7 per 100,000 for females across different age groups.
Even among males aged 12-17 years, the group with the highest incidence of cardiac complications after receipt of a second mRNA COVID-19 vaccine dose, the risk was 1.8-5.6 times higher after SARS-CoV-2 infection than after vaccination, the CDC report notes.
"These findings provide important context for balancing risks and benefits of mRNA COVID-19 vaccination among eligible persons ≥ 5 years," the report states. They also "support the continued use of recommended mRNA vaccines among all eligible persons aged ≥ 5 years," it concludes.
International Study
The international study focused on prevalence, clinical characteristics, and outcomes of clinically manifest acute myocarditis in patients with COVID-19 infection.
The study showed a rate of acute myocarditis of 2.4 per 1000 patients hospitalized with COVID-19.
"A small study previously indicated acute myocarditis is a rare occurrence in people infected with COVID-19. Our analysis of international data offers better insight to the occurrence of acute myocarditis during COVID-19 hospitalization, particularly before the COVID-19 vaccines were widely available," coauthor, Enrico Ammirati, MD, PhD, Niguarda Hospital, Milan, Italy, commented.
"This analysis indicates that, although rare, hospitalized patients with acute myocarditis associated with COVID-19 infection have a much greater need for intensive care unit admission, in up to 70.5% of the cases, despite the average age of the individuals in the study being much younger than expected at 38 years old," added coauthor Marco Metra, MD, University of Brescia, Italy. Cite this: Cardiac Issues After COVID Infection and Vaccination: New Data - Medscape - Apr 13, 2022.
FDA Panel: Concerns Over PI3K Inhibitors in Blood Cancers
| Post date: 2022/04/24 |
Federal advisers have unanimously called for randomized trials for a class of drugs used in the treatment of blood cancers, citing concerns about toxicities of these medicines.
The US Food and Drug Administration (FDA) called on advice from its Oncologic Drugs Advisory Committee (ODAC), which met yesterday to discuss the drugs that act as phosphatidylinositol 3-kinase (PI3K) inhibitors and are used for blood cancers.
Also discussed at the meeting was umbralisib (Ukoniq), which had been indicated for marginal zone and follicular lymphoma, and was awaiting FDA approval for CLL and SLL (to have been discussed at a meeting the following day). However, the manufacturer announced April 15 that it had voluntarily withdrawn the drug from the market and also voluntarily withdrew the approval application.
The FDA explained that it is considering ways to shift away from use of single-arm trials with PI3K inhibitors following disappointing results seen with this class of drugs in more advanced testing. While initial single-arm studies and randomized tests showed good results on progression-free survival (PFS), disturbing trends were seen on overall survival (OS) in more advanced trials.
"The consistent findings of decrements in overall survival in six randomized trials, in the setting of an advantage or potential advantage in PFS, is unprecedented in oncology," the FDA staff said in its briefing document for the ODAC meeting.
"The overall survival information is early and represents a low number of events, yet we have the same pattern observed across multiple trials," the FDA added. "Further, in each trial, there was a higher rate of death due to adverse events in the PI3K inhibitor arm, suggesting the potential detriment in overall survival may be due to toxicity."
The FDA asked ODAC to vote on this question: "Given the observed toxicities with this class, previous randomized trials with a potential detriment in OS, and a narrow range between effective and toxic doses, should future approvals of PI3K inhibitors be supported by randomized data?"
The vote tally was 16-0 in favor of randomized data to support PI3K inhibitor approvals, with one abstention from panelist Anthony Sung, MD, of Duke University.
Sung said he felt uncomfortable with a shift toward expecting drugs in this class to be supported by randomized clinical data. But Sung said he agreed that the findings for the PI3K inhibitor drugs discussed at the meeting were "highly problematic" and randomization in testing may have helped.
The FDA already has publicly expressed clear concerns about the possibility that patients given PI3K inhibitor drugs for blood cancers might be more likely to die than those taking other medicines. The agency announced in February that it was investigating a potential increased risk of death with umbralisib; this is the drug that is no longer awaiting approval, after the manufacturer voluntarily withdrew the application.
Cite this: FDA Panel: Concerns Over PI3K Inhibitors in Blood Cancers - Medscape - Apr 22, 2022.
Pembrolizumab vs. placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma
| Post date: 2022/04/5 |
Researchers investigated whether pembrolizumab, which has improved the prognosis for patients with stage III melanoma, might have a similar effect on survival outcomes in patients with stage II disease. The sample population for the KEYNOTE-716 study included newly diagnosed patients aged 12 years and older from the United States and 15 other countries. Participants were randomly assigned to I.V. pembrolizumab or placebo every 3 weeks for 17 cycles or until reaching disease recurrence or unacceptable toxicity. The main endpoint, recurrence-free survival, was assessed at two different intervals: after about 128 patients experienced events and after 179 patient events. During the first interim analysis, 11% of 487 patients in the intervention group had a first recurrence of disease or died vs. 17% of 489 control patients. For the second interim analysis, first recurrence or death occurred in 15% and 24% of patients in the pembrolizumab and placebo treatment arms, respectively. No treatment-related deaths were documented. "Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile," the study authors wrote.The Lancet (03/31/22) Luke, Jason J.; Rutkowski, Piotr; Queirolo, Paola; et al. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00562-1/fulltext
Audio Interview: Effectiveness of Covid-19 Vaccination in Children
| Post date: 2022/04/5 |
The continuing spread of SARS-CoV-2 remains a Public Health Emergency of International Concern. What physicians need to know about transmission, diagnosis, and treatment of Covid-19 is the subject of ongoing updates from infectious disease experts at the Journal.
In this audio interview conducted on March 29, 2022, the editors discuss a new study of vaccination in 5-to-18-year-olds and what may be a definitive study of ivermectin therapy for Covid-19. Audio Interview Effectiveness of Covid-19 Vaccination in Children (15:58) Download https://www.nejm.org/doi/full/10.1056/NEJMe2204268?query=featured_home
The number of available IV medications continues to expand. Many hospitals have experienced increases in patient acuity and a rise in the number of medications administered to each patient. This increases the likelihood that multiple IV medications will need to be administered concurrently. Separate IV access sites for drug administration are not always practical, and an increase in the number of sites can increase the risk for infectious complications.
These factors contribute to the escalating complexity of IV drug administration and have resulted in an ever-expanding number of possible incompatibilities.The potential for serious and life-threatening adverse drug events exists when incompatible medications are infused together. Therefore, it is important to verify drug compatibility before coadministration. A clear and concise compatibility chart can be a useful tool to help deliver safe, high-quality IV therapy to patients; in some settings, it is considered a preferred reference source due to ease of use.
A chance of incompatibility exists whenever any IV medication is combined with another. A change in pH is the primary characteristic involved in drug incompatibilities. However, compatibility depends on many factors including concentration, temperature, storage vehicle, order of mixing, and administration technique. Incompatibility also can be caused by excipients in a medication.
Three types of incompatibilities are commonly discussed: physical, chemical, and therapeutic. Physical incompatibilities are the most easily detected and are evidenced by visible changes, such as particulate formation, haze, precipitation, color change, and gas evolution. Chemical incompatibilities are those that result in decomposition of a drug. Loss of potency of greater than 10% over the defined testing period is considered chemical incompatibility. Most chemical incompatibilities can be detected only with a suitable analytical method. Therapeutic incompatibilities, in which a drug combination results in undesirable antagonistic or synergistic pharmacologic activity, are beyond the scope of most compatibility references.
The purpose of this chart is to provide concise, easily accessible, Y-site compatibility data. Although there are differing types of incompatibilities, the type of incompatibility or compatibility is not specified in this chart. A designation of “compatible” indicates that the combination evaluated appears to be compatible based on the tests performed, whether these tests measured physical, chemical, or both types of compatibility. All conditions that may affect compatibility cannot be included in such a format, and it is not possible to predict all incompatibilities that may arise, but it is hoped that the information provided may help clinicians minimize their occurrence. Continuing research adding to the existing body of knowledge on IV compatibilities is vital.
FDA Delays Advisory Meeting for COVID-19 Vaccine for Very Young Kids
| Post date: 2022/02/13 |
The FDA postponed the Feb. 15 meeting of the Vaccines and Related Biological Products Advisory Committee that was scheduled to discuss the authorization of Pfizer-BioNTech's COVID-19 vaccine for children 6 months through 4 years of age.
According to Peter Marks, MD, PhD, the director of the FDA Center for Biologics Evaluation and Research, the delay was requested by Pfizer-BioNTech, after the agency—which originally thought it could move forward with authorization of a two-dose schedule—requested more data about a third dose, he said.
“Since the early days of the pandemic, we've always followed the science in this ever-changing situation. Given the recent omicron surge and the notable increase in hospitalizations in the youngest children to their highest levels during the pandemic so far, we felt it was our responsibility as a public health agency to act with urgency and consider all available options, including requesting that the company Pfizer provide us with initial data on two doses from its ongoing study,” Dr. Marks said during a media briefing.
“The goal was to understand if two doses would provide sufficient protection, to move forward with authorizing the use of the vaccine. But at this time, we believe additional information regarding the ongoing evaluation of a third dose should be considered,” he announced. “It makes sense for us to wait until we have the data from the evaluation of a third dose before taking action.”
The trial in children 6 months through 4 years of age is ongoing, and data on the first two 3-mcg doses in this age group are being shared with the FDA on a continuing basis, according to Pfizer. Cases continue to accumulate according to the study protocol, and more data are being generated because rates of infection and illness remain high in children of this age, especially due to the recent omicron surge.
Pfizer-BioNTech said a three-dose schedule may provide a higher level of protection in this age group. “This is also supported by recent observations of three-dose booster data in several other age groups that seems to meaningfully augment neutralizing antibody levels and real-world vaccine protection for omicron compared to the two-dose regimen. The companies expect to have three-dose protection data available in early April,” the companies said in a statement.
The phase 1/2/3 trial initially enrolled 4,500 children 6 months to 11 years of age in the United States, Finland, Poland and Spain at more than 90 clinical trial sites. Additional children have been enrolled in all age groups following study amendments and the trial currently includes approximately 8,300 children.
The study was designed to evaluate the safety, tolerability and immunogenicity of the Pfizer-BioNTech vaccine in three groups:
ages 5 to 11 years;
ages 24 months to 4 years; and
ages 6 to 24 months.
Based on the phase 1 dose escalation part of the trial, children ages 5 to 11 years received a two-dose schedule of 10 mcg each, while children younger than 5 years received a 3-mcg dose for each injection in the phase 2/3 study. The trial enrolled children with or without prior evidence of SARS-CoV-2 infection. On Dec. 17, 2021, Pfizer and BioNTech announced the companies would test a third 3-mcg dose given at least two months after the second dose in children under 5 years of age and a third dose of the 10-mcg formulation in children 5 to 11 years of age.
Dr. Marks said he hopes the decision to wait for more data is reassuring to parents and the public. “We take our responsibility for reviewing these vaccines very seriously because we're parents,” Dr. Marks said. “In looking over these data, I think parents can feel reassured that we have set the standard by which we feel that if something does not meet that standard, we can't proceed forward.
“So, rather than having any issue causing anyone to question the process, I hope this reassures people that the process has a standard, that the process is one that we follow, and we follow the science in making sure that anything that we authorize has the safety and efficacy that people have come to [expect] from our regulatory review of medical product,” Dr. Marks said.
Although it is impossible to predict anything concerning COVID-19, Dr. Marks said, especially in light of recent surges involving more than three-quarters of a million cases per day, and a rise in pediatric cases and hospitalizations caused by omicron, he is hoping that waiting for this information will allow a more expeditious review.
Dr. Marks added that he empathizes with parents who want the vaccine now for their children. “For the next few months while these additional data are gathered, parents will have to rely on what they've come to do well, which is their using masking procedures. They're making sure that they're vaccinated and taking those types of precautions with their youngest children. We will do our part, obviously, to move as fast as we can when we have the data, but for now we'll have to ask parents to help to continue to do what they've been doing.”
He added that he hopes that waiting will allow decisions to be made on clinical data about actual pediatric infections rather than immune-bridging analyses, which generalize clinical data based on using the vaccine in other age groups.
Omicron’s Differences, Sense of Smell, Effects on the Brain and Other News
| Post date: 2022/02/13 |
Omicron Significantly Different From Other Variants
Within only three weeks after the omicron variant was first identified in Houston Methodist patients, this variant rapidly took over and became the cause of a majority of new cases. By contrast, the delta variant took about three months to reach that same milestone after initial detection. Causing 98% of all new COVID-19 cases by the beginning of 2022, omicron had infected 4,468 of Houston Methodist’s patients by Jan. 5.
Houston Methodist has one of the largest, most comprehensive SARS-CoV-2 virus genome sequencing studies in the country, analyzing the genome of every positive COVID-19 sample identified throughout Houston Methodist’s hospital system. Houston Methodist has sequenced nearly 80,000 SARS-CoV-2 virus genomes since the beginning of the pandemic. Image from Houston Methodist Hospital.
Houston Methodist physician-scientists found omicron patients are significantly younger, have increased vaccine breakthrough rates and are less likely to be hospitalized than patients with COVID-19 caused by the alpha or delta variants. Consistent with this decreased disease severity, patients infected with the omicron variant of COVID-19 required less intensive respiratory support and had shorter hospital stays (Am J Path 2022 Feb 3. doi:10.1016/j.ajpath.2022.01.007).
Compared with Houston Methodist patients infected with alpha or delta variants, the median age of omicron patients was 44.3 years versus 50 for alpha and 48.3 for delta; hospital length of stay was 3.2 days for omicron, 5.1 days for alpha and 5.4 days for delta; and omicron resulted in 55.4% of breakthrough cases in vaccinated patients, whereas 5.4% and 0.9% of vaccinated patients were infected with the alpha and delta variants, respectively.
As of mid-January, the researchers had also identified three patients with the BA.2 “stealth omicron” variant, which requires whole-genome sequencing to distinguish it from delta and the original BA.1 omicron strain. These were the first three “stealth omicron” cases discovered in Texas.
Houston Methodist has one of the largest, most comprehensive SARS-CoV-2 virus genome sequencing studies in the country, analyzing the genome of every positive COVID-19 sample identified throughout Houston Methodist’s hospital system. To get ahead of the virus and detect mutations that affect patient outcomes, such as causing more severe disease or impeding effectiveness of treatments and vaccines, Houston Methodist has sequenced nearly 80,000 SARS-CoV-2 virus genomes since the beginning of the pandemic.
Why Does COVID-19 Affect a Person’s Sense of Smell?
Infection with SARS-CoV-2 indirectly dials down the action of olfactory receptors, proteins on the surfaces of nerve cells in the nose that detect odors, leading to olfactory dysfunction (Cell2022 Jan 26. doi:10.1016/j.cell.2022.01.024).
In most cases, the dysfunction lasts only a few weeks, but for more than 12% of COVID-19 patients, olfactory dysfunction persists in the form of ongoing reduction in hyposmia or changes in parosmia.
Led by researchers from NYU Grossman School of Medicine and Columbia University, the new study may also shed light on the effects of COVID-19 on other types of brain cells, and other lingering neurologic effects of COVID-19 like brain fog, headaches and depression.
Experiments showed the presence of the virus near neurons in olfactory tissue brought an inrushing of immune cells, microglia and T cells, which release cytokines that change the genetic activity of olfactory nerve cells, even though the virus does not infect them, the researchers said. Where immune cell activity would dissipate quickly in other scenarios, in the brain, immune signaling appears to persist in a way that reduces the activity of genes needed for the building of olfactory receptors.
To gain insight into COVID-19?induced loss of sense of smell, the researchers explored the molecular consequences of SARS-CoV-2 infection in golden hamsters and in olfactory tissue taken from 23 human autopsies.
They confirmed that SARS-CoV-2 infection, and the immune reaction to it, decreases the ability of DNA chains in chromosomes that influence the formation of olfactory receptor building to be open and active, and to loop around to activate gene expression. In both hamster and human olfactory neuronal tissue, the team detected persistent and widespread downregulation of olfactory receptor building. Other work posted by the authors suggests that olfactory neurons are wired into sensitive brain regions, and that ongoing immune cell reactions in the nasal cavity could influence emotions and cognition consistent with long COVID.
Experiments in hamsters recorded over time revealed that downregulation of olfactory neuron receptors persisted after short-term changes that might affect the sense of smell had naturally recovered. This suggests COVID-19 causes longer-lasting disruption in chromosomal regulation of gene expression, representing a form of “nuclear memory” that could prevent the restoration of olfactory receptor transcription even after SARS-CoV-2 is cleared, they said.
“The realization that the sense of smell relies on ‘fragile’ genomic interactions between chromosomes has important implications,” said co-corresponding author Benjamin tenOever, PhD, a professor in the Department of Microbiology at NYU Langone Health, in New York City.
“If olfactory gene expression ceases every time the immune system responds in certain ways that disrupts interchromosomal contacts, then the lost sense of smell may act as the ‘canary in the coal mine,’ providing any early signals that the COVID-19 virus is damaging brain tissue before other symptoms present, and suggesting new ways to treat it.”
How a SARS-CoV-2 infection Can Become Severe COVID-19
Severe courses of COVID-19 are marked not only by strong immune activation and inflammatory reactions, but also by a dysfunctional endothelium. If this barrier between blood flow and tissue is damaged, the patient’s condition deteriorates (Signal Transduct Target Ther 2021 Dec 10. doi:10.1038/s41392-021-00819-6).
Many clinical symptoms, such as the destruction of blood vessels in the lungs and acute respiratory distress syndrome, pointed to an impact on the endothelium, according to Christine Falk, PhD, a scientist at the Hanover Medical School and the German Center for Infection Research.
The endothelium is a thin layer of cells that line blood vessels, forming a barrier between blood flow and the surrounding tissues. Infection with SARS-CoV-2 appears to cause strong activation of immune and endothelial cells in the lungs, resulting in the release of various soluble plasma proteins. Severe COVID-19 cases are associated with a dysfunction of the endothelium wherein the barrier between the alveoli and the surrounding vessels is no longer intact.
The scientists studied 25 patients with severe COVID-19 and 17 recovered patients in the ICU. They found the severity of the disease is linked to disruption of the endothelial barrier and can be measured by looking at inflammatory and endothelial plasma proteins. A pattern of seven plasma proteins appears to be associated with a severe form of the disease, which is characterized by strong inflammatory processes and in which the endothelium is permanently damaged. Furthermore, recovery from severe COVID-19 seems to be related to the regeneration of this endothelial barrier.
The investigators found excessive activation of T-lymphocytes and natural killer cells as well as development of memory T-cells and strong proliferation of plasmablasts, which are cells that can produce large amounts of antibodies. Furthermore, ICU patients infected with SARS-CoV-2 had high titers of spike- and nucleocapsid-specific antibodies.
The researchers found particularly interesting that the immune cell phenotype of these patients mainly changed over time and was less related to progressive severity of the disease. In contrast, the progression of COVID-19 was closely linked to increased levels of various soluble plasma proteins, namely certain inflammatory mediators and especially endothelial factors.
“We were able to demonstrate that ICU patients with COVID-19 can be divided into different groups based on their plasma protein profile, which are associated with disease severity,” explained lead author Louisa Ruhl, a PhD doctoral student at the Hanover Medical School. This could be a potential biomarker for severe COVID-19 courses, they said.
COVID-19 Vaccination Protects Against Severe Disease Outcomes
Severe COVID-19 outcomes are rare among adults who have been vaccinated against SARS-CoV-2, according to data from 465 facilities (MMWR Morb Mortal Wkly Rep 2022;71[1]:19-25).
A total of 1,228,664 people who completed their primary vaccination series during December 2020 through October 2021 were included in the analysis. Severe disease outcomes were identified as diagnosis of acute respiratory failure, need for noninvasive ventilation, ICU admission or death.
After vaccination, 2,246 people contracted COVID-19, a rate of 18 per 10,000. Of these, 327 were hospitalized, 189 had a severe COVID-19 outcome, and 36 had a COVID-19–related death. All people who developed severe COVID-19 outcomes after vaccination had at least one of eight risk factors: age at least 65 years, being immunocompromised, diabetes mellitus, pulmonary disease, liver disease, chronic kidney disease, neurologic disease and cardiac disease.
“Our study confirms that vaccines are effective in lowering the risk of severe COVID-19,” said Christina Yek, MD, a clinical fellow in the Critical Care Medicine Department of the National Institutes of Health.
“These findings are also critical to help identify persons at continued risk of severe outcomes despite vaccination, who may benefit from targeted interventions including chronic disease management, exposure reduction, additional primary and booster vaccine doses, and effective pharmaceutical therapy, to reduce the risk for severe COVID-19 outcomes,” she added.
The study authors said the findings confirm the overwhelming benefit of COVID-19 vaccination and increasing COVID-19 vaccination coverage is a public health priority.
“Future studies,” Dr. Yek added, “should use contemporary data to describe risk factors for severe disease with the SARS-CoV-2 omicron variant and after booster vaccination.”
This Is Your Brain on COVID-19
The heart is not the only organ affected by COVID-19. A study from researchers at Columbia University Vagelos College of Physicians and Surgeons reports that the brains of a small sample of patients who died of COVID-19 display some of the same molecular changes found in the brains of people with Alzheimer's disease.
The findings could help explain the memory problems reported by sufferers of long COVID, although the researchers caution that the study is small—with data from only 10 patients—and needs to be replicated by others (Alzheimers Dement 2022 Feb 3. doi:10.1002/alz.12558)
Early reports of “brain fog” and persistent cardiac symptoms in COVID-19 survivors prompted the Columbia researchers to investigate how certain molecules, called ryanodine receptors, were affected by the disease.
Defective ryanodine receptors have been implicated in diverse pathogenic processes, ranging from heart and lung disease to the brain's response to stress and Alzheimer's disease, as reported in research led by Andrew Marks, MD, the chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons, in New York City.
“What we found is really, I think, quite unexpected: Not only did we find defective ryanodine receptors in the hearts and lungs of deceased COVID patients, we also found them in their brains,” Dr. Marks said.
Inside neurons, defective ryanodine receptors have previously been linked to an increase in phosphorylated tau, a well-known hallmark protein of Alzheimer's.
In the new study, the Columbia researchers found high levels of phosphorylated tau in the brains of the COVID patients in addition to defective ryanodine receptors.
Phosphorylated tau was found in both areas where tau is typically located in Alzheimer's patientsand where it is not typically located in those patients. That suggests phosphorylated tau in the COVID-19 patients could be a sign of early-stage Alzheimer's and also contribute to other neurologic symptoms observed in COVID patients.
Increased levels of phosphorylated tau in the brain are believed to be associated with memory problems in Alzheimer's and could be causing similar issues in people with long COVID, Dr. Marks said.
Based on the findings, together with additional changes found in the brain, the investigators theorized that the immune response characteristic of severe COVID causes inflammation in the brain, which in turn leads to dysfunctional ryanodine receptors and then increases in phosphorylated tau. No changes in the pathways that lead to the formation of amyloid beta—another hallmark of Alzheimer's—were found. And perhaps, memory and neurologic impairments in long COVID can be traced to defective ryanodine receptors.
“One interpretation of these findings is that long COVID could be an atypical form of Alzheimer's and/or that patients who had severe COVID could be predisposed to developing Alzheimer's later in life,” Dr. Marks said, “but much more research needs to be done before we can make more definitive conclusions.”
FDA Limits Use of Monoclonal Antibodies to Treat COVID-19
| Post date: 2022/01/26 |
The FDA revised the emergency use authorizations (EUAs) for two monoclonal antibody (mAb) treatments for COVID-19—bamlanivimab-etesevimab (Lilly) and casirivimab-imdevimab (Regen-COV, Regeneron)—to limit their use in areas where the omicron variant is widely circulating.
The treatments are highly unlikely to be active against the omicron variant, which is circulating throughout the country, the FDA said. Therefore, “these treatments are not authorized for use in any U.S. states, territories and jurisdictions at this time.”
The National Institutes of Health COVID-19 Treatment Guidelines Panel recently recommended against using these mAbs.
As of Jan. 15, the CDC estimated the omicron variant of SARS-CoV-2 accounts for more than 99% of cases in the United States. “Therefore, it’s highly unlikely that COVID-19 patients seeking care in
the U.S. at this time are infected with a variant other than omicron, and these treatments are not authorized to be used at this time. This avoids exposing patients to side effects, such as injection site reactions or allergic reactions, which can be potentially serious, from specific treatment agents that are not expected to provide benefit to patients who have been infected with or exposed to the omicron variant,” Patricia Cavazzoni, MD, the director of the FDA’s Center for Drug Evaluation and Research, said in a statement.
If the situation changes and a different variant is circulating that is susceptible, then use of these treatments may be authorized in these areas, the FDA said.
Regeneron said it was working to make a next-generation antibody that is active against omicron, delta and other variants of concern.
Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens.
The FDA said several other therapies are still useful for outpatient management of COVID-19 during the omicron surge, including the mAb sotrovimab (GSK). The agency recently expanded the use of remdesivir (Veklury, Gilead) to outpatient use and issued EUAs for two oral medications, nirmatrelvir-ritonavir (Paxlovid, Pfizer) and molnupiravir (Merck). They are authorized to treat patients with mild to moderate COVID-19 who are at high risk for progression to severe disease, including hospitalization or death.
COVID-19 daily case counts and hospitalizations are starting to go down, but deaths are starting to increase. Deaths usually lag behind case and hospitalization data. More than 864,203 people have died from COVID-19 in the United States.
By Meaghan Lee Callaghan
A new electronic health record (EHR) screening tool that identifies iron deficiency in hospitalized patients with heart failure could greatly expand clinical pharmacy services while reducing readmissions and improving patient quality of life, according to a new report.
The tool—which could be easily adapted to various EHR systems—was able to identify iron deficiency in almost 25% of a New York City hospital’s acute decompensated heart failure patient census over six months last year, according to an abstract presented at the ASHP 2021 Midyear Clinical Meeting and Exhibition, held virtually.
Previously, the pharmacy consult service at the hospital intervened on about 20% of heart failure admissions, but never for iron deficiency, said study author Bryan C. Taylor, PharmD, a clinical pharmacist and the vice president of client relations at Creative Educational Concepts, in Lexington, Ky., which created the tool.
“A lot of health systems don’t have an evidence-based algorithm that allows them to identify these patients with iron deficiency because it’s just not something that they commonly look for in patients with heart failure,” Dr. Taylor told Pharmacy Practice News. “There are so many other things to think about in patients with acute decompensated heart failure that clinicians historically have not thought about iron deficiency as an imminent clinical consideration.”
“That study essentially showed that using IV iron, as iron repletion therapy for heart failure patients before they leave the hospital, actually reduced the risk for heart failure readmissions,” Dr. Taylor said. “That not only improves morbidity and mortality, which is the most important thing, but it also reduces readmission rates and decreases healthcare utilization, thus allowing for more efficient resource allocation and reduced costs within health systems.
“This could be a real game changer for patients and for health systems alike.”
Using criteria from the AFFIRM-AHF trial, the EHR tool flagged patients with an ejection fraction of no more than 50%, hemoglobin less than or equal to 13 g/dL, ferritin levels no more than 300 mg/dL and transferrin saturation (TSAT) less than or equal to 20%. Evaluating patients from Jan. 1, 2021, to June 1, 2021, Dr. Taylor and fellow researcher Katherine E. DiPalo, PharmD, were also able to collect data on patient length of stay, inpatient consults including pharmacy consults, discharge disposition and scheduled follow-up.
“As ID frequently is overlooked in hospitalized patients with heart failure, an expanded and novel pharmacist role can include recognizing appropriate patients and providing drug therapy recommendations for iron repletion prior to discharge,” the abstract stated.
Although actual patient outcomes data still need to be evaluated, the researchers said the screening process was a robust success. Of the 1,050 patients admitted for acute decompensated heart failure in the study period, 259 (24.6%) screened positive for iron deficiency. Although that is far fewer than the previous prevalence estimates, Dr. Taylor expects that number to increase, aided in part by the new EHR tool.
“A lot of the international pooled analyses that have been done in the past several years, as far back as 10 years ago, have established an aggregated estimated prevalence [or] approximate prevalence of about 50% for iron deficiency in heart failure, especially in heart failure with reduced ejection fraction,” Dr. Taylor said. This discrepancy is most likely due to a smaller sample size, he explained. “Our sample size isn’t big enough to adequately reflect the real-world population, but as we do additional work, we expect that prevalence figure to actually go up, not down.”
Omicron wave: 9 in 10 pharmacies struggling with staff absences
| Post date: 2022/01/16 |
Exclusive: Eighty-seven per cent of UK pharmacies have had to contend with staff absences since the emergence of the Omicron wave, a new survey indicates.
The Pharmacy Magazine survey, which ran on January 7-8, reveals that just 13 per cent of respondents have had no absenteeism in their pharmacy as a result of Covid since Omicron took hold in Britain in December.
Seventy-four per cent of respondents reported staff absences due to infection, while 60 per cent reported staff having to self-isolate because they had been a close contact of someone with Covid-19.
The survey, which had 220 responses from pharmacists and support staff members, suggests that the average pharmacy has had one pharmacist and two members of support staff off work because they were required to isolate.
Respondents working in independent pharmacies reported slightly higher infection rates, while those working in multiples had slightly higher rates of self-isolation as a result of being a close contact.
Workload and stress levels rising
Ninety per cent said these absences have had a significant impact on workload for remaining staff, while 89 per cent said this had led to increased stress levels among staff. Three-quarters said the level of service provided to patients had been compromised.
“Patients have to wait longer for prescriptions,” said one respondent, adding that some services such as NMS have been suspended.
Discontented patients were a frequently cited issue, with one respondent noting that they “aren’t very understanding when it comes to staff sickness”.
One pharmacist summed up their experience: “Staff cuts during the pandemic have left us with no contingencies. This has created major safety and effectiveness risks”
An individual working at a multiple said it was “hard to keep up with targets from management,” adding that “not much support” had been offered by their company.
Meanwhile, 69 per cent of pharmacists said their pharmacy had faced significant difficulties sourcing locum cover to deal with these absences. One contractor accused locum pharmacists of “misusing the situation” by “texting the day before to cancel shifts and then working elsewhere for higher rates”.
Despite these difficulties, 69 per cent of respondents said their pharmacy was managing well overall, compared to 31 per cent who felt the business was struggling to cope or not coping at all.
One respondent said the current situation “has resulted in staff working many additional hours’ unpaid overtime out of professional pride to ensure patients receive their medicines”
Pharmacies ‘already operating on the edge’
Leyla Hannbeck, chief executive of the Association of Independent Multiple Pharmacies, told Pharmacy Network News: “We are being challenged by the impact on our staffing from Omicron infections daily. Our members have both business interruption and collapse down plans but each new day brings a new set of challenges.
“Pharmacies were already operating on the edge of their available capacity with no slack in the system, even as little as one or two absentees can have devastating effect on business as usual and many pharmacies have been forced to close under this regime of test and isolate.”
Pharmacists' Defence Association director Paul Day said: "Insufficient levels of suitably trained and competent staff seem to have been normalised at some pahrmacies and some pharmacists and their teams are already sacrificing their own wellbeing to keep pharmacies safe for patients. Covid-related absences will amplify those already challenging situations."
Mr Day claimed that some employers have forced PDA members to come to work even after testing positive, and that others have been told to use their annual leave to cover the isolation period.
NPA: Investment needed
Helga Mangion, Policy Manager at the NPA commented: “The sector as a whole is currently under significant pressure with many pharmacies facing challenges in maintaining full services due to the current Omicron wave.
“The overarching factor in England is the lack of NHS investment in community pharmacy services over the past six years.
“Our members have worked very hard to insulate patients from the effects of staff shortages, but the situation is not sustainable.
Company Chemists’ Association chief Malcolm Harrison said the Omicron wave was having a “significant impact, adding: “We are seeing this across all staff roles and, inevitably, in some cases this has forced closures.
“Unfortunately, this short-term crisis is exacerbating the longer term workforce shortage, making it harder and harder to avoid impacting patients.
PSNC legal director Gordon Hockey told PNN: “We know that contractors are working tirelessly to keep their doors open through this latest wave, but the NHS needs to take a pragmatic and flexible approach to support pharmacies over the winter.
“PSNC will continue to monitor the situation but, in the meantime, contractors may still seek to use the emergency pandemic provisions to temporarily close or reduce their opening hours."
No more annual flu shot? New target for universal influenza vaccine
| Post date: 2022/01/8 |
Scientists at Scripps Research, University of Chicago and Icahn School of Medicine at Mount Sinai have identified a new Achilles' heel of influenza virus, making progress in the quest for a universal flu vaccine. Antibodies against a long-ignored section of the virus, which the team dubbed the anchor, have the potential to recognize a broad variety of flu strains, even as the virus mutates from year to year, they reported Dec. 23, 2021 in the journal Nature.
"It's always very exciting to discover a new site of vulnerability on a virus because it paves the way for rational vaccine design," says co-senior author Andrew Ward, PhD, professor of Integrative Structural and Computational Biology at Scripps Research. "It also demonstrates that despite all the years and effort of influenza vaccine research there are still new things to discover."
"By identifying sites of vulnerability to antibodies that are shared by large numbers of variant influenza strains we can design vaccines that are less affected by viral mutations," says study co-senior author Patrick Wilson, MD, who was previously at the University of Chicago and recently recruited to Weill Cornell Medicine as a professor of pediatrics and a scientist in the institution's Gale and Ira Drukier Institute for Children's Health. "The anchor antibodies we describe bind to such a site. The antibodies themselves can also be developed as drugs with broad therapeutic applications."
In a typical year, influenza affects more than 20 million people in the United States and leads to more than 20,000 deaths. Vaccines against influenza typically coax the immune system to generate antibodies that recognize the head of hemagglutinin (HA), a protein that extends outward from the surface of the flu virus. The head is the most accessible regions of HA, making it a good target for the immune system; unfortunately, it is also one of the most variable. From year to year, the head of HA often mutates, necessitating new vaccines.
Researchers have designed experimental influenza vaccines to be more universal, spurring the body to create antibodies against the less-variable stalk region of HA, which extends like a stem between the influenza virion and the HA head. Some of these universal flu vaccines are currently in early clinical trials.
In the new study, a collaborative team of scientists characterized 358 different antibodies present in the blood of people who had either been given a seasonal influenza vaccine, were in a phase I trial for an experimental, universal influenza vaccine, or had been naturally infected with influenza.
Many of the antibodies present in the blood of participants were antibodies already known to recognize either the HA head or stalk. But a collection of new antibodies stood out; the antibodies bound to the very bottom of the stalk, near where each HA molecule is attached to the membrane of the flu virion.
The co-first authors of the manuscript -- Julianna Han, a staff scientist in the Ward lab, and Jenna Guthmiller, a postdoctoral fellow at the University of Chicago -- named this section of HA the anchor, and began studying it further. In all, the scientists identified 50 different antibodies to the HA anchor, from a total of 21 individuals. The antibodies, they discovered, recognized a variety of H1 influenza viruses, which account for many seasonal flu strains. Some of the antibodies were also able to recognize pandemic H2 and H5 strains of influenza in lab tests. And in mice, the antibodies successfully protected against infection by three different H1 influenza viruses.
"In order to increase our protection to these highly mutating viruses, we need to have as many tools as we can," says Han. "This discovery adds one more highly potent target to our repertoire." Importantly, these antibodies appear to be fairly common in people, and belong to a class of antibodies that any person's body can produce -- an important consideration in designing a vaccine to spur their development.
"The human immune system already has the ability to make antibodies to this epitope, so it's just a matter of applying modern protein engineering methods to make a vaccine that can induce those antibodies in sufficient numbers," adds Guthmiller.
The researchers say that future, improved iterations of a universal vaccine could more purposefully aim to generate anchor antibodies. Until now, scientists designing universal vaccines hadn't paid attention to whether the anchor region of the stem was included as a target. Ideally, a universal influenza vaccine will lead to antibodies against multiple sections of the virus -- such as both the HA anchor and the stalk -- to increase protection to evolving viruses.
The researchers are planning future studies on how to design a vaccine that most directly targets the HA anchor of different influenza strains.
In addition to Han and Ward, authors of the study, "Broadly neutralizing antibodies target a hemagglutinin anchor epitope," include Sara Richey and Alba Torrents de la Pena of Scripps; Jenna Guthmiller, Henry Utset, Lei Li, Linda Yu-Ling Lan, Carole Henry, Christopher Stamper, Olivia Stovicek, Haley Dugan, Nai-Ying Zheng, Micah Tepora, Dalia Bitar, Siriruk Changrob, Min Huang and Patrick Wilson of University of Chicago; Meagan McMahon, George O'Dell, Alec Freyn, Fatima Amanat, Victoria Rosado, Shirin Strohmeier, Adolfo Garcia-Sastre, Raffael Nachbagauer, Peter Palese and Florian Krammer of Icahn School of Medicine at Mount Sinai; Monica Fernandez-Quintero and Klaus Liedl of University of Innsbruck, Lauren Gentles and Jesse Bloom of Fred Hutchinson Cancer Research Center; and Lynda Coughlan of University of Maryland School of Medicine
Journal Reference:
Jenna J. Guthmiller, Julianna Han, Henry A. Utset, Lei Li, Linda Yu-Ling Lan, Carole Henry, Christopher T. Stamper, Meagan McMahon, George O’Dell, Monica L. Fernández-Quintero, Alec W. Freyn, Fatima Amanat, Olivia Stovicek, Lauren Gentles, Sara T. Richey, Alba Torrents de la Peña, Victoria Rosado, Haley L. Dugan, Nai-Ying Zheng, Micah E. Tepora, Dalia J. Bitar, Siriruk Changrob, Shirin Strohmeier, Min Huang, Adolfo García-Sastre, Klaus R. Liedl, Jesse D. Bloom, Raffael Nachbagauer, Peter Palese, Florian Krammer, Lynda Coughlan, Andrew B. Ward, Patrick C. Wilson. Broadly neutralizing antibodies target a hemagglutinin anchor epitope. Nature, 2021; DOI: 10.1038/s41586-021-04356-8
Could vitamin D deficiency increase the risk of heart disease?
| Post date: 2022/01/8 |
Vitamin D, also known as the “sunshine” vitamin, is a fat-soluble vitamin that exists in two main forms: D-2 and D-3.
As an essential micronutrient and one that is primarily derived from sunlight, vitamin D is important for the development of bones and teeth and the regular functioning of the immune system.
Beyond these functions, previous studies suggest an association between low vitamin D levels and a higher likelihood of developing cardiovascular disease.
In a new study, researchers have established that it is worthwhile to check vitamin D levels when assessing a person’s cardiovascular risk.
Worldwide, cardiovascular diseases (CVDs)Trusted Source are one of the leading causes of death. Every year, an estimated 17.9 million people around the world die as a result of complications from heart diseases. For context, this means that CVDs are responsible for 32% of all deaths globally.
Prior studiesTrusted Source show that various factors — such as several health conditions, age, family history, diet, and lifestyle — combine to influence the risk of developing CVD.
Using a novel analytical approach, researchers in Australia have discovered an additional factor that may increase a person’s likelihood of CVD.
“We found evidence that vitamin D deficiency can increase blood pressure and the risk of CVD.”
“However,” she added, “increasing vitamin D concentrations will only be helpful for those participants who ‘need it,’ and further benefits from elevating concentrations beyond the nutritional requirement are going to be modest, if they exist.”
Immune Cell Population Potentially Responsible for Inflammation in Multiple Sclerosis
| Post date: 2022/01/1 |
Certain group 3 innate lymphoid cells (ILC3s)—immune cells that typically protect against gastrointestinal inflammation—may have the opposite effect in multiple sclerosis (MS) and other brain inflammation-related conditions, according to a study published in Nature. The investigators said these results suggest that inhibiting the activity of these cells could serve as a new therapeutic approach for neurologic conditions.
While studying ILC3s in a mouse model of MS, the investigators discovered a unique subset of ILC3s that circulate in the bloodstream and can enter the brain. These ILC3s—named inflammatory ILC3s—caused T cells to attack myelinated nerve fibers, leading to MS-like disease symptoms. Similar inflammatory ILC3s were found in the peripheral blood and cerebrospinal fluid of MS patients.
“This work has the potential to inform our understanding of, and potential treatments for, a broad variety of conditions involving T-cell infiltration of the brain,” said Gregory Sonnenberg, PhD, associate professor of microbiology and immunology in medicine in the Division of Gastroenterology and Hepatology and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine, in a press release.
According to the investigators, inflammatory ILC3s present bits of myelin protein—the primary component of the insulating layer around nerve fibers—to T cells. This prompts the T cells to attack myelin and cause the nerve damage that gives rise to disease signs. By removing MHCII from the inflammatory ILC3s, a key component normally used in the antigen-presenting process, the investigators were able to block the cells’ ability to activate myelin-attacking T cells.
“Despite our very best disease-modifying therapies for MS, patients continue to progress, and since disease onset is early in life, they face the prospect of permanent physical and cognitive disability,” said Tim Vartanian, MD, PhD, professor of neuroscience in the Feil Family Brain and Mind Institute at Weill Cornell Medicine, chief of the division of multiple sclerosis and neuro-immunology and a professor of neurology in the Department of Neurology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, in the release. “Identification of inflammatory ILC3s with antigen presentation capabilities in the central nervous system of people with MS offers a new strategic target to prevent nervous system injury.”
The investigators also found that they were able to effectively program ILC3s in other tissues to counter the activity of brain-infiltrating T cells, which prevented the MS-like condition in mice. They said that this study points to the possibility that MS and potentially many other inflammatory conditions could be treated by directly inhibiting the activity of inflammatory ILC3s that infiltrate the brain or by targeting self-antigens to the intestinal ILC3s that promote tolerance in other tissues.
REFERENCE
Novel immune cell population may trigger inflammation in multiple sclerosis and other brain disorders [news release]. EurekAlert; December 1, 2021. Accessed December 3, 2021. https://www.eurekalert.org/news-releases/936550
Coronavirus Can Spread to Heart, Brain Days After Infection
| Post date: 2021/12/29 |
The coronavirus that causes COVID-19 can spread to the heart and brain within days of infection and can survive for months in organs, according to a new study by the National Institutes of Health.
The virus can spread to almost every organ system in the body, which could contribute to the ongoing symptoms seen in "long COVID" patients, the study authors wrote. The study is considered one of the most comprehensive reviews of how the virus replicates in human cells and persists in the human body. It is under review for publication in the journal Nature.
"This is remarkably important work," Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at the Veterans Affairs St. Louis Health Care System in Missouri, told Bloomberg News. Al-Aly wasn't involved with this study but has researched the long-term effects of COVID-19.
"For a long time now, we have been scratching our heads and asking why long COVID seems to affect so many organ systems," he said. "This paper sheds some light and may help explain why long COVID can occur even in people who had mild or asymptomatic acute disease."
The NIH researchers sampled and analyzed tissues from autopsies on 44 patients who died after contracting the coronavirus during the first year of the pandemic. They found persistent virus particles in multiple parts of the body, including the heart and brain, for as long as 230 days after symptoms began. This could represent infection with defective virus particles, they said, which has also been seen in persistent infections among measles patients.
"We don't yet know what burden of chronic illness will result in years to come," Raina MacIntyre, PhD, a professor of global biosecurity at the University of New South Wales, told Bloomberg News.
"Will we see young-onset cardiac failure in survivors or early-onset dementia?" she said. "These are unanswered questions which call for a precautionary public health approach to mitigation of the spread of this virus."
Unlike other COVID-19 autopsy research, the NIH team had a more comprehensive post-mortem tissue collection process, which typically occurred within a day of the patient's death, Bloomberg News reported. The researchers also used a variety of ways to preserve tissue to figure out viral levels. They were able to grow the virus collected from several tissues, including the heart, lungs, small intestine, and adrenal glands.
"Our results collectively show that while the highest burden of SARS-CoV-2 is in the airways and lung, the virus can disseminate early during infection and infect cells throughout the entire body, including widely throughout the brain," the study authors wrote.
Cite this: Coronavirus Can Spread to Heart, Brain Days After Infection - Medscape - Dec 28, 2021.
FDA Gives Nod to Tralokinumab for Adults With Moderate to Severe AD
| Post date: 2021/12/29 |
The Food and Drug Administration has approved tralokinumab for the treatment of moderate to severe atopic dermatitis (AD) in adults whose disease is not well controlled with topical prescription therapies or when those therapies are not advisable.
Administered subcutaneously, tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to interleukin-13, a key driver of underlying inflammation in AD. The drug, which has been developed by LEO Pharma, comes as a single-dose (150 mg) prefilled syringe with needle guard.
In two pivotal phase 3 trials, ECZTRA 1 and ECZTRA 2, tralokinumab monotherapy was superior to placebo at week 16 for all primary and secondary endpoints. For example, at week 16, for the ECZTRA 1 and 2 monotherapy trials, respectively, 16% and 21% of patients treated with tralokinumab 300 mg every other week achieved clear or almost clear skin (IGA 0/1) versus 7% and 9% with placebo.
In addition, 25% and 33% of patients treated with tralokinumab 300 mg every other week achieved an improvement of 75% or more in the Eczema Area and Severity Index score (EASI-75) versus 13% and 10% with placebo. At 52 weeks, 51% and 60% of patients who responded at week 16 maintained IGA 0/1 response with tralokinumab 300 mg every other week in ECZTRA 1 and 2, respectively.
Finally, 60% and 57% of patients who responded at week 16 maintained EASI-75 response with tralokinumab 300 mg every other week.
In the drug's third pivotal trial, ECZTRA 3, researchers evaluated the efficacy and safety of tralokinumab 300 mg in combination with topical corticosteroids (TCS) as needed in adults with moderate to severe atopic dermatitis who are candidates for systemic therapy. At week 16, 38% of patients treated with tralokinumab 300 mg every other week plus TCS achieved clear or almost clear skin (IGA 0/1) versus 27% with placebo plus TCS. In addition, 56% of patients treated with tralokinumab 300 mg every other week plus TCS achieved an improvement of 75% or more in the EASI-75 versus 37% with placebo plus TCS. At 32 weeks, 89% and 92% of patients who responded at week 16 maintained response (IGA 0/1 and EASI-75, respectively) with tralokinumab 300 mg every other week.
Cite this: FDA Gives Nod to Tralokinumab for Adults With Moderate to Severe AD - Medscape - Dec 28, 2021.
Japan Health Panel Approves Merck's Oral COVID-19 Treatment
| Post date: 2021/12/28 |
TOKYO (Reuters) - A Japanese health ministry panel recommended approval of the COVID-19 antiviral pill developed by Merck & Co Inc on December 24, part of plans by Prime Minister Fumio Kishida to roll out new treatments by yearend as concerns rise about the Omicron variant.
The panel decision sets the stage for shipments of 200,000 doses across the country from this weekend, based on preparations announced earlier by Kishida.
Japan is betting heavily on oral treatments to keep serious infections and deaths at bay should a feared sixth wave of the pandemic emerge. The government agreed last month to pay Merck and its partner Ridgeback Biotherapeutics about $1.2 billion for 1.6 million courses of their drug molnupiravir.
In addition, Kishida announced last week a deal to procure 2 million doses of a separate antiviral pill developed by Pfizer Inc. And Japan's Shionogi & Co is expected to soon file for approval of its own treatment, supplying another 1 million doses by early next year.
U.S. regulators on Thursday authorized the Merck pill for certain high-risk adult patients.
Countries rushed to buy Merck's molnupiravir after very promising initial results, but subsequent company data in late November indicated the drug was markedly less effective than previously thought.
Japan this week confirmed the first known cases of Omicron infections that could not be traced back to overseas travelers. Community transmissions of the variant have now been found in the western cities of Osaka and Kyoto, and a suspected case was announced in Tokyo on Friday.
Positive Phase 3 Topline Results for Early Parkinson's Drug
| Post date: 2021/12/28 |
Topline results from a phase 3 trial of P2B001, a fixed-dose combination of extended release (ER) formulations of pramipexole and rasagiline, showed it was superior to its individual components as a first-line treatment for early Parkinson's disease.
Study participants also reported less daytime sleepiness with P2B001, according to a statement from the drug's manufacturer.
The trial data "support our view that P2B001 can provide clinical benefits comparable to higher doses of commercially available dopamine agonists, while mitigating the side effects typically associated with this class of medicine such as somnolence, orthostatic hypotension, and hallucinations," Sheila Oren, MD, chief executive officer of Pharma Two B, said in a statement.
"This is important for PD patients of all ages and is critical for the elderly, who typically do not tolerate side effects of dopamine agonists," Oren added.
Promising Results
The 12-week, international, randomized, double-blind trial was designed to study the efficacy, safety, and tolerability of P2B001 compared to its individual components and to a calibration arm of pramipexole ER in 544 patients with early PD.
Participants received P2B001, a once-daily ER combination product composed of pramipexole 0.6 mg and rasagiline 0.75 mg; pramipexole ER capsule 0.6 mg once daily; rasagiline ER capsule 0.75 mg once daily; or the currently marketed product pramipexole ER capsules titrated to an optimal dose for each individual patient (1.5 to 4.5 mg).
The adjusted mean change from baseline in total Unified Parkinson's Disease Rating Scale (UPDRS) score was -2.66 points for P2B001 vs pramipexole (P = .0018) and -3.30 points for P2B001 vs rasagiline (P = .0001). There was no significant difference in UPRDRS scores between P2B001 and pramipexole ER.
The adjusted mean change from baseline in the Epworth Sleepiness Scale score for P2B001 vs pramipexole ER was -2.66 points (P < .0001).
Treatment-related adverse events were mostly mild or moderate and were similar among groups.
"The initiation of treatment of patients with Parkinson's disease represents an area of unmet need due to the side effects associated with current treatments," Warren Olanow, MD, professor emeritus of neurology and neuroscience at the Icahn School of Medicine at Mount Sinai in New York City, said in a statement from the manufacturer.
"Based on the data from this well-designed, rigorous, active-controlled study, P2B001 has the potential to become a leading treatment option for PD, particularly as first line therapy for early-stage patients of all ages," Olanow added.
The company plans to file a new drug application in 2022.
Cite this: Positive Phase 3 Topline Results for Early Parkinson's Drug - Medscape - Dec 27, 2021.
Abrocitinib Approved for Atopic Dermatitis in Europe
| Post date: 2021/12/14 |
The oral Janus kinase 1 inhibitor abrocitinib has been approved in Europe for the treatment of moderate to severe atopic dermatitis (AD) in adults, who are candidates for systemic therapy, the manufacturer announced.
Approval by the European Commission was based on the results of studies that include four phase 3 clinical trials (JADE MONO-1, JADE-MONO-2, JADE COMPARE, JADE REGIMEN) and an ongoing open-label extension study (JADE EXTEND) in over 2,800 patients, according to the Pfizer press release announcing the approval. The approved doses are 100 and 200 mg a day; a 50-mg dose was approved for patients with moderate and severe renal impairment and "certain patients receiving treatment with inhibitors of cytochrome P450 (CYP) 2C19," the release said.
The approval follows a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency supporting marketing authorization for treating AD, issued in October. It will be marketed as Cibinqo.
Abrocitinib is under review at the Food and Drug Administration. It was approved earlier in 2021 for treating AD in the United Kingdom, Japan, and Korea. Abrocitinib Approved for Atopic Dermatitis in Europe - Medscape - Dec 13, 2021.
Major COVID-19 Case Growth Expected in Coming Weeks
| Post date: 2021/12/14 |
Most of the U.S. will see significant growth in COVID-19 cases during the next four weeks, according to the latest forecasting models by the PolicyLab at Children's Hospital of Philadelphia.
Large metropolitan areas, especially those in the Northeast, are already seeing a major increase in cases following Thanksgiving, and that trend is expected to continue.
"Why? Simply stated, the large amount of Thanksgiving travel and gatherings undermined the nation's pandemic footing and has elevated disease burden in areas of the country that were fortunate to have lower case rates before the holidays," the forecasters wrote.
Case numbers in New York City are expected to double throughout December, the forecasters said. Similar growth could happen across Boston, Philadelphia, and Baltimore.
Overall, COVID-19 cases, hospitalizations, and deaths are rising across the U.S. but remain below levels seen during the summer and last winter's surges, according to The New York Times. The increase is still being driven by the Delta variant, though it remains unclear how the Omicron variant, which has been detected in 27 states, could affect the trends in coming weeks.
During the past week, the U.S. has reported an average of more than 120,000 new cases each day, the newspaper reported, which is an increase of 38% from two weeks ago.
The daily average of COVID-19 hospitalizations is around 64,000, which marks an increase of 22% from two weeks ago. More than 1,300 deaths are being reported each day, which is up 26%.
Numerous states are reporting double the cases from two weeks ago, stretching across the country from states in the Northeast such as Connecticut and Rhode Island to southern states such as North Carolina and Texas and western states such as California.
The Great Lakes region and the Northeast are seeing some of the most severe increases, the newspaper reported. New Hampshire leads the U.S. in recent cases per capita, and Maine has reported more cases in the past week than in any other seven-day period during the pandemic.
Michigan has the country's highest hospitalization rate, and federal medical teams have been sent to the state to help with the surge in patients, according to The Detroit News. Michigan's top public health officials described the surge as a "critical" and "deeply concerning" situation on Friday, and they requested 200 more ventilators from the Strategic National Stockpile.
Indiana, Maine, and New York have also requested aid from the National Guard, according to USA Today. Health officials in those states urged residents to get vaccines or booster shots and wear masks in indoor public settings.
The Omicron variant can evade some vaccine protection, but booster shots can increase efficacy and offer more coverage, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said Sunday.
"If you want to be optimally protected, absolutely get a booster," he said on ABC's "This Week."
In addition, New York Gov. Kathy Hochul has announced a statewide mask mandate, which will take effect on Monday. Masks will be required in all indoor public spaces and businesses, unless the location implements a vaccine requirement instead, the news outlet reported. Cite this: Major COVID-19 Case Growth Expected in Coming Weeks - Medscape - Dec 13, 2021.