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Chemical structure of vitamin C

Chemical structure of vitamin C

Vitamin C megadosage is the consumption of vitamin C (ascorbate) in doses well beyond the current Dietary Reference Intake. This dose is similar to the consumption of ascorbate in other primates which, unlike humans, can synthesize their own vitamin C.^[1] Nearly all animals synthesize vitamin C internally and as such, their cellular vitamin C concentrations are considerably much higher than those achieved with the Reference Daily Intake set for humans.^[2] Vitamin C is a recognized antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life.^[3] Vitamin C has been promoted in alternative medicine as a treatment for the common cold, cancer, polio, and various other illnesses. The evidence for these claims is mixed, although vitamin C is generally regarded as a beneficial antioxidant. There is a strong advocacy movement for such doses of vitamin C, despite a prolonged lack of conclusive medical evidence or large scale, formal trials in the 10 to 200+ grams per day range. Advocates criticize mainstream scientific studies for using doses which are too low, and mainly using oral vitamin C when intravenous vitamin C is preferred.

Background

Vitamin C is needed in the diet to prevent scurvy; however, from the time it became available in pure form in the 1930s, some physicians have experimented with vitamin C as a treatment for diseases other than scurvy.^[4] Orthomolecular-based megadose recommendations for vitamin C are based mainly on theoretical speculation and observational studies. The speculation arises from the fact that most animals synthesize vitamin C, and achieve much higher cellular concentrations than humans. Irwin Stone coined the term hypoascorbia to describe what he thought was a genetic defect in humans leading to a lower level of vitamin C than other primates. Observational studies began with work by McCormick and Klenner, who used intravenous vitamin C to treat a wide range of illnesses. The highest dose treatments, published clinical results of specific orthomolecular therapy regimes pioneered by Drs. Klenner (repeated IV treatments, 400–700+ (mg/kg)/day^[5][6]) and Cathcart (oral use until the onset of diarrhea,^[7] up to ~150 grams ascorbate per day for flu), have remained experimentally unaddressed by conventional medical authorities for decades.

A comprehensive systematic review of vitamin C and the cold found a minor effect (8% in adults, 14% in children) in preventing the cold, but not treating it, and a substantial effect (50%) in preventing the cold in extreme environments.^[8] The minimum dose rate in the studies examined (0.2g) was much lower than the dose advocated by megavitamin proponents. Over 0.2 g dose a day Its effect on cancer has been controversial, beginning with a heavily criticized 1976 study which found significantly increased survival among cancer patients treated with intravenous and oral vitamin C.^[9] Two subsequent studies using only oral ascorbate failed to replicate these findings,^[10] and vitamin C's use as a cancer treatment was dismissed by mainstream medicine. Recently, it has been revived by several Canadian researchers, who have focused on intravenous vitamin C.^[11] Their Phase I trial of intravenous vitamin C on cancer patients found no objective response to cancer, although no toxicity was discovered, either.^[12] However, Phase I trials are designed to assess the safety of a possible treatment, not its efficacy.^[13]

Advocates criticize mainstream scientific studies for using doses which are too low, and mainly using oral vitamin C when intravenous vitamin C is preferred.^{[citation needed]}

Dosage

Oral megadose vitamin C as a prevention element is prescribed as part of a comprehensive individualized vitamin regimen. The typical individual's pharmacokinetics of oral solubilized vitamin C requires 5 or more administrations of immediately dissolvable vitamin C for 24 hour coverage as measured by blood levels. Effective time release formulations of vitamin C may allow 24 hour coverage with only 3 oral administrations. Typical daily orthomolecular doses of oral vitamin C for preventative purposes range 5 - 25 grams of ascorbate per day in healthy adults.^{[citation needed]} Less than 2 grams per day is not considered a principled amount for orthomolecular "megadose" use in healthy people. Linus Pauling's retrospective analyses of several earlier vitamin C studies identified certain subgroups, which involved physical or cold stress, as statistically benefiting from even one gram per day against common respiratory illnesses, but this amount is not considered optimal or even a megadosed daily usage by advocates.^{[citation needed]}

Oral megadose vitamin C as an oral treatment element for infections and toxic exposures, with a comprehensive individualized or naturopathic regimen, is considered to require both a higher frequency and much greater quantity for effectiveness. Typical oral treatment frequencies with vitamin C range 15 minutes to 2 hours, the more frequent dosing considered more effective and tighter, more easy to optimize, especially during the first few hours of administration. Less frequent administrations during illness, every hour or two, reflect convenience of administration. Time release oral formulations are used for longer periods between doses such as during sleep. Pauling's recommendation of 1-2 grams of ascorbate per hour at the first sign or tickle of a cold is considered a minimal principled effort by advocates. Cathcart's "bowel tolerance" regimen, front loaded for higher frequency and amounts during the first several hours, is considered by advocates the most effective and the maximum practical oral use of vitamin C.^{[citation needed]}

The Vitamin C Foundation recommends an initial usage of up to 8 grams of vitamin C every 20–30 minutes^[14] in order to show an effect on the symptoms of a cold infection that is in progress. Equally importantly, the plasma half life of high dose ascorbate is approximately 30 minutes, which implies that most high dose studies have been methodologically defective and would be expected to show a minimum benefit. Clinical studies of divided dose supplementation, predicted on pharmacological grounds to be effective, have only rarely been reported in the literature.

Neutralization

Dissolving ascorbic acid and sodium bicarbonate in water yields a solution of sodium ascorbate and carbonic acid, which releases carbon dioxide into the water. Essentially, what you get is a solution of sodium ascorbate in seltzer water. Sodium ascorbate has been administered intravenously in doses around 50 grams, without adverse affects. Being a neutral salt, it does not upset the pH of the blood. This is not the case if you were to ingest several grams of sodium bicarbonate without ascorbic acid, which could raise the pH of the blood, potentially causing alkalosis. So, it is important not to ingest more sodium bicarbonate than necessary to neutralize the acidity of the ascorbic acid you are taking. It takes one mole of sodium bicarbonate, NaHCO3, to neutralize one mole of ascorbic acid, C6H8O6:

NaHCO3 + C6H8O6 --> NaC6H7O6 + H2CO3

One mole of sodium bicarbonate is 84 grams, and one mole of ascorbic acid is 176 grams. So, the correct (stoichiometric) ratio of sodium bicarbonate to ascorbic acid is 84/176 = 0.477. For example, it would take 477 milligrams of sodium bicarbonate to neutralize 1000 milligrams of ascorbic acid.

 Conditions

 Common cold

The results of three meta-analyses show that vitamin C in doses ranging from 200 mg to 2 grams per day reduce duration, but not incidence, of the common cold by 8% for adults and 14% for children. Incidence appears to be reduced by 50% in stressed adults such as soldiers or athletes in extreme, cold environments. The clinical significance of these effects is uncertain, but the biological effect appears genuine.^[8][15]

One researcher suggested in a 1996 article that "three of the most influential reviews" drawing the conclusion that vitamin C has no proven effects on the cold contained "serious inaccuracies and shortcomings, making them unreliable sources on the topic."^[16]

Heart disease

Vitamin C is the main component of the three ingredients in Linus Pauling's patented but unvalidated preventive cure for lipoprotein(a), which ^[17] related heart disease, the other two being the amino acid lysine and niacin (a form of Vitamin B3). Lp(a) as an atherosclerotic, evolutionary substitute for ascorbate^[18] is still discussed as a hypothesis by mainstream medical science^[19] and the Rath-Pauling related protocols^[20] have not been rigorously tested, nor have they been evaluated by the FDA (because no one has submitted a drug approval application).^{[citation needed]}

Cancer

In 1976 Linus Pauling and Ewan Cameron published a trial of 100 patients treated with intravenous vitamin C for which showed significantly increased lifespans.^[9] Two large, placebo-controlled trials of only oral vitamin C in 1979 and 1985^[21][22] did not find a positive effect of vitamin C in cancer patients. A recent in vitro study found that low levels of vitamin C inhibited tumor growth, but high levels increased tumor growth.^[23]

In 2005 in vitro (test tube) research funded by the National Institutes of Health indicated that vitamin C administered in pharmacological concentrations (i.e. intravenous) was preferentially toxic to several strains of cancer cells. The authors noted: "These findings give plausibility to intravenous ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H₂O₂ may be beneficial."^[11] In 2006 the Canadian Medical Association Journal published a case study of three individuals that demonstrated that intravenous vitamin C might subdue advanced-stage cancer, though the authors concede that spontaneous remissions have been known to occur.^[24]

In 2007, a Phase I trial of intravenous vitamin C on cancer patients was announced. The recently published trial of intravenous vitamin C on cancer patients found no objective response to cancer, although no toxicity was discovered, either.^[12] The primary purpose of this study was to evaluate the safety and tolerability of vitamin C (ascorbic acid) given by injection into the vein. (A Phase I trial assesses only the safety and tolerability of a treatment, not its efficacy.)

In September 2007 a study funded by the NIH at Johns Hopkins University found that Vitamin C prevents the growth of cancer cells in an animal model, supposedly by the elimination of the HIF-1 (hypoxia-induced factor) protein, which is necessary for cancer growth in oxygen starved environments.^[25] The authors, however, noted that this study was very preliminary and people "should not rush out and buy bulk supplies of antioxidants as a means of cancer prevention."

A pilot study of intravenous vitamin C on cancer patients was conducted in 2005. Based upon their findings, the researchers suggested that "intravenous vitamin C therapy for cancer is relatively safe, provided the patient does not have a history of kidney stone formation."^[26]

In 2008 researchers at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, gave vitamin C intravenously to mice with human derived cancers and found that it slowed tumor growth by up to 53%. By injecting into the bloodstream it is possible to get much larger amounts of the vitamin to a tumor than is possible with oral supplements. The Cancer Treatment Centers of America (CTCA) in Zion, Illinois, is currently (2008) testing the safety of intravenous vitamin C in late-stage cancer patients for whom there is no other treatment option.^[27]

Vitamin C supplementation may interfere with effective cancer chemotherapy. A 2008 study from Memorial Sloan-Kettering Cancer Center found that vitamin C was taken up by cancer cells and protected the cells from chemotherapy drugs, raising the possibility that vitamin C might impair the effectiveness of chemotherapy.^[28][29]

 Treatment of phencyclidine psychosis

Large dosages of vitamin C can be used in the acute treatment of phencyclidine (PCP) psychosis, It operates as a secondary rather than primary treatment. Usually, 1000-2000 mg. of vitamin C are given intravenously over the course of 5–10 minutes. It is given in combination with a DA-2 antagonist such as haloperidol or risperidone. The antagonist is given intramuscularly and not combined with vitamin C. The vitamin acts synergistically with phencyclidine or its metabolites.^[30]

Gout

In 2008 researchers established that higher vitamin C intake reduces serum uric acid levels, and is associated with lower incidence of gout. The effect is more pronounced as intake increases into the megavitamin range.^[31]

Diabetes

In 2009 a study found that intravenous megadosage of vitamin C, given in conjunction with insulin can repair the damage to blood vessels caused by diabetes.^[32][33]

Lifespan

A 10-year study from UCLA showed that in a population of more than 11,000 US adults aged 25–74, men who took 800 mg of vitamin C daily lived about six years longer than men who took only 60 mg of vitamin C daily.^[34] Nevertheless, this study has been challenged on the basis that the age structure of the group taking vitamin C was different from that of the men who did not, thus creating a misleading result.^[35] The authors of this second, seemingly contradictory, study, taking into account details such as overall food consumption, found no evidence of such a protective effect.

Possible adverse effects

While being harmless in most typical quantities, as with all substances to which the human body is exposed, vitamin C can still cause harm under certain conditions. In the medical community, these are known as contraindications.

• As vitamin C enhances iron absorption for iron deficiency, iron overload may become an issue to people with rare iron-overload conditions, such as Beta (β) thalassemias.

• A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD), can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances (favism), such as very large dosages of vitamin C. There are common, inexpensive tests for G6PD deficiency.

• There is a longstanding belief among the mainstream medical community that vitamin C causes kidney stones, which seems based little on science.^[36] Although some individual recent studies have found a relationship^[37] there is no clear relationship between excess ascorbic acid intake and kidney stone formation.^[38]

Side-effects

Although vitamin C can be well tolerated at doses well above the RDA recommendations, megadosing may cause side effects such as stomach upset and laxative effects such as diarrhea. The dose at which these effects may occur varies with the individual and health condition.

• High quantities of any acid will raise the acidity of the stomach and potentially cause heartburn, but the pH of the acid can be simply neutralized with baking soda if mixed in ratio 1,000 mg L-ascorbic acid / 477 mg baking soda. Too much of baking soda makes the solution salty, too little will leave the solution tasting sour, just right will make it neutral with no taste. This process has no effect on vitamin C content, only on the pH of the solution and taste.
• Relatively large doses of vitamin C may cause indigestion, particularly when taken on an empty stomach. This generally occurs at doses larger than 10,000 mg / day, but may occur at much higher doses if the patient is ill.^[39]
• When taken in large doses, vitamin C causes diarrhea. The minimum dose that brings about this laxation effect varies on the individual. The amount of vitamin C that is just short of the dose which produces diarrhea has been called the "bowel tolerance" dose. It is said to range from 4 to 15 grams per day in healthy individuals, and up to 200 grams per day or more illness. Robert Cathcart M.D. reported that the sicker a patient is, the more ascorbic acid he can tolerate by mouth before diarrhea is produced.^[40]
• It has been suggested that large doses of acidic vitamin C solution (ascorbic acid) swished around the mouth, rather than swallowed directly without a neutral rinse, may erode dentition.^[41]
• A 31-year-old Australian woman who had received a kidney transplant died soon afterward as a result of calcium oxalate deposits that destroyed her new kidney function. Doctors concluded that high-dose vitamin C therapy should be avoided in patients with kidney failure.^[42] However, oxalate-induced kidney failure has been reported in people with no apparent kidney problem.^{[citation needed]}
• It has been speculated that high dosage vitamin C ingestion may cause early onset of puberty in females. The source of the vitamin is said to be independent of the effect.^{[43][verification needed]}

Chance of overdose

As discussed previously, vitamin C generally exhibits low toxicity. The LD₅₀ (the dose that will kill 50% of a population) is generally accepted to be 11900 milligrams per kilogram in rat populations.^[44] Vitamin C proponent Dr. Robert Cathcart M.D. reports that he has used intravenous doses of 60 grams, with simultaneous oral doses of unspecified amount, with no adverse effects.^[7]

Conflicts with prescription drugs

Pharmaceuticals designed to reduce stomach acid, such as the proton pump inhibitors (PPIs), are among the most widely-sold drugs in the world. One PPI, omeprazole (Prilosec), has been found to lower the bioavailability of vitamin C by 12%, independent of dietary intake. The probable mechanism of vitamin C reduction, intragastric pH elevated into alkalinity, would to all other PPI drugs, though not necessarily to doses of PPIs low enough to keep the stomach slightly acidic.^[45]

Potential harmful effects

• Some test-tube experiments have interpreted that Vitamin C may have possible adverse effects on decomposition of lipid peroxides^[46] in nonviable in vivo quantities and conditions^[47] and inhibit caspase-8 dependent apoptosis.^[48] In April 1998 the journal Nature reported pro-oxidant effects of excessive doses of vitamin C / ascorbic acid.^[49] The effects were noted in test tube experiments and on only two of the 20 markers of free radical damage to DNA. They have not been supported by further evidence from living organisms.^[47]

• In June 2004, Duke University researchers reported an increased susceptibility to osteoarthritis in guinea pigs fed a diet high in vitamin C. However, a 2003 study at Umeå University in Sweden, found that "the plasma levels of vitamin C, retinol and uric acid were inversely correlated to variables related to rheumatoid arthritis disease activity."

• A speculated increased risk of kidney stones may be a side effect of taking vitamin C in larger than normal amounts (more than 1 gram). The potential mechanism of action is through the metabolism of vitamin C to dehydroascorbic acid, which is then metabolized to oxalic acid,^[50] a known constituent of kidney stones. However, this oxalate issue is still controversial, with evidence being presented for^[51] and against^[52] the possibility of this side effect.

• "Rebound scurvy" is a theoretical, never observed, condition that could occur when daily intake of vitamin C is rapidly reduced from a very large amount to a relatively low amount. Advocates suggest this is an exaggeration of the rebound effect which occurs because ascorbate-dependent enzyme reactions continue for 24–48 hours after intake is lowered, and use up vitamin C which is not being replenished.

• Some writers^[53] have identified a risk of poor copper absorption from high doses of vitamin C. Ceruloplasmin levels seem specifically lowered by high vitamin C intake. In one study, 600 milligrams of vitamin C daily led to lower ceruloplasmin levels similar to those caused by copper deficiency.^[54] In another, ceruloplasmin levels were significantly reduced.^[55]

• Some alternative medicine proponents suggest that doses of around 6-10 grams per day of vitamin C can induce an abortion in women under 4 weeks of pregnancy.^[56] This is based on evidence that high-dose vitamin C increases estrogen levels that may contribute to abortion in early-stage pregnancy, and that these properties have been demonstrated in laboratory animals.^[57] This theory however is in direct opposition to Dr. Klenner's claim that there were no miscarries in over 300 consecutive pregnant patients who received 3g to 6g per day of Vitamin C,^[58] whereby Dr. Klenner concluded that failure to use this agent in sufficient amounts in pregnancy borders on malpractice.

Genetic deficiency and broad spectrum hypotheses

Since its discovery vitamin C has been considered almost a universal panacea^{[citation needed]} by some, although this led to suspicions of it being overhyped by others.^[59]

Humans and higher primates, as well as guinea pigs and small number of other animal species, carry a mutated and ineffective form of the enzyme L-gulonolactone oxidase, the fourth and last step in the ascorbate-producing machinery. This mutation likely occurred 40 to 25 million years ago (in the anthropoids lineage). The three surviving enzymes continue to produce the precursors to vitamin C but the process is incomplete and the body then disassembles them.

It is agreed by most researchers, proponents and critics altogether, that the amounts of vitamin C consumed by our common anthropoid ancestor in its normal habitat (African rainforests) was amply sufficient to prevent death from scurvy and did not limit its ability to reproduce: i.e., it was an evolutionarily feasible change. Bourne^[60] (quoted in Stone^[61]), Pauling^[1] and, recently, Milton,^[62] showed that these amounts were likely 10 to 20 times higher than what modern humans consume when eating cultivated species, as opposed to the less palatable vitamin-C-rich plant species growing in rainforests.

Linus Pauling's popular and influential book How to Live Longer and Feel Better, first published in 1986, advocated very high doses of vitamin C.

In the 1960s, the Nobel-Prize-winning chemist Linus Pauling, after contact with Irwin Stone, began actively promoting vitamin C as a means to greatly improve human health and resistance to disease. His book How to Live Longer and Feel Better was a bestseller and advocated taking more than 10,000 milligrams per day orally, thus approaching the amounts released by the liver directly into the circulation in other mammals: an adult goat, a typical example of a vitamin-C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and as much as 100,000 mg daily when faced with life-threatening disease, trauma, or stress.^[63] Pauling's book sold widely and many advocates today see its influence as the reason there was a marked downward trend in US heart disease from the early 1980s onwards.^{[citation needed]}

Stone's work also informed the practise of Dr. Robert Cathcart, in the 1970s and 1980s. Cathcart developed the concept of bowel tolerance, the use until the onset of diarrhea, followed by tapering of dose. He found that, unlike healthy people, seriously ill persons could tolerate levels of hundreds of grams per day before their bowel tolerance limit is reached.

Matthias Rath is a controversial German physician who once worked with Pauling and published in the National Academy of Sciences.^[64][65] He is an active proponent and publicist for high dose vitamin C. Pauling's and Rath's extended theory ^[66] states that deaths from scurvy in humans during the ice age, when vitamin C was scarce, selected for individuals who could repair arteries with a layer of cholesterol, provided by lipoprotein(a), a lipoprotein found in vitamin C-deficient species (higher primates and guinea pigs). Pauling and Rath theorised that, although eventually harmful, lipoprotein deposition on artery walls was beneficial to the Human species and a "surrogate for ascorbate" in that it kept individuals alive until access to vitamin C allowed arterial damage to be repaired. Atherosclerosis is thus a vitamin-C-deficiency disease.

Based on another study by Pauling and colleagues published in the National Academy of Sciences^[67] and other studies,^[68][69][70] Rath argued publicly that high doses of vitamin C can be effectively used against viral epidemics such as HIV,^[71] SARS and bird flu.^[72][73]

It has been suggested by some advocates that vitamin C is really a food group in its own right, like carbohydrates or protein, and should not be seen as a pharmaceutical or vitamin at all. {Irwin Stone: "The Healing Factor"}

Genetic rationales for high doses

Four gene products are necessary to manufacture vitamin C from glucose. The loss of activity of the gene for the last step, Pseudogene ΨGULO (GLO) the terminal enzyme responsible for manufacture of vitamin C, has occurred separately in the history of several species. The loss of this enzyme activity is responsible of inability of guinea pigs to synthesize vitamin C enzymatically, but this event happened independently of the loss in the haplorrhini suborder of primates, including humans. The remains of this non-functional gene with many mutations are, however, still present in the genome of the guinea pigs and in primates, including humans.^[74][75] GLO activity has also been lost in all major families of bats, regardless of diet.^[76] In addition, the function of GLO appears to have been lost several times, and possibly re-acquired, in several lines of passerine birds, where ability to make vitamin C varies from species to species.^[77]

Loss of GLO activity in the primate order supposedly occurred about 63 million years ago, at about the time it split into the suborders haplorrhini (which lost the enzyme activity) and the more primitive strepsirrhini (which retained it). The haplorrhini ("simple nosed") primates, which cannot make vitamin C enzymatically, include the tarsiers and the simians (apes, monkeys and humans). The suborder strepsirrhini (bent or wet-nosed prosimians), which are still able to make vitamin C enzymatically, include lorises, galagos, pottos, and to some extent, lemurs.^[78]

Stone^[79] and Pauling^[80] calculated, based on the diet of our primate cousins^[81] (similar to what our common ancestors are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day.

The established RDA has been criticized by Pauling to be one that will prevent acute scurvy, and is not necessarily the dosage for optimal health.^[82]

Regulation of vitamin C

Regulation

There are regulations in most countries which limit the claims on the treatment of disease that can be placed on food, drug, and nutrient product labels. Regulations include:

• Claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the Food and Drug Administration (in the USA, and by the corresponding regulatory agencies in other countries) unless the substance has gone through a well established clinical trial with neutral oversight.
• In the United States, the following notice is mandatory on food, drug, and nutrient product labels which make health claims: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.^[83]

Advocacy arguments

Vitamin C advocates argue that there is a large body of scientific evidence that the vitamin has a wide range of health and therapeutic benefits but which they claim have been ignored. They claim the following factors affect the marketing and distribution of vitamin C, and the dissemination of information concerning the nutrient:^[84]

• There is some evidence of the applications and efficacy of vitamin C, but governmental agency dose and frequency of intake recommendations have remained relatively fixed. This has led some researchers to challenge the recommendations. In 2003 Steve Hickey and Hilary Roberts of the Manchester Metropolitan University published a fundamental criticism of the approach taken to fix the nutritional requirement of vitamin C. They again argued in 2004 that the RDA which is based on blood plasma and white blood cell saturation data from the National Institutes of Health (NIH) was based on flawed data.^[85] According to these authors, the doses required to achieve blood, tissue and body "saturation" are much larger than previously believed. They allege that the Institute of Medicine (IoM) and the NIH have failed to respond to an open letter from a number of scientists and medical researchers, notably Doctors Steve Hickey, Hilary Roberts, Ian Brighthope, Robert Cathcart, Abram Hoffer, Archie Kalokerinos, Tom Levy, Richard Passwater, Hugh Riordan, Andrew Saul and Patrick Holford, which called for revision of the RDI (Reference Daily Intake).

See also

Food portal

• Ascorbic acid
• Micronutrient
• Macronutrient
• Megavitamin therapy
• Orthomolecular medicine
• Uric acid
• Vitamin

Posted by Katherina Perez.