Patrick Girard

French historian of science, Patrick R. Girard, in updating his 1981 Ph.D. dissertation submitted to the University of Wisconsin-Madison, Department of History of Science, into a book entitled History of Einstein’s General Relativity: Conceptual Development of the Theory (2020) available at https://hal.science/tel-02893156v1/file/Girard-History%20GTR.pdf, writes as follows.

“Annexe A EINSTEIN’S PRIORITY IN THE MATTER OF THE FIELD  EQUATIONS. Though the majority of physicists correctly attribute the priority of the field equations to Einstein, a priority issue between Einstein and Hilbert is sometimes raised. Thus, I shall briefly analyze that question for the sake of historical accuracy. Shortly before Einstein’s communication to the Berlin Academy on 25 November 1915, David Hilbert gave a lecture to the Mathematische Gesellschaft in Göttingen in which he developed a sweeping theory yielding in particular a set of generally covariant gravitational field equations. The talk appears to have been given on 20 or 23 November. (The printed version of the lecture indicates “Presented at the session of 20 November 1915” whereas Hilbert on a postcard to Einstein dated 14 November gives 23 November as the date of the lecture. Since, in the lecture Hilbert apparently did not mention Einstein’s contributions but did so extensively in the printed version, the latter was clearly a revised one. Hence, having only this document available we do not know for sure which field equations exactly were given during the lecture but can only assume them to have been the same as the ones of the printed version, which appears likely.

This assumption having usually been made, the apparent similarity of Hilbert’s field equations with Einstein’s final ones has led to various claims of priority. Thus, Hermann Weyl, in his 1918 book, stated that Hilbert formulated the gravitational field equations “about the same time as Einstein, though only in the framework of Mie’s theory”; Wolfgang Pauli, in 1921, went further and stated “at the same time as Einstein, and independently, Hilbert formulated the generally covariant field equations.” Similarly, Pascual Jordan in his book Schwerkraft und Weltall speaks of the Einstein-Hilbert equations. More recently, the claim of independent discovery has been rejected by Eugene Guth, who referred to it as a “myth” but was taken over again by Jagdish Mehra who wrote: “During the third period, 1915 − 16, the field equations of gravitation were formulated by Einstein, were independently derived by Hilbert …,” and further below, added: “There can be no doubt that Hilbert’s derivation was entirely independent.” The whole issue of the origin of the field equations was analyzed in detail by John Earman and Clark Glymour, who surprisingly left the claim of independent discovery undecided and even suggested the possibility of an influence of Hilbert on Einstein with respect to Einstein’s renunciation of the Einstein-Grossmann theory and the discovery of the final field equations. I shall side with Hilbert himself and Guth and show: (a) that the priority of the field equations belongs to Einstein ; (b) that the suggestion of an influence of Hilbert on Einstein is essentially unfounded. We shall examine successively the claims of simultaneous, independent discovery and the suggestions of an influence of Hilbert on Einstein.

The expression “simultaneous discovery” implying that the discovery relates to the same object at about the same time, it must first be pointed out that Hilbert’s theory as a whole was basically different from Einstein’s. Whereas Einstein’s theory, in 1915, dealt only with gravitation, Hilbert’s theory, by attempting to synthesize Gustav Mie’s and Einstein’s ideas, aimed, as the title of the paper “Die Grundlagen der Physik” indicates, at deriving all of physics
from two axioms. . . .” (internal citations omitted)

“Footnote 34: A recent paper has disclosed the original text of Hilbert’s conference : Leo Corry et al., “Belated Decision in the Hilbert-Einstein Priority Dispute”, Science, 278, 1270-1273 (1997). The paper shows that Hilbert’s equations of his conference are not covariant and are not the same as those of Einstein, thus putting a definitive end to the debate in favor of Einstein.”

Alan Guth anecdote in re: Remembering Dr. Murray Gell-Mann

alan_guth's picture
Cosmologist; Victor F. Weisskopf Professor of Physics, MIT; Inaugural Recipient, Fundamental Physics Prize; Author, The Inflationary Universe

[Alan Guth (with help from Jenny Guth):] One of my favorite stories about Murray Gell-Mann comes from my daughter, Jenny Guth, who in the summer of 2006 was a student of theoretical neuroscience, attending a summer program for undergraduates at the Santa Fe Institute. Murray had apparently seen Jenny’s name on a list of visiting students and identified her as my daughter. He approached her one day and began a conversation with the surprising comment “I know your grandfather.” It turned out that Murray had always assumed—I suppose because Guth is not too common a name—that I was the son of Eugene Guth, a theoretical physicist who made important contributions to polymer, nuclear, and solid state physics from the 1930’s through the 1960’s. But it isn’t true.

Jenny was somewhat startled and was trying to figure out what Murray was talking about. Her actual grandfather, Hyman Guth, was not a physicist; he was the owner of a small dry cleaners in New Brunswick, New Jersey. “How do you know my grandfather,” she tried to ask. “I’ve known Eugene Guth for many years,” Murray replied, giving the name an authentic Hungarian pronunciation that made it difficult for Americans to recognize. “But that’s not my grandfather,” Jenny tried to interject, but Murray had gone into a monologue that could not be slowed down. He had apparently expected her not to recognize the name, due to the correctness of his pronunciation. He continued with a lecture about how Jenny should learn how her grandfather’s name was properly pronounced, and how she should be proud of her Hungarian roots and learn more about them. Try as she did, Jenny could not get in a word.

It is not completely clear how this conversation ended, but apparently Jenny was eventually able to cause Murray to realize that there might be a flaw in his theory about the Guth family connections. But Murray was not the kind of person to dwell on his mistakes—or even discuss them—so he quietly walked away and did not bring up the subject again.

Source: https://www.edge.org/conversation/murray_gell_mann-remembering-murray  (accessed Dec. 4, 2024).

Surgical Implantation of Autologous Dopamine Neuron Progenitor Cells (DANPCs) Into the Putamen of Patients with Parkinson’s Disease

Parkinson’s Disease

  • Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. Performed market assessment for some of the latest (2024) treatments for PD. (1) Produodopa—a new treatment approved by NICE for people with PD who experience movement-related symptoms. It’s delivered continuously by a small pump that’s inserted under the skin. (2) Vyalev—(foscarbidopa and foslevodopa) is a solution of carbidopa and levodopa prodrugs for 24-hour continuous subcutaneous infusion that’s been approved for PD motor fluctuations. (3) Crexont—a new formulation of immediate- and extended-release levodopa with carbidopa. (Levodopa is converted in the brain to dopamine, the chemical that goes missing in PD; carbidopa helps levodopa get into the brain and decreases side effects.) (4) Safinamide— a novel experimental drug that shows potential in the treatment of PD and epilepsy. It works by blocking voltage-dependent sodium and N-type calcium channels, inhibiting glutamate release. (5) Methylphenidate and atomoxetine—noradrenaline reuptake inhibitors that are being investigated for their effects on balance and gait. (6) Levodopa inhalation powder—a formulation of levodopa that can be used as needed when medication effects wear off. (7) Focused ultrasound—a minimally invasive treatment that uses beams of heat to generate acoustic energy and precisely target areas of the brain that control voluntary movement. (8) Deep brain stimulation—a surgical procedure that involves implanting electrodes in the brain to deliver electrical impulses and disrupt abnormal circuitry. (9) Bemdaneprocel—a cell therapy that’s showing positive results in clinical trials, including improved motor function and symptom control.
  • ASPIRO Clinical Trial (Phase 1 & 2a). Autologous dopamine neuron progenitor cells (DANPCs) are surgically implanted into the putamen of patients with PD. The putamen is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. The putamen is a subcortical structure that is part of a group of structures known as the basal ganglia or basal nuclei. (“Basal nuclei” is technically more accurate, because “ganglia” usually refers to clusters of nerve cell bodies outside the central nervous system.) The putamen is adjacent to the globus pallidus and together they are sometimes referred to as the lentiform or lenticular nucleus. The putamen is involved in (reward-related) learning and motor control, including speech articulation, language functions, reward, cognitive functioning, and addiction.
    • PD affects the putamen in several ways, including Dopamine depletion—PD causes a gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which leads to a depletion of dopamine in the putamen. This depletion causes motor dysfunction. Atrophy—the putamen can undergo atrophy, which is associated with motor symptoms and cognitive status.  Shape changes—The putamen can undergo shape changes, particularly in the right putamen. Decreased activity.
  • Other parts of the brain that are affected by PD include the caudate and nucleus accumbens, which can also experience dopamine depletion. Dopamine replacement therapy can partially restore motor function, but long-term treatment can lead to motor complications.
  • The effect on PD symptoms, safety and tolerability, and cell survival are assessed for 5 years post-transplant (with MRI and PET imaging scans of the brain). Safety and tolerability are assessed annually for an additional 10 years via telephone call (total follow-up of 15 years).
  • The biologic implanted, ANPD001, is an experimental product derived from autologous skin cells converted to induced pluripotent stem cells. The stem cells were differentiated into DANPCs. Dose escalation will be achieved by bilateral injection of these DANPCs into the putamen.
  • Primary outcome measures: incidence and severity of treatment emergent adverse events (TEAE) and serious adverse events. Secondary outcome measures: “ON” time without troublesome dyskinesia [Time Frame: 1 year (primary follow up) and 5 years (long term follow up)]. Post-injection change in Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II (Activities of Daily Living – ADL) and Part III (motor score) in the ON state. “ON” time or ON state simply means the period when the Parkinson’s medication is effectively managing symptoms, allowing for normal movement with minimal side effects.
  •  The anterior commissure (AC) is a bundle of nerve fibers that connects different parts of the brain and is important for communication between the brain and the body. The AC is a white matter tract that connects the two cerebral hemispheres across the midline, in front of the fornix columns. Although PD is primarily considered a gray matter (GM) disease, alterations in white matter (WM) have gained increasing attention in PD research recently. Recent evidence from MRI scans reveals correlations between WM changes and specific PD symptoms, and these WM abnormalities may be caused by changes of oligodendrocyte (OLs)/myelin in PD.

An Independent Review of Camrelizumab-Rivoceranib Combination Therapy for the Treatment of Hepatocellular Carcinoma and Rivoceranib for Gastric Cancer

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf 

https://www.researchgate.net/publication/383861594_An_Independent_Review_of_Camrelizumab-Rivoceranib_Combination_Therapy_for_the_Treatment_of_Hepatocellular_Carcinoma_and_Rivoceranib_for_Gastric_Cancer/

Abstract: The CARES-310 clinical trial compared the safety and efficacy of camrelizumab, an anti-PD-1 antibody, combined with rivoceranib, a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted tyrosine kinase inhibitor (TKI), versus the obsolete standard of care sorafenib as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC). In this independent analysis of the CARES-310 trial, potential bias in the choice of comparator and the clinical significance of the results are reexamined. Although rivoceranib (also known as “apatinib”) is approved in China to treat patients with advanced gastric cancer, the clinical trial conducted in the USA for patients with gastric cancer seems to indicate missed endpoints and weak evidence to justify FDA approval. Due to a nondisclosure agreement, the principal investigators are unable to comment on these results. However, from a table of functional benefits and harms, readers might well conclude that palliative hospice care is non-inferior to rivoceranib for patients with Stage 4 gastric cancer.

RCCEP can cause red-nevus-like, pearl-like, mulberry-like, patch-like, and even tumor-like skin lesions in patients with HCC

https://biomedres.us/pdfs/BJSTR.MS.ID.009118.pdf

Conclusion

The CARES-310 clinical trials produced a new longest median OS of 23.8 months for patients with uHCC treated with C-R.  However, the CARES-310 clinical trial may have been overweighted with an Asian population with preexposure to antiviral therapy and better preservation of liver function at time of HCC diagnosis. Conversely, the CARES-310 trial was underweighted with Western patients who have NAFLD, diabetes, obesity, and other co-morbidities and confounding factors.  Oncologists already have 1L patient treatment experience for uHCC with Roche’s FDA-approved anti-PD-L1/VEGF combination Tecentriq and Avastin and with AstraZeneca’s CTLA-4 checkpoint inhibitor Imjudo combined with its PD-L1 antagonist Imfinzi for treatment of uHCC. It would be useful to compare the C-R proposed therapy with these drug combinations and determine if C-R maintains an 8.6-month median OS advantage over the new comparator(s).

When rivoceranib plus hospice care was compared to hospice care alone in a clinical trial of patients with advanced gastric cancer or gastroesophageal adenocarcinoma, the results data were mixed. For some measures of functional benefits and harms, the patients with hospice care alone had higher percentages for certain functional benefits and lower percentages for some harms and adverse events.  The rivoceranib-treated group failed to consistently outperform hospice care alone using these measures.  Based on those benefits and harms, hospice care alone was not inferior to rivoceranib + hospice care, which calls into question the underlying clinical value, if any, of rivoceranib to the American patient population with advanced gastric cancer.  The fact that rivoceranib, known as apatinib, is approved in China for treatment of advanced gastric raises anew questions about fundamental differences in patient populations between China and the USA or Europe for medical conditions such as uHCC and advanced gastric cancer.

References

  1. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003 May 31;326(7400):1167-70. (“Systematic bias favours products which are made by the company funding the research. Explanations include the selection of an inappropriate comparator to the product being investigated and publication bias.”)
  2. Sismondo S. Epistemic Corruption, the Pharmaceutical Industry, and the Body of Medical Science. Front Res Metr Anal. 2021 Mar 8;6:614013 (“Put simply, if a pharmaceutical company funds a trial, the chances of results and conclusions in that company’s favor are increased.”)
  3. Bradley SH, DeVito NJ, Lloyd KE, Richards GC, Rombey T, Wayant C, Gill PJ. Reducing bias and improving transparency in medical research: a critical overview of the problems, progress and suggested next steps. J R Soc Med. 2020 Nov;113(11):433-443 (“[A]voidable methodological failings and biases lead to ‘research waste’, which is estimated to account for 85% of all medical research funding.”)
  4. Sismondo S (2007) Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry? PLoS Med 4(9): e286. https://doi.org/10.1371/journal.pmed.0040286[1]
  5. Mann H, Djulbegovic B. Comparator bias: why comparisons must address genuine uncertainties. J R Soc Med. 2013 Jan;106(1):30-3.
  6. Setoguchi S, Gerhard T. Comparator Selection. In: Velentgas P, Dreyer NA, Nourjah P, et al., editors. Developing a Protocol for Observational Comparative Effectiveness Research: A User’s Guide. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. Chapter 5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126184/
  7. Pinato DJ, D’Alessio A, Celsa C, Manfredi GF, Fulgenzi CAM. The price and value of therapeutic synergy in liver cancer. Lancet. 2023 Sep 30;402(10408):1108-1110.
  8. Lee, W.S., Yang, H., Chon, H.J. et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 52, 1475–1485 (2020). https://doi.org/10.1038/s12276-020-00500-y
  9. Qin S, Chan SL, Gu S, et al., CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023 Sep 30;402(10408):1133-1146.
  10. Supplement to: Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet 2023; published online July 24. https://doi.org/10.1016/S0140-6736(23)00961-3.
  11. Wang, F., Qin, S., Sun, X. et al. Reactive cutaneous capillary endothelial proliferation in advanced hepatocellular carcinoma patients treated with camrelizumab: data derived from a multicenter phase 2 trial. J Hematol Oncol 13, 47 (2020).
  12. Liu Y, Chen T, Zhang C, Pan W. Emerging Treatments for Reactive Cutaneous Capillary Endothelial Proliferation. Indian J Dermatol. 2023 Jan-Feb;68(1):85-90.
  13. Vogel A., Chan SL, Ren Z et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Final overall survival analysis of the phase 3 CARES-310 study. Journal of Clinical Oncology 42(16_suppl) https://doi.org/10.1200/JCO.2024.42.16_suppl.4110.
  14. Li, J., Qin, S., Wen, L. et al.Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study. BMC Med 21, 173 (2023). https://doi.org/10.1186/s12916-023-02841-7
  15. Liu, Angus, “FDA snubs another China-made PD-1 with rejection of Elevar, Hengrui’s liver cancer combo,” Fierce Pharma. 2024 May 17.https://www.fiercepharma.com/pharma/fda-pd-1-combo-elevar-hengrui-camrelizumab-liver-cancer
  16. Kansteiner, Fraiser, “Elevar commits $600M-plus to take Hengrui’s liver cancer cocktail to market in US and beyond,” Fierce Pharma. 2023 Oct 17. https://www.fiercepharma.com/ pharma/elevar-ponies-600m-take-hengruis-investigational-liver-cancer-cocktail-market-us-and-beyond
  17. Elevar Therapeutics, “Elevar Therapeutics Reports Plans for Near-Term Resubmission of NDA for First-Line Treatment Option for Unresectable Hepatocellular Carcinoma Following Type A FDA Meeting,” Press Release. 2024 Jul 9. https://elevartherapeutics.com/2024/07/09/ elevar-therapeutics-first-line-treatment-option/
  18. Liu, Angus, “UPDATED: Elevar, Hengrui eye accelerated refile for PD-1 liver cancer combo after surprise FDA rejection” Fierce Pharma. 2024 Jul 12. https://www.fiercepharma.com/ pharma/elevar-hengrui-eye-quick-refile-pd-1-liver-cancer-combo-after-surprise-fda-rejection

Acknowledgments

Christopher Coleman, Pharm.D., provided useful comments.

Conflict of Interests

None.

COVID-19 Treatment Strategies: September 2024 update

Moving Simulation of SARS-CoV-2 Delta Variant

Image:  Computer Simulation of SARS-CoV-2. Reprinted with kind permission of Janet Iwasa of http://animationlab.utah.edu/cova

Update September 2024

COVID-19 Treatment Strategies

  • As of 2023, a few small-molecule antiviral drugs (nirmatrelvir-ritonavir, remdesivir, and molnupiravir) and 11 monoclonal antibodies have been marketed for the treatment of COVID-19, mostly requiring administration within 10 days of symptom onset.
  • Hospitalized patients with severe or critical COVID-19 may benefit from treatment with previously approved immunomodulatory drugs, including glucocorticoids such as dexamethasone, cytokine antagonists such as Genentech’s tocilizumab, and Janus kinase inhibitors such as Lilly’s baricitinib.
  • Repurposing RNA polymerase nucleotide drugs, such as Gilead’s remdesivir and Merck’s molnupiravir, to inhibit viral RNA synthesis should have a relatively high probability of success, but it remains a trial-and-error endeavour to identify nucleotide/nucleoside analogs that escape the SARS-CoV-2 proofreading mechanism.
  • Repurposing DNA polymerase inhibitors, such as Gilead’s tenofovir, to inhibit the RNA synthesis of SARS-CoV-2 is likely to fail due to their different mechanisms of action.
  • HIV protease inhibitors, such as lopinavir, should not be repurposed for SARS-CoV-2 treatment due to the lack of similarity between the drug-binding pockets in HIV and SARS-CoV-2 proteases.
  • Except for nucleoside/nucleotide inhibitors such as tenofovir, ribavirin, and lamivudine, other virus-targeted inhibitors have not been approved by the FDA to treat more than one infectious disease. They are not good repurposing candidates because their chemical structures are often designed to target a particular drug-binding pocket with high selectivity, and thus they are unlikely to have a similar level of potency against an unrelated target.
  • Cationic amphiphilic drugs (such as hydroxychloroquine, azithromycin, and amiodarone) that induce phospholipidosis should not be repurposed, because cellular phospholipidosis is often misinterpreted as antiviral efficacy.
  • A new one-step immunoassays has been developed for rapid and sensitive detection of SARS-CoV-2 by using a single-chain variable fragment (scFv) fused to alkaline phosphatase (AP) or NanoLuc (NLuc) luciferase. First, a high-affinity scFv antibody specific to the SARS-CoV-2 nucleocapsid (N) protein was screened from hybridoma cells-derived and phage-displayed library. Next, prokaryotic expression of the scFv-AP and scFv-NLuc fusion proteins were induced, leading to excellent antibody binding properties and enzyme catalytic activities.
  • Upregulation of interleukin-6 (IL-6) has been associated with worse prognosis in COVID-19 patients. Janssen conducted a phase 2 randomized control trial to evaluate the efficacy and safety of free IL-6 sequestration by the monoclonal antibody sirukumab in severe and critical COVID-19 patients. In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19.

From Dec. 1, 2021

The CDC confirmed today the first case of the Omicron variant, which is officially known as B1.1.529,  in the United States.  The most concerning aspect of this new variant is the number of mutations associated with it.  Viruses are not living organisms; they require a host to continue or survive. The more hosts that viruses can find, the more likely they are to mutate further and potentially become more harmful to the hosts. Viruses cannot replicate on their own.  Instead they capture or “hijack” the reproductive mechanism in the host cell, redirect it to copy the genetic code of the virus, and seal it in a packet called a capsid. In a single human being, there can be a billion or even a trillion copies of the SARS-CoV-2 virus. Most of the time, these mutations or mistakes involve different amino acid sequences that may give rise to different proteins but do not enhance the ability of the virus to infect or replicate any better than the original copy. Occasionally, a mutation will increase infectivity and may, or may not, code for a new protein that the immune system fails to recognize.

The spike protein on SARS-CoV-2 interacts specifically with the ACE2 receptor, which is found on the surface of our cells mainly in the GI tract, the respiratory tract, and our vasculature. When the new  viral particles are created, they may have slightly different proteins either inside or outside the viral particle.  Of particular interest, the mutation may exist on the outer tip of the spike protein, which is called the receptor binding domain (RBD).  Our immune system recognizes the SARS-CoV-2 based on the RBD. Thus any mutation that changes the proteins in areas that make it easier for the virus to bind to our cells’ receptors or evade detection by the immune system will be advantageous to virus survival.

Let’s compare Omicron to two prior variants:  Alpha and Delta.  As to the virus particle itself, Alpha had 23 mutations, Delta had 17 mutations, and Omicron has 50 mutations.  As to the spike protein, Alpha had 9 mutations, Delta had 7 mutations, and Omicron has 32 mutations. As to the RBD, Alpha had 1 mutation, Delta had 2 mutations, and Omicron has 10 mutations.  The number and variety of mutations associated with the Omicron variant deserves serious concern.

Variants

Alpha Delta Omicron

Virus

23 mutations 17 mutations 50 mutations
Spike 9 mutations 7 mutations

32 mutations

RBD 1 mutation 2 mutations

10 mutations

Scientists are now focused on three questions: (1) what is the transmissibility of the Omicron variant?, (2) how well does it evade our current COVID-19 vaccines?, and (3) is there a change in the virulence (the variant is more deadly)?

 

From July 24, 2021

  • The Delta variant (B.1.617.2) has proven to be more contagious than the original SARS-CoV-2 (R0 = 3.5–4.5 vs R0 ~ 2.5) perhaps through better binding or better evasion of the immune system. (The spike protein of SARS-CoV-2 is coated with sugar molecules, or glycans, that help it evade the immune system.) The REACT-1 round 12 report (Imperial College London) found the Delta variant prevalence in those aged 5–49 was 2.5 times higher at 0.20% (0.16%, 0.26%) compared with those aged 50 years and above at 0.08% (0.06%, 0.11%). While people over age 50 may have higher vaccination rates, the Delta variant may pose a higher risk of infection for younger-aged individuals. As to hospitalization, The Lancet published correspondence (June 26, 2021) on a study in Scotland that the Delta variant had a 1.85 times higher risk of getting the person infected admitted to the hospital with severe COVID-19 [hazard ratio 1.85 (95% CI 1.39–2.47)].  The Scottish study used Reverse Transcription Polymerase Chain Reaction (RT-PCR) tests and a Cox regression analysis, which adjusts for age, sex, economic status/deprivation, temporal trend, and comorbidities.
  • As of July 2021, the Pfizer-BioNTech vaccine was shown to be effective against the Delta variant symptomatic infection at 88% (UK study), 87% (Canadian study), 64% (Israeli study), 79% (Scottish study), and effective against the Delta variant resulting in hospitalization at 96% (UK study) and 98% (Israeli study). The data for the Moderna vaccine are more limited and show the vaccine is 72% effective against symptomatic infection and 96% effective against hospitalization for the Delta variant after just the first dose of the two-dose vaccine. The Oxford-Astrazeneca vaccine was found to be effective against the Delta variant at 60% (UK study), 67% (Canadian study for single dose), 60% (Scottish study) for symptomatic infection and 93% (UK study), 88% (Canadian study) effective against Delta variant hospitalization. For the J&J vaccine, real-world evidence on effectiveness against the Delta variant is not yet available; however, J&J’s internal lab study showed it was highly effective against the South African variant, which was most prevalent at the time, and that the antibody response to the Delta variant is even better: a very good antibody response to the Delta variant based on lab testing.

From May 27, 2021

For early-onset COVID-19 cases (positive COVID-19 test and at-risk for progression of the disease but not experiencing symptoms requiring hospital-ization): “The FDA has halted the distribution of Lilly’s combination of bamlanivimab and etesevimab in Arizona, California, Florida, Indiana, Oregon and Washington––all states where coronavirus variants from Brazil and South Africa account for more than 10% of those with the disease. The antibody combo had previously been paused in Illinois and Massachusetts.

Providers in those states should use Regeneron’s antibody treatment of casirivimab and imdevimab, as per the FDA. Lab studies have shown that option is more effective against the Brazilian (P.1) and South African (B.1.351) strains, according to the agency.” [https://www.fiercepharma.com/pharma/fda-halts-use-lilly-covid-19-antibody-treatment-6-states-where-variants-are-prevalent]

Timing is important: MABS are very good at stopping the virus outside the cells. Once the SARS-CoV-2 has infected the cells, antibodies are not able to neutralize the virus. The patient then needs cytotoxic T-cells.

Two randomized clinical trials of Vitamin D, one from India (SHADE study) and one from Spain (calcifediol study), have shown that Vitamin D supplementation definitely benefitted patients with COVID-19. Emerging evidence shows Vitamin D combined with either or both Vitamin K2 and Magnesium potentiates the benefits of Vitamin D. Source for K2 synergy: https://pubmed.ncbi.nlm.nih.gov/29138634/

QUERCETIN in combination with vitamins C and D, may exert a synergistic antiviral action. Source: https://journals.sagepub.com/doi/full/10.1177/1934578X20976293

N-ACETYL-CYSTEINE (NAC) (600 mg) has known antiviral and liver protective properties. One argument for use with COVID-19 is https://pubmed.ncbi.nlm.nih.gov/32780893/ and another https://pubmed.ncbi.nlm.nih.gov/24968347/ and https://pubmed.ncbi.nlm.nih.gov/9230243/

SLEEP (7 – 9 hours): antibody and immune response after (flu) vaccination is improved if the patient has had a good night’s sleep, particularly the hours of sleep before midnight (slow wave sleep). Optimal T-cell production for disease prevention also requires optimal sleep. Melatonin may help patients get to sleep and has anti-viral properties. https://pubmed.ncbi.nlm.nih.gov/32347747/ https://pubmed.ncbi.nlm.nih.gov/32768490/

At the early stages of COVID-19 infection, the innate immune system is responsible for attacking the virus (primarily using monocytes & natural killer cells) through production of Interferon (IFN). SARS-CoV-2 delays the body’s IFN response. Patients with severe disease had less type I IFN activity in their blood compared to patients with mild to moderate disease. (The innate immune system diminishes with aging.) Any method to enhance the innate immune response in the early course of the disease could limit progression of COVID-19. Sauna baths, hot water baths, and other sources of human hyperthermia can induce a tenfold increase IFN-gamma synthesis. https://pubmed.ncbi.nlm.nih.gov/3132509/ These results suggest that raising the core body temperature akin to a mild fever may stimulate the innate immune system (particularly if followed by a cold shower or rapid cooling) and thereby attenuate COVID-19.

From APRIL 2020

“To be clear, SARS-CoV-2 is not the flu. It causes a disease with different symptoms, spreads and kills more readily, and belongs to a completely different family of viruses. This family, the coronaviruses, includes just six other members that infect humans. Four of them—OC43, HKU1, NL63, and 229E—have been gently annoying humans for more than a century, causing a third of common colds. The other two—MERS and SARS (or “SARS-classic,” as some virologists have started calling it)—both cause far more severe disease. Why was this seventh coronavirus the one to go pandemic? Suddenly, what we do know about coronaviruses becomes a matter of international concern.” Why the Coronavirus Has Been So Successful, The Atlantic

This article was inspired by the work of Jon Barron shown here: https://www.jonbarron.org/colds-flus-infectious-diseases/using-anti-pathogens. To combat the coronavirus, I have stocked my medicine cabinet with the following anti-viral pathogen natural products. In addition to providing the names and doses of the products, after each one, I provide the ten most recent citations from PubMed.gov pertaining to that substance and viruses.

  1. AHCC (Active Hexose-Correlated Compound) – 500 mg, taken on an empty stomach up to four capsules per day at outset of symptoms
  2. Olive Leaf Extract (Olea europaea) (standardized to minimum 20% oleuropein) – 500 mg, taken with food once or twice per day.
  3. Oil of Oregano (Origanum vulgare) (leaf) (10:1 extract) – 150 mg, taken up to four gelcaps per day with water
  4. Star Anise Oil – 1 fluid oz, blended and diluted with extra virgin olive oil or extra virgin coconut oil
  5. Minced Garlic — 1 tbsp added to main meal

 

AHCC (Active Hexose-Correlated Compound)

“Mushrooms have been used for various health conditions for many years by traditional medicines practiced in different regions of the world although the exact effects of mushroom extracts on the immune system are not fully understood. AHCC® is a standardized extract of cultured shiitake or Lentinula edodes mycelia (ECLM) which contains a mixture of nutrients including oligosaccharides, amino acids, and minerals obtained through liquid culture. AHCC® is reported to modulate the numbers and functions of immune cells including natural killer (NK) and T cells which play important roles in host defense, suggesting the possible implication of its supplementation in defending the host against infections and malignancies via modulating the immune system. Here, we review in vivo and in vitro effects of AHCC® on NK and T cells of humans and animals in health and disease, providing a platform for the better understanding of immune-mediated mechanisms and clinical implications of AHCC®.” Shin MS, Park HJ, Maeda T, Nishioka H, Fujii H, Kang I. The Effects of AHCC®, a Standardized Extract of Cultured Lentinura edodes Mycelia, on Natural Killer and T Cells in Health and Disease: Reviews on Human and Animal Studies. J Immunol Res. 2019;2019:3758576. Published 2019 Dec 20. doi:10.1155/2019/3758576 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942843/

Possible therapeutic role of a highly standardized mixture of active compounds derived from cultured Lentinula edodes mycelia (AHCC) in patients infected with 2019 novel coronavirus.

Di Pierro F, et al. Minerva Gastroenterol Dietol 2020. PMID 32162896
The outbreak of SARS-CoV-2 disease (COVID-19) is currently, March 2020, affecting more than 100000 people worldwide and, according to the WHO (World Health Organization), a pandemic is shortly expected. The virus infects the lower respiratory tract and causes severe pneumonia and mortality in approximately 10% and 3-5%, respectively, of cases, mainly among the elderly and/or people affected by other diseases. AHCC is an α-glucan-based standardized mushroom extract that has been extensively investigated as an immunostimulant both in animals and/or in humans affected by West Nile virus, influenza virus, avian influenza virus, hepatitis C virus, papillomavirus, herpes virus, hepatitis B virus and HIV by promoting a regulated and protective immune response. Although the efficacy of AHCC has not yet been specifically evaluated with respect to SARS-CoV-2 disease, its action in promoting a protective response to a wide range of viral infections, and the current absence of effective vaccines, could support its use in the prevention of diseases provoked by human pathogenic coronavirus, including COVID-19.

The prognostic factors between different viral etiologies among advanced hepatocellular carcinoma patients receiving sorafenib treatment.

Yeh ML, et al. Kaohsiung J Med Sci 2019. PMID 31254328 Free article.
Pre-treatment clinical data and viral hepatitis markers were collected and analyzed with their outcomes. The primary endpoint of the study was overall survival. …There were different prognostic factors stratified by viral etiologies in aHCC patients receiving sorafenib. Viral eradication increased survival in chronic hepatitis C patients….
Ito T, et al. Nutr Cancer 2014 – Clinical Trial. PMID 24611562
The objective of this study was to evaluate the safety and effectiveness of a mushroom product, active hexose correlated compound (AHCC), on chemotherapy-induced adverse effects and quality of life (QOL) in patients with cancer. Twenty-four patients with cancer received their first cycle of chemotherapy without AHCC and then received their second cycle with AHCC. …
Roman BE, et al. Nutr Res 2013 – Clinical Trial. PMID 23351405
In this study, we hypothesized that AHCC will also improve the immune responses of healthy individuals to influenza vaccine. …Immediately post-vaccination, the AHCC group began supplementation with AHCC (3 g/d). Flow cytometric analysis of lymphocyte subpopulations revealed that AHCC supplementation increased NKT cells (P < .1), and CD8 T cells (P < .05) post-vaccination compared to controls. …
Nogusa S, et al. Nutr Res 2009. PMID 19285605
We hypothesized that AHCC supplementation would influence the immune response to influenza infection in a dose-dependent manner. …In conclusion, these data suggest that the effects of AHCC on the immune response to influenza infection are dose dependent and that low-dose AHCC supplementation improves the response to influenza infection despite no effect on total NK cell cytotoxicity….
Wang S, et al. J Nutr 2009. PMID 19141700 Free PMC article.
AHCC administration in aged mice attenuated viremia levels but led to no difference in mortality rate. Overall, our data suggests that AHCC enhances protective host immune responses against WNV infection in young and aged mice. Dietary supplementation with AHCC may be potentially immunotherapeutic for WNV-susceptible populations….
Momiyama K, et al. Cancer Chemother Pharmacol 2009. PMID 19011857
CONCLUSIONS: The percentage of Th2 cells increased in LC patients with aHCC as the efficacy of intra-arterial combination chemotherapy decreased. These results indicated that intra-arterial chemotherapy might be not useful for patients with aHCC, because it induces Th2 dominant host immunity….

Th1/Th2 balance: an important indicator of efficacy for intra-arterial chemotherapy

Nagai H, et al. Cancer Chemother Pharmacol 2008. PMID 18259753
The aim of this study was to assess the influence of intra-arterial combination chemotherapy on the Th1/Th2 balance in LC patients with aHCC. …RESULTS: Thirteen of the 21 aHCC patients (group R) showed an objective response, but the other 8 patients (group N) showed no response. …
Ritz BW, et al. J Nutr 2006. PMID 17056815
However, the effects of AHCC on the response to viral infections have not been studied. In this study, young C57BL/6 mice were supplemented with 1 g AHCC/(kg body weight x d) for 1 wk prior to and throughout infection with influenza A (H1N1, PR8). …These data suggest that AHCC supplementation boosts NK activity, improves survival, and reduces the severity of influenza infection in young mice. …

 

OLIVE LEAF EXTRACT

“The olive tree (Olea europaea) is native to the Mediterranean region. Olive leaf extract has a long history of use against illnesses in which microorganisms play a major role. In more recent years, studies of olive leaf extracts (containing oleuropein, calcium elenolate, and/or hydroxytyrosol) were effective in eliminating a very broad range of organisms, including bacteria, viruses, parasites, yeast, mold, and fungi.25 Pio Maria Furneri, Anna Piperno, Antonella Sajia, and Giuseppe. “Antimycoplasmal Activity of Hydroxytyrosol, Antimicrob Agents.” Chemother. 2004 December; 48(12): 4892–4894. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC529223/ , 26 Harold E. Renis. “Inactivation of Myxoviruses by Calcium Elenolate.” Antimicrobial Agents and Chemotherapy Aug. 1975, p. 194-199. http://aac.asm.org/cgi/reprint/8/2/194.pdf In addition, Olive leaf has demonstrated antiviral activity against both HIV infection and replication,27 Lee-Huang S1, Zhang L, Huang PL, Chang YT, Huang PL. “Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment.” Biochem Biophys Res Commun. 2003 Aug 8;307(4):1029-37. http://www.ncbi.nlm.nih.gov/pubmed/12878215 primarily by blocking the entry of the virus into host cells in the body’s immune system.28 Bao J1, Zhang DW, Zhang JZ, Huang PL, Huang PL, Lee-Huang S. “Computational study of bindings of olive leaf extract (OLE) to HIV-1 fusion protein gp41.” FEBS Lett. 2007 Jun 12;581(14):2737-42. http://www.ncbi.nlm.nih.gov/pubmed/17537437

Studies have also shown that oleuropein exhibits a significant antiviral activity against respiratory syncytial virus and para-influenza type 3 virus.29 Ma SC, He ZD, Deng XL, But PP, et al. “In vitro evaluation of secoiridoid glucosides from the fruits of Ligustrum lucidum as antiviral agents.” Chem Pharm Bull. 2001;49:1471–1473. http://www.jstage.jst.go.jp/article/cpb/49/11/49_11_1471/_pdf In addition, it has been found to be effective against viral hemorrhagic septicemia rhabdovirus, a highly deadly and infectious virus that afflicts over 50 species of both freshwater and marine water fish. 30 Micol V, Caturla N, Perenz-Fons L, Mas L, Perez L, Estepa A. “The olive leaf extract exhibits antiviral activity against viral haemorrhagic septicaemia rhabdovirus (VHSV)” Antivir Res. 2005;66:129–136. http://www.ncbi.nlm.nih.gov/pubmed/15869811 There are studies that demonstrate that olive leaf extracts augment the activity of the HIV-RT inhibitor 3TC. In fact, cell-to-cell transmission of HIV was inhibited in a dose-dependent manner, and replication was inhibited in an in vitro experiment.31 Lee-Huang S, Zhang L, Chang YY, Huang PL. “Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment.” Biochem Biophys Res Commun. 2003;307:1029–1037. http://www.ncbi.nlm.nih.gov/pubmed/12878215 One of the suspected targets for olive leaf extract action is the HIV-1 gp41 (surface glycoprotein subunit), which is responsible for HIV entry into normal cells. In order to establish HIV protein targets of olive leaf extract and its inhibitory action at the molecular level, researchers reported a joint theoretical and experimental effort has been carried out to help achieve this goal.32 Lee-Huang S, Huang PL, Zhang D, Lee JW, Bao J, et al. “Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and Hydroxytyrosol: Part I.” Integrase Inhibition Biochem Biophys Res Commun. 2007;354:872–878. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790717/

Source: Jon Barron, Using Anti-Pathogens

[Comparison of Antiviral Effect of Olive Leaf Extract and Propolis with Acyclovir on Herpes Simplex Virus Type 1].

Altındiş M, et al. Mikrobiyol Bul 2020. PMID 32050880 Turkish. Free article.
In this in vitro study, olive leaf extract (OLE) and propolis alone or in combination with acyclovir were investigated for their antiviral efficacy in HSV-1.Toxic doses of OLE, propolis, and dimethyl sulfoxide, propolis diluent, for Hep-2 (ATCC, CCL-23) cells were determined by conventional cell culture. Using “endpoint” method, the viral dose infecting half of the cell culture (TCID50) was calculated, and viral quantity was determined with Spearman-Karber method. …

 

Oil of Oregano

Antifungal Activity of Selected Natural Preservatives against Aspergillus westerdijkiae and Penicillium verrucosum and the Interactions of These Preservatives with Food Components

Schlösser I and Prange A. J Food Prot 2019. PMID 31538828
The present study examined the influence of primary food components on the antifungal activity of the essential oil of Origanum vulgare, carvacrol, thymol, eugenol, and trans-cinnamaldehyde against Penicillium verrucosum and Aspergillus westerdijkiae. …The presence of oil had the strongest influence. At a concentration of 1% oil, the antifungal activity decreased significantly, and at 10% oil, almost no inhibition was observed. …

Star Anise Oil (Pimpinella Anisum)

[Potential antiviral therapeutics for 2019 Novel Coronavirus]

Li H, et al. Zhonghua Jie He He Hu Xi Za Zhi 2020. PMID 32164080 Chinese.
Antiviral drugs commonly used in clinical practice, including neuraminidase inhibitors (oseltamivir, paramivir, zanamivir, etc.), ganciclovir, acyclovir and ribavirin, are invalid for 2019-nCoV and not recommended. …

Screening for antiviral activities of isolated compounds from essential oils

Astani A, et al. Evid Based Complement Alternat Med 2011.
Essential oil of star anise as well as phenylpropanoids and sesquiterpenes, for example, trans-anethole, eugenol, β-eudesmol, farnesol, β-caryophyllene and β-caryophyllene oxide, which are present in many essential oils, were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. Antiviral activity was analyzed by plaque reduction assays and mode of antiviral action was determined by addition of the drugs to uninfected cells, to the virus prior to infection or to herpesvirus-infected cells. Star anise oil reduced viral infectivity by >99%, phenylpropanoids inhibited HSV infectivity by about 60-80% and sesquiterpenes suppressed herpes virus infection by 40-98%. Both, star anise essential oil and all isolated compounds exhibited anti-HSV-1 activity by direct inactivation of free virus particles in viral suspension assays. All tested drugs interacted in a dose-dependent manner with herpesvirus particles, thereby inactivating viral infectivity. Star anise oil, rich in trans-anethole, revealed a high selectivity index of 160 against HSV, whereas among the isolated compounds only β-caryophyllene displayed a high selectivity index of 140. The presence of β-caryophyllene in many essential oils might contribute strongly to their antiviral ability. These results indicate that phenylpropanoids and sesquiterpenes present in essential oils contribute to their antiviral activity against HSV.

Chemical Constituents of Essential Oils Possessing Anti-Influenza A/WS/33 Virus Activity

Choi HJ. Osong Public Health Res Perspect 2018. PMID 30584499 Free PMC article.
The chemical composition detected by GC-MS analysis, differed amongst the 3 most potent anti-viral essential oils (marjoram, clary sage and anise oils) except for linalool, which was detected in all 3 essential oils. CONCLUSION: This study demonstrated anti-influenza activity in 11 essential oils tested, with marjoram, clary sage and anise essential oils being the most effective at reducing visible cytopathic effects of the A/WS/33 virus. …

Antiviral and immunostimulating effects of lignin-carbohydrate-protein complexes from Pimpinella anisum.

Lee JB, et al. Biosci Biotechnol Biochem 2011. PMID 21389629 Free article.
Three antiviral and immunostimulating substances (LC1, LC2 and LC3) were isolated from a hot water extract of seeds of Pimpinella anisum by combination of anion-exchange, gel filtration and hydrophobic interaction column chromatographies. …

Efficacy of anise oil, dwarf-pine oil and chamomile oil against thymidine-kinase-positive and thymidine-kinase-negative herpesviruses.

Koch C, et al. J Pharm Pharmacol 2008. PMID 18957177
The effect of anise oil, dwarf-pine oil and chamomile oil against different thymidine-kinase-positive (aciclovir-sensitive) and thymidine-kinase-negative (aciclovir-resistant) herpes simplex virus type 1 (HSV-1) strains was examined. …No significant effect on viral infectivity could be achieved by adding these compounds during the replication phase. These results indicate that anise oil, dwarf-pine oil and chamomile oil affected the virus by interrupting adsorption of herpesviruses and in a different manner than aciclovir, which is effective after attachment inside the infected cells. …

Inhibitory effect of essential oils against herpes simplex virus type 2

Koch C, et al. Phytomedicine 2008. PMID 17976968
In order to determine the mode of the inhibitory effect, essential oils were added at different stages during the viral infection cycle. …These results indicate that essential oils affected HSV-2 mainly before adsorption probably by interacting with the viral envelope. …

 

Garlic

Garlic for the common cold.

Lissiman E, et al. Cochrane Database Syst Rev 2014 – Review. PMID 25386977 Free PMC article.
Background Garlic is alleged to have antimicrobial and antiviral properties that relieve the common cold, among other beneficial effects. …The trial reported 24 occurrences of the common cold in the garlic intervention group compared with 65 in the placebo group (P value < 0.001), resulting in fewer days of illness in the garlic group compared with the placebo group (111 versus 366). …

The effect of Allium sativum (Garlic) extract on infectious bronchitis virus in specific pathogen free embryonic egg.

Mohajer Shojai T, et al. Avicenna J Phytomed 2016. PMID 27516987 Free PMC article.
This study evaluated the inhibitory effects of garlic extract on IBV. MATERIALS AND METHODS: The constituents of garlic extract were detected by gas chromatography. …CONCLUSION: The garlic extract had inhibitory effects on IBV in the chickens embryo….

Compounded Tirzepatide Therapy for Weight Loss: A Health Outcomes Researcher’s Perspective

Objective:  A male health outcomes researcher, age 55 – 65, with BMI ≥ 27 kg/m2, but without type 2 diabetes, took compounded tirzepatide 7.5 mg/week therapy with a goal of losing 10% of body weight over approximately four weeks and restoring BMI ≤ 25 kg/m2.  This study was also intended to offer a more sophisticated perspective of what compounded tirzepatide therapy entails and dispel some of the hype and myths currently circulating in popular media about tirzepatide and the glucagon-like peptide 1 (GLP-1) class of injectable drugs. All previous medical journals articles that mention tirzepatide have referred to the branded product, while this article is the first one focused solely on compounded tirzepatide.

 

Methods: The patient received subcutaneous injections of 7.5 mg compounded tirzepatide over four and a half weeks.  In the first, third, and fourth weeks, the patient received 7.5 mg of compounded tirzepatide as a bolus injection.  In week 2, the 7.5 mg dose was distributed over two injections of approximately 3.75 mg each given two days apart.  The primary end point in the trial was the percentage change in body weight from initiation to end of treatment.

 

Results: With a little over four weeks of compounded tirzepatide therapy, the patient achieved a 5% reduction in body weight and a BMI = 25.8. Despite having a healthy vegan diet and supplementing with many vitamins, minerals, electrolytes, and nutrients, the patient experienced most of the adverse events associated with the branded tirzepatide drug and the GLP-1 receptor agonist class of injectable drugs. However, the study revealed an undulating pattern  in which the compounded tirzepatide lost efficacy—or the patient built up resistance/tolerance for the drug—and also produced desirable side effects, both of which were findings not previously reported in the literature. 

 

Conclusions: Although compounded tirzepatide represents a welcome addition to the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist class of drugs in chronic weight management, a 7.5 mg weekly dose of compounded tirzepatide over four weeks is unlikely to produce a lasting 10% reduction in body weight over the course of a month even for average-weight (male) patients, even for those patients practicing intermittent fasting and choosing a vegan diet, let alone those patients with the typical American eating habits and diet. Neither the Center for Medicare and Medicaid Services (CMS) nor other payers should cover the ten times more expensive branded version of these drugs for weight loss until the manufacturers can prove with real-world evidence (RWE) that the patients’ weight losses are permanent as desired. In contrast, the compounded versions of these peptide drugs are affordable and reasonable tools for continued clinical study.  

Conflict of interest statement

The author has no affiliation with any pharmaceutical firm or compounding pharmacy and no financial or ownership interest in any pharmaceutical firm or compounding pharmacy.  He has no conflicts of interests that in any way affected the research or analysis reported in this article.

Current research on drug used for obesity and weight loss

In the obesity landscape, glucagoon-like peptide-1 (GLP-1) agonists dominate the weight loss market. Amylin agonists work differently from GLP-1s but may be able to induce similar weight loss with fewer adverse events. My client wanted to understand the molecular differences between various amylin assets and their hypothetical impacts on the efficacy / adverse event profile.

Project’s key research questions/topics include:
(1) Describe the medical literature as it pertains to Amylin for obesity specifically – e.g. years researching, articles on Amylin published, clinical trials, or other types of experience – please specify.

(2) Comment on the differences between cagrilintide, petrelintide, amycretin and any other amylin agonists?

(3) Describe the theoretical physiologies of the various subsets within amylin receptors (calcitonin, AMY1R, AMY2R, AMY3R).

(4) Comment on whether the pH of the assets differ, and whether these could have material impacts on the drug profile?

(5) Comment on the solubility of cagrilintide and other amylin assets, as well as the corresponding impacts on the drug profile (e.g. half-life)?

Despite the similarities between GLP-1 and Amylin agonists (e.g. both molecular classes slow gastric emptying, decrease glucagon, and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on hyperglycemia and energy balance.

Can Proteins be Modified to Fight Diseases and Cancer?

Alternative Title: Medical Writer Michael A. S. Guth’s Summary of External Research on Cancer Treatment Using Proteolysis Targeting Chimera (PROTAC) Biochemistry and the Body’s Ubiquitin-Proteasome System (UPS) Natural Degradation Process to Eliminate Disease-Causing Proteins. Oral PROTACs have shown encouraging clinical trial results in the treatment of some genotypes (ER+/HER-) of breast cancer and in previously treated metastatic castration-resistant prostate cancer (mCRPC). PROTACs degrade a targeted protein by attaching ubiquitin molecules (a process called “ubiquitinating”) the target proteins and stopping tumor growth. PROTACs—which are bivalent chemical protein degraders—are multifunctional molecules that act on specific endogenous proteins through the E3 ubiquitin ligase pathway.

Protein degradation is required for maintaining homeostasis of cell proteins and to regulate numerous cell processes, such as gene transcription, DNA pairing, cell cycle control, and apoptosis. The UPS is a crucial way to specifically degrade proteins that are involved in various metabolic activities, mainly including cyclin, spindle related proteins, cell surface receptors (epidermal growth factor receptor, etc.), transcription factors (NF-κB, etc.), tumor suppressor factors such as p53, oncogene products, and intracellular denaturing proteins, whose deregulation is related to the pathogenesis of many diseases. UPS relies on adenosine triphosphate (ATP) and consists of two steps: polyubiquitination of target protein and proteolysis of polyubiquitin by 26S proteolytic enzyme complex. 

Compared to UPS, two conventional treatment methods, small molecule inhibitors (SMIs) and monoclonal antibodies (mAbs), suffer from some inherent limitations due to their mechanisms of actions. The FDA has approved over 62 SMIs that target about 20 different protein kinases. However, for most protein kinases, there is a lack of suitable active sites to target. In addition, molecule-targeted therapy is easy to induce drug resistance. mAbs have a large molecular weight and mainly target proteins located at the plasma membrane.

Beautiful Reflection on Water House by a Lake

Heather Cox Richardson image (002)

Pictures shot by Heather Cox Richardson while kayaking.

The State of Cancer Research

From Jon Barron’s Lessons from the Miracle Doctors book.

“Most current research is a waste of time and money. It is magic bullet nonsense. Take the search for the cancer gene. Are there genes that give one a predisposition for getting cancer? Absolutely. This is exactly what the Baseline of Health talks about when it refers to your Personal Health Line at the time of birth.

But looking for a cancer cure by finding the cancer gene will do nothing to eliminate all of the other factors responsible for cancer. And we already know how small a role the cancer gene plays in the onset of cancer: there has been an 8-fold to 17-fold increase in the incidence of cancer in the last hundred years, but not even one-millionth of 1 percent of that increase can be related to genes.

Genes evolve over hundreds of thousands (if not millions) of years, which means that the so-called cancer gene has had no impact on the huge increase we’ve seen since 1900. Virtually 90 percent of the cancer that we see today cannot possibly have anything to do with genes. So, at best, genes are responsible for only a small percentage of the minimal cancer rates we had in the early 1900s, and finding the cancer gene will affect only that tiny percentage of cancer. Genes may create tendencies, but in most cases they are not the underlying cause. Bottom line: look not for a cure in the cancer gene.

There is, however, a ray of hope in the world of medical research. In the last few years, medical research has started committing resources to the development of methods to harness and enhance the body’s natural tendency to defend itself against malignant tumors. Immunotherapy represents a new and powerful weapon in the arsenal of anticancer treatments. Sometimes referred to as biological response modifiers or as biological therapies, these new treatments–such as interferons and other cytokines, monoclonal antibodies, and vaccine therapies–have generated renewed interest and research activity in immunology.”

From Jon Barron of jonbarron.org