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Following Up on Your Suggestions – September 2022

Updates on Alzheimer's Disease, Anti-Inflammatories, Prostate Cancer, Vitamin D and more...

By Michael Jorrin, "Doc Gumshoe", September 26, 2022

No surprise, the first comment to Doc Gumshoe’s piece on inflammation was this simple statement: “Next, I would like to read about anti-inflammatories.” It probably would have made sense to follow up the inflammation piece with a piece about anti-inflammatories, but COVID and monkeypox summoned me to the battle lines. Let me make up for that gap, at least to some extent.

A look at anti-inflammatories

“Anti-inflammatory” is a loose term in that it doesn’t specifically define any particular kind of drug. That’s because inflammation occurs through a multitude of pathways. A very large number of agents in our bodies take part in causing inflammation – many different kinds of cells and many, many different complex molecules. And inflammation, as we saw, is a cause, or at least a feature, of many diseases and conditions. Any drug that interferes with the action of any of those agents, or treats any of those diseases or conditions, would fall into the category of an anti-inflammatory. And drugs can block or interfere with the action of the same inflammatory agent in completely different ways.

Let’s look at one inflammatory agent as an example: tumor necrosis factor, which is the cause of rheumatoid arthritis. Tumor necrosis factor, which we’ll call TNF, is a cytokine, which sometimes serves the valuable purpose of attacking tumors in the body. However, TNF is also responsible for damage to the body: it attacks the tissues that provide lubrication to our joints, so as the unlubricated joints grind against each other, they wear down, causing considerable pain and inflammation.

Rheumatoid arthritis is effectively treated by TNF inhibitors – drugs that block the action of TNF; thus these drugs are anti-inflammatories. However, TNF inhibitors can have different mechanisms of action. One class of TNF inhibitors bind to TNF itself and effectively block the mechanism that the TNF uses to attach to the joint lining. And another class of TNF inhibitors attaches to the joint lining tissue, protecting the tissue from the TNF. An example of the first kind of TNF inhibitor is etanercept (Enbrel, from Amgen), and of the second kind, infliximab (Remicade, from Pfizer).

Another drug sometimes used to treat rheumatoid arthritis and other autoimmune diseases such as inflammatory bowel disease is methotrexate, a drug, with a highly complex mechanism of action. Methotrexate is also used to treat some forms of cancer, but it could be considered an anti-inflammatory. Its principal anti-inflammatory effect is to decrease the production of interleukins, which are pro-inflammatory agents.

A large category of anti-inflammatory drugs is the group known as NSAIDs – non-steroidal anti-inflammatory drugs. Some of the principal NSAIDs are ibuprofen (Advil and Motrin), naproxen (Aleve, Anaprox, and Naprosyn), celecoxib (Celebrex), and, of course, aspirin. Aspirin has a number of mechanisms of action (MOAs), but the MOAs of ibuprofen, naproxen, and celecoxib are closely similar. They are cyclooxigenase (COX) inhibitors, COX being an enzyme that leads to the production of prostaglandins, which are agents of inflammation.

But the story gets more complicated. It appears that there are two kinds of COXs, COX-1 and COX-2. And there are also two kinds of prostaglandins – the previously-mentioned agents of inflammation, but also prostaglandins that protect the stomach and kidneys. COX-2 mostly produces the inflammatory prostaglandins, and COX-1 mostly produces the beneficial prostaglandins. NSAIDs do not inhibit the two COXs to a similar extent, and some NSAIDs inhibit one type more than the other. Attempts have been made to develop NSAIDs that limit their action to the inhibition of COX-2, leaving COX-1 to do its beneficial work.

However, focusing the inhibition on COX-2 alone has its definite downside. COX-2 has a role in keeping the vascular system healthy, in that it aids in the production of prostaglandins that are beneficial to the arteries by participating in vasodilation. Inhibiting COX-2 is thought to be a contributing factor to the increased risk of developing hypertension, heart attacks, stroke, and congestive heart failure.

The most common side effects with NSAIDS are related to their anti-clotting action; prolonged use can lead to gastrointestinal (GI) bleeding. However, those side effects are more linked to the inhibition of COX-1 rather than COX-2. Picking an NSAID for a patient necessarily involves deciding whether the patient is at greater risk of GI bleeding than cardiovascular effects. Fortunately, those difficult choices apply only if the prospect is that the patient has to be taking the NSAID for an extended period; taking an NSAID to deal with a temporary condition is generally thought to be quite safe.

Of the NSAIDs mentioned above, aspirin and naproxen tend to be more COX-1 inhibitors, Celebrex is more a COX-2 inhibitor, and ibuprofen straddles the line.

Aspirin is in a category by itself. In addition to its anti-inflammatory characteristics as a COX inhibitor, it has three other highly important qualities. It is a pain-reliever, it brings down fevers, and it inhibits blood platelets from clotting, thus reducing the risk of stroke. The mechanisms through which aspirin works those four valuable actions are highly complex, and were certainly not understood when the benefits of the infusion of willow-bark were first recognized.

Another class of anti-inflammatory drugs are the glucocorticoids, a hormone produced in our own bodies for a variety of purposes. They control the metabolism of carbohydrates, proteins, and fats, and also help to manage the immune system. Several artificial glucocorticoids have been developed, including cortisone, prednisone, dexamethasone, triamcinolone, and budesonide. Cortisone in particular is given by injection in order to ease inflammation in the joints. Prednisone and dexamethasone are given orally for a number of diseases including allergies, asthma, and vision problems. Triamcinolone is mostly used topically for skin conditions. Budesonide is used for autoimmune diseases such as ulcerative colitis and Crohn’s disease.

Finally, there are foods that are considered by nutritionists to be anti-inflammatory. The list is fairly long and includes quite a lot of what is in my usual diet, so I should feel smug. However, I’m not sure of the soundness of the evidence. The list includes berries of every kind, cherries, grapes, tomatoes, apples, broccoli, avocadoes, some fish (especially salmon), mushrooms, peppers, olive oil, green tea, turmeric, and (to top it off with a bang) chocolate.

You notice that it avoids the usual villains – red meats, sugar, and starches – and complies with the standard nutritionists mantras, including the exaltation of turmeric. The emphasis seems to be on foods that contain flavonoids, which are present in most brightly colored foods, and are generally considered (and not just by nutritionists) to be effective anti-inflammatories.

My conclusion is that the anti-inflammatory has to be specific to the disease or condition that is associated with inflammation – i.e., if you have rheumatoid arthritis, you need a TNF inhibitor, and if you have Crohn’s disease, you need a glucocorticoid such as budesonide. The target has to be more specific.

Don’t throw out your vitamin D pills just yet

Just about a month ago a New England Journal of Medicine study was published that got quite a bit of attention. The study reported that, contrary to what had been assumed for quite some time, vitamin D supplementation did not prevent middle-aged men and women from sustaining bone fractures. The study was part of a larger ongoing vitamin D study which investigated whether supplemental vitamin D would prevent cancer and cardiovascular disease in men 50 years of age or older or women 55 years of age or older.

The fracture study compared supplemental vitamin D3 with placebo in 25,871 participants, just over half of whom were women, and 20% of whom were black, for a median of 5.3 years. During the study period, 1551 of the subjects experienced a total of 1991 fractures. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures, which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group. There was no modification of the treatment effect according to baseline characteristics, including age, sex, race, ethnic group, or body-mass index. (LeBoff, M. N Engl J Med 2022; 387:299-309)

Since bone-health (as it says on the label of the vitamin D3 package) is a principal reason why lots of people take vitamin D3 supplements, the results of the study were picked up by media outlets with the suggestion that most people no longer need to take the supplement.

However, information to the contrary has also recently been published. A group of epidemiologists at the University of South Australia used data from the UK Biobank to look into the relationship between vitamin D levels and the levels of C-reactive protein (CRP) which is a well-known indicator of inflammation. They analyzed data from 294,970 participants, and an inverse relationship between vitamin D and CRP emerged. They examined the findings from 2006 to 2009 and saw that the subjects with lower serum vitamin D levels had higher levels of CRP, and also that as individuals’ levels of vitamin D rose out of severe deficiency, their CRP levels declined. (Zhou A. Int J Epidemiol. 2022 May 17; doi: 10.1093)

We make our own vitamin D, but we do need sun-exposure to make the process work. It’s estimated that about 40% of people in the US are vitamin D deficient to some extent, and that most of them don’t know it, unless they have annual blood tests and a physician who will look over the results and spot the deficit.

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Here’s a quote on the subject from the Harvard T. H. Chan School of Public Health:

“Few foods naturally contain vitamin D, though some foods are fortified with the vitamin. For most people, the best way to get enough vitamin D is taking a supplement because it is hard to eat enough through food.”

Improved survival for men whose prostate cancer persists after treatment

Prostate cancer is the single most common form of cancer (other than skin cancers) affecting men in the US; about one out of six men will develop prostate cancer at some point in their lives. Treatment for prostate cancer usually consists of surgical removal of the prostate gland (prostatectomy) or targeted radiation. However, currently as many as 40% of patients will experience some form of recurrence after treatment.

There has been considerable controversy around the treatment of prostate cancer, which you may remember we have discussed in these Doc Gumshoe missives. The accepted way of attempting to control this common disease has been a routine test for a prostate cancer marker called prostate specific antigen (PSA) which at one time had been recommended for all men starting around age 50. When the PSA level is above a certain marker, the usual follow up is a biopsy of the prostate gland, and if cancer cells are found, the form of treatment – surgery or radiation – depends on those specific findings.

The United States Preventive Services Task Force (USPSTF) has cast doubts on that sequence of procedures, noting that prostate cancer usually progresses very slowly, and that many men are likely to die of other causes before the cancer becomes life-threatening. In 2012 the USPSTF made a recommendation against routine prostate cancer screening, instead recommending what is termed “watchful waiting” for many men, depending on a range of factors. This practice works well for some men with elevated PSA levels. However, it has been noted that in some cases, watchful waiting leads to delayed treatment, which means that the cancer has progressed, sometimes to metastasis. And, indeed, the incidence of metastatic prostate cancer has increased since the USPSTF’s recommendations were made public – by 41% in men 45 to 74 years of age, and by 43% in men older than 75.

Treatment for recurring prostate cancer consist either of radiotherapy or androgen deprivation therapy, androgen being the male sex hormone that tends to favor the growth of cancer cells. The five-year survival rate for men with recurring prostate cancer who receive either of those two forms of therapy is about 70%.

However, a recent clinical trial conducted by the Cedars-Sinai Cancer Center found that that survival rate could be increased to nearly 90% by combining two modes of radiotherapy with androgen deprivation therapy.

The Phase III trial enrolled 1,716 subjects globally and assigned them to three forms of treatment. Group 1 was assigned to receive conventional radiation therapy directed to the location of the prostate before it was removed. This group had a median five-year survival rate of 71%.

Group 2 underwent androgen deprivation therapy in addition to the conventional radiation therapy described above. The median five-year survival rate for these individuals was 81%.

Group 3 received conventional salvage prostate bed radiotherapy, androgen deprivation therapy, and, in addition, pelvic lymph node radiation. These patients had a five-year freedom from progression of just over 87%.

Note that for Groups 1 and 2, the outcome measure was five-year survival, while for Group 3 the outcome measure cited was five-year freedom from progression, a significantly higher standard.

My recollection is that prior to the USPSTF’s anti-recommendation of annual PSA testing and prostate biopsies in men with elevated PSA levels – that is, when most cases of prostate cancer were detected earlier – 10-year survival after a prostatectomy was higher than 90%. Now, in men whose prostate cancer has returned after treatment, intensive therapy employing not only androgen deprivation, but two modes of radiation therapy, only begins to approach that survival rate – 5 years and 87% compared with 10 years and 90%. Yes, we aren’t comparing apples to apples, and yes, that 87% five-year freedom from progression rate is a distinct improvement. But my conclusion is that men were better protected from prostate cancer before the USPSTF got into the mix.

A drug that reduces the number of days that migraine sufferers endure migraines

The drug is eptinezumab (Vyepti, from Lundbeck Seattle Biopharmaceuticals), given by intravenous infusion four times a year. The Phase 3b DELIVER clinical trial recruited 891 subjects in 96 study locations, mostly in Europe, and tested two dosing levels of eptinezumab and placebo over a period of 72 weeks. The trial subjects that received the 100 mg dose experienced on average 4.8 fewer days per month with migraines, while those that were given the 300 mg dose had 5.3 fewer migraine days per month. Placebo patients experienced 2.1 fewer migraine days per month. The differences from placebo were highly significant (P<0.0001) for both eptinezumab dosage levels.

The trial subjects were migraineurs who had failed two to four previous treatments with drugs intended to prevent migraines. Clearly, eptinezumab is not intended for use by persons who have an occasional migraine. Those who have occasional migraines are much more likely to use drugs that are intended to treat migraines rather than a drug like eptinezumab that requires quarterly intravenous infusions. The class of drugs most likely to be used in response to a migraine (rather than as a migraine preventative) are the triptans, such as sumatriptan (Imitrex, from GSK), zolmitriptan (Zomig, from Impax), almotriptan (Axert, from Janssen), eletriptan (Relpax, from Pfizer), and others.

Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a molecule involved in triggering migraine attacks. Eptinezumab received FDA approval for migraine prevention in adults on February 21st, 2020. In a previous clinical trial enrolling over 1000 subjects, between 10% and 17% of those receiving eptinezumab experienced at least one migraine-free month at some point, and also more migraine-free months as time passed.

Four other anti-CGRP monoclonal antibodies — eptinezumab, erenumab (Aimovig, from Amgen), galcanezumab (Emgality), and fremanezumab (Ajovy) — are approved in the U.S. for migraine prevention. Erenumab was the first CGRP approved by the FDA, on 17 May 2018.

Another CGRP inhibitor is galcanezumab, given the brand name Emgality by its developer, Eli Lilly. In clinical trials it has been demonstrated to reduce migraine incidence in patients who do not respond to prophylaxis with Botox, which has been used to try to prevent migraines. Moreover, galcanezumab is also effective in cluster headaches, which are different from migraines, and for which there has been no approved prophylactic treatment.

The fact that effective treatment for migraines is provided by agents that inhibit the action of CGRP provides a certain amount of validation for the vascular hypothesis, namely that the pain in migraines comes from the pressure of dilated blood vessels on nerve endings, because what CGRP does appears to be to dilate those very blood vessels. But perhaps it works in some other way that has yet to be figured out. We’ll see!

A drug that may repair injuries to the nervous system

The company is NervGen Pharma Corp, and their drug is NVG-291. The suggestion came by way of an Irregular who sent me a good deal of information about the company, which Doc Gumshoe appreciates. I was able to dig up a bit of interesting information about NVG-291.

NVG-291 was discovered by Dr Jerry Silver at Case Western Reserve in 2013. In the following years, it was demonstrated in animal models to aid in the regeneration of damaged nerves. An early mouse study demonstrated that NVG-291 led to the repair of spinal cord injuries, and more recently the drug was demonstrated to promote nervous system repair and functional recovery in mice that had experienced severe ischemic strokes, even when treatment with NVG-291 was initiated as long as 7 days after the stroke event.

Currently, the drug is in a Phase 1 clinical trial in healthy human subjects. Phase 1 trials are meant to demonstrate the safety of a drug and to establish the optimal dosing levels. NervGen is preparing to launch a Phase 1b/2 clinical trials to determine the efficacy of NVG-291 in repairing nervous system damage from spinal cord injury, Alzheimer’s disease, and multiple sclerosis (MS).

What is of particular interest is the mechanism through which NVG-291 aids the repair of damaged nerves in spinal cord injuries and other traumas and diseases. The drug modulates the activity of a specific region of the protein tyrosine phosphatase (PTP) sigma, which normally acts to put the brakes on systems that help the nervous system repair itself from damage. By modulating PTP signaling, NVG-291 can help to promote various mechanism of nervous system repair, including remyelination — restoration of the damaged myelin sheath.

The damage in these events leads to an accumulation of dead neurons which impair the capacity of neighboring undamaged living neurons to recover full functionality. NVG-291 prompts neurons to rewire existing connections and create new connections, a process termed neuroplasticity. It also fosters the reconnection of severed nerve fibers, called axonal regeneration. These three actions of NVG-291 restore the neuron’s capacity to transmit signals.

In laboratory rats which had experienced significant spinal cord injury, treatment with NVG-291 lead to the sprouting of new neural pathways, allowing these previously crippled creatures to walk again and even climb ladders. Besides treating spinal cord injury, based on animal studies, NVG-291 has also shown promise in the treatment of multiple sclerosis, traumatic brain injury, stroke, and Alzheimer’s disease.

For members of the Gumshoe tribe whose main focus is whether the drug maker is a promising investment or speculation, I emphasize that it’s very early days to venture a guess as to whether NervGen is a good bet. As of this time, the only clinical trial listed is the Phase 1 trial mentioned above, whose final results are not yet known. The Phase 1b/2 trial, which would begin to shed some light on whether NVG-291 is actually efficacious in treating those conditions in humans, is not even listed in the clinical trials registry as “recruiting.”

All told, I will continue to keep an eye on this interesting and promising drug – not only whether it will actually deliver on its promises to treat those above-mentioned ailments, but on the way it fosters the regeneration on neural connections, which could have a number of other possible effects.

A few interesting glimmers of news on the Alzheimer’s picture

One of the most frustrating aspects of the prospect of developing successful treatment options for Alzheimer’s disease is that in the great majority of cases, the disease itself is not recognized until it is too late for even the marginally effective treatments now available to  bring any significant benefit. Among the many obstacles to overcome are that, at least in its early stages, Alzheimer’s is difficult to distinguish from the forgetfulness that affects many elders, and, even in the later stages, difficult to distinguish from ordinary dementia. For most of the period during which the emergence of Alzheimer’s was recognized as a serious societal health problem, there was no simple, inexpensive way to diagnose the disease. For a long time, the only certain way to identify the disease was by a post-mortem examination of the brain. This was succeeded by the development of PET scans, but these are expensive, time-consuming, and cumbersome, in that there’s no way patients are going to have PET brain-scans as part of a normal physical examination.

A major breakthrough took place on May 4th this year, when the FDA permitted the marketing of a rapid test for the early detection of the amyloid beta (Aβ) plaques that are present in the brains of persons diagnosed with Alzheimer’s. The test, Lumipulse G β-Amyloid Ratio (1-42/1-40) test is intended to be used in adult patients, aged 55 years and older, presenting with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. The Lumipulse test measures the difference between two proteins in the cerebrospinal fluid – Aβ I-42 and Aβ I-40. It is known that Aβ I-42 favors the formation of Aβ. The trial that led to the FDA’s decision found that in almost all the subjects that had higher ratios of Aβ I-42 to Aβ I-40, amyloid plaques were present on brain scans, whereas those with higher Aβ I-40 ratios did not have amyloid plaques.

Then, just last month, Roche announced that its blood-based biomarker test for Alzheimer’s has gotten the FDA’s breakthrough device designation. The test is the Elecsys Amyloid Plasma Panel, which measures the amount of phosphorylated tau 181 (pTau-181) and apolipoprotein e4 (ApoE4) in an individual’s blood sample. Elevated levels of pTau have been shown to correlate with the onset of Alzheimer’s, while the presence of the ApoE4 gene is believed to be among the strongest risk factors for the disease.

By quantifying those two biomarkers, Roche’s diagnostic can pinpoint which individuals should undergo confirmatory testing for Alzheimer’s via amyloid PET scans or cerebrospinal fluid assessment. Meanwhile, those who test negative with the panel can be directed toward follow-up testing for other potential causes of cognitive decline.

Roche’s Elecsys Amyloid Plasma Panel could be a big step forward in Alzheimer’s management. While the Lumipulse test might exceed the Roche test in accuracy, a test of cerebrospinal fluid is highly unlikely to be part of a regular annual assessment, whereas Roche’s blood test could be more routine. And if such a test could lead to earlier initiation of such Alzheimer’s treatment options as have shown even limited effectiveness, the benefit to individuals whose disease progression was slowed down could be considerable.

A member of the Alzheimer’s-susceptible family that beat the odds

The family we’re referring to is the 6,000 member group of a family in Colombia,
many of whom share the mutation known as Presenilin-1 E280. The PSEN1 E280A
mutation is autosomal dominant, meaning that only a single copy of the gene is
required to cause disease. Those family members with the mutation are almost
certain to develop AD dementia, usually showing signs of cognitive impairment in
their mid-40s and full-fledged AD in their 50s, leading to death well before age 60.

One member of that family, Aliria Rosa Piedrahita de Villegas, should have developed Alzheimer’s disease in her 40s and died from the disease in her 60s because of a rare genetic mutation. Instead, she lived dementia-free into her 70s and died, not of Alzheimer’s disease, but of malignant melanoma, at age 77. Within less than two hours after her demise, her brain was removed and examined. Now her brain is yielding important clues about the pathology of dementia and possible treatments for Alzheimer’s disease.

The key difference in the Colombian woman’s ability to fend off the disease for three decades appeared to be that in addition to having the PSEN1 E280A mutation, she was also a carrier of both copies of a mutation known as APOE3 Christchurch.

The APOE family of genes control production of apolipoproteins, which transport lipids in blood and other bodily fluids. The APOE2 variant is known to be protective against Alzheimer’s dementia, while the APOE4 variant is linked to an increased risk for the disease. APOE3, the most common variant, is not typically associated with either reduced or increased risk for Alzheimer’s.

Yakeel T. Quiroz, director of the Multicultural Alzheimer Prevention Program (MAPP) at Mass General, and associate professor of psychology at Harvard Medical School, reported in Acta Neuropathologica, (July 2022) that the woman did, in fact, have pathologic features of Alzheimer’s disease in her brain, but not in regions of the brain where the hallmarks of Alzheimer’s are typically found.

The study identified an enormous burden of amyloid beta plaques, but also an odd distribution of tau tangles. The woman’s frontal cortex was relatively free of tangles, while her occipital cortex was replete with them. In what seemed to be a contradiction, regions of her brain that had managed to fend off tangles expressed more APOE4. Hinting at the power of the Christchurch variant, the researchers noticed that neurons considered exquisitely vulnerable to tau-induced neurodegeneration were doing fine in the frontal cortex and hippocampus. The findings suggest that the protective APOE3 Christchurch variant somehow severs an inflammatory cord linking Aβ plaques to tau tangles, buying decades of life without dementia for at least this one carrier of the gene that usually consigns carriers to early Alzheimer’s.

The researchers expressed optimism that what they learned from this single woman would bear fruit in the management of Alzheimer’s disease.

“This patient gave us a window into many competing forces — abnormal protein accumulation, inflammation, lipid metabolism, homeostatic mechanisms — that either promote or protect against disease progression, and begin to explain why some brain regions were spared while others were not.

Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of Alzheimer’s disease, suggesting possible therapeutic strategies.

It is seldom that we have nice surprises while studying familial Alzheimer’s disease brains. This case showed an amazingly clear protected phenotype. I am sure our molecular and pathologic findings will at least suggest some avenues of research and elicit hope for a successful treatment against this disorder.”

The researchers have their work clearly laid out for them. They need to find out exactly what the mechanism of the Christchurch variant is, and whether this mechanism can be replicated by other means – in other words, exactly what the variant latches onto, by what means that attachment is made and maintained, and what the effects of that attachment bring. Without question, Aliria Rosa Piedrahita de Villegas’ escape from the fate that consigned great numbers of her extended family to early Alzheimer’s presents a major learning opportunity and the possibility of finding a genuinely effective means of preventing Alzheimer’s disease in those persons whose genetic characteristics appear to point to succumbing to Alzheimer’s and its consequences.

May these researchers find success!

* * * * * * *

A short but significant COVID-related news item, which most of Tribe Gumshoe has already heard, but is worth repeating: on Wednesday, August 31st, the FDA authorized a bi-valent COVID booster, bi-valent meaning that it is effective not only against the original coronavirus strains, but also against the Omicron strain, including the BA.4 ad BA.5 variants and subvariants. The infectious disease experts tell us that the booster should be more widely protective than any vaccine targeting single strains, since our immune systems, when challenged with multiple antigens, will develop wider sensitivity. The booster is now generally available.

Thanks for all the comments and suggestions. Be well and stay well! Michael Jorrin (aka Doc Gumshoe)

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lalgulab12
September 26, 2022 11:32 am

One of the best natural anti inflammatory drug is ASHWARGANDHA an now finally available in Publix, Walgreens etc. Also research has shown use of probiotics and prebiotics can prevent onset of AD

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Martin Satter
Martin Satter
September 26, 2022 11:45 am

Doc … the revelation that “And, indeed, the incidence of metastatic prostate cancer has increased since the USPSTF’s recommendations were made public – by 41% in men 45 to 74 years of age, and by 43% in men older than 75.” is very striking indeed. Can you provide a link to that publication or reference. Thanks.

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BARBARA STEWART
Member
BARBARA STEWART
September 26, 2022 11:55 am

Thank you for all this research. Much appreciated.

Gambini
Member
Gambini
September 26, 2022 12:05 pm

As always, interesting information. Thanks for investing your time and energy into researching and sharing .

Peter Huttemeier
Peter Huttemeier
September 26, 2022 12:12 pm

thank you for an enlightening science report
I was particularly struck by your thoughts on the value
of the PSA; of course the survival comparisons are as u mentioned yourself
difficult to do ….
but still hm

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chris hannaman
Member
chris hannaman
September 26, 2022 12:12 pm

I wonder if NVG-291 would be a suitable treatment for ALS.

Lloyd
Guest
Lloyd
September 26, 2022 12:50 pm

Wonderful article, which addresses some key issues faced by a growing number of people. As someone who is currently receiving treatment for prostate cancer – I took part in a clinical trial for high intensity focussed ultrasound (HIFU) back in 2012 with very good results, but it has remerged – I am coming to the conclusion that if men are not unhappy to receive androgen blockers and other anti-androgen medication, then this modality of treatment (radiotherapy/HIFU, radical prostatectomy combined with drug therapy) could be started earlier in the disease process. Prostate cancer cells also produce testosterone so there are good reasons for adopting androgen blockers earlier.

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$INMB__S-TNF
Guest
$INMB__S-TNF
September 26, 2022 1:14 pm

Doc – always appreciate the writeups. Curious if you’re familiar with the S-TNF (S=Selective) that Inmune Bio (INMB) is working on: https://www.inmunebio.com/science/xpro1595/overview

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jimbama
Irregular
jimbama
September 26, 2022 1:31 pm

Great easily read article AGAIN. Could you comment on the Novavax Covid Vaccine vs its RNA based competitors. I am wondering if by its design it should provide a broader base of coverage against this virus and its current and potential variants?

Charles Colson
Member
Charles Colson
September 26, 2022 2:53 pm

As a long-time consumer of vitamin D3 supplements (2000 mg/day), I am REALLY glad to hear about the inverse relationship between vitamin D levels and the evil sCRP levels.

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KEith Keller
KEith Keller
October 1, 2022 4:48 pm
Reply to  Charles Colson

D3 should be taken with K2 to increase effectiveness; although nothing beats Sunshine.

Mike Tremont
Member
Mike Tremont
September 26, 2022 3:15 pm

Doc – once again you have an opportunity to talk about AVXL 2-73 which will be providing phase 2b/3 Alzheimer Disease results this fall and results from the Attention-AD OLE study by year end complete data on completion of Excellence phase 2/3 pediatric trial on Rett syndrome.
They have had excellent results with PD and PDD.
They have published a scientific MOA educational video on its SIGMA1 platform. It is on there website. Please watch/investigate and advise.
This is in my opinion by far the most advanced drug to treat CNS diseases(Ad/PD//Rett/fragile x/schizophrenia ETC.) would appreciate your insight.
Thank you

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rgalvin
rgalvin
September 26, 2022 5:12 pm

i was concerned about my constant use of NASIDS for inflammation pain control. I was directed to a drug in the form of a tincture called CBDA. I had heard of CBD but not CBDA. I started to use this tincture and have been pain free from my arthritis. Have you any info on CBDA ? I understand from papers I have read that is is 100 time more effective then just CVBD. Any info you could supply using CBDA and effectiveness or concerns would be gratefully appreciated

LI have only been abl to get CBDA from a source in Ca.

Thanking you in advance for any response and info you can provide.

Roger Galvin

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larkn1412
September 26, 2022 5:24 pm

Doc, masterful as ever , thank you . One area that might be worth a follow up re inflammation and production of nasties associated with that, is that of cellular senescence and reduction of associated SASP by use of i) all natural flavanones such as Fistein and Quercetin and ii) repurposed drugs such as Rapamycin and Dasatinab… there are even some great studies ( non clinical but peer reviewed) about positive effects of Fistein when used against malignant skin melanoma for example: the Fisetin essentially acting as a targeted senolytic. We are as a fast developing species unfortunately condemned to the diseases of ageing caused by inflammation in the main , with the main causative link being cellular senescence, whereas the humble crocodile ( an exceedingly slow developing species) shows little difference between senescent load and associated SASP production between a 40 yo and a 100 yo Croc…. could the medicine of the future migrate from the current ‘ whack a mole” approach as it pertains to diseases of ageing to one where we approach ageing as the disease with use of senolytics and telomere extension therapies…….

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Richard
Richard
September 26, 2022 5:53 pm

Excellent work Doc!

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Deborah Waroff
September 27, 2022 1:01 am

Doc Gumshoe, I recently read an article (NYTimes? WSJ?) discussing the new booster in which Dr. Paul Offit said he was not planning to take it. Offit is perhaps the best-known and most vociferous advocate for vaccines in America and occupies a seat on the CDC’s Vaccine Advisory board. This, and the fact that the new booster has only been tested for safety and effiicacy on eight mice (genetically engineered to better represent humans) leaves me somewhat wary, though previously I had been double vaxxed and once boosted.

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dan meier
dan meier
September 27, 2022 10:24 am

Thanks so much for the time’ knowledge and efforts put into this writings.
Much appreciated.

John Gallo
Member
John Gallo
September 28, 2022 9:27 pm

AVXL If it gets to phase 3 will take off again BIG!

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