To prevent Alzheimer's, edit key gene in human nerve cells?

 A team of researchers at Laval University has found evidence that it might be possible to the chances of developing Alzheimer's disease by editing a key gene in nerve cells. In their paper uploaded to the bioRxiv preprint server, the group describes experiments they conducted that involved editing genes and what they learned from them.

Prior research has shown that one of the factors involved in the development of Alzheimer's disease is a buildup of beta-amyloid—a type of protein—on brain cells. Prior research has also shown that some people have a gene variant called A673T—those who express it are four times less likely than the general populace to develop Alzheimer's disease. In this new effort, the researchers looked into the possibility of editing human brain cells to give people the gene variant A673T and thereby reduce their chances of developing Alzheimer's disease.

The team noted that the A673T mutation differs from its cognate in those who do not express it by a single DNA letter, suggesting it might be relatively easy to add the mutation. They next tried editing brain cells using a CRISPR technique. And while that attempt proved relatively successful, other aspects of the technique drove the researchers to try another—prime editing. This relatively new technique allows for directly converting one base letter to another. Using this technique, the researchers found that they were able to edit approximately 40% of the brain cells in vitro. They note that such an amount is likely not high enough to prevent buildup of beta-amyloid, and thus not enough to slow the onset of Alzheimer's disease. But more research might lead to better results.

The researchers also note that such editing of brain cells in humans would require early diagnosis because by the time symptoms present, it might be too late to conduct gene editing to prevent the buildup of beta-amyloid. They note that future efforts might instead involve editing the DNA of only those who are deemed at risk of developing the disease while they are still young.

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Uncovering potential pathway to slowing Alzheimer's

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More information: Antoine Guyon et al. Base editing strategy allows insertion of the A673T mutation in APP gene to prevent the development of Alzheimer's disease, bioRxiv (2020). DOI: 10.1101/2020.10.27.357830

https://medicalxpress.com/news/2020-11-alzheimer-disease-key-gene-human.html

Docs Can Prescribe Opioids Via Telemedicine, for Now

 In the COVID-19 era, under relaxed federal emergency orders, licensed clinicians have been able to prescribe opioid analgesics for their patients even if they've only ever seen the patient via telehealth, rather than in person.

For providers like Stephen Bekanich, MD, a palliative care physician for Ascension Texas in Austin, this provision allows him to help seriously ill patients without requiring in-person visits that may be difficult for them or could expose them or their caregivers to the virus.

Still, he worries, given ongoing national concerns about prescription drug overdoses, that this privilege might be on shaky ground, although he is not aware of opioid prescribers being targeted by regulators during the current crisis.

But what happens when the current COVID emergency order issued by the Department of Health and Human Services (HHS) expires? Palliative care doctors who have learned how to manage patients remotely via telemedicine may have to return to old ways -- including a requirement that they see a patient in person before prescribing opioids.

The Prescribing Situation

The Ryan Haight Online Pharmacy Consumer Protection Act, passed in 2008, included a prohibition on writing prescriptions for controlled substances such as opioids by means of the internet unless the clinician first conducted an in-person exam. It came with a number of exceptions and carve-outs, one of which is for public health emergencies such as the one declared by HHS Secretary Alex Azar, MD, on Jan. 31. It effectively put the Ryan Haight Act provision on hold for the duration of the emergency.

The Drug Enforcement Agency issued an exception allowing prescribing of controlled substances via telemedicine without a prior in-person visit during the pandemic, though it specifies that telephone-only communications are not part of that exception.

CMS has indicated that it will revisit guidelines around telehealth services generally at the time when the emergency order is phased out, Bekanich noted. "But will it address the prescribing situation?"

This question plays out in the context of the other, ongoing national epidemic of prescription opioid overdoses, with federal agencies trying to curb excessive opioid prescribing, said attorney Sarah Churchill Llamas, chair of the healthcare industry group at the law firm Winstead PC in Austin.

"Doctors in general are concerned about prescribing opioids," she said. The Texas Medical Board has rules for how to establish the patient-doctor relationship, and it should still meet the same standard of care whether virtually or in person. For some regulators, it's an ongoing question whether it's even possible to establish a professional relationship with a patient via telemedicine.

Because every state is different, both for opioids and telehealth, Llamas encourages providers to take a close look at existing state law. Patients receiving hospice or palliative care and those with cancer may be treated differently in the regulations, but that is no guarantee the prescribing physician won't draw regulatory scrutiny, she added. For those who want to practice across state lines, it's even more complex.

"At the end of the day, even if doctors do everything they're supposed to, they could still get reviewed by their state medical board. Now that you're overlaying telemedicine on top of opioid prescribing, I could see where a physician might say: 'I just don't feel comfortable going out on a limb with this,'" she said. "My advice, do what's best for your patients' care, but plan for the future. You have to know that the relaxation of regulations due to the emergency orders is going to end, and that may be tough for your patients."

Not a Viable Future Strategy

Llamas recently consulted with Iris Plans, a telehealth-based advance care planning firm, regarding the future of opioid tele-prescribing.

"At Iris, we are doing (virtual) advance care planning for many patients, but some of them could also benefit from medical management," explained Bekanich, who is a cofounder of Iris Plans. "We wondered if there is a way we could start to do that via telehealth, in multiple states. But we wouldn't want to start a tele-palliative practice if we couldn't prescribe opioids remotely for seriously ill patients. After obtaining legal advice from Sarah (Llamas) we decided it won't be a viable business model."

Bekanich said his advocacy for tele-prescribing goes only as far as the population he normally sees, patients with a firmly established diagnosis of serious illness. Research suggests they are unlikely to become addicted to opioids in the absence of a prior history of opioid use disorder.

He is also familiar with the mitigation strategies of the addiction management field, such as urine drug screening and patient contracts aimed at minimizing the potential for abuse while still allowing for pain management -- which can be incorporated into virtual practice.

"For those facing serious illness who could benefit from opioids, I generally do not start with a urine drug screen. For me it's more about establishing trust and rapport, getting to a place of comfort with my patients where they'll talk honestly with me. I want that to be an open conversation, not punitive," he said, although in a small handful of cases something more prescriptive may be needed.

"The exception for telehealth should be made permanent, for the sake of the patients, not just the convenience of the prescriber," he added. "Telemedicine is an important capability to have for patients you haven't seen face-to-face, even though it's not for everyone. I worry about what happens after COVID. That creates a lot of uncertainty -- which is bad for our work."

https://www.medpagetoday.com/practicemanagement/telehealth/89881

Colchicine Approval Took a Huge Toll on CMS

 Colchicine, the old gout drug often cited as a cheap anti-inflammatory, hasn't been such a good deal since FDA approval, a study showed.

The inflation- and rebate-adjusted Medicaid price per pill jumped from $0.24 in 2008 to $4.20 after the FDA officially approved a branded form, Colcrys, through the agency's Unapproved Drug Initiative pathway in 2009.

As subsequent authorized generics emerged with only "marginally lower" prices, the price per pill actually rose further to $4.66 in 2015, reported Natalie McCormick, PhD, of Massachusetts General Hospital in Boston, and colleagues in JAMA Internal Medicine.

"Accordingly, Medicaid spending on single-ingredient colchicine rose 2833%," they wrote, and "58% of this increase was attributable to price increases alone."

Their study used Medicaid and Medicare data files through 2017, when combined Medicaid and Medicare claims exceeded $340 million for colchicine.

"Colcrys's manufacturer, which conducted a 1-week trial (n=185), received 3 years' market exclusivity for treatment of acute gout, and the unapproved formulations were soon ordered off the market, resulting in a virtual monopoly," McCormick's group noted.

"Furthermore, Colcrys was granted patents for this centuries-old drug until 2029. Thus, although more than six independent generics have FDA approval to date, only authorized generics with price points set by brand-name companies are currently available to treat acute gout, pericarditis, and now potentially millions with myocardial infarction" following the COLCOT trial.

The issue could gain even more relevance as colchicine looks promising for severe COVID-19. The drug has been added as a potential therapy for COVID-19 in the pragmatic RECOVERY trial that uncovered the survival benefit of dexamethasone.

"Only a fraction of an investment was required for Colcrys, a product that has provided no increased value and an unnecessary, long-term cost burden to the health care system," argued B. Joseph Guglielmo, PharmD, of the University of California San Francisco, in an accompanying editorial. "The current study findings illustrate that we can never allow such an egregious case to take place again."

Disclosures

McCormick reported grants from Canadian Institutes of Health Research.

Guglielmo disclosed no relevant relationships with industry.

Primary Source

JAMA Internal Medicine

Source Reference: McCormick N, et al "Prolonged increases in public-payer spending and prices after unapproved drug initiative approval of colchicine" JAMA Intern Med 2020; DOI: 10.1001/jamainternmed.2020.5017.

Secondary Source

JAMA Internal Medicine

Source Reference: Guglielmo BJ "The colchicine debacle revisited" JAMA Intern Med 2020; DOI: 10.1001/jamainternmed.2020.5044.

https://www.medpagetoday.com/rheumatology/generalrheumatology/89927

Possible benefit of regular use of potent mouthwashes in treatment of COVID-19

  

View ORCID ProfileKhalid Mukhtar, Suelen Qassim, Ibn-Masud Danjuma, Mohamed Elhassan Babiker, Mohamed Mohamedali, Housamaddeen Alfarhan, Abdel Rehim El-Tayeh, Mohammed Fakhri Khudhair, Muna Al.Maslamani, Mohammed Al-Dosari, Rumaisa Mohamed Elmustafa, Ahmed Hassib, Wesal Elhadary, Morwan Abdulkarim, Rajvir Singh

doi: https://doi.org/10.1101/2020.11.27.20234997

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2020.11.27.20234997v1.full.pdf

Abstract

As recently more in vitro studies demonstrated bactericidal and virucidal role for some of the over-the-counter mouthwash solutions. Meanwhile, Game theory and Evolutionary Biology suggests that inhibiting cooperation -reciprocal altruism- between two organisms can negatively affect their survival. Based on a set of relevant publications, it is proposed here that 2019-nCoV may be relying on a complicit; be it a certain organism (e.g. bacterial species), or a state of dysbiosis in general. On this premise, the regular use of potent disinfectant, (Hydrogen peroxide 2% and chlorhexidine gluconate mixed solution) for oral rinsing and gargling three times daily, through the repeated reduction in microbial load, was tested to determine whether it is able to induce a strain sufficient to inhibit reciprocal altruism, and hence halt the progression of the disease. through an RCT, (n = 93, intervention group: 47, control group: 46) the outcome tested in terms of in relation to the PCR/CT test of nasopharyngeal-oropharyngeal swabs from the baseline (at diagnosis), changes in the clinical category (improvement Vs. deterioration), and the final disposition (discharge Vs. Death) in different disease categories. Our findings showed, upon the regular use of mouthwash, more symptoms improvement after 2 days of treatment, higher rate of conversion to COVID19-negative PCR by 5 days of treatment, and less intubation and mortality, with all P-value < 0.05. There was also a trend of improvement in other outcome variables, though with no significant statistical difference; namely shorter hospital stay, less progression in Oxygen requirements, less rate of plasma transfusion, and extent of improvement in terms of disposition in relation to the clinical category on admission. were that can be justified by the complicit hypothesis, predict a rather preventive than therapeutic advantage, suggestive for a possible role for the regular use of potent mouthwash as an additional control measure in the community level.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

ISRCTN10197987 https://doi.org/10.1186/ISRCTN10197987

Funding Statement

The study is funded by Hamad Medical Corporation's Medical Research Center

https://www.medrxiv.org/content/10.1101/2020.11.27.20234997v1

BioNTech slips post-market following BofA downgrade

 

• BioNTech (NASDAQ:BNTX) falls as much as 4.4% after-hours as Bank of America advises investors to cash in profits from the stock's run higher, saying the company now faces heightened competition from peers that also are developing coronavirus vaccines.
• There's limited room for additional gains with the inevitable approval for the COVID-19 vaccine developed with partner Pfizer, which are now reflected in BNTX's 268% YTD rally, BofA analyst Tazeen Ahmad says in downgrading shares to Neutral from Buy with a $126 price target.
• https://seekingalpha.com/news/3640169-biontechminus-2-post-market-following-bofa-downgrade

Powell: 'Challenging' months until vaccine clears production, distribution hurdles

 A slowing recovery and a surging pandemic mean the United States is entering a “challenging” few months, with the potential deployment of a vaccine still facing the hurdles of production and mass distribution before its impact on the economy becomes clear, Fed chair Jerome Powell said on Monday.

“The rise in new COVID-19 cases, both here and abroad, is concerning and could prove challenging for the next few months,” Powell said in remarks prepared for delivery to a congressional hearing on Tuesday morning.

“Recent news on the vaccine front is very positive for the medium term. For now, significant challenges and uncertainties remain, including timing, production and distribution, and efficacy across different groups. It remains difficult to assess the timing and scope of the economic implications of these developments with any degree of confidence.”

Powell’s remarks are his most detailed yet on how the potential arrival of a vaccine may influence the Fed’s outlook, and the evolution of a recovery that the Fed chair acknowledged is slowing.

That, in turn, could shape opinions about how much more government support may be needed to help families and businesses bridge the gap between the current recession and the post-pandemic economy.

Vaccinations could begin before Christmas, U.S. Health Secretary Alex Azar said on Monday. [L1N2IG1LN]

In separate testimony to be delivered at the same hearing, Treasury Secretary Steven Mnuchin said the economy had made “remarkable progress” recovering ground lost due to the pandemic, and that any further government help should be targeted to “workers and small businesses that continue to struggle,” as opposed to spread broadly in the economy.

Mnuchin recently told the Fed to shut down several emergency lending programs, and suggested that $455 billion remaining for those facilities be reallocated for such a program.

With the vaccine on the horizon, some analysts say they expect a strong bounce in the economy in coming months as Americans are inoculated and broad immunity to the coronavirus is achieved.

However, Powell said the fate of the economy will remain hinged to the success of that process, and until then the impact of the pandemic will remain - and fall particularly hard on women, minority groups and those in the service sector.

“A full economic recovery is unlikely until people are confident that it is safe to re-engage in a broad range of activities,” Powell said.

https://www.reuters.com/article/us-usa-fed-powell/powell-challenging-months-until-vaccine-clears-production-distribution-hurdles-idUSKBN28A2ZS

COVID R&D Alliance launches trial of Amgen, UCB, Takeda drugs

 Amgen Inc, UCB SA and Takeda Pharmaceuticals Inc on Monday launched a global trial to identify whether any of three different drugs can reduce the severity of COVID-19 in hospitalized patients by moderating the immune system's response to the disease.

The drugmakers are part of the COVID Research & Development Alliance, a group of more than 20 pharmaceutical and biotechnology companies cooperating to speed development of therapies for the disease that has killed more than 1.4 million people worldwide.

The study initially will test whether Amgen’s psoriasis drug Otezla, Takeda’s experimental anti-inflammatory lanadelumab, and UCB's experimental immune system-inhibitor zilucoplan can prevent the body's own defenses from overreacting to the coronavirus, which can lead to serious, sometimes fatal, tissue and organ damage.

The three compounds "have a plausible biologic rationale in terms of effect on immune response or the hyper-immune response that some people develop," said Amgen research chief David Reese.

"We hope to find options that could potentially save lives ... before widespread availability of a vaccine,” he said.

Health experts do not expect vaccines to be available to most people until well into 2021. Meanwhile, COVID-19 hospitalizations are at record levels in the United States, threatening to overwhelm health systems.

The multiple candidates will be tested against a placebo with all trial patients also receiving standard care. Other drugs that work in a variety of ways, including antivirals, medicines that also modulate immune response and vascular agents may enter the study in coming months.

So far, only a generic class of steroids used since the 1960s to reduce inflammation in diseases such as arthritis has been shown in a controlled study to improve survival for severely ill hospitalized COVID-19 patients. Steroids are not recommended for patients with less severe illness.

The COVID R&D trial will enroll both hospitalized intensive care unit and non-ICU patients.

In anticipation of a rise and fall of COVID-19 cases in various geographic regions, the trial will include sites in the United States, Brazil, Mexico, Russia, South Africa and other countries.

“COVID is not confined to one country ... We have included a broad range of different countries," said Dhavalkumar Patel, UCB's chief scientific officer. 

https://www.marketscreener.com/quote/stock/AMGEN-INC-4847/news/COVID-R-D-Alliance-launches-trial-of-Amgen-UCB-Takeda-drugs-31903555/