Pharmacists Urged to Do Their Part in Fight Against False Dietary Supplement Claims

 | Post date: 2022/11/27 | 

The FDA’s latest warnings against the dangers of dietary supplements that claim to cure, treat, mitigate or prevent cardiovascular disease have one pharmacist urging the profession to let the agency know when such false claims are being made.

On Nov. 17, the FDA issued warning letters to seven companies for illegally promoting their supplements for a variety of cardiovascular conditions, including atherosclerosis, stroke or heart failure, in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 

The FDA warned consumers not to use these or similar products because the agency has not deemed them safe or effective for their intended use, and may in fact be harmful.

C. Michael White, PharmD, FCP, FCCP, the department head and a professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs, explained why the FDA may need the help of pharmacists to protect patients from these deceptive marketing practices.

“Although the FDA has the authority to act, they have limited resources to finding these bad players making false claims,” Dr. White said. 

He pointed out that under the FD&C Act, products that claim to mitigate or prevent disease are justifiably considered as drugs by regulators, and thus subject to the requirements that apply to any medication intended for human consumption. “And that’s the case even if the products are being marketed as dietary supplements,” he told Pharmacy Practice News.

The FDA underscored the need for that higher level of regulatory scrutiny for products marketing to alleviate cardiac conditions. “Cardiovascular disease is the leading cause of death in the United States,” the agency stressed. Thus, “it’s important that the FDA protect the public from products and companies that make unlawful claims to treat it.”

The possibility that patients might choose these dietary supplements over agency-approved prescription medications is another cause for concern, according to the FDA. Such products “could potentially harm consumers who use [them] instead of seeking safe and effective FDA-approved treatments from qualified healthcare providers,” said Cara Welch, PhD, the director of the Office of Dietary Supplement Programs in the FDA’s Center for Food Safety and Applied Nutrition. 

“We encourage consumers to remain vigilant when shopping online or in stores to avoid purchasing products that could put their health at risk,” Dr. Welch said.

Dr. White echoed the need to educate patients about the dangers of leaving prescription cardiovascular medicines on the shelf. “If a patient comes to you and asks about these natural alternatives for lipid management, it’s important to remember that their ability to lower LDL [low-density lipoprotein] is usually small—about 15% or less—whereas statins and PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors reduce it by 50% at maximal doses,” he said. “Patients also need to understand there is no proof that these products actually reduce heart attacks and strokes. So, the money spent might not be providing benefits.”

Efficacy Claims That Cross the Line

The FDA’s warning letters on cardiovascular dietary supplements were issued to Essential Elements (Scale Media Inc.); Calroy Health Sciences LLC; Iwi; BergaMet North America LLC; Healthy Trends Worldwide LLC (Golden After 50); Chambers’ Apothecary; and Anabolic Laboratories LLC.

An examination of the letter sent to Healthy Trends Worldwide illustrates the degree to which the FDA is calling these companies to task for making efficacy claims that indicate a product “is intended for use as a drug,” and thus running afoul of the agency’s review process.

In several website statements, Healthy Trends Worldwide claimed its product can “reduce blood pressure” and “add a healthy 10, 15, even 20+ years to your life.” These outcomes were attributed to hawthorn berry and magnesium, two ingredients in the company’s BPS-5 supplement.

The FDA is not convinced. “Your BPS-5 product is not generally recognized as safe and effective for the above referenced uses and, therefore, this product is a ‘new drug’ under [FDA law],” the agency stated in a Nov. 14, 2022, warning letter to the company. “With certain exceptions not applicable here, new drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from FDA.”

Counseling Tips

As for other claims often made by companies marketing cardiovascular supplements, Dr. White cited statements regarding LDL cholesterol as particularly problematic. “Consumers are being told that these dietary supplements are effective at reducing LDL cholesterol, which in turn lowers the risk for heart disease. But aside from statins, ezetimibe [Zetia, Organon] and the monoclonal antibody PCSK9 inhibitors, there is no proof that these products can reduce atherosclerotic events.”

But it’s not just a question of a lack of efficacy. As the FDA rightly warned, these dietary supplements can be harmful, Dr. White stressed. 

“There is limited information on adverse events and drug interactions because the products are not well studied,” he said. “This is problematic especially for patients on other medications and with other diseases. For example, red yeast rice, a common ingredient in supplements marketed for lipid lowering, contains natural lovastatin, so it must also be a CYP3A4 [cytochrome P450 3A4] substrate inhibitor and would therefore accumulate if combined with itraconazole or grapefruit juice.”

Similarly, “some products containing natural statins or niacin could negatively affect the liver, and so in an ideal world, liver function testing would be done for patients who take them.” But if a patient is ingesting them on their own—as usually is the case with over-the-counter products—there is no opportunity for a clinician to order such tests, he noted.

“Finally, unless the products are certified by an independent laboratory, they could be contaminated with heavy metals and microbes or adulterated with prescription drugs,” Dr. White said. 

And then there’s the question of cost. “In many cases, generic statins are less expensive than the so-called ‘natural’ products these companies are marketing,” he said. 

Coupled with the fact that FDA-approved cardiovascular medications “are more effective, do not have contamination or adulteration, and your pharmacist can watch out for drug interactions and other adverse events,” he said, it’s clear that caveat emptor should be the main message when the subject of these supplements come up during patient encounters.

https://www.pharmacypracticenews.com/Online-First/Article/12-22/Pharmacists-Urged-to-Do-Their-Part-in-Fight-Against-False-Dietary-Supplement-Claims/68760


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Data Support Use of Novavax COVID-19 Vaccine as Booster

 | Post date: 2022/11/16 | 

Topline results from Novavax’s phase 3 Boosting Trial for the SARS-CoV-2 rS Variant Vaccines (COVID-19) found that the company’s BA.1 vaccine candidate (NVX-CoV2515) met the primary strain-change endpoint.

Further, the data show that the neutralizing responses produced by the BA.1 vaccine neutralizing responses were greater than those of the prototype (NVX-CoV2373) among individuals not previously exposed to COVID-19, which enables a shift to a new variant vaccine if necessary, according to Novavax.

"[The] results show that use of our prototype vaccine as a booster induces cross-reactive responses to a broad range of variants with the potential to protect against future strains. This is a hallmark of our vaccine technology and shows the suitability of our current prototype vaccine as a booster even as the COVID-19 landscape continues to evolve," said Gregory M. Glenn, MD, president of Research and Development, Novavax, in a press release. "Our vaccine, which provides broad immune response even in the face of evolving variants, presents a potential strategy to protect against COVID-19 now and into the future."

NVX-CoV2373 is a protein-based vaccine developed from the genetic sequence of the first strain of SARS-CoV-2. The vaccine was created using Novavax’s recombinant nanoparticle technology to produce antigens derived from the COVID-19 spike protein.

The vaccine is formulated with Novavax’s patented saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies. NVX-CoV2373 contains purified protein antigen and can neither replicate nor cause COVID-19.

Further, the vaccine is packaged as a ready-to-use liquid formulation in a vial containing 10 doses, with two 0.5 ml doses administered intramuscularly 21 days apart. The data show no benefit for the Novavax bivalent vaccine candidate compared to the BA.1 vaccine candidate or prototype vaccine in the overall trial population.

The immunoglobulin G (IgG) antibody responses were similar against BA.1 and prototype strains across the 3 vaccine groups (prototype [n=273], BA.1 vaccine candidate [n=279], and bivalent – prototype + BA.1 vaccine candidate [n=277]).

For the BA.5 strain, pseudoneutralization responses found that there was no benefit for the BA.1 or bivalent vaccine candidates compared to the prototype vaccine.

The data demonstrated that the prototype vaccine induced a broad immune response against the original prototype, BA.1 and BA.5 strains. The vaccine produced robust IgG responses to both BA.1 and the matched prototype strain. Additionally, pseudoneutralization responses against BA.5 for the prototype vaccine were comparable to those induced by the

more closely matched BA.1 vaccine and bivalent vaccine candidates.

All 3 vaccine formulations were similarly well-tolerated when given as a second booster dose (fourth dose), which was consistent with the well-established safety profile of the prototype vaccine. The most common local solicited symptom was pain/tenderness, and the most common systemic solicited symptoms were fatigue and malaise, muscle pain, and joint pain, with most reactions being mild or moderate.

REFERENCE

Novavax Phase 3 COVID-19 Omicron Trial Supports the Continued and Future Use of Novavax Prototype Vaccine as a Booster. Novavax. November 8, 2022. Accessed November 8, 2022. https://ir.novavax.com/2022-11-08-Novavax-Phase-3-COVID-19-Omicron-Trial-Supports-the-Continued-and-Future-Use-of-Novavax-Prototype-Vaccine-as-a-Booster


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Capivasertib Plus Faslodex Meets Both Primary Endpoints in Phase 3 Trial for Breast Cancer

 | Post date: 2022/10/31 | 

Fulvestrant (Faslodex; AstraZeneca) in combination with capivasertib (AstraZeneca) demonstrated a statistically significant and meaningful improvement in progression-free survival (PFS) compared with the placebo and fulvestrant in individuals with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low of negative locally advanced or metastatic breast cancer, following progression or recurrence on or after endocrine therapy, according to results from the CAPItello-291 (NCT04305496) phase 3 trial.

“The CAPItello-291 phase 3 trial results show capivasertib offers a clinically meaningful improvement in progression free survival for patients with HR-positive breast cancer. This potential new medicine could give people more time with their cancer under control, which is a priority for patients and their families,” Nicholas Turner, MD, PhD, professor of molecular oncology at the Institute of Cancer Research in London and the Royal Marsden NHS Foundation Trust in London, United Kingdom, said in a statement.

The trial met both primary endpoints, which included improving PFS in the overall patient population and in a prespecified biomarker subgroup of individuals whose tumors had alterations in the PIK3CA AKT1 or PTEN genes. In the trial, approximately 40% of tumors had these alterations.

The overall survival data was immature at the analysis, but investigators said they will continue to assess it as a key secondary endpoint, as the early data are positive.

Additionally, the safety profile of the drug combination was similar to that observed in previous trials with the same combination.

The CAPIello-291 trial is a randomized trial that is part of a larger clinical program investigating capivasertib. Investigators enrolled 708 individuals with histologically confirmed HR+, Her2-low or negative breast cancer whose disease had progressed or recurred during or after aromatase inhibitor therapy with or without a CDK4/6 inhibitor and up to 1 line of chemotherapy for those with advanced disease.

“These exciting data in an all-comers population indicate that capivasertib could become a new first-in-class treatment option for patients with HR-positive breast cancer. These patients often experience tumor progression on, or resistance to, available endocrine therapies for advanced disease and urgently need new therapies that extend the effectiveness of endocrine-based treatment approaches,” Susan Galbraith, PhD, executive vice president of oncology research and development at AstraZeneca, said in the statement.

The data will be presented at an upcoming medical meeting, as well as shared with global health authorities.

Fulvestrant is indicted as a monotherapy for HR+, HER2- advanced breast cancer in postmenopausal women who were not previously treated with endocrine therapy and HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy.

Furthermore, it is indicated as a combination therapy for HR+, HER2- advanced or metastatic breast cancer in postmenopausal womenwith ribociclib as initial endocrine-based therapy or following disease progression on endocrine therapy and HR+, HER2- advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy.

Reference

Capivasertib plus Faslodex (fulvestrant) significantly improved progression-free survival vs. Faslodex in CAPItello-291 phase III trial in advanced HR-positive breast cancer. News release. Businesswire. October 26, 2022. Accessed October 27, 2022. https://www.businesswire.com/news/home/20221026005411/en


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FDA Approves Vegzelma, a Biosimilar to Bevacizumab, for Six Types of CancerFDA Approves Vegzelma, a Biosimilar to Bevacizumab, for Six Types of Cancer

 | Post date: 2022/09/13 | 

By PPN News Staff
The FDA has approved bevacizumab-adcd (Vegzelma, Celltrion USA), a biosimilar to bevacizumab (Avastin, Amgen), for the treatment of metastatic colorectal cancer; recurrent or metastatic non-squamous non-small cell lung cancer (nsNSCLC); recurrent glioblastoma; metastatic renal cell carcinoma; persistent, recurrent or metastatic cervical cancer; and epithelial ovarian, fallopian tube or primary peritoneal cancer.

“Biosimilars have been used in many disease areas, including oncology, and have shown to be safe and effective while lowering the drug cost and increasing the access to more patients around the world,” said Professor Claire Verschraegen, the director of the Division of Medical Oncology at The Ohio State University Comprehensive Cancer Center, in Columbus, in a Celltrion press release. “With the availability of biosimilars such as Vegzelma in the U.S., oncologists will have additional treatment options for patients across multiple cancer types.”

The approval of bevacizumab-adcd was based on the totality of evidence, including a pivotal phase 3 trial in patients with metastatic or recurrent nsNSCLC presented at the 2022 annual meeting of the American Association for Cancer Research, in New Orleans. 

In the phase 3 trial, patients were randomly assigned (1:1) to receive bevacizumab-adcd or bevacizumab with carboplatin-paclitaxel for up to 18 weeks (six cycles), followed by up to 24 weeks (eight cycles) of bevacizumab monotherapy.

The primary objective was to examine overall response rate (ORR) during the first 18 weeks. A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 (95% CI, 0.83-1.12) and the difference in ORR was −1.6 (95% CI, −9.0 to 5.9) between treatment arms. The confidence intervals were within the predefined equivalence margins. 

The results showed “that as a first-line treatment, bevacizumab-adcd is highly similar to the reference product in terms of efficacy, safety and pharmacokinetics,” the Celltrion press release stated.

Overall, the incidence of treatment-related adverse events and serious adverse events was comparable. Treatment-related anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (bevacizumab-adcd, 6.5%; bevacizumab, 4.8%). 

The incidence of neutralizing antibody post-baseline was lower in the bevacizumab-adcd arm (0.6%) than the bevacizumab arm (2.5%).

Bevacizumab-adcd is Celltrion’s third oncology biosimilar approved for use in the United States, following the approval of rituximab-abbs (Truxima) and trastuzumab-pkrb (Herzuma). The newly approved drug is a recombinant, humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis. 

Bevacizumab-adcd inhibits the binding of VEGF to its receptors Flt-1 (VEGFR-1), and kinase insert domain receptor (KDR) (VEGFR-2), on the surface of endothelial cells. 

More Safety Data

Although bevacizumab-adcd and the reference product are deemed to be similar in terms of safety, both medications carry several warnings and precautions about potentially severe adverse reactions, including gastrointestinal perforation and fistula, severe or fatal hemorrhages and arterial thromboembolic events.

For more details, see the full prescribing information.

https://www.pharmacypracticenews.com/FDA-Approvals/Article/09-22/FDA-Approves-Vegzelma-a-Biosimilar-to-Bevacizumab-for-Six-Types-of-Cancer/68177


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FDA Approves Oral Liquid Formulation to Treat Gastric Issues

 | Post date: 2022/09/3 | 

The FDA has approved omeprazole and sodium bicarbonate for oral suspension (Konvomep, Azurity) to treat active benign gastric ulcers and reduce the risk of upper gastrointestinal bleeding in critically ill patients.1

"We are very pleased that patients will soon have access to this FDA-approved oral liquid formulation option of a commonly prescribed proton pump inhibitor," said Richard Blackburn, CEO of Azurity Pharmaceuticals, in a press release.1

The omeprazole and sodium bicarbonate for oral suspension is a combination of proton pump inhibitor omeprazole (PPI) with sodium bicarbonate.2 Proton pump inhibitors are the most common prescribed drug to reduce stomach acid which, in excess, can inflame or irritate the esophagus and cause heartburn or peptic ulcers.3,4

While they can treat ulcers, PPIs can prevent ulcers as well. Many individuals also take PPIs for gastroesophageal reflux disease (GERD), which occurs when acid travels up the esophagus, inflaming the tissue.3

A gastric ulcer line is an open sore that lines the stomach.3 It is one of 2 types of peptic ulcers—the other is called a duodenal ulcer and it lines the first part of the small intestine.4 Symptoms of a peptic ulcer include pain, nausea, back pain, burning that feels like a hunger pain, and pain aggravated by meals.4

Practitioners test for a peptic ulcer by measuring serum gastrin in a lab, performing a Barium contrast radiology (X-ray) of the upper gastrointestinal tract, or performing a gastrointestinal endoscopy to examine the mucous lining of the upper gastrointestinal tract.4

Treatment for gastric ulcers and bleeding can take many shapes, but omeprazole and sodium bicarbonate for oral suspension is a liquid formulation.1

"Patients who struggle with taking solid oral dosage forms may be overlooked and have historically had limited FDA-approved treatment options available as liquid formulations," said Olga Hilas, PharmD, MPH, BCPS, BCGP, Professor, Clinical Health Professions, St. John's University College of Pharmacy & Health Sciences, Queens, New York, in a press release.1

Common PPIs are lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), rabeprazole (AcipHex), and esomeprazole (Nexium).3 They are the most potent stomach acid inhibitor that is proven effective for chronic gastrointestinal issues.3 Omeprazole and sodium bicarbonate for oral suspension is projected to be commercially available in 2023.1

"Patients are our priority, and our purpose is to bring them new formulations that help them benefit from established medicines,” concluded Blackburn in the press release. “Konvomep™ may give patients, particularly patients with difficulty swallowing pills or capsules, an option for treatment tailored to their needs."1

References

  1. Azurity Pharmaceuticals. AZURITY PHARMACEUTICALS, INC. ANNOUNCES FDA APPROVAL OF KONVOMEP™ (omeprazole and sodium bicarbonate for oral suspension). September 2, 2022. Accessed on September 2, 2022.https://www.health.harvard.edu/newsletter_article/proton-pump-inhibitors
  2. KONVOmep. KONVOmep website. Accessed on September 2, 2022. https://konvomep.com/
  3. Harvard Medical School. Proton-pump inhibitors: What you need to know. Harvard Health website. September 30, 2021. Accessed on September 2, 2022.
  4. Johns Hopkins. Peptic Ulcer Disease. Johns Hopkins Medicine website. Accessed September 2, 2022.

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Common Antibiotic Associated with Rare, Severe Adverse Effects for Patients with Advanced Chronic Kidney Disease

 | Post date: 2022/08/17 | 

A new study warns that fluoroquinolone could increase the risk of altered mental status and hospitalizations for advanced chronic kidney disease patients, though it is rare.

Older patients with chronic kidney disease (CKD) who were administered fluoroquinolone at higher than recommended doses were more likely to be hospitalized, according to a study published in JAMA Open Network.

Fluoroquinolone is the most prescribed broad-spectrum antibiotic, even though the FDA has severe black box warnings about its risks. Fluoroquinolones (ciprofloxacin, levofloxacin, or norfloxacin) are typically eliminated by the kidneys, but patients with reduced kidney function excrete the antibiotic at a lower rate.

Population-based studies and meta-analyses already show an association between fluoroquinolone and rare but serious adverse events (AEs). These AEs include nervous system disorders, psychiatric disorders, hypoglycemia, and collagen-associated AEs.

Researchers analyzed these AEs and whether they were associated with a higher vs lower dose of fluoroquinolone in older patients with advanced CDK. Primary endpoints included hospitalization due to AEs during the first 14 days of taking medication. Secondary outcomes included hospital visits due to sepsis, retinal detachment, all-cause hospitalization, all-cause mortality, or sudden cardiac death.

From January 2008 to March 2020, researchers conducted a new user, population-based cohort study in Ontario, Canada, analyzing 11,917 CKD patients taken from 8 health care databases. Participants were 66 years of age and older, most of whom with an estimated glomerular filtration rate [eGFR] of less than 30 mL/min/1.73 m2.

Researchers gave participants either a single higher dose of oral fluoroquinolone—which includes ciprofloxacin (501 to 1000 mg/d), levofloxacin (501 to 750 mg/d) or norfloxacin (401 to 800 mg/d)—or a low-dose prescription of ciprofloxacin (500 mg/d), levofloxacin (250 to 500 mg/d), or norfloxacin (400 mg/d). The thresholds were determined by current patient guidelines for patients with advanced CKD.

In 2021, the team found that the higher fluoroquinolone dose associated with a higher risk of severe AEs, supporting the primary outcome. Neither the high- nor low-dose groups were associated with any secondary outcomes. Researchers also discovered that 46% of patients with advanced CDK were being prescribed higher than recommended doses.

In the study, participants taking the larger dose of fluoroquinolone also had a significantly higher risk of hospitalization for altered mental status, which was the most common AE.

The study authors further conducted 4 post hoc sensitivity analyses, showing a consistent survival analysis, low confidence of primary outcomes, insignificant risk of heart failure on the antibiotic, and overall consistent results.

In the study, there was only 1 hospitalization for every 256 patients. In total, only 1.2% of high-dose users were hospitalized for AEs.

The authors identified some limitations to the study, specifically being that it is the first of its kind to evaluate this association. Other factors such as age and disease limit the results of this drug, and researchers used multiple types of fluoroquinolones, generalizing the entire antibiotic.

The findings suggest that fluoroquinolones should be prescribed at lower doses to adults with advanced CKD due to their high-risk AEs, the authors concluded.

Reference

Muanda, Flory, Sood, Manish, Weir, Matthew, et al. Association of Higher-Dose Fluoroquinolone Therapy With Serious Adverse Events in Older Adults With Advanced Chronic Kidney Disease. JAMA Netw Open. 2022;5(8):e2224892. doi:10.1001/jamanetworkopen.2022.24892.


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Experts release appropriate use recommendations for Alzheimer’s disease blood biomarkers

 | Post date: 2022/08/1 | 

Alzheimer’s disease blood biomarkers (BBMs) may revolutionize the diagnosis of Alzheimer’s in the future, but are not yet ready for widespread use, according to a newly-published article by leading international clinicians and researchers convened by the Alzheimer’s Association®. At the same time, they are important and valuable for current research trials and cautious initial use in specialized memory clinics.

Blood-based markers show promise for improving, and possibly even redefining, the diagnostic work-up for Alzheimer's. Remarkable progress has been made, but additional data are needed before BBMs can be used as a stand-alone test for diagnosis, and before considering broad use in primary care settings."

Maria C. Carrillo, Ph.D., Alzheimer's Association chief science officer and co-author of the article

"In this article, the expert workgroup clearly defines both short- and long-term research priorities needed to fill significant knowledge gaps that still exist, such as how well these blood-based markers work in diverse communities and in those living with multiple health conditions," Carrillo added. "Also included are consensus appropriate use recommendations for use of BBMs in the clinic and in research trials."

"The Alzheimer's Association Appropriate Use Recommendations for Blood Biomarkers in Alzheimer's Disease," by Oskar Hansson, M.D., Ph.D., et al, is published online today by Alzheimer's & Dementia: The Journal of the Alzheimer's Association. The recommendations will be reported today and tomorrow at the Alzheimer's Association International Conference® (AAIC®) 2022 in San Diego and online.

"Blood-based biomarkers for Alzheimer's are already improving the design of clinical trials, and they are very likely to revolutionize the diagnosis of Alzheimer's in the future," said Oskar Hansson, M.D., Ph.D., director of the Center for Neurodegenerative Diseases at Lund University and Skane University Hospital, Malmo, Sweden, and first author on the newly published article. "That said, the implementation of such markers in trials and practice must be done in a careful and controlled way so as not to accidentally cause more harm than good. Much more research is needed before widespread clinical use of BBMs."

According to the article, BBMs show "great promise" — especially markers for Alzheimer's-related brain changes related to nerve cell damage/death, and tau and beta amyloid accumulation — for "future use in both clinical practice and trials. However, few prospective studies have investigated the implementation of such BBMs in more heterogeneous populations."

Source:
https://www.news-medical.net/news/20220731/Experts-release-appropriate-use-recommendations-for-Alzheimere28099s-disease-blood-biomarkers.aspx


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PCSK9 inhibitors seem to benefit those with high cardiovascular risk

 | Post date: 2022/08/1 | 
PCSK9 inhibitors appear to lower nonfatal myocardial infarction in adults with high or very high cardiovascular risk but not in those with low or moderate risk, according to a new study published in the BMJ.
Results from 14 randomized controlled studies informed this network meta-analysis measuring the effect of ezetimibe and PCSK9 inhibitors on cardiovascular outcomes in 83,660 adult patients regardless of statin use.
The researchers also found that initiating ezetimibe or PCSK9 inhibitors as an add-on in patients receiving maximally tolerated statin therapy or in patients who cannot tolerate statins seems to have no significant effect on cardiovascular mortality nor on death for any other reason.
Prescribing ezetimibe or PCSK9 inhibitors “should be considered among appropriate candidates with very high or high cardiovascular risk patients to achieve desired cardiovascular benefits,” the authors wrote.

https://www.pharmacytoday.org/article/S1042-0991(22)00569-2/fulltext

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Scientists develop an improved pharmaceutical drug for the treatment of atrial fibrillation

 | Post date: 2022/07/25 | 

Scientists from the National University of Singapore (NUS) Department of Pharmacy have developed an improved pharmaceutical drug for the treatment of the most common heart rhythm disturbance – atrial fibrillation (AF). The 8-member research team took 8 years to achieve this technological breakthrough which could benefit millions of AF patients worldwide.

AF is a serious condition that can lead to heart failure, early mortality and stroke. For AF patients, there are currently medications which are used to control AF and maintain normal rhythm. Ironically, these drugs whilst treating AF can promote a different type of heart rhythm disturbance in the lower heart chambers, also known as ventricular arrhythmia, which is potentially more dangerous or even fatal. Some of these existing AF medications are also toxic to other organs such as the liver, lungs and thyroid gland. Hence, there is an unmet need to develop efficacious and safer medications to treat AF.

Patents have been filed for the new drug candidate, termed as poyendarone. The research team has tested poyendarone in laboratory studies and the promising results position the drug to be a gamechanger with greater safety and efficacy for clinical trials. It is noteworthy that there has not been a regulatory approved AF drug since 2009.

The findings were first published in the journal Acta Phamaceutica Sinica B on 16 March 2022.

New effective drug with reduced side effects

The research team led by Professor Eric Chan from the NUS Department of Pharmacy discovered that a current drug for AF, called dronedarone, causes the inactivation of a key heart enzyme. Normally, the enzyme converts an unsaturated fatty acid to metabolites that facilitate heart physiological functions such as normal beating and heart muscle cell well-being. Dronedarone is metabolised by the heart enzyme to form a drug metabolite that can irreversibly bind to the enzyme's active site, hence inactivating it. The inactivation of the enzyme in turn causes ventricular arrhythmia. Patients who experience ventricular arrhythmia due to dronedarone have to stop the medication immediately while other treatment options are considered.

Armed with this knowledge, the NUS team successfully circumvented this potentially lethal side effect by modifying the chemical structure of dronedarone. This was done through the subtle replacement of selected hydrogen atoms present on the drug molecule with deuterium atoms, in a process known as deuteration. Through this change, the reactivity of the metabolite is reduced and it is no longer able to inactivate the key heart enzyme. Through laboratory studies, the team also found that the improved drug retained several favourable drug-related properties such as how it treats AF efficaciously and can be processed by the body efficiently. Like dronedarone, the new drug molecule poyendarone is expected to be administered as tablets.

The development of an improved version of an existing drug that is both efficacious and safer is important to address the unmet medical need in AF therapy. Prof Chan said, "This is the first time deuteration as a drug discovery strategy is applied to optimise the efficacy while mitigating the side effects of a drug molecule. Our research findings demonstrate an innovative discovery platform that can enhance patient care via the development of efficacious and safe pharmaceuticals."

There is a strong need to develop safe, efficacious and accessible anti-arrhythmic treatments to manage the ever-growing number of AF patients around the world, which is currently estimated to be more than 35 million. Poyendarone represents a paradigm shift in enhancing the characteristics of current drugs, selectively eliminating dangerous side effects and organ toxicities whilst maintaining its ability to regulate abnormal heart rhythm."

Dr Pipin Kojodjojo, clinical collaborator, cardiologist from the Asian Heart & Vascular Centre (AHVC) Singapore and Adjunct Associate Professor at the NUS Yong Loo Lin School of Medicine

 
Source:
Journal reference:

Karkhanis, A.V., et al. (2022) Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts. Acta Pharmaceutica Sinica B. doi.org/10.1016/j.apsb.2022.03.008.


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CDC: COVID-19 vaccines recommended for young children

 | Post date: 2022/06/27 | 

Today, CDC Director Rochelle P. Walensky, M.D., M.P.H., endorsed the Advisory Committee on Immunization Practices' (ACIP) recommendation that all children 6 months through 5 years of age should receive a COVID-19 vaccine. This expands eligibility for vaccination to nearly 20 million additional children and means that all Americans ages 6 months and older are now eligible for vaccination.

Parents and caregivers can now get their children 6 months through 5 years of age vaccinated with the Pfizer-BioNTech or Moderna vaccines to better protect them from COVID-19. All children, including children who have already had COVID-19, should get vaccinated.
COVID-19 vaccines have undergone-;and will continue to undergo-;the most intensive safety monitoring in U.S. history. Parents and caregivers can play an active role in monitoring the safety of these vaccines by signing their children up for v-safe – personalized and confidential health check-ins via text messages and web surveys where they can easily share with CDC how a child feels after getting a COVID-19 vaccine.
Distribution of pediatric vaccinations for these younger children has started across the country, and will be available at thousands of pediatric practices, pharmacies, Federally Qualified Health Centers, local health departments, clinics, and other locations this week. Children in this younger age group can be vaccinated with whichever vaccine is available (either Moderna or Pfizer-BioNTech). Parents can reach out to their doctor, nurse, local pharmacy, or health department, or visit vaccines.gov to see where vaccines for children are available.

The following is attributable to CDC Director Dr. Rochelle P. Walensky:    

"Together, with science leading the charge, we have taken another important step forward in our nation's fight against COVID-19. We know millions of parents and caregivers are eager to get their young children vaccinated, and with today's decision, they can. I encourage parents and caregivers with questions to talk to their doctor, nurse, or local pharmacist to learn more about the benefits of vaccinations and the importance of protecting their children by getting them vaccinated."

https://www.news-medical.net/news/20220623/CDC-COVID-19-vaccines-recommended-for-young-children.aspx


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FDA Approves Risankizumab-rzaa for Moderately to Severely Active Crohn Disease

 | Post date: 2022/06/21 | 

The FDA has approved risankizumab-rzaa (Skyrizi) for the treatment of adults with moderately to severely active Crohn disease (CD). The approval makes risankizumab-rzaa the first and only specific interleukin-23 (IL-23) inhibitor for this indication.

"We are proud to offer the first new treatment option in 6 years for moderately to severely active CD, which may provide patients with a meaningful level of endoscopic improvement," said Thomas Hudson, MD, senior vice president, research and development, chief scientific officer, AbbVie. "With more than 30 ongoing or planned trials in inflammatory bowel disease, AbbVie is committed to advancing the standards of care for patients by exploring and investing in research for those living with immune-mediated, gastroenterological conditions."

Risankizumab-rzaa is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of the IL-23 cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.

In a pair of induction trials, ADVANCE and MOTIVATE, and a maintenance trial called FORTIFY, risankizumab-rzaa produced significant improvements in endoscopic response, defined as a reduction of greater than 50% from the baseline Simple Endoscopic Score in CD (SES-CD) or patients with isolated ileal disease and SES-CD of 4, at least a 2-point decrease from baseline and clinical remission, defined as a CD Activity Index (CDAI) of less than 150, compared to placebo.

In the 12-week induction studies, ADVANCE and MOTIVATE, the primary endpoints were endoscopic response and clinical remission, The study showed that a significantly greater proportion of patients administered risankizumab-rzaa experienced an endoscopic response and clinical remission versus placebo. As early as week 4, clinical response and remission were observed in a significantly greater proportion of patients administered risankizumab-rzaa versus placebo.

In the FORTIFY trial, a significantly greater proportion of patients achieved the co-primary endpoints of endoscopic response and clinical remission versus the placebo cohort (risankizumab induction responders) after 1 year.

Dosing for risankizumab-rzaa is 600 mg administered by intravenous infusion over at least one hour at week 0, week 4, and week 8. This is followed by 360 mg self-administered by subcutaneous injection with an on-body injector at week 12, and every 8 weeks thereafter. The FDA is currently reviewing the 180 mg self-administered subcutaneous maintenance dose option.

"In both the induction and maintenance clinical trials, a significantly greater number of adult patients saw few or no symptoms and a meaningful reduction of visible signs of intestinal inflammation, compared to placebo," said Marla Dubinsky, MD, chief, division of pediatric gastroenterology for the Mount Sinai Health System, co-director of the Susan and Leonard Feinstein IBD Center at Mount Sinai, in a press release. "This approval provides healthcare professionals with a greatly needed additional option for treating the disruptive symptoms of Crohn's disease."
 

Reference

SKYRIZI® (risankizumab-rzaa) Receives FDA Approval as the First and Only Specific Interleukin-23 (IL-23) to Treat Moderately to Severely Active Crohn's Disease in Adults. AbbVie. News release. June 17, 2022. https://news.abbvie.com/news/press-releases/skyrizi-risankizumab-rzaa-receives-fda-approval-as-first-and-only-specific-interleukin-23-il-23-to-treat-moderately-to-severely-active-crohns-disease-in-adults.htm


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FDA Withdraws Umbralisib Due to Elevated Mortality Risk

 | Post date: 2022/06/6 | 

The FDA announced that it has withdrawn approval for umbralisib (Ukoniq, TG Therapeutics), based on an updated analysis of the phase 3 UNITY-CLL clinical trial, which continues to show “a possible increased risk of death” in patients receiving the medication, the agency noted.

Umbralisib, a dual inhibitor of PI3 kinase-delta and CK1-epsilon, was approved in February 2021 to treat marginal zone lymphoma (MZL) and follicular lymphoma (FL). 

Although UNITY-CLL did not include patients with MZL and FL—it was part of a supplemental application seeking approval to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)—“we believe [the elevated mortality risk in the trial has] implications for its approved uses,” the FDA stated. “In  addition, clinical trials of other medicines in the same PI3 kinase inhibitor class as Ukoniq have shown similar safety concerns.”

The FDA announcement is not the first to cite safety concerns related to umbralisib. On April 15, 2022, TG Therapeutics issued a statement noting that it was withdrawing its application for the CLL and SLL indications, based on updated data on overall survival (OS) from the UNITY-CLL trial. Those data “showed an increasing [survival] imbalance in favor of the control arm, differing from the improved results provided to the FDA” in an earlier data submission, the company noted. 

The April announcement from TG Therapeutics followed a February statement from the FDA which noted that the agency was investigating the elevated mortality risk in the UNITY trial.
 

The FDA has instructed healthcare professionals to stop prescribing umbralisib and to switch patients to alternative treatments. Additionally, patients who are currently taking the medication should be “informed of the increased risk of death seen in the clinical trial” and advised to stop taking the medicine.

“In limited circumstances in which a patient may be receiving benefit from Ukoniq, TG Therapeutics plans to make it available under expanded access,” the agency added.

The FDA also urged healthcare professionals and patients to report side effects of umbralisib to the FDA MedWatch program.

Approval Data

For practitioners considering continuing patients on umbralisib under expanded access, the drug’s initial safety and efficacy data, detailed when it was approved for MZL and FL in February 2021, may be instructive. 

The drug was approved for adults with relapsed or refractory MZL who have received at least one prior anti–CD20-based regimen and adults with relapsed or refractory FL who have received at least three prior lines of systemic therapy.

Approval was based on the multicenter, multicohort, open-label, phase 2 UNITY-NHL trial (ClinicalTrials.gov Identifier: NCT02793583), which included 69 patients with MZL who received at least one prior therapy, including an anti–CD20-containing regimen, and 117 patients with FL after at least two prior systemic therapies. Patients received 800 mg of umbralisib orally once daily until disease progression or unacceptable toxicity. Efficacy was analyzed by overall response rate (ORR) and duration of response (DOR) using modified 2007 International Working Group criteria assessed by an independent review committee.

For patients with MZL, the ORR was 49% (95% CI, 37.0%-61.6%), with 16% achieving a complete response (CR) and 33% achieving a partial response (PR). Median DOR was not reached (95% CI, 9.3 months-NE) in these patients. For patients with FL, the ORR was 43% (95% CI, 33.6%-52.2%), with 3% achieving a CR and 39% achieving a PR. Median DOR was 11.1 months (95% CI, 8.3-16.4 months).

The safety of umbralisib was assessed in a pooled population from the 221 adults with MZL and FL in three single-arm, open-label trials and one open-label extension trial. The most common (≥15% of patients) adverse events (AEs) were increased creatinine, diarrhea/colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite and rash. Serious AEs, most often diarrhea/colitis and infection, occurred in 18% of patients.

The prescribing information provides warnings and precautions for AEs, including infections, neutropenia, diarrhea and noninfectious colitis, hepatotoxicity, and severe cutaneous reactions.

For more information, read the full prescribing information for umbralisib.


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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.

https://www.pharmacytoday.org/article/S1042-0991(22)00369-3/fulltext#relatedArticles

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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.


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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.

The drugs discussed included idelalisib (Zydelig), indicated for use in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and follicular lymphoma (FL); copanlisib (Aliqopa), indicated for FL; and duvelisib (Copiktra), indicated for CLL, SLL, and FL.

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.


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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

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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


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Compatibility of Commonly Used IV Drugs

 | Post date: 2022/02/20 | 

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.

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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.

https://www.pharmacypracticenews.com/Review-Articles/Article/12-21/Compatibility-of-Commonly-Used-IV-Drugs/65818

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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.

https://www.pharmacypracticenews.com/Covid-19/Article/02-22/FDA-Delays-Advisory-Meeting-for-COVID-19-Vaccine-for-Very-Young-Kids/66148


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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 (Cell 2022 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.”

https://www.pharmacypracticenews.com/Covid-19/Article/02-22/Omicron-s-Differences-Sense-of-Smell-Effects-on-the-Brain-and-Other-News/66059


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