In Atopic Dermatitis Trial, Abrocitinib Offers Faster Itch Relief Than Dupilumab

 | Post date: 2021/10/6 | 

In patients with moderate to severe atopic dermatitis (AD), abrocitinib, an oral JAK inhibitor, relieved itch more quickly than the monoclonal antibody dupilumab (Dupixent), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.

The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that "is clinically relevant" for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.    

The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.

Over 700 Patients Randomized

JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area ≥10% and Eczema Area Severity Index (EASI) ≥16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.

The co-primary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.

The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs 14.6%; P < .001)

Advantage for Pruritus Control Dissipates

For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs 40.8%) and week 8 (65.8% vs 52.7%) remained sizeable, there were very small differences thereafter. However, Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.

The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs 47.6%).

Based on the data collected to date, "abrocitinib is clearly superior early on," Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.

"It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids," Reich maintained.

Both Drugs Are Well Tolerated

The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.

Nausea (19% vs 2%), acne (13.5% vs 2%), and headache (13% vs 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs 2%).

The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.

Abrocitinib's relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.

Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.  

In September, the FDA approved the first JAK inhibitor for treating AD — a topical JAK inhibitor, ruxolitinib.

Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial.

European Academy of Dermatology and Venereology: Abstract 2933. Presented October 2, 2021.

Ted Bosworth is a medical journalist based in New York City.

Cite this: In Atopic Dermatitis Trial, Abrocitinib Offers Faster Itch Relief Than Dupilumab  - Medscape - Oct 05, 2021.


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First-in-Class TYK Inhibitor Shows Durable Effect for Psoriasis

 | Post date: 2021/10/2 | 

Deucravacitinib, a novel inhibitor of the JAK kinase tyrosine kinase 2 (TYK2), continues to demonstrate strong efficacy and acceptable safety after 52 weeks of follow-up, according to late-breaking data from two pivotal trials presented at the European Academy of Dermatology and Venereology (EADV) Annual Meeting.

From benefit reported on the two co-primary endpoints previously reported at 16 weeks, longer follow-up showed further gains out to 24 weeks and then persistent efficacy out to 52 weeks across these and multiple secondary endpoints, reported Richard Warren, MBChB, PhD, professor of dermatology and therapeutics, University of Manchester, Manchester, UK.

"This could be a unique oral therapy and an important treatment option for moderate to severe psoriasis," Warren contended.

The multinational double-blind trials, called POETYK PSO-1 and PSO-2, enrolled 666 and 1020 patients, respectively. The designs were similar. Patients with moderate to severe plaque psoriasis were randomly assigned in a 2:1:1 ratio to deucravacitinib (6 mg once daily), placebo, or apremilast (Otezla; 30 mg twice daily). At 16 weeks, those on placebo were switched to deucravacitinib.

For the co-primary endpoint of PASI 75 (75% clearance on the Psoriasis and Severity Index), the similar rate of response for deucravacitinib in the two studies (58.7% / 53.6%) at week 16 was superior to the rates observed on both apremilast (35.1% / 40.2%) and placebo (12.7% / 9.4%).

By week 24, the proportion of deucravacitinib patients with a PASI-75 response had reached 69.3% and 58.7% in the POETYK PSO-1 and PSO-2 trials, respectively. The proportion of patients on apremilast with PASI 75 at this timepoint did not increase appreciably in one study and fell modestly in the other.

By week 52, the response rates achieved with deucravacitinib at week 24 were generally unchanged and nearly double those observed on apremilast.

The pattern of relative benefit on the other co-primary endpoint, which was a score of 0 or 1, signifying clear or almost clear skin on the Physicians Global Assessment (sPGA), followed the same pattern. At week 16, 53.6% of patients had achieved sPGA 0/1. This was significantly higher than that observed on either apremilast or placebo, and this level of response was sustained through week 52.

When patients on placebo were switched to deucravacitinib at week 16, the PASI 75 response climbed quickly. There was complete catch-up by 32 weeks. In both groups, a PASI-75 response rate of about 65% or higher was maintained for the remainder of the study.

On a prespecified analysis, prior treatment exposure was not associated with any impact on the degree of response with deucravacitinib. This included a comparison between patients exposed to no prior biologic, one prior biologic, or two or more biologics, Warren reported.    

Unlike patients in POETYK PSO-1, those with a PASI 75 response at 16 weeks in the POETYK PSO-2 trial were re-randomized to remain on deucravacitinib or switch to placebo. Designed to evaluate response durability, this analysis showed a relatively gradual decline in disease control.

Cite this: First-in-Class TYK Inhibitor Shows Durable Effect for Psoriasis - Medscape - Oct 01, 2021.


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Top Questions Answered About COVID Boosters for Your Patients

 | Post date: 2021/09/26 | 

Confusion continues to circulate in the wake of decisions on booster doses of the Pfizer/BioNTech COVID-19 vaccine, all announced within 1 week. Many people — including those now eligible and those who officially have to wait for their shot at a third dose — have questions.

Multiple agencies are involved in the booster decisions, and they have put out multiple — and sometimes conflicting — messages about booster doses, leaving more questions than answers for many people.

On September 22, the US Food and Drug Administration (FDA) granted an emergency use authorization (EUA) for a booster dose of the Pfizer mRNA COVID vaccine for those 65 and older and those at high risk for severe illness from the coronavirus, including essential workers whose jobs increase their risk for infection — such as frontline healthcare workers.

Early this morning, the Centers for Disease Control and Prevention (CDC) Director Rochelle Walensky, MD, overruled advice from the agency's Advisory Committee on Immunization Practices (ACIP) to recommend boosters for essential workers such as those working on the frontlines during the pandemic.

As it stands now, the CDC recommends that the following groups should get a third dose of the Pfizer vaccine:

  • People aged 65 years and older

  • People aged 18 years and older in long-term care settings

  • People aged 50 - 64 years with underlying medical conditions

The CDC also recommends that the following groups may receive a booster shot of the Pfizer vaccine, based on their individual benefits and risks:

  • People aged 18 - 49 years with underlying medical conditions

  • People aged 18 - 64 years at increased risk for COVID-19 exposure and transmission because of occupational or institutional setting

The CDC currently considers the following groups at increased risk for COVID-19:

  • First responders (healthcare workers, firefighters, police, congregate care staff)

  • Education staff (teachers, support staff, day care workers)

  • Food and agriculture workers

  • Manufacturing workers

  • Corrections workers

  • US postal service workers

  • Public transit workers

  • Grocery store workers

Healthcare professionals, among the most trusted sources of COVID-19 information, are likely to encounter a number of patients wondering how all this will work.
https://www.medscape.com/viewarticle/959737


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More older adults are taking drugs that can lead to falls

 | Post date: 2021/09/7 | 
Older adults increasingly are taking medications that are prescribed for valid reasons but that also elevate their risks for falls, as indicated in a new study published in Pharmacoepidemiology & Drug Safety earlier this year. In their analysis of government data, researchers found that the share of patients matching this profile surged from 57% in 1999 to a staggering 94% in 2017.
Deaths attributed to falls among older adults more than doubled over the study period. Major contributors to the trend include more frequent use of antihypertensives and antidepressants within this demographic. Women—in particular, Black females overall and white females ages 85 years and older—appear to be especially vulnerable.
The research team, led by Amy Shaver, PhD, PharmD, MPH, does not necessarily believe older adults should be deprived of important medications solely because those drugs could increase the risk of falling. However, they do emphasize the importance of awareness. Shaver, who is a postdoctoral researcher at the University of Buffalo School of Public Health and Health Professions, said it is critical that patients look for the warning labels on their medications and ask questions.
“They should talk to their doctors and pharmacists about what those side effects could mean and what they can do to ensure they stay safe and not fall,” she said.

Source: https://www.pharmacytoday.org/article/S1042-0991(21)00547-8/fulltext

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mRNA vaccines reduce risk of infection by 91% for fully vaccinated

 | Post date: 2021/09/7 | 

According to CDC, the Pfizer and Moderna mRNA COVID-19 vaccines authorized by FDA lower the risk of infection by 91% for fully vaccinated individuals.
“Findings from the extended timeframe of this study add to accumulating evidence that mRNA COVID-19 vaccines are effective and should prevent most infection—but that fully vaccinated people who still get COVID-19 are likely to have milder, shorter illness and appear to be less likely to spread the virus to others,” said CDC Director Rochelle Walensky, MD, MPH, in a news release. “These benefits are another important reason to get vaccinated.”
The report is based on 4 weeks of additional data from CDC's HEROES-RECOVER study of health care workers, first responders, frontline workers, and other essential workers. Preliminary results from the study were first announced in March 2021. In the new findings, nearly 4,000 participants completed weekly SARS-CoV-2 testing, from December 13, 2020, to April 10, 2021, in eight U.S. locations. If the tests came back positive, the specimens were further tested to determine the amount of detectable virus in the nose and the number of days that participants tested positive. Participants were followed over time, and the data were analyzed according to vaccination status.
To evaluate vaccine benefits, the study investigators accounted for the circulation of SARS-CoV-2 viruses in the area and how consistently participants used personal protective equipment at work and in the community.
Once fully vaccinated, participants’ risk of infection was reduced by 91%. After partial vaccination, their risk of infection was reduced by 81%. The study findings support CDC's recommendation to get fully vaccinated against COVID-19 as soon as possible.

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Long COVID Symptoms Can Persist for More Than 1 Year, Study Shows

 | Post date: 2021/08/30 | 

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Nearly one half of people who are hospitalized with COVID-19 suffer at least one lingering symptom 1 year after discharge, according to the largest study yet to assess the dynamic recovery of a group of COVID-19 survivors 12 months after the illness.

The most common lingering symptoms are fatigue and muscle weakness. One third continue to have shortness of breath.

Overall, at 12 months, COVID-19 survivors had more problems with mobility, pain or discomfort, and anxiety or depression, and had lower self-assessment scores of quality of life than matched COVID-free peers, the investigators report. 

The study was published online August 26 in The Lancet.

"While most had made a good recovery, health problems persisted in some patients, especially those who had been critically ill during their hospital stay," Bin Cao, MD, from the National Center for Respiratory Medicine at the China-Japan Friendship Hospital and Capital Medical University, both in Beijing, said in a Lancet news release.

"Our findings suggest that recovery for some patients will take longer than one year, and this should be taken into account when planning delivery of healthcare services post-pandemic," Cao said.

Long COVID is a modern medical challenge of the first order

"As the COVID-19 pandemic continues, the need to understand and respond to long COVID is increasingly pressing," says a Lancet editorial.


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No Sequelae From Lab Abnormalities in Pediatric Isotretinoin Study

 | Post date: 2021/07/12 | 

Isotretinoin use contributed to abnormal lipid lab values in pediatric patients, but no secondary effects were observed, results from a single-center retrospective study demonstrated.

"Isotretinoin is a very effective treatment for severe acne," Varsha Parthasarathy said at the annual meeting of the Society for Pediatric Dermatology. "However, initiating this medication requires a complex process of laboratory testing," which includes human chorionic gonadotropin pregnancy testing, because isotretinoin is a teratogen, as well as lipid labs and liver function tests, she noted. "Importantly, triglycerides are measured due to an association in adults between isotretinoin and hypertriglyceridemia-associated pancreatitis. However, these findings in children are limited to case reports, as are findings of retinoid-induced hepatotoxicity."

To identify the role of isotretinoin on changes in lipids, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), and to determine the impact on treatment course, Parthasarathy, a 4-year medical student at George Washington University, Washington, and colleagues retrospectively reviewed the charts of 130 patients aged 12-21 years who were cared for at Children's National Hospital between January 2012 and October 2020. Nearly two-thirds (65%) were male, their average age was 16 years, and the mean time to obtain follow-up labs after starting isotretinoin was 3.25 months.

Between baseline and follow-up, the researchers observed increases in total cholesterol, triglycerides, and LDL (P less than .001 for all associations) and a decrease in HDL (P = .001), but there were no significant changes in AST or ALT levels. These findings were consistent with prior studies in adults examining the utility of these laboratory tests, most notably a 2016 study by Timothy J. Hansen, MD, and colleagues.

Among the 13 patients with elevated triglycerides at baseline, 9 (69%) were overweight or obese. Of the 20 patients with elevated triglycerides at follow-up, 11 patients (55%) were obese. At follow-up, 11 patients had levels of 200-500 mg/dL (grade I elevation), and 2 patients had levels of 501-1,000 mg/dL (grade II elevation). Isotretinoin was stopped in the latter two patients, who also had obesity as a risk factor for their hypertriglyceridemia.

"None of these patients had clinical sequelae from their hypertriglyceridemia, such as pancreatitis at baseline or follow-up," Parthasarathy said. "However, since pancreatitis would be expected to be exceedingly rare, the sample size may be limited in identifying this adverse effect."

She noted that while isotretinoin might cause a significant increase in lipid levels, the mean levels remained within normal limits at both baseline and follow-up. "Of the patients with elevated triglycerides at baseline and follow-up, obesity may have been a potential risk factor," she said. "This could suggest a possible strategy for reduced testing in nonobese isotretinoin patients, which can be further explored in larger study populations."

In addition, "there was a lack of significant change in AST and ALT in this study and adult studies, as well as minimal evidence for pediatric retinoid-induced hepatotoxicity, which raises the question of the necessity of baseline and follow-up comprehensive metabolic panel testing," Parthasarathy added. "Clinicians must weigh the laboratory values with the costs of laboratory testing, including opportunity costs such as time, monetary costs, and the discomfort of testing for pediatric patients."

The study's senior author was A. Yasmine Kirkorian, MD, chief of dermatology at Children's National Hospital, Washington. The researchers reported having no relevant financial disclosures.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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CDC and Pfizer at Odds Over Need for COVID-19 Booster Shots

 | Post date: 2021/07/12 | 

Shortly after Pfizer announced its intention to seek FDA authorization for a third COVID-19 vaccine shot on Thursday, the CDC, FDA, and NIH countered with a joint statement the same day saying, essentially, it's still too soon.

In a battle of the booster shot statements, the vaccine manufacturer and the US government are drawing very different conclusions based on the evidence to date.

Pfizer points to "encouraging data" for a third shot to be given 6 months after initial vaccination in an ongoing trial of its COVID-19 vaccine. The company said the study supports vaccine efficacy against the Beta variant of concern first identified in South Africa.

Furthermore, a study published last month in the journal Nature found two doses of their vaccine produced strong neutralizing antibodies against the Delta variant in laboratory testing. "The companies anticipate that a third dose will boost those antibody titers even higher," the Pfizer statement reads.

Pfizer, along with its partner BioNTech, also pointed to evidence from Israel that the existing two-dose mRNA vaccine regimen provides less protection against infection as the Delta variant levels continue to grow in the US and elsewhere.

Putting the Brakes on a Booster?

Just hours later, the US government agencies released a two-paragraph joint statement.

"Americans who have been fully vaccinated do not need a booster shot at this time. FDA, CDC, and NIH are engaged in a science-based, rigorous process to consider whether or when a booster might be necessary," the agencies said.  

The US government appeared to acknowledge Pfizer's move but emphasized they will continue to look at the big picture. "This process takes into account laboratory data, clinical trial data, and cohort data — which can include data from specific pharmaceutical companies, but does not rely on those data exclusively."

The agencies add, "We continue to review any new data as it becomes available and will keep the public informed. We are prepared for booster doses if and when the science demonstrates that they are needed."

Medscape Medical News © 2021 

Send news tips to newsmedscape.net.

Cite this: CDC and Pfizer at Odds Over Need for COVID-19 Booster Shots - Medscape - Jul 09, 2021.


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Antibiotic Linked to Rise in Early-Onset Colon Cancer?

 | Post date: 2021/07/7 | 

Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early onset colorectal cancer (CRC) that is being documented, say UK researchers.

The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8000 cases of CRC and over 30,000 healthy controls.

The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.

"To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades," said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland, UK.

"Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults," Perrott said in a statement.

"We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer especially in younger people," added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.

"It's a complex situation as we know that the microbiome can quickly revert to its previous state even when the bowel has been cleared out for a diagnostic procedure," Samuel continued.

The research was presented on July 2 at the ESMO World Congress on Gastrointestinal Cancer 2021.

Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.

 

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CDC recommends pregnant women get COVID-19 vaccine

 | Post date: 2021/06/30 | 
Pregnant women should get the COVID-19 vaccine, said CDC Director Rochelle Walensky, MD, noting that vaccination surveillance systems found “no safety concerns” for more than 35,000 women in their third trimester or for their babies.
She explained that initial vaccine trials did not include pregnant women, so data on possible issues were limited, and the guidance was cautious or even conflicting. “We know that this is a deeply personal decision,” she said. “I encourage people to talk to their doctors and their primary care providers to determine what is best for them and for their baby.”
Peer-reviewed data from national surveillance systems, which were published in a recent issue of the New England Journal of Medicine, back the new recommendation. Between December 14, 2020, and February 28, 2021, data on thousands of pregnant women were collected from CDC's Safe App and the Safe Pregnancy Registry, as well as the vaccine adverse event reporting system. The data show that pregnant women experienced adverse effects similar to those observed in the rest of the population, primarily minor symptoms such as injection site pain, headache, chills, and fever.
Severe reactions were not more common among pregnant women compared with those who were not pregnant, except for nausea and vomiting, which were reported slightly more often among pregnant women following the second dose, according to the research. Early data showed no “obvious safety signals” for pregnancy or neonatal outcomes.
https://www.pharmacytoday.org/article/S1042-0991(21)00373-X/fulltext

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EAS Lipid Guidance: Start High-risk Patients on Combo Drug

 | Post date: 2021/06/30 | 

Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.

The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.

Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.

The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis.

Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance with theheart.org | Medscape Cardiology at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.

He explained that the motivation for creating the practical guidance was "very simple," and concerns something already embedded in the ESC/EAS guidelines, it's just that "people didn't notice" it.

Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels "you can get by starting with high-intensity therapy and/or starting with a combination therapy."

The guidelines, he said, suggest steps for achieving lipid control: begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.


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Cannabis could help manage symptoms of some neurological conditions

 | Post date: 2021/06/27 | 
The data on cannabis and its components for treatment of neurological disorders are plentiful, according to Michele Faulkner, PharmD, FASHP. “Cannabis and neurological disorders is a huge topic,” said Faulkner during an APhA2021 Virtual session on cannabis products to treat neurological disorders.
Most pharmacists are probably familiar with cannabis as a treatment for epilepsy. In 2018, FDA approved Epidiolex (Greenwich Biosciences) as the first-ever product containing cannabidiol. The drug is indicated for two rare and severe forms of epilepsy in patients ages 2 years and older. “The overwhelming majority of data concerning cannabis as a potential therapy in neurology has been derived from surveys of users [and] from open-label studies, and there is quite a high potential for bias in a lot of this information,” said Faulkner.
Faulkner, a professor of pharmacy practice and neurology at Creighton University Schools of Pharmacy and Medicine in Nebraska, said there is no evidence that cannabis can cure any neurological disease or that it slows down any progressive diseases, such as Parkinson's.

What is cannabis?

The cannabis plant contains 554 compounds. These compounds, or active chemicals, include 113 cannabinoids, two of which are tetrahydrocannabinol (THC) and cannabidiol (CBD).
“As we look at pharmacological actions and expected therapeutic responses, a name label is not going to help us, but instead knowing whether it's a THC type, or CBD type, or hybrid type,” said Kari Franson, PharmD, PhD, BCPP, professor and associate dean at the University of Southern California.
Although it's still an area of evolving research, cannabinoids such as THC and CBD are known to have different effects on the body. THC binds to cannabinoid receptors in the body, while CBD may interact indirectly with cannabinoid receptors. THC is the chemical responsible for the psychoactive quality of cannabis, but it also has antinausea and analgesic effects. CBD, which has no psychoactive properties, is said to help with inflammation. Other compounds in the plant, such as the terpenes and flavonoids, may play a synergistic role in the therapeutic effects of cannabis—what's known as the “entourage effect.”
Fiona Oxsher, PhD, cofounder and general manager of LKN Extractions, said that learning about the body's endocannabinoid system—which was only discovered in 2002—helps us understand how cannabinoids work.
The endocannabinoid system controls a person's response to stress, as well as one's mood, appetite, energy balance, and more. In an April 21, 2021, APhA webinar, Oxsher explained that our bodies have been increasingly void of cannabinoids because of our environment, the food we eat, and other factors. Plants with cannabinoids are a way to saturate this system—the CB1 and CB2 receptors, specifically—she said.
Cannabinoids are also present in rosemary, echinacea, kava, and other plants. “But cannabis has the highest percentage of cannabinoids,” said Oxsher.

Inconclusive data

For most neurological diseases, cannabis can help with symptom management. During her presentation, Faulkner discussed the research on a few neurological conditions outside of epilepsy: multiple sclerosis, Parkinson's disease, and headache disorders.

Full- vs. broad-spectrum cannabis products

Full spectrum has the full complement of major and minor cannabinoids—these products have both CBD and THC as well as terpenes and phytochemicals. On the other hand, broad-spectrum products are a THC alternative to full-spectrum products; they have everything in them but THC.
Hemp and marijuana fall under different federal designations. Hemp is a variety of cannabis grown specifically for fiber that is used for industrial purposes. The 2018 Farm Bill legalized the production and sale of hemp and its extracts. Hemp has less than 0.3% of THC. Marijuana has greater than 0.3% of THC. Marijuana is considered a Schedule I drug by DEA and is federally illegal.
“We need to be honest with our patients that the efficacy data is inconclusive,” said Faulkner. “Changes in legal status have outpaced scientific development in the area of cannabis research, and it's really unprecedented that we have indications without any strong clinical data that are being included as acceptable indications for the receipt of medical cannabis.”
For example, Parkinson's disease is included in the accepted indications for medical cannabis in 17 states, despite statements from organizations like the American Academy of Neurology that say cannabis does not work for motor symptoms or levodopa-induced dyskinesia in patients with Parkinson's disease.

Drug interactions

Most pharmacists are probably familiar with patients inquiring about CBD products.
“Patients are already using [CBD] or will come to pharmacists saying they want to explore it,” said Michael Deme, PharmD, a clinical pharmacist at RxClinic Pharmacy in Charlotte, NC, during the April 21 APhA webinar.
Even though data are lacking on CBD and specific drug interactions, Deme said it's an area where a pharmacist's expertise is needed.
“We do know that CBD is metabolized by the liver with enzymes CYP2C19 and CYP3A4,” said Deme. “Most pharmacists know those are major players in all other drug metabolism.”
To cite just one example, if a patient is using a CBD product and is on carbamazepine, which is a CYP2C19 inducer, the CDB dose might not be as effective for them. “Maybe the patient is not getting any benefits from CBD after being on it for a while. Maybe their dose is too low because they are on an inducer medication.” The opposite can also hold true when a patient is on a CYP2C19 inhibitor, in which CBD might not be metabolized as well and could be causing an adverse effect.
According to Faulkner, there are some known drug interactions with cannabidiol. “In particular, it interacts with several of the other antiepileptic medications that we use for the treatment of these same disorders,” she said.
Faulkner said medication doses for diazepam, clobazam, and stiripentol, for example, will likely need to be reduced to prevent toxicity in patients.
She said it's also worth noting that elevations in liver enzymes seem to occur more readily with coadministration of valproic acids. “This is important to know if you have a family member who is seeking out cannabis for use in a child with seizures who is on some of these conventional therapies without the oversight of a medical practitioner,” Faulkner said.

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Long COVID’ needs to be addressed by multiple specialties

 | Post date: 2021/06/27 | 
More and more cases of “long COVID” are surfacing—but what does it mean, and how can clinicians respond? Patients who present with long COVID—also called long-haul COVID or postacute COVID-19—typically report symptoms of severe fatigue, headache, or brain fog 4 weeks or longer after the acute phase of SARS-CoV-2 infection. Some patients also experience respiratory issues, sleep difficulties, depression, and anxiety.
“There is still a lot we do not understand, and empathy toward patients experiencing long COVID is fundamental,” said Alfonso Hernandez-Romieu MD, MPH, LCDR, from the U.S. Public Health Service, during a January 28, 2021, CDC webinar on treating long COVID.
Long COVID can be hard to define because it can overlap with other COVID-19 illness, Hernandez said. For example, patients hospitalized with severe COVID-19 may develop a range of long-term consequences, especially if they've been in the ICU.
However, many patients who have experienced long COVID had mild COVID-19 illness and were never hospitalized, according to several reports.
Allison Navis, MD, a neurologist at Mt. Sinai hospital in New York City, said she was surprised to learn how many COVID-19 patients have been referred to neurology since the pandemic hit. “The majority of [those] patients had not been hospitalized,” she said.
Although Navis and her team have been seeing a broad range of neurological symptoms in patients, brain fog is one of the most common.
“There is no clear correlation with COVID-19 severity, age, or comorbidities,” said Navis, who presented her clinical experience during the CDC webinar.
Jennifer Possick, MD, a pulmonologist at Yale New Haven Hospital, said that most long COVID data has focused on patients who needed to be hospitalized because of COVID-19.
“But the limited number of studies with [patients] with more mild illness indicate their [long COVID symptoms] are indistinguishable from those with more severe COVID-19,” she said during the CDC webinar. “This has been our anecdotal experience as well.”

Long COVID research

In one of the most comprehensive studies to date on long COVID, researchers evaluated 1,733 patients who were first diagnosed with COVID-19 in Wuhan, China, between January and May 2020. Seventy-six percent of these patients had at least one symptom 6 months after symptom onset, according to the research, which was published this January in the Lancet.
The study revealed that the most common symptoms to persist were fatigue and muscle weakness (63%), followed by sleep difficulties (26%), and anxiety and depression (23%). Patients who were hospitalized with severe COVID-19 illness showed more impaired lung function and abnormalities in chest imaging 6 months after symptom onset.
According to an April 2021 study in JAMA conducted by researchers in Sweden, 1 in 10 health care workers still had at least one moderate to severe symptom that negatively affected their life 8 months after having mild COVID-19 illness.
The first phase of the study took place in the spring of 2020 with roughly 2,000 employees at Danderyd Hospital in Sweden. In January 2021, the research team took a closer look at the participants who had reported long-term symptoms after mild COVID-19 at least 8 months earlier. This group consisted of 323 health care workers who were compared with roughly 1,072 health care workers who did not have COVID-19 during the study period.
The most common reported long-term symptoms among participants who had mild COVID-19 were loss of smell and taste, fatigue, and respiratory issues.

Clinician experience

Possick, from Yale New Haven Hospital, said that most long COVID patients have multiple symptoms simultaneously after COVID-19. She added that in her experience, the dominant symptoms may shift over time as patients are followed longitudinally.
Treatment options for these symptoms are still in the exploratory phase, however. Navis from Mt. Sinai said her team addresses any abnormalities in the patient's blood work, but they also treat other contributing factors such as sleep issues or mood disorders patients are experiencing.
“It's important to address mental health, but also [not] attribute everything to it,” she said. “We do know depression, anxiety, and PTSD can affect cognition.”
Possick said that going forward, acknowledging and treating long COVID “will undoubtedly need to be addressed by multiple, different specialties.”

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Researchers develop new therapeutic approach for treating acute myeloid leukemia

 | Post date: 2021/06/22 | 

Leukemia stem cells are rare cells that can renew themselves while continuing to generate malignant cells known as leukemic blasts. These cells are difficult to eradicate using chemotherapy drugs and frequently lead to recurrence of leukemia.

Leukemia stem cells, however, are dependent on a protein complex called polycomb repressive complex 1, or PRC1, which interacts with chromatin and turns genes off.

Now a team of researchers led by Tomasz Cierpicki, Ph.D., and Jolanta Grembecka, Ph.D., from the University of Michigan has developed the first small-molecule inhibitors of PRC1 -; a first step toward developing a potential new therapeutic approach to treating acute myeloid leukemia by shutting down the activity of leukemia stem cells.

These inhibitors demonstrate activity in leukemia cells and patient samples, as reported in Nature Chemical Biology, and also open new opportunities to study the development of leukemia at the molecular level.

Our lead compound, RB-3, represents an attractive and unique agent for studying PRC1 biology. This work demonstrates that directly targeting the activity of PRC1 is indeed feasible and could lay the groundwork for the development of new pharmaceutical agents for leukemia and possibly other cancers."

Tomasz Cierpicki, Associate Professor, Biophysics and Pathology, University of Michigan

Source:
Journal reference:

Shukla, S., et al. (2021) Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain. Nature Chemical Biology. doi.org/10.1038/s41589-021-00815-5.


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Moderna Applies for Full Approval for Its Vaccine

 | Post date: 2021/06/2 | 

Last month, Pfizer applied to the FDA for approval of their vaccine in people 16 and older.

"We look forward to working with the FDA and will continue to submit data from our phase III study and complete the rolling submission," Stéphane Bancel, Moderna's chief executive, said in a press release.

Moderna's vaccine was authorized for emergency use in December, which gave conditional approval of its use based on 2 months of safety data. In order to get full approval, Moderna must provide 6 months of data to prove it is safe to market the shots to consumers directly. Over 151 million doses have already been administered, according to the CDC.

Full U.S. approval will allow the vaccine to stay on the market once the U.S. is no longer in a public health emergency. It will also allow the company to begin advertising the shots on TV and other media platforms.

Approval could also help raise public confidence in the vaccine, after the rate of vaccinations has dropped sharply since April.

Moderna's vaccine, which requires two doses given 4 weeks apart, has been found to be more than 90% effective at protecting against coronavirus and more than 95% effective against severe disease up to 6 months after the second dose.

If the FDA grants Moderna's request, it would be the company's first-ever fully approved product.

"I think there are many people who were on the fence, who were worried about things moving too rapidly and about possible side effects," William Schaffner, MD, medical director of the National Foundation for Infectious Diseases and a vaccine expert, said. "But those concerns are being allayed as they see more of their friends and acquaintances celebrating getting vaccinated."

Sources

The New York Times: "Moderna applies for full F.D.A. approval for its Covid vaccine," "See How Vaccinations Are Going in Your County and State."


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Novel Drug Approved by FDA for Some Bile Duct Cancers

 | Post date: 2021/06/2 | 
It was granted an accelerated approval by the US Food and Drug Administration (FDA) on the basis of response rate data from a single arm, open label phase 2 trial, dubbed CBGJ398X2204. This trial involved 108 patients with locally advanced or metastatic cholangiocarcinoma — including 107 with stage IV disease, the FDA noted in a press release.
 
These types of bile duct cancers, which affect about 20,000 people in the United States and European Union each year, are aggressive and often diagnosed in later stages when treatment options are limited and prognosis is poor. The median 5-year survival rate is 9%, the drug's maker, BridgeBio Pharma affiliate QED Therapeutics, and its partner, Helsinn Group, noted in their joint press release.
 
The FDA also approved the FoundationOne comprehensive diagnostic (CDx) genomic profiling test as the registrational companion CDx device for identifying patients with FGFR2 fusion or other rearrangement who might benefit from treatment with infigratinib.
 
FoundationOne CDx is a comprehensive genomic profiling (CGP) test for solid tumors, currently approved as a CDx test for 26 unique therapies. It is the only tissue-based CGP test approved as a companion diagnostic test for infigratinib, according to the device maker, Foundation Medicine
Details of Infigratinib Results
 
Patients enrolled in CBGJ398X2204 received infigratinib at a once-daily dose of 125 mg for 21 consecutive days followed by 7 days off therapy, in 28-day cycles until disease progression or unacceptable toxicity.
 
The overall response rate was 23%. One patient experienced complete response and 24 had partial response.
 
The duration of response was 5 months, and in eight of the 23 responders the response was maintained for 6 months or more.
 
The study results were reported at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium by lead investigator Milind Javle, MD, professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, Houston.
 
Adverse reactions occurring in at least 20% of patients included hyperphosphatemia, increased creatinine, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, and vomiting.
 
"Serious risks include hyperphosphatemia and retinal pigment epithelial detachment and monitoring for these adverse reactions during treatment is recommended," the FDA notes in its press release, adding that "[c]ontinued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s)."
 
In addition to the pivotal second-line trial of infigratinib for bile duct cancer, QED Therapeutics is also enrolling patients in the phase 3 PROOF trial comparing the agent with gemcitabine plus cisplatin in the first-line setting.
 
Enrollment is also ongoing in trials looking at infigratinib for bladder and urinary tract cancers and achondroplasia.
 
The company has also launched ForgingBridges, a "comprehensive patient support program designed specifically to provide education, access and affordability resources for patients during their TRUSELTIQ journey."
 
Sharon Worcester is an award-winning reporter for MDedge News, part of the Medscape Professional Network.
 
 
Cite this: Novel Drug Approved by FDA for Some Bile Duct Cancers - Medscape - Jun 01, 2021.

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COVID-19: More evidence that monoclonal antibodies reduce risk of death

 | Post date: 2021/05/22 | 
  • Antibodies fight infection, and the body produces them naturally, but it is possible to introduce antibodies into the body artificially.
  • A new study suggests that the monoclonal antibody bamlanivimab may effectively reduce the chance of hospitalization and death in people with a SARS-CoV-2 infection.
  • Use of bamlanivimab treatment was associated with a decrease in hospitalization and mortality, especially among adults over 65 years.
SARS-CoV-2 is a virus that has impacted people worldwide, causing drastic changes in daily life, illness, and death. According to the Centers for Disease Control and Prevention (CDC), over 32 million people in the United States have developed COVID-19.
In addition to respiratory symptoms, COVID-19 can cause serious complications, including cardiovascular complications, acute kidney injury, acute liver injury, acute respiratory failure, blood clots, and neurological complications.
As noted by the CDCTrusted Source, some individuals have a higher chance of becoming seriously ill after contracting SARS-CoV-2, meaning they may require hospitalization for treatment, use of a ventilator to help with breathing, or the illness may result in death.
Individuals with a higher chance of developing severe illness related to COVID-19 include older adults and those with other medical conditions, such as cancer, COPD, asthma, and diabetes.
Stay informed with live updates on the current COVID-19 outbreak and visit our coronavirus hub for more advice on prevention and treatment.
The COVID-19 vaccine focuses on prevention, but researchers are also studying treatments for reducing symptoms and complications caused by COVID-19 infections. Treatment of COVID-19 using monoclonal antibodies may be an effective option for people at risk of severe illness.
 
Antibodies to treat COVID-19
The body produces antibodies to help it fight infections. Introducing monoclonal antibodies into the body to help block the virus has shown promiseTrusted Source as a treatment for those with a SARS-CoV-2 infection.
Based on the nature of the virus and how it replicates, these specific antibodies can neutralize the virus, decreasing the amount of the virus present in the body.
Medical News Today spoke with Dr. Arturo Casadevall, chair for Molecular Microbiology & Immunology at Johns Hopkins Bloomberg School of Public Health in Baltimore, MD. He said:
Antibody treatments have a long […] record of efficacy in infectious diseases but have not been used as much as they could have, as physicians have been more focused on antimicrobials and antivirals. This experience with antibody therapies against COVID-19 could help bring back wider use of antibodies for infectious diseases.”
The authors of the present study write that between November 2020 and February 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization for four types of monoclonal antibodies. Doctors can provide these monoclonal antibodies to individuals with mild to moderate COVID-19 symptoms up to 10 days after their symptoms began.
People at risk of developing serious complications and severe symptoms from infection with SARS-CoV-2 are more likely to benefit from monoclonal antibodies as a treatment option.
 

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Convalescent Plasma Flops for Hospitalized COVID Patients

 | Post date: 2021/05/19 | 
A red COVID-19+ stamped bag of plasma

Hospitalized COVID-19 patients treated with high-titer convalescent plasma showed no survival benefits or clinical improvements compared to patients only receiving usual care, according to data from the U.K.'s RECOVERY trial.

Both groups had a mortality rate of 24% at 28 days (RR 1.00 95% CI 0.93-1.07, P=0.95), reported Peter Horby, PhD, of the University of Oxford in England, and colleagues.

There was also no difference between groups in hospital stay duration or chance of disease progression, the authors wrote in The Lancet.

"This study is significant since the Recovery Collaborative Group organized the largest randomized trial in reporting COVID-19 convalescent therapy mortality results," Horby and colleagues wrote.

Convalescent plasma has been used as a "passive immunotherapy" in treating influenza pneumonia and for SARS-CoV-1, the authors explained. Previous studies examining convalescent plasma's ability to reduce mortality in severe COVID-19 and other respiratory infections (influenza and Ebola) have been of poor quality, or reached limited or inconclusive results.

In February, the FDA limited the use of high-titer convalescent plasma, used under emergency use authorization, to patients early in their disease course and for those with impaired humoral immunity.

"The often unpredictable disease course of COVID-19 creates a substantial challenge for clinical researchers when identifying ideal patient populations who might benefit from investigational interventions," wrote Sean Liu, MD, PhD, and Judith Aberg, MD, both of the Icahn School of Medicine in Mount Sinai in New York City, in an accompanying editorial. "Special populations, such as patients with impaired humoral immunity, who were not actively considered in this study, might still benefit from convalescent plasma when admitted."

The U.K.'s Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial is coordinated by the University of Oxford in the Nuffield Department of Population Health, at 177 U.K. hospitals. From May 28, 2020, to Jan 15, 2021, 11,558 (71%) of the trial's 16,287 patients were eligible to receive convalescent plasma and were randomly placed in a "usual care" group or a "usual care plus high-titer convalescent plasma" group.

The primary outcome was 28-day mortality, as analyzed on an intention-to-treat basis. Secondary outcomes were hospital discharge time and among patients not on ventilators, a composite endpoint of progression to invasive mechanical ventilation or death.

Mean patient age was about 64, roughly two-thirds were men, and 77% to 78% were white. Median time to symptom onset was 9 days.

At randomization, 5% of patients required invasive mechanical ventilation, 87% received oxygen-only therapy, and 8% of patients received no oxygen therapy. Corticosteroids were taken by 92% of patients at randomization.

There was no difference in 28-day mortality in any subgroup, including age, sex, ethnicity, duration of symptoms before randomization, level of respiratory support, or use of corticosteroids.

Convalescent plasma therapy didn't affect the number of patients discharged within 28 days; both groups showed a 66% discharge rate (RR 0.99, 95% CI 0.94-1.03, P=0.57). Regardless of not being randomly placed on a ventilator, 29% of patients in each group still experienced disease progression resulting in ventilator intervention/death (RR 0.99, 95% CI 0.93-1.05, P=0.79).

In the convalescent plasma group, the median time to discharge was 12 days and for the usual care group, 11 days.

The authors mentioned limitations, including that "disease stage could impact the benefits of convalescent plasma." This study only assessed admitted hospital patients with a long median time (9 days) from symptom onset to randomization, and patient ethnic diversity was underrepresented.

Researchers highlighted the need for additional trials to study convalescent plasma therapy for COVID-19 in other patient groups.

"Future ambulatory trials with convalescent plasma might need to be matched against monoclonal antibody therapies or hyperimmune immunoglobulin, eligibility criteria must include tightly defining the population most likely to benefit," wrote editorialists Liu and Aberg.


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Obesity: New drug turns ‘energy-storing’ fat into ‘energy-burning’ fat

 | Post date: 2021/05/18 | 
According to the World Health Organization (WHO), the prevalence of obesity worldwide has more than tripledTrusted Source since 1975.
In 2016, the WHO estimates, 39% of all adults worldwide were overweight, and 13% had obesity. These conditions are associated with diabetes, cardiovascular disease, and some cancers.

Changing exercise and dietary habits can help people reach and maintain a healthy weight. However, taking these steps effectively can be challenging for many reasons, and some people also look to appetite-suppressing medication.
Over the years, various drugs that suppress the appetite by acting directly on neurotransmitter systems in the brain have been withdrawn from the market due to adverse effects, particularly involving mood and the function of the heart.
Most current prescribed treatments are aimed at reducing food intake by targeting the central nervous system,” says Dr. Yanchuan Shi, who leads the neuroendocrinology group at the Garvan Institute of Medical Research, in Sydney, Australia.
However, these can have significant psychiatric or cardiovascular side effects, which have resulted in over 80% of these medications being withdrawn from the market,” she notes.
Dr. Shi and colleagues wanted to test a new way of reducing weight gain without affecting the central nervous system. Their research has been published in Nature CommunicationsTrusted Source.
Conserving energy stores
The team focused on a nerve signaling molecule called NPY. It helps many animals, including mice and humans, survive conditions in which food shortages are commonplace.
NPY increases food intake and conserves energy stores by reducing heat generation in a type of fat tissue called brown adipose tissue.
In an environment where people have ready access to food and do not get sufficient exercise, however, NPY may make it particularly difficult to lose weight.
NPY is a metabolism regulator that plays a critical role during states of low energy supply, where it helps store fat as a survival mechanism,” says Prof. Herbert Herzog, head of the Eating Disorders Lab at the Garvan Institute.
Today, however, these advantageous effects can exacerbate existing diet-induced weight gain, leading to obesity and metabolic disease.”
Dr. Shi, Prof. Herzog, and colleagues investigated the effects of a drug called BIBO3304 on mice and human fat cells from people with obesity. The drug blocks a type of cell receptor for NPY called Y1 that is found in fat tissue and other tissues in the body.
Crucially, BIBO3304 cannot cross the blood-brain barrier, so it is unlikely to adversely affect mood.



Increased heat generation
For 7 weeks, the researchers fed mice a high-fat diet, with or without BIBO3304.
They found that the mice given the drug gained 40% less weight. This, the team discovered, resulted from increased heat generation in the animals’ brown adipose tissue and reduced overall fat mass.
The Y1 receptor acts as a ‘brake’ for heat generation in the body. In our study, we found that blocking this receptor in fat tissues transformed the ‘energy-storing’ fat into ‘energy-burning’ fat, which switched on heat production and reduced weight gain.”
Dr. Yanchuan Shi.
Interestingly, the scientists discovered that the fat tissue from both mice and humans with obesity had higher activity of the genes for the Y1 receptor than tissue from individuals with a healthy weight.
This may partly explain why losing weight can be so difficult, given that NPY increases food intake and reduces energy output when it binds to Y1.
When the researchers applied BIBO3304 to fat cells from people with obesity, the cells switched on the same genes involved in heat generation as those that had been activated in the mice.
This suggests that the drug, or similar molecules, could work in the same way in people as it does in mice.
Added benefits
In addition to reducing weight gain in mice, the authors discovered that blocking Y1 has several knock-on effects, including improving glucose metabolism.
As Y1 contracts blood vessels, blocking Y1 with BIBO3304 may widen blood vessels, a process called vasodilation, which lowers blood pressure.
We predict that blocking this receptor could cause vasodilation that may be beneficial in the context of hypertension, but further study needs to be done to confirm this,” Dr. Shi told Medical News Today.
The researchers had previously shown that BIBO3304 also stimulates bone cell growthTrusted Source, which could help maintain bone density, preventing osteoporosis in older people.
Dr. Shi acknowledged that the study did not directly test whether the drug could promote weight loss in people with obesity. Rather, it demonstrated that BIBO3304 could prevent weight gain in mice.
While we didn’t test the approach in models of obesity, obesity is, similarly, a condition of energy oversupply due to the accumulation of fat,” she said. “Therefore, our study suggests that a treatment like BIBO3304 could help treat obesity by increasing energy expenditure through the burning of fat, leading to weight loss.”
It is also worth noting that metabolism in mice and humans differs in important ways. Keith Frayn, emeritus professor of human metabolism at the University of Oxford, in the United Kingdom, told MNT:
I don’t place a lot of weight on studies in small rodents, especially in this field. Small rodents have a much greater capacity than do humans for up-regulating thermogenesis [increasing their heat generation]. So we cannot assume that these studies in mice will translate to humans until they are tested.”  

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COVID-19 Anticoagulation Trials 'Paused' for Futility, Safety

 | Post date: 2020/12/28 | 

Parts of three linked studies investigating increased levels of anticoagulation in hospitalized COVID-19 patients have been "paused" because of futility and safety concerns, a statement from the US National Heart, Lung, and Blood Institute (NHLBI) confirms.

The trials involved are the REMAP-CAP, ACTIV-4, and ATTACC studies.

All three trials have paused enrollment of critically ill COVID-19 patients requiring intensive care unit support for whom therapeutic doses of anticoagulation drugs did not reduce the need for organ support, the NHLBI statement notes.

The statement also says that a potential for harm in this subgroup could not be excluded, noting that increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses, which will be made available as soon as possible.   

The three clinical trial platforms are working together to test the effects of full therapeutic doses of anticoagulants vs lower prophylactic doses in COVID-19 patients.

Informed by the deliberations of the data safety monitoring boards of these trials, all of the trial sites have paused enrollment of the most critically ill hospitalized patients with COVID-19. 

Enrollment continues in the trials for moderately ill hospitalized COVID-19 patients, the statement notes.  

"Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question," the NHLBI statement says.

Patients who require full dose anticoagulants for another medical indication are not included in these trials.

The statement explains that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, myocardial infarction, and stroke

The three trials are the result of a collaboration between major international partners. The trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).

The trials, which span four continents, have the common goal of assessing the benefit of full doses of anticoagulants to treat moderately ill or critically ill adults hospitalized for COVID-19, compared with a lower dose often used to prevent blood clots in hospitalized patients.


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