rewrite this title Thanksgiving Small Bits & Pieces

I’m going to kick off this Doc Gumshoe missive with a bit of definitely good news, albeit news that is not likely to affect many citizens of Gumshoe Nation. In a nutshell, it is this: on September 26th, the FDA approved the first new drug to treat schizophrenia in more than 30 years. The drug is Cobenfy (xanomeline/trospium chloride, a fixed-dose combination medication. It was initially developed by Lilly (LLY), which sold the license to Karuna Therapeutics. Karuna has since been acquired by Bristol Myers Squibb (BMY).

Dr Tiffany Farchione, director of the FDA’s Division of Psychiatry, said “This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed. Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life.”

For many decades, treatment of schizophrenia relied on blocking dopamine receptors. Common dopamine receptor blockers include Thorazine (chlorpromazine), Prolixin (fluphenazine), and Haldol (haloperidol). These have been around a long time. For example, Thorazine got its FDA approval in 1954.

Blocking dopamine receptors has benefits as well as drawbacks. It reduces symptoms like hallucinations and paranoia to a level that patients find livable. But dopamine receptor blockers frequently result in significant weight gain, such that patients taking these drugs tend to have higher rates of cardiac diseases, resulting in reduced life expectancy. And many patients have discontinued taking these simply because those drugs made them feel sluggish and unmotivated.

Cobenfy has an effect on dopamine levels, but its principal target is another neurotransmitter, acetylcholine.

About 25 years ago, the muscarinic acetylcholine receptor agonist xanomeline (which is one of the two compounds in Cobenfy) was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer’s disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia.

The origins of the word “schizophrenia” suggest that the essential disorder is a brain whose different functions are essentially disjointed – essentially a “split mind.”

According to the National Institute of Mental Health, schizophrenia is a mental disorder characterized by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions. Although the course of schizophrenia varies among individuals, schizophrenia is typically persistent and can be both severe and disabling.

Schizophrenia is relatively uncommon. In the US, it affects between 0.25 and 0.75% of the population. However, it is a disproportionately expensive condition. The financial burden of schizophrenia includes the direct cost of healthcare, which often involves life-long institutionalization, but also costs such as lost productivity, involvement with the criminal justice system, and social services.

Symptoms of schizophrenia include psychotic symptoms such as hallucinations, delusions, and thought disorder (unusual ways of thinking), as well as reduced expression of emotions, reduced motivation to accomplish goals, difficulty in social relationships, motor impairment, and cognitive impairment.

The evidence supporting Cobenfy as a treatment for schizophrenia is, so far, rather sparse. There have been only three controlled trials of the drug, and each trial lasted only five weeks. In these trials, Cobenfy reduced the symptoms of schizophrenia to a manageable level, without producing the side effects linked with dopamine receptor blockers such as cardiac disease or weight gain. BMY released results of long-term observational studies of Cobenfy, in which patients did not experience metabolic changes or movement disorders such as affected patients taking other drugs to control schizophrenia.

Pharmaceutical companies are enthusiastic about the Cobenfy results, and are working on similar medications which could be effective in treating such conditions as bipolar disorder, autism, and Alzheimer’s disease.

BMY has set the wholesale price of Cobenfy at about $22,500 per year. It is expected to generate revenues between $3 billion and $5 billion per year.

Eisai and Eli Lilly conceal cases of brain injuries linked to their Alzheimer’s drugs

Obviously, those are genuinely dreadful news items. The drugs in question are Eisai’s Leqembi (lecanemab) and Eli Lilly’s Kisunia (donanemab). The NY Times recently devoted more than a full page to this situation, describing several cases in which patients taking these drugs experienced brain injuries, which could have been anticipated based on their genetic profiles.

In 2021, Eisai put out a call for volunteers to participate in a clinical trial of their experimental drug lecanemab (then called BAN2401) for the treatment of Alzheimer’s disease. Nearly 2,000 persons answered the call. Eisai sought specifically to include individuals whose genetic profiles made them especially susceptible to develop Alzheimer’s. But these same individuals were more susceptible to brain bleeding or swelling if they received the drug.

Eisai made a public statement that all volunteers would be given a genetic test to identify the specific individuals who were at particular risk for brain injuries. However, Eisai did not inform these trial volunteers that they were at especially high risk of experiencing these brain injuries. It has been revealed that a total of 274 volunteers joined the trial unaware that they were at elevated risk. Two of these volunteers died of their brain injuries, and more than 100 others experienced brain bleeding or swelling.

On July 6, 2023, the FDA granted accelerated approval to Leqembi/lecanemab for the treatment of Alzheimer’s, noting that its modest benefit outweighed its risks. The benefits of Leqembi/lecanemab for the treatment of Alzheimer’s are indeed modest. Treatment with the drug slows cognitive decline for a few months only.

A similar situation has emerged with regard to Eli Lilly’s anti-Alzheimer’s drug Kisunia (donanemab). Lilly chose not to inform 289 volunteers in a clinical trial of donanemab that their genetic profiles made them especially vulnerable to brain injuries. About a quarter of volunteers in the Kisunia trials experienced brain swelling or bleeding.

The FDA granted approval to Kisunia almost exactly a year after Leqembi’s FDA blessing – July 2, 2024.

In both the Leqembi and Kisunia trials, volunteers first had to sign consent forms that said that people with certain genetic characteristics faced higher risks of brain injuries from receiving the drugs, and that participants in the trial would be given genetic tests for these characteristics. But they were told that they would not be informed as to the results.

Essentially, the volunteers in these trials were expected to go ahead and participate in the trials without knowing whether they were at increased risk for brain damage. The people conducting the trial would know, but the trial subjects would not know.

Both Leqembi/lecanemab and Kisunia/donanemab are BACE inhibitors (beta-site amyloid precursor protein cleaving enzyme inhibitors), meaning that they target amyloid beta, a form of plaque that clogs brain connections. The unfortunate Aduhelm/aducanumab (from Biogen), which was taken off the market due to its poor performance as well as the tendency to result in brain bleeds, is also a BACE inhibitor.

Brain bleeding and brain swelling is especially prevalent in persons with the APOE4 gene. About 40% of individuals with two copies of the gene experienced brain bleeding, and about 35% experienced brain swelling. This gene is highly correlated with Alzheimer’s disease. People with one copy of APOE4 have double or triple the risk of developing Alzheimer’s disease, while people with two copies have an eight- to twelvefold increase in risk.

It should be pointed out that the benefit these BACE inhibitors deliver is minimal. It slows the onset of dementia in certain Alzheimer’s patients for less than a year before the disease resumes its destructive course.

The annual cost of Leqembi/lecanemab is $26,500. For Kisunia/donanemab it is $32,000. Evidently, neither Eisai nor Lilly want to permit unfortunate details, such as the frequency of brain bleeds, to interfere with their sales prospects.

A drug-free nasal spray may shield against respiratory infections

The nasal spray we’re discussing is a gel-like spray formulated without active pharmaceutical ingredients. It has yet to be tested in humans, but the researchers say it created a protective coating that lasted for up to eight hours in the nasal cavities of mice. If the spray’s safety and efficacy are confirmed in humans, the research team said the approach could play an important role in reducing respiratory diseases and safeguarding public health against new threats.

The nose is a common passage into the body for many viruses and bacteria. Most respiratory infections, such as flu and COVID, are transmitted when a person inhales tiny droplets of fluid that carry the pathogen. Once they get inside the nose, the viral or bacterial particles inside the droplets infect the cells that line the nasal cavity. These pathogens replicate and travel further down the respiratory tract of the infected individual, sometimes reaching the lungs, where they can cause bronchitis and pneumonia. Pathogens can also be released back into the air when an infected person sneezes, coughs, laughs, sings, talks, or even just breathes in and out.

Current nasal sprays offer limited protection against respiratory pathogens because they have a single mechanism of protection. They either neutralize pathogens or block their entry into the cells lining the nose, and they perform both tasks with limited efficacy.

The projected new drug-free nasal spray was developed to block germs in three ways — the spray forms a gel-like matrix that enhances the capture of respiratory droplets, immobilizes the germs, blocking their transport into the nasal lining, and effectively neutralizes the germs, preventing infection. The nasal spray, called Pathogen Capture and Neutralizing Spray (PCANS), was developed with nonpharmaceutical ingredients already used in approved nasal sprays or listed in the FDA’s Generally Recognized as Safe (GRAS) list.

The researchers designed the formulation and studied its ability to capture respiratory droplets in a 3D-printed replica of the human nasal passages. The experiments showed that when administered into the nasal cavity model, the spray captured twice as many droplets as naturally occurring mucus produced as part of the body’s innate defense system.

The researchers tested the spray’s protective effects against a strain of influenza in mice. The spray was rapidly activated following administration into the nose and lasted up to eight hours. A single dose could effectively block infection from an influenza virus at 25 times the lethal dose of the virus. This means that the spray was capable of warding off infection even when animals were exposed to a heavy load of the virus. According to the investigators, virus levels in the lungs of pretreated animals were reduced by nearly 100% percent, compared with virus levels in the lungs of nontreated animals.

The nasal spray was developed by Harvard Medical School researchers working with Brigham and Women’s Hospital. The information above came from a Harvard Medical School release.

It would be expected that the developers of the nasal spray would be highly enthusiastic about its benefits. Doc Gumshoe’s skeptical turn of mind poses a question: even if this amazing drug-free nasal spray accomplished in human subjects results comparable to those in mice, would ordinary humans be likely to routinely spray a gel coating into their nasal passages to protect themselves against pathogens? Individuals who had frequently experienced upper respiratory diseases, or who had been warned that they were at elevated risk for upper respiratory diseases might use this device. Such persons might take up the habit of a daily dose of this nose spray, more or less as a routine practice, like brushing their teeth. I emphasize the word “might” in that sentence. It would depend, to a considerable degree, on what the nose spray felt like when you press the button or squeeze the tube. More significantly, it would depend on whether these individuals perceived actual improvement: did spraying gel in their noses actually result in fewer cases of colds or the flu?

At this moment, the protective nasal spray is a long way from the clinical trials that would be necessary to satisfy the FDA and get the nasal spray approved as a medical device. Designing clinical trials themselves would be a challenge. The trial would need to enlist voluntary subjects, some of whom would be spraying a placebo in their noses. Then, in order to verify the efficacy of the nasal spray in preventing infection, the subjects – including those in the placebo arm – would have to be exposed to pathogens, in order to verify that the nasal spray reduced infection. Therefore, some trial subjects would definitely experience actual infections. Based on the experimental evidence that the gel captured twice as many respiratory droplets as naturally occurring mucus, those who got the real nasal spray would presumably experience infections at half the rate, but they would be exposed to infectious viruses and bacteria, and if the infection rate matched that in the mice, perhaps half of the subjects would actually get sick. And the infection rate in the placebo group would be twice as high.

There may be ways around this, but it strikes this observer as a long, long shot.

Trying to make sense of long COVID

Yes, COVID 19 is still with us, although much less of a threat. The most recent figures for deaths, hospitalizations, emergency department visits, and positive tests are way, way down. There were 444 deaths in the US due to COVID during the week ending November 3. This was about 1.0% of all the deaths in the US at that point. And only 0.5% of the emergency department visits were due to COVID. Here are some mortality figures going back to the start of the epidemic to provide some perspective about the current state.

Week ending 09/14/2024 – 563 deaths due to COVIDWeek ending 08/31/2024 – 663 deaths due to COVIDWeek ending 05/18/2024 – 336 deaths due to COVIDWeek ending 01/27/2024 – 2,131 deaths due to COVIDWeek ending 01/17/2023 – 3,870 deaths due to COVIDWeek ending 01/15/2022 – 19,078 deaths due to COVIDWeek ending 01/19/2021 – 25,974 deaths due to COVID

The parade of variants continues. Currently, the dominant variant nationwide is KP.3.1.1, which accounts for 52% of cases, followed by XEC, with 28% of cases, and MC.1, with 6% of cases. The original Omicron variant has been replaced by subvariants, including LB.1, KP.2, and KP.3. As I have tediously noted, as the virus mutates, the most “successful” variants – successful in terms of their own survival as a viral species – are the variants that permit the human disease victim to survive and pass the virus on to other. A virus that kills its victims quickly is doomed to extinction.

All in all, COVID as an acute infection is receding. But what continues to affect lots of people, and cause a great deal of concern to the healthcare community, is long COVID, which continues to be a puzzle. Long COVID symptoms are similar to the symptoms of an acute COVID infection. Commonly reported long COVID symptoms included fatigue, brain fog, muscle pain, joint pain, back pain, headache, sleep disturbance, loss of smell or taste, and gastrointestinal symptoms.

The CDC’s criterion for long COVID is that the virus that causes COVID-19 is “present for at least three months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.”

According to the CDC, estimates of the prevalence of long COVID vary due to different study criteria, symptoms investigated, patient populations, and timing of when symptoms are assessed. In 2022, 6.9% of adults and 1.3% of children (roughly 17 million and 1 million, respectively) in the United States reported ever experiencing long COVID. The most recent figures I could find, dated February 15th of this year, ranged from 1.9% in the US Virgin Islands to 10.6% in West Virginia. Those are clearly outliers; overall, the prevalence remained at the same level as it had been in 2022.

I should add here that an AI-enabled approach, developed by Mass General Brigham, suggests that long COVID prevalence is much higher – about 22%. The algorithm used was developed by drawing anonymous patient data from the clinical records of nearly 300,000 patients across 14 hospitals and 20 community health centers in the Mass General Brigham system. That algorithm could identify more people who should be receiving care for this debilitating condition.

While long COVID can occur in anyone who gets the coronavirus infection, some people or groups of people are at higher risk of developing long COVID. These include women, people with underlying conditions, people who experienced more severe outcomes of COVID-19, and people of Hispanic ethnicity.  Approximately 1 in 4 adults with long COVID reported experiencing significant limitations in their daily activity.

A study conducted by a team of researchers at Brigham and Women’s Hospital focused specifically on long COVID. Researchers found people with wide-ranging long COVID symptoms were twice as likely to have SARS-CoV-2 proteins in their blood, compared to those without long COVID symptoms.

The team found that 43% of those with long COVID symptoms affecting three major systems in the body – the cardiovascular, digestive, and respiratory systems – tested positive for COVID viral proteins within 1 to 14 months of their initial positive COVID test. But only 21% of those who didn’t report any long COVID symptoms tested positive for the COVID virus in this same period.The hope expressed by the researchers is that by identifying a subset of people who have a reservoir of the coronavirus in their bodies, it may be possible to treat these persons with effective antivirals to alleviate their symptoms.

The study analyzed 1,569 blood samples collected from 706 individuals, including 392 participants from the National Institutes of Health-supported Researching COVID to Enhance Recovery (RECOVER) Initiative, who had previously tested positive for a COVID infection. Using SIMOA, an ultrasensitive test for detecting single molecules, researchers looked for whole and partial proteins from the SARS-CoV-2 virus. They also analyzed data from the participants’ long COVID symptoms, using electronic medical chart information or surveys that were gathered at the same time as the blood samples were taken.

Researchers pointed out that it is possible that a persistent infection explains some but not all of the long COVID symptoms. If this is the case, testing and treatment could aid in identifying patients who may benefit from alternative treatments.

One of the questions raised by the study is why more than half of patients with wide-ranging long COVID symptoms tested negative for persistent viral proteins.

Dr David Walt, principal investigator on the study observed that the finding noted above suggests there is likely more than one cause of long COVID. For example, another possible cause of long COVID symptoms could be that the virus harms the immune system, such that immune dysfunction continues after the virus is cleared.

Dr Walt and his team are currently conducting follow-up studies to better understand whether an ongoing infection is behind some people’s long COVID symptoms. They are analyzing blood samples and symptom data in larger groups of patients, including people of wide age ranges and those with compromised immune symptoms. It would be important to identify individuals who are more likely to have persistent virus in their bodies, leading to long COVID.

The coronavirus causing COVID is not unique in staying in the body and causing ongoing symptoms months after the initial acute infection. Animal studies have found Ebola and Zika proteins in tissues post-infection and these viruses have also been associated with post-infection illness.

My take on this matter is that, while acute COVID infections are much less frequent and seldom cause serious illness or death, they can and do lead to long COVID, which is an outcome to be assiduously avoided. Therefore, cautious individuals (my wife and myself) continue to wear masks in some public places, including the line at the pharmacy to pick up our medications and medical facilities.

Who knows when – if ever! – it will really and truly be over.

A Department of Energy regulation could drastically change our light bulbs

That regulation could have a significant adverse effect on the health of many people in the US, especially epileptics and migraineurs.

The regulation is scheduled to take effect in July 2028, and it is focused entirely on energy efficiency, as one would expect of a regulation coming from the Department of Energy. The relevant statement is as follows:

“The adopted standards, which are expressed in minimum lumens (“lm”) output per watt (“W”) of a lamp or lamp efficacy (“lm/W”). These standards apply to all products manufactured in, or imported into, the United States starting on July 25, 2028.”

At present, the only light bulbs (“lamps,” in the official DOE parlance) that would meet those standards are the LEDs that emit light in the 460 – 495 nm (nanometer) range. A nanometer, by the way, is a billionth of a meter. Light in that range is emphatically at the blue end of the spectrum, ranging into the ultraviolet.

But light at that frequency has clear and distinct issues. In the evening, it messes up our circadian rhythms. Our brain thinks it’s still broad daylight, definitely not time to go to sleep. Blue light suppresses the production of melatonin, which helps us go to sleep and stay asleep. We have all been told that staring into our computer screens or watching television in the half-hour or so before bedtime is a very bad idea, because the blue light will make it more difficult to get a good night’s sleep.

Beyond the circadian rhythm issue that affects us all, blue LED light is a major public health issue for epileptics and migraineurs, many of whom are extremely sensitive to the quality of light and simply cannot tolerate blue LED light. Yellow and white LEDs, although problematic, are more acceptable, but the LEDs at the blue end of the spectrum are beyond what these persons can tolerate.

For these individuals, even brief exposure to unnatural light, particularly at the blue end of the spectrum, can trigger epileptic seizures and migraine headaches. And a migraine is much more and much worse than a bad headache. In addition to the pounding pain, a migraine can bring on other symptoms, such as severe nausea and vomiting, as well as extreme sensitivity to any light, such that the migraineur needs to shelter in a dark room.

The prevalence of migraines in the US population is surprisingly high – almost 10% of men and about 21% of women report migraines or exceptionally severe headaches during a three-month period.

What we need is light whose frequencies are more evenly distributed over the visible spectrum, not concentrated at the blue end. Yes, broader spectrum light bulbs are less energy efficient, but they are healthier and much, much more pleasant.

It’s worth pointing out that we humans, along with all other creatures whether animal or vegetable, evolved with incandescent light, and I don’t mean Edison light bulbs. The sun and all the stars in our cosmos emit incandescent light, as do candles and torches and cooking fires. Incandescence is light produced by any hot or burning matter.

The particular quality of incandescent light sources, which cannot be matched by LEDs, is that it emits light throughout the entire continuous spectrum. LED manufacturers can make light bulbs that mimic the entire spectrum, blending diodes that emit radiation at a range of points, from the ultraviolet to the infrared. But no matter how many diodes the LED contains, it will not be a continuous spectrum like incandescent light. Parts of the spectrum will be missing, and what we are able to see illuminated by LEDs will not cover the entire visible spectrum.

In Rockland, Maine, there is an art museum, the Farnsworth, which houses an excellent collection of the works of Andrew Wyeth. The Wyeth paintings are illuminated by LEDs – all except for one painting which is adjacent to a large window that permits the painting to be lit by daylight. The difference between the LED-lit paintings and the single painting near the window is huge. The LED-lit paintings look drab in comparison.

It might be possible to make LEDs that are superior to the ones in the Farnsworth, but absence of the entire visible spectrum will be a deficit. I would like to think that at some point the Authorities, whether the Department of Energy or the Department of Health and Human Services, will come to realize that light bulbs that span the visible spectrum are, at least in some cases, a necessity.

Energy-efficient light bulbs that emit a pleasant light that can be tolerated by epileptics and migraineurs and are sympathetic to the needs of our circadian rhythms should, I deeply hope, become available well before that dire date in 2028.

Brief comment: is Lesstranol the answer to elevated cholesterol?

A regular reader and internet friend sent a piece about this supplement with the question “Is there anything to this?”

My answer is a cautious “maybe.”

The advertisement promoting Lesstranol is not a wild overstatement. Here is the principal statement of Lesstranol’s value:

“After decades of treating thousands of patients with unhealthy cholesterol levels, I came to the conclusion that there had to be an easier all-natural way to help my patients support their cholesterol levels. After meticulous research, I identified 1 all-natural key nutrient that helps maintain both normal cholesterol and triglyceride levels while promoting optimal LDL/HDL balance and cardiovascular health.

This key nutrient is Red Yeast Rice. Ancient Chinese healers believed red yeast rice could promote good blood circulation. Today, modern scientists know that it contains monacolins, substances known to promote normal cholesterol levels. These monacolins stop the action of the HMG-CoA reductase, an enzyme that helps make cholesterol.”

Indeed, red yeast rice can have a beneficial effect on cholesterol levels. Here’s what the Mayo Clinic says about it:

“Research shows that red yeast rice containing considerable amounts of monacolin K can lower your total blood cholesterol level, your low-density lipoprotein (LDL, or “bad”) cholesterol level and your triglyceride level.

While the supplement is generally considered safe, it might carry the same potential side effects as statin cholesterol drugs.

Red yeast rice might cost less than a statin. However, with a supplement, there’s less assurance regarding quality and how much active ingredient is actually in the product. Some red yeast products might contain only small amounts of monacolin K and potentially have little effect on cholesterol levels.”

And who knows how much of that monocolin K is in the Lesstranol supplement. As has been frequently pointed out in these pieces, supplements are entirely unregulated. There is no way of knowing what is actually in the Lesstranol tablets. Speaking for myself, if I had elevated cholesterol (which, thankfully, I don’t!), I would follow the advice of my physician, which would likely point me to a statin.

* * * * * * * *

In past Doc Gumshoe epistles, we have discussed elevated cholesterol and ways of managing that condition, and also noted the introduction of new statins. Is it perhaps time to muster up an overview of that picture?  Please let me know!

I was only able to cover a few of the recent developments in this installment, so in the next one I’ll pick up where I left off and bring you more bits and pieces.

In the meantime, thanks for all comments and enjoy the holidays, as well as the non-holidays. Michael Jorrin (aka Doc Gumshoe).

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]