Welcome to the Krampade Literature Library
This is our collection of literature covering the various subjects pertinent to Krampade®. This includes potassium and its benefits, magnesium, chloride, Advantame®, and hydration. Literature is open to the public or referenced from the public abstract through the US National Library of Medicine (NLM).
Potassium
The core electrolyte in our formulations
Potassium Tissue Distribution
- Distribution of Injected Radioactive Potassium in Rats; revolutionary 1940 study in which researchers injected radioactive potassium into rats, measuring the radiation emitted to determine where the potassium had been distributed in the body. 98% of potassium is found to be in tissues, which is rapidly removed from the blood.1
- Distribution of Potassium in Liver, Kidney, and Brain of the Rat and Guinea Pig; is a 1955 study examining where inside the cell potassium is found in the liver, kidney, and brain. 65-85% is found in the soluble cytoplasm while 15-30% is found in the mitochondria. The brain had much more in the mitochondria than the other tissues with an average of 27.4 mM versus 9.9 and 10.2 mM in kidney and liver respectively.2
Potassium Regulation
- Potassium physiology; is a short review of potassium regulation and impacting factors such as the use of certain pharmaceuticals, such as beta blockers, on potassium secretion regulation.3
- Regulation of Potassium Homeostasis; is a more recent 2015 review of potassium regulation more globally, including within muscle cells and various kidney cells, under a variety of conditions.4
Potassium Intake and Requirements
- Potassium and the Diet; is a quick facts sheet outlining what you need and how activity can other conditions affect this number. A good example is how 1-2 hours of exercise makes you lose about a banana’s worth of potassium.5
- Canadian Dietary Intake Data for Adults from Ten Provinces, 1990-1997 ; is a dataset showing that Canadians are generally low in potassium consumption and high in sodium consumption.6
- Potassium; is the USDA dietary reference intake for potassium. This goes into quite a bit of detail as to what is needed each day and why.7
- Potassium Intake of the U.S. Population; is a convenient publication by the USDA that outlines what was found in the comprehensive NHANES study on potassium intake. This robust document shows how men and women chronically under-consume potassium through life.8
Potassium Replacement
- The rates of absorption of the radioactive isotopes of sodium, potassium, chlorine, bromine, and iodine in normal human subjects; is a revolutionary study in 1938 that measured gamma radiation emitting from hands after ingestion of salts made radioactive using a cyclotron. The salts were aged to isolate a specific atom, taking advantage of the variable half-lives. The salts other than potassium took 3-6 minutes to be detectable while potassium took 6 to 15 minutes to be detectable.9
- Pharmacokinetics and effects on fecal blood loss of a controlled release potassium chloride tablet; examined potassium chloride solution in comparison with a controlled release tablet of potassium chloride in humans on a controlled diet. The solution was taken up much faster after ingestion with peak urine content at 2 hours. Potassium given chronically was virtually all taken up by the body. Potassium depleted subjects took up KCl solution and, over the first couple days, presumably incorporated potassium into tissues (such as heart, which started to have a slightly abnormal rhythm) and returned blood levels to normal.10
- Pharmacokinetics of potassium chloride in wax-based and syrup formulations; is a 1985 study that examined a small sample of men on potassium changes in plasma and subsequent excretion in urine. The syrup, which is most similar to Krampade, peaked in plasma concentration at a median of 60 minutes after ingestion and was completely excreted in 36 hours.11
Potassium and Exercise
- Plasma K+ changes during intense exercise in endurance-trained and sprint-trained subjects; is a 1994 study examining the differences in potassium regulation during treadmill sprints to exhaustion and non-exhaustion. The sprint-trained athletes tended to have more potassium released into the plasma from muscles, but also cleared potassium from the plasma faster.12
- Potassium Regulation During Exercise and Recovery in Humans: Implications for Skeletal and Cardiac Muscle; is a review from 1994 on potassium flows during exercise and recovery. Peak potassium in blood is strongly correlated to exhaustion and a plateau of potassium in the plasma is found in non-exhaustive exercise. This is followed by rapid loss of potassium in the blood after exercise stops and an extended period of having less potassium in the plasma than before exercise began.13
- K+ balance in humans during exercise; is a 1996 study that examines potassium efflux rate out of exercising tissues at various exercising intensities. High intensity exercise has a rapid increase of potassium until exhaustion while non-exhaustive reaches a plateau. Low-intensity exercise does not have a significant change in plasma potassium concentration which indicates a redistribution of potassium from the exercised muscle into other tissues. Redistribution is impaired by blocking the beta-adrenergic increasing hyperkalemia while alpha-adreneric bloackade reduces hyperkalemia.14
- Potassium regulation during exercise and recovery; is a 1991 study that also examines the loss of potassium from muscles and subsequent gain of potassium in plasma. The rate of loss is directly proportional to exercise intensity and potassium loss is a direct contributor to muscle exhaustion.15
Potassium and Fatigue
- Role of exercise-induced potassium fluxes underlying muscle fatigue: a brief review; is a 1990 review of the proposed cause of muscle fatigue, focusing on the site of muscle fatigue which is identified as the membrane. The key component of muscle fatigue is the loss of potassium from inside the cell, decreasing the membrane potential, and hence, eventually lead to the inability to contract e.g. exhaustion.16
- Role of Interstitial Potassium; is a 1995 review of the unique role of interstitial (the space between tissues and blood vessels) potassium. When exercising the concentration of potassium in this compartment increases which both promotes and postpones fatigue. Higher interstitial potassium reduces the excitability of both muscle cells and motor neurons which reduces muscle contraction strength and frequency. However, interstitial potassium also increases respiration rate and blood flow to the muscle which increases the amount of fuel/nutrients available (oxygen, sugars, fats, etc) which slows fatigue.17
- Potassium and fatigue: the pros and cons; is a 1996 paper examining the conflicting data on whether calcium or potassium is the source of fatigue in exercise. The source of fatigue likely varies depending on the intensity of exercise. Intense and moderate exercise likely has the source of fatigue due to depletion of potassium and the reduction of the ability to repolarize the membrane (activation of the muscle firing mechanism) while low-intensity exercise fatigue is likely due to depletion of ATP (fuel).18
- Dynamics and Consequences of Potassium Shifts in Skeletal Muscle and Heart During Exercise; is a comprehensive 2000 review of potassium dynamics in skeletal muscle and heart. The heart has much better regulation of potassium and maintains homeostasis much better than skeletal muscle due to a much higher rate of pumping sodium out and potassium back into the cell. Otherwise, the findings are similar in that potassium shift from inside to outside the cell is the core cause of skeletal muscle fatigue during moderate to intense exercise.19
- The inhibitory effect of shakuyakukanzoto on K+ current in H9c2 cells; is a 2014 study using a model skeletal muscle cell in which it was found that inhibiting or downregulating potassium channels prevented tetany, or cramping, in cell culture. Thus, maintaining intracellular potassium levels are critical for maintaining normal muscle function.20
Potassium and Cardiovascular Health
- Potassium Feeding Reduces Hyperactive Central Nervous System Pressor Responses in Dahl Salt-Sensitive Rats; is a 1981 study using a salt-sensitive rat model of high blood pressure. Adding 2% potassium chloride reduced the change in mean blood pressure in these rats compared to the normal controls. This indicates that potassium supplementation could be beneficial to those with salt sensitivity.21
- Double-Blind, Placebo-Controlled Trial of Potassium Chloride in the Treatment of Mild Hypertension; is a 1987 study that indicated there could be a decrease in systolic blood pressure when patients are given 120 mEq or ~4680 mg of potassium each day. Interestingly, the study indicated that the African-American population could be especially sensitive to increases of potassium decreasing blood pressure.22
- Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analysis; is a comprehensive review of 22 randomized control studies. It concludes that there is high quality evidence that by increasing potassium consumption there is a correlating decrease in blood pressure, especially in hypertensive individuals. Furthermore, there is moderate evidence that increased potassium intake is correlated with a 24% lower risk of stroke. Increased potassium intake is defined in this study as ~3500 mg per day. which is below the 4700 mg per day recommended.23
Potassium and Cognition
- Potassium signalling in the brain: its role in behaviour; is a 2000 review examining how glial cells (the non-neuronal cells of the brain) redistribute potassium and alter the behavior of animals.24
Potassium and Immunity
- K+ regulates Ca2+ to drive inflammasome signaling: Dynamic visulization of ion flux in live cells; is a 2015 study studying macrophages, a kind of white blood cell, and the coordination of potassium and calcium to drive inflammasome formation to create reactive oxygen species as a part of innate immunity, but also macrophage mediate chronic inflammatory diseases. High extracellular potassium inhibits inflammasome formation which is induced by having too much calcium in the mitochondria.25
Advantame
Advantame Safety
- A two-generation reproductive toxicity study of the high-intensity sweetener advantame in CD rats; is a 2011 study examining whether Advantame poses any teratogenic risks (risks to unborn). There were no adverse effects for reproductive health or development.
- Acute and multiple-dose studies to determine the safety, tolerability, and pharmacokinetic profile of advantame in healthy volunteers; is a 2011 study examining how high levels of Advantame affect human subjects. This study showed that even at very high quantities ingested, Advantame was not quantifiable in the blood, indicating that it passes through the gut.
- Chronic oral toxicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the dog; is a 2011 study that followed dogs consuming about 2100 mg/kg body weight Advantame daily for a year. No changes were seen in a plethora of factors indicating Advantame is safe to use chronically.
- Chronic toxicity and carcinogenicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame)in the rat; is a 2011 study that followed rats consuming upwards of 3400mg/kg body weight of Advantame per day for 2 years. There was no observed adverse effect in the rats after the 2 year period.
- Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame)in the rat and rabbit; is a 2011 study that examined if Advantame could harm the offspring of rats and rabbits. There was no direct effects observed on fetal health indicating Advantame is safe for use during pregnancy.
- In vitro and in vivo assessment of the mutagenic activity of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame); is a 2011 study that evaluated whether Advantame can cause genetic mutations in both bacteria and mammalian cells. There were no mutations in any tested cell line indicating that there is not mutagenic potential of Advantame.
- Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man; is a 2011 study that examined the metabolic fate using radiolabeled Advantame. More than 90% is passed through the gut in humans and metabolites found are consistent across species.
Advantame and the Gut
- Measuring Artificial Sweeteners Toxicity Using a Bioluminescent Bacterial Panel; is a 2018 study that examined the FDA approved artificial sweeteners for their toxic effects on gut bacteria, specifically genotoxic, cytotoxic, and membrane toxicity. Interestingly, Advantame was the only FDA approved sweetener to not have any toxic effects, but did enhance growth indicating it could be a prebiotic.
- Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials; is a 2019 review of the literature in this somewhat new field. Advantame is one of the few high intensity sweeteners that did not affect the gut microbiota.
