Jacob Hyatt 1/10/23 Jacob Hyatt 1/10/23

Tale of Tamiflu

Practicing pharmacy over the years you start to get a feel for what works and what does not. Feedback is constant both welcome and otherwise. Some drugs just seem to work for a wide range of people. Amoxicillin, cefdinir, and azithromycin are just a few of our greatest hits from behind the counter. On the opposite side we have drugs that despite approval and mass marketing never really seemed to take off. Tamiflu is a great example. It was hailed and marketed as a cure for the flu and there was a point due to demand, I would spend an inordinate amount of time opening capsules to compound it into a suspension for younger patients when the commercial product would go on back order.

Tamiflu’s story would become more complicated as a multiyear effort spearheaded by the British Medical Journal would highlight many problems with clinical transparency that still resonate today. Approval of Tamiflu and subsequent billions spent by world governments stockpiling it for a potential swine flu pandemic was all based upon recommendations by the CDC, WHO, and EMA. None of which ever actually vetted the primary data and took it at face value. A Cochrane review would conclude after a four-year legal fight to obtain the primary data that there was no clear evidence to support the claims that Tamiflu improved influenza complications or infections but did raise concerns about side effects like nausea, vomiting, headaches, hallucinations and depression.

None of these shenanigans are the fault of the drug, oseltamivir phosphate the generic name for Tamiflu is an effective antiviral but studies have shown it needs to be started early and even a 24-hour delay in therapy causes a significant decrease in benefit. In reality once the patient had sought care, obtained a positive flu test and filled a prescription it was likely to late to be of any benefit. Like many drugs though it may still prove useful for other purposes and a recent study has shown that it may be an alternative therapy for liver cancer.

We now know that the toxicity from oseltamivir occurs as the drug hangs around in the GI tract waiting to be absorbed. Increasing the rate of absorption has been proposed to reduce its associated toxicity. A potential new formulation of oseltamivir that replaces the phosphate salt with an organic salt ethoxysuccinate has been proposed. The new formulation retained its antiviral properties and due to its increased rate of absorption expressed less toxicity compared to the phosphate version. Since changing the salt would be a new product don’t be surprised to see oseltamivir come back again with a new name and a fresh patent.

Jacob Hyatt Pharm D.
Father of three, Husband, Pharmacist, Realtor, Landlord, Independent Health and Medicine Reporter
https://substack.com/discover/pharmacoconuts

hyattjn@gmail.com

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Radon Gas

The leading cause of lung cancer in non-smokers happens to be due to a naturally occurring radioactive gas called radon. Uranium which is found in rock all over the earth’s crust in small amounts decays over time into radium which then releases the gas. The higher the concentration of uranium the greater likelihood of having an issue. Radon gas is very heavy so it escapes from the ground and will be most concentrated below your knees. Outdoors the gas freely dissipates into the atmosphere and is unable to collect in dangerous concentrations. Inside however radon gas can enter a building through the crawlspace or foundation and accumulate to unsafe levels. Because of this historically radon exposure was related to mostly cold environments where the population would spend a great deal of their time indoors. In our modern age however hot environments such as the South also force much of the population to seek refuge indoors with air conditioning. It has been estimated that the average North American spends 86% of their lives indoors and that was before lockdowns. This combined with new construction trends like greater square footage, greater ceiling height, reduced window openings, and ever improving R-values all increase radon risk. A study published in Nature has shown an increase in radon exposure to the population over time due to all these trends.

Radon gas combined with cigarette smoking is about as good a recipe for lung cancer as humanity has ever come across. Ionizing radiation from the decaying radon particles damage our DNA and create genomic instability which leads to cancer. Approximately 3% of the population also has a genetic mutation which causes increased radiation sensitivity making them further susceptible to this runaway cascade.

Excessive exposure comes with a cost and we can look to Hollywood for a great example of that. The 1956 film “The Conqueror” made by eccentric filmmaker Howard Hughes would bring the story of Genghis Khan to the big screen starring none other than John Wayne. The film would become infamous, with out of 220 crew members, 91 would develop cancer and 46 would die from one form of cancer or another. Snow Canyon in Utah where the film was shot was only a hundred miles from a government atomic testing site that detonated 11 nuclear bombs in the previous year. Normally outdoors is safe from excessive radon exposure but two exceptions happen to be fallout zones and close proximity to uranium-mine shafts. If that wasn’t bad enough the dirt from the set was shipped back to California and kept in an enclosed sound stage for reshoots. Radioactive sand in a box as it were.

Much of our awareness of radon and its negative health effects are due to a dark period of American history and the occupational hazards of early uranium miners. The federal government was the sole purchaser of uranium ore until 1971 for national security reasons. Their neglectful operation of the mines to harvest it would result in the Radiation Exposure Compensation Act, the 1990 act of congress, acknowledging responsibility for their mistreatment of uranium miners.

If you have ever purchased a home, you may have performed a radon test as part of the home inspection. It’s a good investment since that is the air you will be breathing for the rest of your life. Virginia has land that falls in all three risk zones that the EPA establishes. In 1986 the Virginia Department of Health surveyed 800 homes and found that 12% of them had radon levels above 4 picocuries/L the cutoff for remediation. The tidewater area of the state, east of Interstate 95 has the least risk since it is below the fall line with sandier soil. West of the fall line we have rockier soil sitting at the foot of the Appalachian Mountains which have been crumbling for an eternity in the geologic sense. The Coles Hill Uranium deposit in southwestern Virginia has been the point of contentious legal debate. It is described as the largest known undeveloped uranium deposit in the United States and has an estimated mineral value of 427 million dollars. Virginia currently has a ban on uranium mining despite multiple functioning nuclear reactors in the state and multiple legal attempts to repeal it.

Virginia Uranium Map

Jacob Hyatt Pharm D.

Father of three, pharmacist, Realtor, Landlord, freelance health and medicine reporter

hyattjn@gmail.com www.Jeffersongroverva.com

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References and Further reading

https://www.epa.gov/radon/citizens-guide-radon-guide-protecting-yourself-and-your-family-radon

https://www.wideopencountry.com/how-did-john-wayne-die/

https://www.vdh.virginia.gov/radiological-health/indoor-radon-program/history/

https://www.epa.gov/radon/health-risk-radon

https://www.nature.com/articles/s41598-019-54891-8

https://world-nuclear-news.org/Articles/Judge-upholds-Virginias-uranium-mining-ban

Stanley, F.K.T., Irvine, J.L., Jacques, W.R. et al. Radon exposure is rising steadily within the modern North American residential environment, and is increasingly uniform across seasons. Sci Rep9, 18472 (2019). https://doi.org/10.1038/s41598-019-54891-8

https://pubmed.ncbi.nlm.nih.gov/31955264/

Ćujić M, Janković Mandić L, Petrović J, Dragović R, Đorđević M, Đokić M, Dragović S. Radon-222: environmental behavior and impact to (human and non-human) biota. Int J Biometeorol. 2021 Jan;65(1):69-83. doi: 10.1007/s00484-020-01860-w. Epub 2020 Jan 18. PMID: 31955264.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042664/

Garcia-Rodriguez JA. Radon gas-the hidden killer: What is the role of family doctors?. Can Fam Physician. 2018;64(7):496-501.

https://pubmed.ncbi.nlm.nih.gov/2654404/

Samet JM. Radon and lung cancer. J Natl Cancer Inst. 1989 May 10;81(10):745-57. doi: 10.1093/jnci/81.10.745. PMID: 2654404.

Gilliland FD, Hunt WC, Pardilla M, Key CR. Uranium mining and lung cancer among Navajo men in New Mexico and Arizona, 1969 to 1993. J Occup Environ Med. 2000 Mar;42(3):278-83. doi: 10.1097/00043764-200003000-00008. PMID: 10738707.

Samet JM, Kutvirt DM, Waxweiler RJ, Key CR. Uranium mining and lung cancer in Navajo men. N Engl J Med. 1984 Jun 7;310(23):1481-4. doi: 10.1056/NEJM198406073102301. PMID: 6717538.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222290/

Brugge D, Goble R. The history of uranium mining and the Navajo people. Am J Public Health. 2002 Sep;92(9):1410-9. doi: 10.2105/ajph.92.9.1410. PMID: 12197966; PMCID: PMC3222290.

Jacob Hyatt 1/9/23 Jacob Hyatt 1/9/23

Ivermectin Maybe?

Ivermectin was discovered in 1967 at the Japanese Kitasato Institute. First approved for river blindness, a neglected tropical disease caused by Onchocerca volvulus, a parasitic worm. Ivermectin would prove effective against many parasites by manipulating the chloride ion channels that are imperative to their motor function, paralysis of the parasite ensues which ultimately leads to starvation and death. Fortunately for us mammals our blood brain barrier protects us from this toxicity. It was an effective drug for parasitic infections and would prove safe and effective over several decades against a variety of conditions including malaria, trichomoniasis, scabies, and leishmaniasis.

Evidence continues to mount for the use of Ivermectin as a potential treatment for Covid-19. We have long known the drug has broad antiviral properties, with even some evidence for use against cancer. One recent article in the Journal of Molecular Structure would summarize its history well with a single sentence.

“Ivermectin has gained much popularity due to a strong background of magical applications against a broad spectrum of pathogens.”

These in vitro experiments are intriguing but converting agar plate results into real life treatments is rarely a straight line. The concentration levels required to achieve those results for example are basically unreachable in the tissue or plasma. Despite that fact it appears to somehow be working to reduce mortality and multiple theoretical mechanisms have been proposed.

Spike protein shielding – Ivermectin binds to the ACE2 enzyme and the spike protein giving it the ability to shield the viral spike and inhibit viral entry by two pathways both on the cell and on the virus.

P2X4 Receptor Allosteric Modulation- It appears two distinctive sites on the P2X4 receptor bind to Ivermectin causing enhanced ATP-mediated secretion of CXCL5 a pro inflammatory chemokine which attracts neutrophils perhaps helping kickstart our immune response.

Nuclear transport inhibition - Importin α/β1 is vital to viral entry into the cell Ivermectin antiviral effects upon HIV, West Nile Virus, Dengue Virus and other RNA viruses appear to be mediated via this pathway. Recently, Ivermectin was shown to inhibit replication of covid-19 as well but the mechanism it accomplished this by is unclear.

Viral protein inhibition – Nucleotide and nucleoside inhibitors like Remdesivir and Favipiravir are FDA approved for HIV and were used early on, showing some effectiveness with 68% clinical improvement reported in a compassionate clinical use. Viral RNA polymerase is a potential therapeutic drug target and Ivermectin has a high affinity for it thereby obstructing its function.

Ionophor theory – Coming from the deepest part of left field; an ionophor is a compound with the ability to bind cations and transport them across a membrane in a small hydrophilic pocket surrounded by a hydrophobic shell. This class of compounds has shown antibiotic activity and their role as an antiviral has been hypothesized. When two Ivermectin particles bind to each other in a head to tail fashion a basic ionophor is made. The consequence of this is an ionic imbalance that could have several deleterious effects upon the virus. If the concentration gradient is great enough osmotic lysis could occur. Covid-19 would be susceptible to this because its genetic material is protected only by a thin phospholipid layer. There are some viruses that have a proteic capsid, this gives them increased resistance to osmotic pressure and a stronger structure. Thankfully we have finally found an evolutionary advantage that the creator chose not to bestow upon Covid-19. Cation depletion may also inhibit viral protein synthesis by inhibiting key enzymes such as RNA polymerase.

It is uncertain which of these proposed theories are the true culprit and maybe in reality it is multiple mechanisms acting in concert to varying degrees. What is certain is that a year and a half into this debacle that a safe and cost-effective potential alternative therapeutic agent has been so ignored that we are unable to say with any real confidence whether it works or not due to a lack of properly powered randomized clinical trials. Meanwhile International pressure continues to stack up as it begins to get approval elsewhere in the world.

Jacob Hyatt Pharm D.

Father of three, pharmacist, Realtor, Landlord, freelance health and medicine reporter

www.pharmacoconuts.com

www.Glenallenliving.com

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fear For festivus

As our holiday season began Thanksgiving dinner was marked with the arrival of a new and unwelcome guest. The omicron variant knocked the turkey right off the table and made sure you were aware of its presence. News of the omicron spread around the world overnight faster than Santa. Starting in South Africa a press conference from the Minister of Health who would announce a new variant that would present “challenges” moving forward. That evening headlines would document the fifty mutations that the omicron variant had and point out that many of these mutations could be found on the spike particle, the scariest part of the virus. International travel restrictions would follow as the world felt a collective sense of dread and Deja vu. Financial markets would tank with their biggest drop of the year and ironically within twenty-four hours of the travel restrictions the variant was discovered in the Netherlands, Germany, and England. The panic first principle was in full effect.

The WHO has several designations for variants that act as a sliding scale. The lowest is the variant being monitored (VBM) and these include alpha, beta, gamma, eta, iota, kappa, lambda and any other variant not named delta or omicron currently. Next is the variant of interest (VOI) there currently are none in that category. Climbing the ladder, we arrive at a variant of concern (VOC) which contains both delta and omicron for now. At the top but with no examples yet would be variants of high concern (VOHC). As the variant emerges it is placed into one of these four tiers based on WHO criteria, and as time passes it may move down the scale. Epsilon for example is the only variant to have been a VOC, VOI, and now a VBM. If you think the full court fear mongering was bad thus far just wait until we hit a level four variant (VOHC).

Viruses being simple strands of RNA with a high error rate constantly walk the line between mutating themselves to death and simply mutating enough to gain an edge. It mutates so much that even thinking of the virus as a single species or one variant or another does not do justice to the phenotypic diversity it expresses. Viral quasispecies may be the best way to imagine covid, a mutant swarm with dominant variations winning out. Autopsies have demonstrated different strains being dominant in different tissue from the same host. Virus variants are competing against one another for survival and for them the most transmissible wins, thus as variants have evolved the most successful ones have been more and more transmissible. Fears of increased death or hospitalizations seem misplaced since no previous variant has been more virulent as of yet. Since a more virulent virus is likely to be less transmissible by nature that should bode well for both humanity and the virus.

Despite the media panic omicron has not delivered and weeks out from its discovery we don’t have a single death associated with it as of yet. Early data indicated that it may cause less severe symptoms and shorter hospital stays, this appears to be holding up as it spreads across the world. The best way for this virus to transmit faster is to cause less problems for the host, not more. Unfortunately, more transmissible still means more infections thus more mutations leading to the next variant. Pi would be next unless they skip that one because it does not sound very threatening. Despite their mutations these are still coronaviruses and many of our current treatments and the new oral therapeutics will likely remain effective.

Merry Christmas and thank you for reading!

Jacob Hyatt Pharm D.
Father of three, Pharmacist, Realtor, Landlord, Independent Health and Medicine Reporter
https://substack.com/discover/pharmacoconuts

hyattjn@gmail.com

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Vaccine Escape and Drug Resistance – No free lunch

Vaccinations are meant to provide an edge for at risk patients to help them fight off infections that they may otherwise succumb to. They don’t necessarily prevent infection all the time but the positive effects on reduced hospitalization and mortality are very apparent. Their use should be guided by the individual risk and benefits of therapy. This should be obvious; your grandmother is more in need of a flu or covid vaccine than you are, mostly to protect her from all the filthy things you bring over. This has been an accepted fact in medicine for a long time, vaccines for things like shingles and pneumonia are not even thought about unless the patient is over a certain age or immunocompromised. If you're old and overweight I will most certainly harp on getting a flu shot every year, if you're young and healthy I will encourage you to do so as well but when met with resistance my oxygen is best spent elsewhere.

Many fools heralded penicillin as the end of microbial infections since it was such a wonder drug. If only we had given penicillin to everyone in the world at the same time there would be no more bad bacteria left. Surely the greatest generation could have taken one for the team and had mandatory antibiotic therapy to slow the spread. Only two decades previously the horrors of World War I and trench warfare had failed to take as many American lives as the Swine Flu Pandemic of 1918. Yet this opportunity to once and for all stop the bacterial menace slipped away.

Replacing vaccination with penicillin in this story above allows its absurdity to come into full focus. Indeed prior to Covid antimicrobial stewardship was a big deal and the debate about over prescribing antibiotics was heated on both sides. Multidrug resistant organisms are now quite common, and penicillin has been pushed to the back of the shelf in favor of more modern and effective antibiotics which are slowly losing ground to emerging resistances. Giving antibiotic therapy to those that did not need it was almost universally frowned upon as a bad idea, so much so that telling you to go home and suck it up was as likely an outcome of a doctor visit as getting a prescription. In the age of Covid however antimicrobial stewardship be damned, Doxycycline and Azithromycin were prescribed like opiates in 2003 as a throw the entire kitchen sink at the virus attitude was adopted.

Like all policies the vaccine mandate comes from a place of good intentions, so we are told at least that’s the beauty of intentions they are always golden in appearance no matter how bad the smell. You must all be vaccinated of course so that you do not pass the infection onto others. The theory being that once we have all gotten the vaccine Covid will have nowhere to hide and disappear completely. Unfortunately, this idea is based on a foundation shakier than a Haiti high rise. There is no such thing as a free lunch, there is always push back in nature. Coronaviruses have always been with us causing a variety of our common colds and thanks to a boost from humans have now skipped a few centuries ahead on the evolutionary ladder.

You won’t find vaccine resistance in the literature very often because the term that is used to describe this situation is vaccine escape. As the virus has spread worldwide mutations and variants have flared up. The Delta variant has received the most attention, originating in India it is more transmissible and has shown to reduce the effectiveness of our current vaccines. A recent analysis of 506,768 genome isolates from positive Covid patients would identify a hundred mutations that have increased affinity for the ACE2 enzyme and the receptor binding complex compared to the initial alpha version. The researchers have hypothesized that further genetic evolution of the virus could compromise our existing vaccines and antibody therapies. My greatest fear is that our excessive use of these vaccines in a population that arguably may not need them could result in a reduced effectiveness for the population that does. I hope this proves to not be the case but expressing the idea should not be verboten.

This principle of stratifying therapeutics most effectively throughout the population has now reared its head in our public booster battle between the CDC, FDA, and the White House. The FDA advisory panel rejected the boosters for all plans that had already been announced by the administration, while giving the ok for the elderly and immunocompromised. Two long standing FDA doctors would retire in objection and take their complaints public with an opinion article in the Lancet. A few days later the CDC would expand the guidance a little further to include healthcare workers as well. Dr. Fauci would take to Sunday morning talk shows to promise new future science and data that would take us back to the boosters for all. All of this has created a quagmire of public confusion, resentment and animosity towards one another over personal healthcare decisions that due to patient privacy laws none of us even have a right to know about.

Jacob Hyatt, Pharm D.
Father of three, Pharmacist, Realtor, Landlord, Independent Health and Medicine Reporter
https://substack.com/discover/pharmacoconuts

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