ESSENTIAL ELEMENTS OF THE PRESS/PULSE PROTOCOL
Glucose & Ketone control
Therapeutic metabolic control of glucose and ketone values via the administration of precision nutrition, over time, such that glucose values are consistently close to or within 55-65mg/dL (3.0-3.5mMol/L), and ketones are consistently close to or within 4-7mMol/L, and such that the threshold of glucose available to disease is chronically lowered, while normal tissue efficiently metabolizes resulting ketone bodies, which cancer cells cannot.
By what means, both experimentally and clinically, can we demonstrate to ourselves that lowering the threshold availability of glucose to disease, in fact, slows down disease progression?
How can we know, epistemologically from the history of the scientific record, that in fact, glucose and glutamine are the primary fermentable fuel substrates of any tissue of origin?
By what study design and methodology, can we know how the standard for the therapeutic zone of disease management of 3.0-3.5mMol/L blood glucose and 4.0-7.0mMol/L blood ketones, was established?
As such, let’s begin to answer these questions by reading Chapter 18 of Dr. Seyfried’s book, which you can purchase, here.
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"Blood glucose ranges between 3.0 and 3.5 mM (55-65 mg/dL) and B-OHB ranges between 4 and 7 mM should be effective for reducing tumor growth in most patients. These values are within normal physiological ranges of glucose and ketones and have antiangiogenic, anti-inflammatory, and proapoptotic effects. This treatment will induce metabolic isolation and significant growth arrest of tumor cells. We refer to these glucose and ketone levels as the zone of metabolic management."
Hyperbaric Oxygen Therapy
The implementation of Hyperbaric Oxygen Therapy, three days per week for 90 minutes per session, at 2.5AT, as a pro-oxidant, pro-apoptotic intervention.
What are the mechanisms of action by which HBOT induces tumor cell death?
By what study design and methodology are these effects demonstrated, and at what depths and durations of HBOT?
How can we ascertain and confirm that the effects of up regulated Reactive Oxygen Species as a result of HBOT, can in fact predictably induce tumour cell death, and what other conditions must be met?
Mebendazole
The independent administration of the repurposed drug, Mebendazole, at 50mg/Kg daily, as a microtubule inhibiting, anti-proliferative.
Following are some considerations as regards the use of Mebendazole as an anti-proliferative agent, and inhibitor of mitosis. One can begin to familiarize themselves generally with it’s use for managing disease, here:
Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent
Mebendazole causes degenerative alterations in the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of glucose and depletes glycogen stores. Degenerative changes in the endoplasmic reticulum, the mitochondria of the germinal layer, and the subsequent release of lysosomes, result in decreased production of adenosine triphosphate (ATP), which is the energy required for cellular survival.
Notably, Mebendazole is remarkably well tolerated, even at single doses of 10,000mg.
More to the point however, is Mebendazole’s use as a key component of the Press/Pulse protocol, which Dr. Seyfried covers here:
6-Diazo-5-Oxo-L-Norleucine
The independent administration of the novel drug 6-Diazo-5-Oxo-L-Norleucine at 0.2-0.4mg/Kg every fourth day for 6 doses prior to a two-week interval break, controls glutaminolysis.
Exactly what is 6-Diazo-5-Oxo-L-Norleucine, and why would it be included in Dr. Seyfried’s Press/Pulse protocol? Why would taking a drug which down-regulates glutaminolysis, have any detrimental effect on tumour viability?
Notably, 6-Diazo-5-oxo-L-norleucine (D.O.N.) is a glutamine antagonist, which was originally isolated from Streptomyces from a sample of Peruvian soil, just like any number of other antibiotics.
This particular diazo compound was first biosynthesized in 1956 by Henry W. Dion, et al, from lysine via three enzymes in bacteria, producing a non-proteinogenic amino acid, which was suggested as a possible cancer therapeutic.
D.O.N.’s antitumoral efficacy was confirmed in different animal models as well as a chemotherapeutic agent in different clinical studies, but was never approved. In 2019, D.O.N. was shown to kill tumor cells while reversing disease symptoms and improve overall survival in late-stage experimental glioblastoma in mice, when combined with a calorie and macronutrient controlled nutritional regimen.
Hence, D.O.N. is used as inhibitor of different glutamine utilizing enzymes. Due to its similarity to glutamine it can enter the catalytic centres of these enzymes, and inhibit them by covalent binding, or more precisely, via alkylation.
Following are the particulars of exactly which enzymes and metabolic pathways, D.O.N. targets:
Enzymes Inhibited by D.O.N.
Enzyme Metabolic pathway
Carbamoyl phosphate synthase (CAD)
CTP synthase (CTPS)
FGAR amidotransferase
Guanosine monophosphate synthetase (GMPS)
PRPP amidotransferase
Mitochondrial glutaminase
NAD synthase
Asparagine synthetase
We're Not "DON" Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine
Cortisol Control/ stress management
Stress management (cortisol control), such that glucose values remain consistently within the zone of metabolic management.
Consider the following from Dr. Seyfried’s 2017 paper (Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutrition & Metabolism | Full Text (biomedcentral.com)):
“Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1). In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models.”
So, exactly what is cortisol?
Well, it is the main glucocorticoid released from the zona fasciculata layer of the adrenal cortex. The hypothalamus-pituitary-adrenal axis regulates both production and secretion of cortisol.
Notably, the presence of glucocorticoids, such as cortisol, increase the availability of blood glucose to the brain. Cortisol acts on the liver, muscle, adipose tissue, and pancreas. In the liver, high cortisol levels increase gluconeogenesis and decrease glycogen synthesis.
Gluconeogenesis is a metabolic pathway that results in the production of glucose from glucogenic amino acids, lactate, or glycerol 3- phosphate found in triglycerides. Gluconeogenesis reverses glycolysis, a cytoplasmic pathway used to convert glucose into pyruvate molecules. This pathway is used to release energy through substrate-level phosphorylation and oxidation reactions. Unlike glycolysis, gluconeogenesis becomes active when the body needs energy. Muscles have their own internal glycogen supply that allows them to respond to changes in ATP requirements rapidly. In the presence of cortisol, muscle cells decrease glucose uptake and consumption and increase protein degradation; this supplies gluconeogenesis with glucogenic amino acids.
The following literature review offers explanatory depth as regards the function that cortisol control has on not just biochemical function, but also on lifestyle and success with disease management:
In many respects, ‘Stress Management’ is the most determinative component regarding the coherent and effective implementation of Press/Pulse, given that is consequentially a key driver of the most important aspect of predictive success- namely, consistency over time.