Welcome to the Krampade Literature Library
This is our collection of literature covering the various subjects pertinent to Krampade®. 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. Another exceedingly important point is that there is no tolerable upper oral intake limit on potassium in healthy individuals.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. Highlights include that 4.7 grams of potassium reduces salt-sensitive hypertension (high blood pressure), higher potassium intake and lower sodium intake lowers blood pressure, stroke risk, increases bone density, and decreases kidney stone formation.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, with men consuming ~3172 mg per day and women consuming ~2408 mg per day.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 and was much more bioavailable than the wax-based pill form.11
- New Guidelines for Potassium Replacement in Clinical Practice; argues the point that every effort should be made to keep serum potassium levels above 4.0 mmol despite 3.5 mmol being considered clinically normal.
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. Adrenaline increases the plasma potassium concentration and arterial potassium is the primary factor for interstitial potassium concentration. Hence, adding exogenous potassium shifts the balance driving potassium back into cells and delays fatigue.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. Repeated bouts of exercise extend the length of time to potassium reuptake by the cells resulting in increased recovery time required prior to another bout of exercise. Adding an external source of potassium, such as Krampade, is likely to speed recovery.15
- Skeletal Muscle Resting Membrane Potential in Potassium Deficiency; is a groundbreaking 1973 study examining what was observed in man, specifically soldiers during basic training, on animal models. Dogs had significantly depressed action potential, -54.8 mV prior to potassium depletion versus -90.1 mV in the same dogs after potassium depletion. The dogs had observed muscle cell death due to necrosis and some had signs of paralysis.
- On the Mechanism of Rhabdomyolysis in Potassium Depletion; is an extension of the study above and determined that rhabdomyolysis (muscle cell death) by necrosis is a result of decreased blood flow to potassium depleted muscles during exercise which was only increased 19%, drastically less than 136% increase in the same dogs with normal potassium. Potassium infusion increased blood flow in resting muscles of both normal (90%) and depleted dogs (63%), but potassium depleted dogs lagged behind when exercised (50% increase in potassium infused normal dogs versus a 4% decrease in potassium depleted dogs). Tissue slices demonstrated significant muscle cell deformity and death and immune cell infiltration. Blood indicators of rhabdomyolyisis in the dogs mirrored that seen in Army recruits and football players that had signs of rhabdomyolysis and were potassium depleted.
- Pathophysiology of Intense Physical Conditioning in a Hot Climate; is a revolutionary study done by the US Army to determine a cause of the 1700 cases of heat injury per 100,000 Soldiers stationed in the Southwest United States in the late 1960s. These otherwise healthy young men had complications of rhabdomyolysis and renal failure when suffering heat stroke. The study found that during the first 2 weeks of basic training in the heat, recruits lost 20% of their total body potassium despite consuming 3900 mg potassium per day. While potassium loss decreased considerably when not training after a recruit became potassium depleted, training increased aldosterone production and potassium loss remained the same when training and already potassium depleted. Interestingly, increased sodium intake had no effect on potassium loss during training, but did show increased sodium loss in urine and sweat. This study demonstrates that to combat heat injury significantly increasing potassium intake is a key component of combating heat injury.
Potassium and Fatigue
- Plasma potassium changes with high intensity exercise; investigates how potassium fluxes in muscle tissue during repeated bouts of intense exercise. Repeated bouts of exhaustive exercise resulted in lower peak plasma potassium and also less time to reach exhaustion. Muscles become hyperpolarized after cessation of exercise for at least 3 minutes resulting in difficulty of triggering a muscle contraction.
- 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 in exercise higher than 2 contractions per second (aka moderate to intense exercise) 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
- Elevated muscle glycogen and anaerobic energy production during exhaustive exercise in man; is a 1992 study that determined that increased muscle glycogen stores results in more potassium being released during a single bout of exercise and faster potassium recovery after a single bout of exercise. Interestingly, there was no difference in subsequent bouts.
- 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 Kidney Function
- Potassium depletion in permanent inhabitants of hot areas; is a study examining how miners that live and work in the heat (113-117°F) become potassium deficient. These miners are unable to concentrate their urine with none above 1200 mOsm/kg and 30% below 800 mOsm/kg, but when supplemented with 8 grams of potassium per day for 1 week their kidney function recovered and their urine concentration became normal with 21% of miners having urine above 1200 mOsm/kg and only 7% below 800 mOsm/kg.
- The Renal Lesions of Electrolyte Imbalance: The Structural Alterations in Potassium-Depleted Rats; is a 1957 study that examined anatomical changes in the rat kidney as a result of potassium depletion. During the early stage of potassium depletion the kidneys developed lesions in the collecting tubules. These developed into swelling and hyperplasia (excessive cell division rate) in which the mitochondrial pattern changes and cell death occurs while rapid division attempts to maintain kidney function. These disturbances can be linked to an inability to concentrate urine.
- The Renal Lesions of Electrolyte Imbalance: The Combined Effect on Renal Architecture of Phosphate Loading and Potassium Depletion; is an extension of the 1957 study in which lower dose phosphate loading and potassium depletion are examined together. The potassium depletion acts synergistically with the moderate phosphate load and exasperates the phosphate-specific alterations in kidney anatomy seen in high dose phosphate loading.
- A Prospective Study of Dietary Calcium and Other Nutrients and the Risk of Symptomatic Kidney Stones; is a 1993 study that shows that increasing potassium intake lowers the incidence of kidney stone formation.
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
Potassium and Diabetes
- Effects of potassium supplements on glucose metabolism in African Americans with prediabetes: a pilot trial; is a clinical trial in which participants averaged 2456 mg of potassium per day in their normal diet. Participants were given an additional 1500 mg of potassium for 12 weeks bringing them to an average of 3956 mg per day, which is still short of the 4700 mg per day recommended. The potassium supplementation resulted in a significant decrease in fasting glucose, showing that increased potassium intake may help with controlling prediabetes.
- Serum an Dietary Potassium and Risk of Incident Type 2 Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study; is a large clinical study that demonstrated that individuals with a plasma potassium level below 4.5 mEq/L have a higher incident rate of becoming type 2 diabetic. This rate increases when low serum potassium is combined with diuretic use and is measurable over an extended time period.
- Potassium intake and risk of incident type 2 diabetes mellitus: theCoronary Artery Risk Development in Young Adults (CARDIA) Study; is a large clinical study that young people with low urinary potassium levels have a higher incidence of developing type-2 diabetes. Furthermore, those with low potassium intake also have higher incidence of developing type-2 diabetes.
- Serum potassium is a predictor of incident diabetes in African Americans with normal aldosteron: the Jackson Heart Study; is another clinical trial focusing on African Americans that showed that subjects with serum potassium above 4.3 mmol/L have significantly lower risk of developing type-2 diabetes than those with serum potassium lower than 4.1 mmol/L
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.
Sodium
Sodium Intake
- Sodium intake status in United States and potential reduction modeling: an NHANES 2007-2010 analysis; is a comprehensive study that shows both men and women have significantly higher sodium intake of ~4400 and ~3000 mg per day respectively, than the 2300 mg per day limit. Overall sodium intake has remained unchanged from 2001-2010, though intake per kg food has decreased.
Sodium Regulation
- Sodium and Chloride; is a comprehensive review of sodium chloride intake, regulation, and corresponding health issues. An obligatory minimum of 185 mg of sodium is required per day. The rate of sodium loss is highly variable and is determined by the amount of sodium ingested. Sodium balance can be maintained even under hot conditions and acclimation to heat is a rapid process in which sodium lost in sweat can decrease from, for example, 11.2 g per day to 1.6 g per day without a decrease in total body sodium. This means that reduced sodium intake is unlikely to affect physical performance. Other risk factors associated with high (above 2.3 grams per day) sodium intake include higher calcium excretion and hence kidney stone formation, increased blood pressure, higher incidence of cardiovascular disease, more severe asthma, higher risk of stomach cancer, and impeded post exercise lung function. The upper limit of sodium consumption is established at 2.3 grams per day.
- The effect of sodium balance on sweat sodium secretion and plasma aldosterone concentration; is a foundational study that demonstrates that sodium balance can be maintained under extreme conditions, 104°F for extended periods, independent of sodium intake, in this case 1.5, 4.0, or 8.0 grams per day. The only discernible affect of high sodium intake is a lowering of aldosterone levels under the hot conditions relative to the low sodium intake group.
Sodium and Cognition
- Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response; is a pioneering study in mice that shows how high sodium intake may increase the risk of neurodegenerative disease via constriction of blood vessels in the brain. This occurs as the sodium increases TH17 production from T-helper cells (a type of immune cell) in the gut. TH17 then inhibits nitric oxide production (normally causes vasodialation) and results in restricted blood flow in the brain. The high salt animals had significant cognitive decline, but were able to recover when the high sodium diet was removed.
Sodium and Cardiovascular/Kidney Function
- Dietary Sodium and Health: More Than Just Blood Pressure; is an interesting review of sodium literature. High sodium intake stiffens arterial endothelial cells and also damages the pericellular matrix which can lead to atherosclerosis. High sodium intake also increases the mass of the left ventricle of the heart independent of blood pressure which increases the risk of cardiovascular complications such as heart attack or stroke, but can be reduced by decreasing sodium intake. High sodium intake also decreases plasma flow in and filtration rate while increasing protein excretion in the kidney. This proteinuria affect can be reduced by reducing sodium intake. When sodium intake is chronically high the sympathetic nervous system may become disrupted resulting in salt-sensitive hypertension. The amount of sodium required to maintain homeostasis in most adults is only 500 mg, far below the 2300 mg upper limit and the 4400 and 3000 mg ingested by men and women on average respectively.
- Effect of Plasma Sodium on Aldosterone Secretion during Angiotensin 2 Stimulation in Normal Humans; is a small clinical trial that demonstrated that small increases of sodium can substantially alter aldosterone secretion, but only when Angiotensin 2 levels are elevated.
