Pantothenic Acid Gregory S

Monograph amr

Pantothenic Acid Gregory S. Kelly, ND

Description

Pantothenic acid (vitamin B5) is a water-soluble Unless otherwise speci!ed, the supplemental

B-complex vitamin that was identi!ed in 1933, form of vitamin B5 used in studies referenced in isolated and extracted from liver in 1938, and !rst this monograph is calcium pantothenate. synthesized in 1940.1 R. J. Williams is credited with coining the name from the Greek word Dietary Sources and Intake panthos, which translates as “from everywhere.” It Foods that are considered to be exceptionally was given this name because of its widespread good dietary sources of pantothenic acid include presence in food.2 peanut butter (5-8 mg/100 g), liver (5-7 mg/100 g),

Most vitamin B5, and its derivatives or precur- kidney (4-6 mg/100 g), peanuts (2-3 mg/100 g), sors, added to foods and beverages, or used in almonds (2-3 mg/100 g), wheat bran (2-3 mg/100 dietary supplements, is made by chemical synthe- g), cheese (1.5 mg/100 g), and lobster (1.5 mg/100 2,3 sis. Only the Dextrorotatory (D) isomer of g). "e vast majority of vitamin B5 in foods is found pantothenic acid – D-pantothenic acid – possesses already incorporated into Coenzyme A (CoA) and biologic activity. Pure D-pantothenic acid can be as phosphopantetheine.2 Re!ning, freezing, used as a dietary supplement: it is water-soluble, canning and cooking food causes losses of panto- viscous, and yellow in color. Because D-pantothenic thenic acid, so a modern processed food diet would

acid is relatively unstable – it can be destroyed by be expected to have lower amounts of vitamin B5 heat and acid and alkaline conditions – the more than a whole foods diet.2 stable calcium pantothenate is the form of vitamin "e Dietary Reference Intake (DRI) is 5 mg/d of

B5 usually found in dietary supplements. It is pantothenic acid for males and females 14 years water-soluble, crystalline, and white in color. Ten old and over, 6 mg/d during pregnancy, and 7 mg/d mg of calcium pantothenate is approximately during lactation.7 A 1981 study estimated that the equivalent to 9.2 mg of pure D-pantothenic acid.2 average American diet contains about 5.8 mg/d of [Note: A monograph on pantethine was pub- pantothenic acid.8 A 2010 population study lished in volume 15 of Alternative Medicine Review conducted in Japan, using data from the Nation in 2010.5] Health and Nutrition Survey, estimated a daily "e disulphide form of pantothenic acid – pante- intake of 4.52 mg/d of pantothenic acid.9 thine – is also available as a dietary supplement. While the average intake appears to approximate Gregory S. Kelly, ND – Senior "is is considered to be the most active form of the DRI, subsets of the population might be at editor for Alternative Medicine vitamin B because it contains the sulfhydryl-group higher risk for insu#cient intake. A dietary Review; consultant for 5 Lifestrive; co-owner of Health needed for biological activity in Coenzyme A analysis of healthy adolescents reported that 49 4 Coach; author of the book (CoA). percent of the females and 15 percent of the males Shape Shift. A liquid form of vitamin B5 – dexpanthenol, consumed less than 4 mg/day of pantothenic acid Email: [email protected] D-pantothenyl alcohol, D-panthenol, or panthenol in their diet.10 A study of Hispanic children, – is also available. "is is an alcohol pro-vitamin of considered to be of low socioeconomic status,

vitamin B5 (i.e., it is converted into pantothenic conducted in Houston, Texas, indicated that acid in the body), which is used primarily as a pantothenic acid intake was extremely variable and topical or injected form for cosmetic purposes or below recommended intake for many of the wound healing.6 studied subjects.11 "e diet of residents of a

northern Utah nursing home had a mean daily -cardiolipin), as well as plasmalogen, sphingenin, Keywords: pantothenic 12 acid, vitamin B5, B5, acne, pantothenic acid content of 3.75 mg. A study and ceramide, require CoA. Directly or indirectly, adrenal, aldehydes, alopecia, conducted at a long-term care facility for the aged CoA is involved in the breakdown of the carbon anti-aging, celiac, chemicals, a#liated with the University of Toronto’s Medical skeleton of most of the amino acids. "e break- ergogenic, hyperlipidemia, lifespan, lupus, obesity, School reported that neither of the two most down of the pyrimidine bases, cytosine, uracil, and osteoarthritis, rheumatoid commonly fed diet types – unrestricted diet and thymine, is also dependent on CoA.2 arthritis, SLE, stress, lactose-free diet – supplied su#cient quantities of ACP is involved in fatty acid synthases, ulcerative colitis, wounds pantothenic acid.13 A study conducted in 100 polyketide synthases, lysine synthesis, and free-living elderly individuals in Greece reported nonribosomal peptide synthetases.2 that their Mediterranean-style diet was insu#cient Most plants and microorganisms accomplish in pantothenic acid.14 biosynthesis of pantothenic acid by enzymatically Other circumstances might also be risk factors combining pantoic acid with ß-alanine. Mammals for insu#ciency. A study reported that pantothenic lack the enzyme for this synthetic step, so are acid levels were signi!cantly lower in females using unable to synthesize pantothenic acid.3 oral contraceptives compared with females who In mammals, endogenous synthesis of CoA and were not.15 "e daily mean dietary intake of ACP can begin with pantothenic acid. "e biosyn- pregnant women was estimated as 2.75 mg/1,000 thetic pathway begins with a phosphorylation kcal.16 "is would supply an inadequate amount of reaction catalyzed by a magnesium-dependent pantothenic acid for pregnant women consuming enzyme – pantothenate kinase (also called panto- the low-to-moderate range of recommended thenic acid kinase) – resulting in the formation of calories during pregnancy. "e mean pantothenic 4’-phosphopantothenic acid (4’-PPA).2,3,19 "is step acid intake of lactating women was estimated as is considered the most important control step in 7.6 mg/d over a 6-month period,17 which exceeds the biosynthesis of pantothenic acid-dependent their DRI.7 enzymes.2 "e next step is a condensation reaction To elicit severe signs of pantothenic acid with cysteine, producing 4’-phosphopantothenoyl de!ciency in mice, treatment with an antibiotic is cysteine. In the absence of cysteine, 4’-PPA will necessary. Presumably this occurs because su#- accumulate, suggesting that the absence of cient pantothenic acid to ward o$ signs of severe cysteine as a substrate is a limiting factor in the de!ciency is produced by intestinal bacteria.18 It’s biosynthesis of pantothenic acid’s down-line possible that intestinal %ora contributes to overall metabolites. 4’-Phosphopantetheine (4’-PP) is then 2,3 vitamin B5 status in humans; however, this area formed by a decarboxylation reaction. "e has not been investigated. reaction rate of this enzymatic step is also increased by the availability of protein-sulfhydryl Biochemistry compounds such as cysteine.20 "e !nal two steps Pantothenic acid is used in CoA and acyl carrier in the synthesis of CoA involve the addition of an proteins (ACP), which carry and transfer acetyl and adenosyl group derived from ATP and the phos- acyl groups, respectively. In vivo e$ects of panto- phorylation of this molecule. Both of these thenic acid are generally thought to be a result of enzymatic reactions require magnesium as a its incorporation into these molecules.2 cofactor.2,3 CoA is an essential cofactor in fatty acid oxida- tion, lipid elongation, and fatty acid synthesis. It is involved in the production of many secondary metabolites such as polyisoprenoid-containing compounds (e.g., dolichol, ubiquinone [CoQ10], HCH HOOCCH2CH2NH 3 squalene, and cholesterol), steroid molecules (e.g., steroid hormones, vitamin D and bile acids), acetylated compounds (e.g., acetylated derivatives C CCCH2OH of amino sugars [e.g., N-acetylglucosamine], O acetylated neurotransmitters [e.g., OH CH3 N-acetylserotonin, acetylcholine]), and prostaglan- dins and prostaglandin-like compounds. Biosynthesis of phospholipids (e.g., phosphatidyl- choline, -ethanolamine, -serine, -inositol,

While CoA accounts for a large proportion of To produce a de!ciency in animal experiments, cellular pantothenic acid, ACP also contains the semisynthetic diets free of pantothenic acid have pantothenic acid molecule. "e synthesis of ACP is been used, often in combination with drugs that not completely elaborated; however, as in CoA, act as pantothenic acid antagonists. Antibiotics 4’-PP has been identi!ed as the prosthetic group.21 have also been used in some experiments to inhibit gut micro%ora-produced pantothenic acid.2,18 Bioavailability and Pharmacokinetics Early nutritional research indicated that panto- Existing evidence suggests that the bioavailabil- thenic acid de!ciency produced a loss of fur color in ity of pantothenic acid is in the range of 40-63 brown and black rats and dermatitis in chickens. percent.8,22 Pantothenic acid appears to be "is led to pantothenic acid being thought of as an absorbed rapidly following an oral dose, resulting “anti-gray” and “anti-dermatitis” factor.28 While in increased tissue levels of CoA and other panto- graying of fur can occur, it does not occur in all thenic acid metabolites within six hours.23 Content animals. Even in a single type of animal, it does not of CoA and pantothenic acid increases signi!cantly occur consistently in all animals subjected to the in leukocytes and urine 6-24 hours after oral same degree of de!ciency.30 Other outwardly administration.23 visible e$ects of de!ciency in mice include weight In mice, pantothenic acid absorption occurs in loss (or reduced growth), poor grooming, hair loss, the small intestine, and is sodium-dependent and exudation around the eyes, diarrhea, and hind leg saturable. Varying the dietary intake of pantothenic paralysis.18,30 acid – low, normal, or high doses – has no physi- One of the consistent !ndings in animal experi- ologically signi!cant e$ect on small intestinal ments of pantothenic acid de!ciency has been a uptake.18 progressive morphological and functional change After pantothenic acid is absorbed and trans- to the adrenal glands. In early de!ciency, the ported into cells, it can be converted to CoA or ACP adrenal gland hypertrophies.29,31 "e adrenal cortex, by the series of enzymatic reactions previously speci!cally, becomes enlarged and there is a described. In animals, pantothenic acid appears to progressive depletion of ketosteroids from the concentrate in the liver,24,25 muscles, and blood.24 zona reticularis and fasciculata.31,32 "e eventual Animal experiments suggest that pantothenic acid result of de!ciency is adrenal hypofunction, with can enter and leave the brain and cerebral spinal an inability to respond appropriately to stress.29,33,34 %uid by saturable transport systems.26 In late-stage de!ciency, the adrenals atrophy and Pantothenic acid is found in the breast milk of morphological damage occurs.33,35 If pantothenic lactating women. Amounts found correlate to the acid is supplied early enough after de!ciency is amount of pantothenic acid in the diet of the induced (i.e., before adrenal exhaustion occurs), mother the day preceding milk collection.17 the response to stress can be improved and "e amount of pantothenic acid found in a morphological changes to the adrenals can be 24-hour urine sample appears to accurately re%ect reversed. After adrenal exhaustion has occurred, intake during the past several days in humans.10,22,29 pantothenic acid administration is no longer Blood pantothenic acid levels respond less readily e$ective for these purposes.29 to intake than levels found in urine and are not De!ciency causes the thymus of mice to atro- considered as reliable an indicator.22 Levels of phy31,36 and the spleen to enlarge.18,31 Lymphopenia pantothenic acid in erythrocytes correlate with followed by lymphocytosis can occur.31 "e ability dietary intake and urinary excretion.10 to produce antibody titers against various infec- tious agents can also be reduced.36 De!ciency In male rats, a pantothenic acid de!ciency Outright de!ciency of pantothenic acid does not results in increased weight of the testes, reductions appear to occur under usual circumstances. in sperm motility, and decreased plasma concentra- Presumably this is a result of (1) pantothenic acid tions of testosterone and corticosterone.37 being found in a wide variety of foods in adequate An increase in triglycerides might be a non- amounts to prevent de!ciency, and (2) other speci!c sign of mild de!ciency. In rats, a mild vitamin de!ciencies being limiting factors in de!ciency produced by a diet low, but not devoid of, persons eating nutritionally poor diets (i.e., signs pantothenic acid signi!cantly increased serum and symptoms of other nutrient de!ciencies are triglycerides.38 produced before pantothenic acid de!ciency is Knowledge about pantothenic acid de!ciency in evident).2 humans comes from several sources – prisoners of

war, controlled de!ciency experiments, and the produced were inconsistent between individuals unintentional side e$ects produced by a panto- and from experiment to experiment. "e same was thenic acid antagonist drug. true for prompt and complete recovery from all Malnourished prisoners of war during World symptoms, which did not always follow panto- War II reported numbness and burning sensations thenic acid administration. "ey suspected in their feet, which was remedied with pantothenic biochemical individuality, unrecognized variations acid supplementation.39 in the composition of the diet, the activity of, or "e most extensive investigations of human response to, a drug antagonist of pantothenic acid, pantothenic acid de!ciency took place in the or possible other factors might be involved in mid-to-late 1950s.40-43 A diet low in pantothenic producing these inconsistencies. Whatever the acid, generally in combination with the drug reason(s), there was a wide variation in normal omega-methyl pantothenate (a pantothenate persons in response to their attempts to induce kinase inhibitor), was used to produce pantothenic pantothenic acid de!ciency and to corrective doses acid de!ciency in healthy subjects. A severe of pantothenic acid.40 depletion of pantothenic acid for approximately six "e last mechanism for producing pantothenic weeks was required before clear signs and symp- acid de!ciency in humans was the administration toms of de!ciency – many of which mirror the of calcium hopantenate (also called homopantothe- e$ects of de!ciency in animals – were produced.40 nate; a pantothenic acid antagonist). Cases of "e triad of fatigue (including apathy and malaise), reversible encephalopathy, hepatic steatosis, and a headache, and weakness was the most consistent Reye-like syndrome were reported in persons !nding. Other common e$ects included gastroin- receiving this drug. It has been suggested that testinal disturbances (nausea, abdominal cramps, these outcomes might have been produced by a occasional vomiting, increased %atulence, and medication-induced pantothenic acid de!ciency.44 epigastric burning sensations); sleep disturbances; and personality changes and emotional disorders. Clinical Indications/Mechanisms A less regular occurrence was signs of cardiovascu- Acne vulgaris lar instability (tachycardia and lability of arterial One hundred cases of acne – 45 males and 55 blood pressure, with a tendency to orthostatic females of Chinese descent – were treated with hypotension). Paresthesias, burning sensations of high-dose pantothenic acid. Participants were the hands and feet, and muscle cramps and between the ages of 10-30 years of age with most weakness occurred in several subjects. Impaired (80 percent) between the ages of 13-23. A total of motor coordination also occurred in some subjects, 10 g/d of pantothenic acid was given in four and was accompanied by a peculiar gait. In some divided doses. Participants were also asked to apply de!ciency experiments, infections were common; a cream to the a$ected area 4-6 times daily; the in others they were not. Several biochemical cream contained 20 percent by weight pantothenic abnormalities were reported. A loss of the normal acid. "e face became noticeably less oily and a eosinopenic response to adrenocorticotropic decrease in facial sebum secretion occurred usually hormone (ACTH) was the most consistent lab within 2-3 days after initiation of therapy. Within !nding. Less consistent lab !ndings among studies two weeks, facial pore size had become noticeably of pantothenic acid de!ciency include a reduction smaller, existing acne lesions had begun to heal, in the degree of urinary acetylated para-aminoben- and the rate of new acne eruptions had slowed. By zoic acid (PABA) and 17-ketosteroids, abnormal eight weeks, acne was usually controlled – most glucose tolerance, increased sensitivity to insulin, acne lesions were gone and new eruptions only reduced secretion of gastric hydrochloric acid and occurred occasionally – in cases of moderate pepsin, decreased and increased cholesterol, and severity. In the participants with severe acne, hypokalemia.40-43 Administration of pantothenic treatment for six months or longer was occasion- acid was followed by improvement of the paresthe- ally needed to control acne. "e author noted that sias and muscle weakness, but fatigue and some in some of the severe cases, daily doses of 15-20 degree of irritability persisted. "ere was also a g/d of pantothenic acid would produce a faster prompt correction of the impaired eosinopenic response. "irty-!ve patients were monitored for response to ACTH and most of the other clinical 18 months; the maintenance dose needed to symptoms when pantothenic acid was supplied.40 control acne ranged from 1 to 5 g/d of pantothenic One of the key !ndings remarked upon by the acid.45 researchers was that the de!ciency results

A single study suggested that a 5-percent lactate levels and decreased oxygen consumption dexpanthenol cream could help treat mucocutane- during prolonged exercise at 75-percent VO2max in ous adverse reactions caused by isotretinoin highly trained endurance runners,55 a dose of 1 g/d treatment for acne.46 for two weeks failed to increase run time to exhaustion in highly trained distance runners.56 A

Alopecia combination of vitamin B1 and pantothenic acid A case study from the early 1950s reported (1.8 g/d of a 55%/45% pantethine/pantothenic bene!ts of using the alcohol pro-vitamin form of acid mix) or placebo was given to highly trained pantothenic acid (dexpanthenol) topically for hair cyclists for seven days. No signi!cant di$erences loss.47 were observed in cycling performance.57 "e only study that used oral pantothenic acid as a sole intervention for di$use alopecia in women Hepatitis A reported that there was no clear evidence of An abstract of an untranslated Russian study bene!t. "e dose used was 100 mg/d for 4-5 suggested that both calcium pantothenate (300- months.48 600 mg) and pantethine (90-180 mg) could be Two studies reported that use of a proprietary useful additions to therapy for viral hepatitis A. product containing pantothenic acid (60 mg/ "e abstract noted that bene!ts with calcium

capsule), vitamin B1, yeast, L-cystine, keratin, and pantothenate were not as pronounced as with PABA improved hair quality and slowed hair loss pantethine.58 after four months of use in persons with di$use e&uvium capillorum and agnogenic structural Hyperlipidemia 49,5 alterations of hair. "e pantethine form of vitamin B5 has been reported to have lipid-lowering e$ects, with Celiac Disease supplementation capable of reducing cholesterol A letter to the editor of the British Medical and triglyceride levels.59 No studies have investi- Journal in 1972 suggested the hypothesis that gated whether pantothenic acid has lipid-lowering patients with celiac disease who respond only e$ects. partially to a gluten-free diet might potentially bene!t from the administration of pantothenic In!ammatory Bowel Disease acid. No clinical evidence in support of this "ree patients with ulcerative colitis were hypothesis was provided in this letter (i.e., the administered dexpanthenol (1,000 mg) as part of author did not mention results of any cases of an enema. "e treatment was not considered giving pantothenic acid to persons with celiac e$ective.60 disease).51 Lifespan Extension (Anti-Aging) Chemical Exposure to Aldehydes and Phenols Several old studies suggested that pantothenic Abstracts from untranslated Russian research acid supplementation extends the lifespan of have suggested that pantothenic acid might play a animals. Royal jelly was reported to extend the role in protecting against exposure to certain lifespan of Drosophila melanogaster (common fruit chemicals. Pantothenic acid and its derivatives %y); pantothenic acid was the primary anti-aging decreased the acute toxicity of acetaldehyde, as factor isolated from royal jelly.61 "e combination well as the duration of the narcotic action of of pyridoxine, biotin, and sodium yeast nucleate ethanol, in mice and rats.52 In animals, a combina- extended the lifespan of Drosophila melanogaster; tion of vitamins including pantothenic acid helped addition of pantothenic acid further increased protect against poisoning from phenol vapors.53 In lifespan.62 A dose of 300 mcg/d (approximately 10 humans, pantothenic acid combined with vitamin mg/kg/d) of calcium pantothenate extended the 63 B1 protected workers engaged in manufacturing of lifespan of black mice by 19 percent. phenol-formaldehyde resins.54 Lupus Erythematosus Ergogenic Aid (Exercise Performance) Several reports exist on the use of pantothenic Existing evidence is not supportive of panto- acid for persons with lupus erythematosus from thenic acid supplementation improving exercise the 1950s. One indicated that pantothenic acid performance. While a study reported that 2 g/d of (10-15 g/d), when taken together with vitamin E pantothenic acid for two weeks decreased blood (1,500-3,000 IU/d) for up to 19 months, showed

e#cacy.64 Another reported that the combination As mentioned in the section on de!ciency, a of oral pantothenic acid and topical dexpanthenol progressive morphological and functional change was not e$ective.65 occurs to the adrenal glands when there is a pantothenic acid de!ciency. "e eventual result of Obesity de!ciency is adrenal hypofunction, with an Aurothioglucose injection into the hypothalamus inability to respond appropriately to stress. If is used as a means to induce hypothalamic obesity pantothenic acid is supplied early enough after – an increase in food intake, weight gain primarily as de!ciency has been induced (i.e., before adrenal body fat, and blood sugar and lipid increases – in exhaustion occurs), the response to stress can be animal experiments. Pantothenic acid and several of improved.29,31-35 its derivatives – phosphopantothenate, pantethine, Supplementation of pantothenic acid when the dexpanthenol – countered hypothalamic obesity diet is adequate in pantothenic acid also appears to after injection of aurothioglucose. "e e$ects with impact adrenal function. In male rats, adding dexpanthenol were more pronounced than with the pantothenic acid (0.03%) to drinking water for other forms of pantothenic acid used.66 nine weeks increased adrenal gland weight, basal One hundred individuals of Chinese descent, all plasma levels of corticosterone, and the release of following a calorie-restricted diet that only corticosterone in response to ACTH.71 Supple- provided 1,000 calories/d, were supplemented with mentation also increases urinary excretion of 10 g/d of pantothenic acid in four divided doses. 17,21-dihydroxy-20-ketosteroids – a sign of Average weight loss was reported to be 1.2 kg (2.6 functional activation of the adrenal gland.72 lbs) per week. Ketone bodies in urine were either Results of several animal studies suggest that absent or detected in trace amounts. Dieters did providing supplemental pantothenic acid might not complain of hunger or weakness. A mainte- improve the response to certain types of stress. nance dose of 1-3 g/d, along with continued Supplementing the diet of rats with 43.6 mg of adherence to a strict diet, was needed to maintain calcium pantothenate per 100 g of chow increased weight loss. "e author claimed that no side e$ects adrenal weight signi!cantly in response to surgical were observed with this protocol.67 stress. In unstressed animals supplementation of A product containing pantothenic acid, Garcinia pantothenic acid had no e$ect on adrenal weight.73 cambogia, Matricaria chamomilla, Rosa damascena, Since adrenal hypertrophy in response to stress is Lavandula o!cinalis and Cananga odorata was believed to be an adaptive response,74 this suggests reported to produce an average weight loss of 4.67 that pantothenic acid supplementation improved percent after 60 days of supplementation.68 the stress response. Exposure to gamma radiation reduces blood levels of pantothenic acid and its Osteoarthritis and Rheumatoid Arthritis derivatives by about 80 percent. It also produces a A double-blind trial compared taking the signi!cant increase in oxidative stress – lipid combination of pantothenic acid and L-cysteine peroxidation increases and liver levels of CoA and against placebo in the treatment of osteoarthrosis reduced glutathione decrease. Administration of of the knees. No di$erence was observed either dexpanthenol, in amounts su#cient to increase subjectively or objectively between the two blood pantothenic acid levels signi!cantly above groups.69 control (non-irradiated) levels, normalized these A double-blind study of persons with rheumatoid markers of oxidative stress.75 arthritis patients, who had not responded to Pantothenic acid appears to be involved in previous drug treatment with salicylates, compared optimizing the response to cold stress. A de!ciency the addition of pantothenic acid (500 mg/d initially, of pantothenic acid increases the sensitivity of increasing to 500 mg four times daily by the 10th undernourished rats to cold.76 De!ciency also day) with placebo. A signi!cant reduction in signi!cantly decreases average survival time of rats morning sti$ness, degree of disability, and severity exposed to cold stress.77 Supplementing the of pain was reported for persons taking panto- combination of calcium pantothenate and a small thenic acid.70 amount of hydrocortisone prolonged survival of cold-stressed, adrenalectomized rats.78 Stress Supplementation of pantothenic acid allowed rats Animal and human evidence suggests that that had undergone removal of the adrenals to pantothenic acid is needed for adrenal function and swim in cold water for as long as rats with intact might be involved in the adrenal response to stress. adrenals.79 In rats with intact

adrenals, supplementation with large amounts of As mentioned in the section on de!ciency, two pantothenic acid doubled the length of time they drugs – omega-methyl pantothenate (a pantothe- were able to swim in, and survive in, cold water.80 nate kinase inhibitor) and calcium hopantenate (a Men receiving pantothenic acid (10 g/d for six pantothenic acid antagonist) – can produce de!cien- weeks) had a less pronounced drop in white blood cies in pantothenic acid. Neither of these medica- cell counts and vitamin C levels subsequent to tions is currently an FDA-approved drug product for cold-water immersion stress, compared to pre- human use.87 supplementation values.81 Animal research on adrenal function suggests that A report indicated that a high proportion of pantothenic acid supplementation might augment schizophrenic patients had impaired adrenal the response to corticosteroids.71,78,79 function. When pantothenic acid was given to A study reported that pantothenic acid levels were these patients, adrenal function improved.82 signi!cantly lower in females using oral contraceptives compared with females who were not.15 Wound Healing Pantothenic acid has been reported to have no In animal research, oral and topical pantothenic estrogenic action itself, but enhanced the action of acid have been associated with accelerated closure estradiol in rats.88 of skin wounds and increased strength of scar Experimental work from the 1950s suggested tissue; however, no signi!cant bene!ts were that pantothenic acid might interfere with the observed with wound healing in a randomized, ability of some antibiotics – aureomycin,89 erythro- double-blind study of humans who took 200 mg of mycin,90 and streptomycin91 – to inhibit the growth pantothenic acid and 1,000 mg of vitamin C by of certain microorganisms under in vitro condi- mouth during recovery from surgical tattoo tions. It has been speculated that this might be removal.83 because these antibiotics inhibit enzymes involved in the biosynthesis of pantothenic acid or its Drug-Nutrient Interactions downstream coenzymes (CoA or ACP); supplying Pantothenic acid helps prevent cisplatin-induced pantothenic acid overcomes this enzyme inhibi- deafness in guinea pigs when both drugs are tion.91 In vivo research, also conducted in the 1950s, administered jointly. When deafness has been did not indicate a decrease in clinical e#cacy when previously produced by cisplatin, recovery can streptomycin was combined with pantothenic sometimes occur after the administration of acid.92-94 Vestibular ototoxicity – nausea, vomiting, pantothenic acid.84 and vertigo – is an established side e$ect of Animal experiments suggest that pantothenic streptomycin. A report indicated that administra- acid might help prevent some side e$ects of tion of 50 mg pantothenic acid three times daily valproic acid (VPA). In utero exposure to VPA improved symptoms of vestibular ototoxicity during pregnancy is associated with an increased caused by streptomycin in 30 out of 31 persons.94 risk of neural tube defects (NTDs) in animals. However, another report indicated that adding 150 Pretreatment of pregnant mice with pantothenic mg/d of pantothenic acid to the combination of acid protects against VPA-induced NTDs.85 Hepatic streptomycin and isoniazid failed to prevent failure is a rare, but possible, side e$ect of VPA. symptoms of vestibular ototoxicity.92 Presumably this side e$ect is in part related to a Analogs of pantothenic acid – N-substituted VPA-induced depletion of CoA, which results in pantothenamide (pantothenamides), and anti- abnormalities in CoA-dependent liver processes. In metabolites such as N-pentylpantothenamide and developing mice, the combination of pantothenic N-heptylpantothenamide – have antibiotic activity acid and carnitine helped prevent this side e$ect.86 and are under investigation as potential novel A single study reports that a 5-percent dexpan- antibiotics. "ese anti-metabolites compete for and thenol cream can help treat mucocutaneous adverse use enzymes involved in the biosynthesis of CoA reactions caused by using isotretinoin for acne.46 and/or ACP, producing biologically inactive analogs. A theoretical concern exists that pantothenic acid, "e result is an inhibition of bacterial growth. since it is involved in the biosynthesis of acetylcho- Extracellular availability of pantothenic acid does line, might increase the e$ects of acetylcholinester- not appear to prevent the bacterial growth inhibi- ase inhibitor drugs (i.e., drugs that inhibit the tion of pantothenamides under test conditions.95-99 cholinesterase enzyme and so prevent the break- "e e$ects of exogenous supplementation of down of acetylcholine). pantothenic acid on pantothenamides has not been investigated.

Sulfonamides reduced the fecal elimination of amount of weight increase and the food intake less pantothenic acid and produced marked reductions than those of controls. "e no-observed-adverse- of pantothenic acid concentrations in the liver of e$ect-level (NOAEL) was 1 percent of the diet rats.100 However, young men did not have a comprised of calcium pantothenate.107 Although it reduction in pantothenic acid excretion when given is not possible to derive a numerical upper limit for the sulfonamide, phthalylsulfathiozole.101 pantothenic acid in humans, evidence available "ere have been anecdotal reports that dexpan- from clinical studies using high doses of pantothenol may increase bleeding time. "ese reports thenic acid indicates that intakes considerably in have not been substantiated and increased risk of excess of current DRI do not represent a health risk bleeding is not regarded as a serious potential risk. for the general population.106,109 Nevertheless, because of this, it has been recom- "e existing clinical studies on pantothenic acid mended that pantothenic acid be used with caution were not designed to monitor and assess side in persons taking anticoagulants or other medi- e$ects, so information of adverse e$ects on cines capable of prolonging bleeding time.6 humans is limited. "e most commonly reported side e$ect is mild transient gastrointestinal Nutrient-Nutrient Interactions disturbance such as nausea, heartburn, and Ascorbic acid appears to have a pantothenic diarrhea. Adverse e$ects typically do not occur acid-sparing e$ect in rats. "e addition of ascorbic until doses exceed 1 gram daily.6,109-111 acid (2 percent of the diet) to a rat diet de!cient in "ere is one reported case of eosinophilic pantothenic acid allowed many of the animals to pleuropericardial e$usion (%uid around the heart grow normally and prevented signs of de!- and lungs) in a patient taking 300 mg/d of panto- ciency.102,103 Augmenting a pantothenic acid-de!- thenic acid in combination with 10 mg/d of biotin cient diet with ascorbic acid (2 percent of the diet) for 2 months. "e condition resolved after the in female rats resulted in o$spring with signi!- vitamins were stopped.112 cantly higher blood, hepatic and tissue pantothenic "ere are reported cases of contact urticaria113 acid levels compared with the o$spring of females and dermatitis114 occurring with the use of hair fed a diet de!cient in pantothenic acid without lotions and conditioners containing dexpanthenol. added ascorbic acid. Ascorbic acid also prevented Pantothenic acid has an FDA Pregnancy category some of the histochemical di$erences in the A rating for doses at or below the DRI level. What adrenals of the o$spring.104 this means is that well-controlled studies have In vitro evidence suggests that biotin and failed to demonstrate a risk to the fetus in the !rst pantothenic acid use the same sodium-dependent, trimester of pregnancy (and there is no evidence of specialized carrier-mediated system for uptake in risk in later trimesters) for doses at or below the colonic epithelial cells. In this experiment, panto- DRI level. Pantothenic acid has a Pregnancy thenic acid caused a concentration-dependent category C rating when dosed above the DRI (i.e., competitive inhibition in biotin uptake.105 "is has animal reproduction studies have shown an led to speculation that high doses of pantothenic adverse e$ect on the fetus and there are no acid might inhibit the absorption of biotin in the adequate and well-controlled studies in humans, large intestine;6 however, whether competitive but potential bene!ts may warrant use of the drug inhibition occurs under in vivo conditions has not in pregnant women despite potential risks).108 been investigated. Dosing Side E"ects and Toxicity Data "e Dietary Reference Intake (DRI) established

Acute oral LD50 values for pantothenic acid are by the Institute of Medicine for pantothenic acid is 10,000 mg/kg in mice and rats, with lethal doses as follows:7,108 producing death by respiratory failure.106 ! 1–3 years old: 2 mg/d Chronic administration for 6 months produced ! 4–8 years old: 3 mg/d no toxic signs, weight loss, or histopathological ! 9–13 years old: 4 mg/d changes in rats (dose up to 2,000 mg/kg, dogs (50 ! 14 years old and over: 5 mg/d mg/kg), and monkeys (200-250 mg/kg).106 ! Pregnancy: 6 mg/d Calcium pantothenate at 3 percent of the diet ! Lactation: 7 mg/d was the lowest-observed-adverse-e$ect-level (LOAEL) in rats, with enlargement of the testes, diarrhea, and hair damage observed, and the

Oral supplementation of pantothenic 10. Eissenstat BR, Wyse BW, Hansen RG. 23. Moiseenok AG, Tsverbaum EA, Rybalko acid has been signi!cantly in excess of Pantothenic acid status of adolescents. MA. Pantothenic acid biotransforma- the DRI for several months or longer. In Am J Clin Nutr 1986;44:931-937. tion in human vitamin de!ciency. Vopr clinical studies the dose used has varied 11. Wilson TA, Adolph AL, Butte NF. Med Khim 1981;27:780-784. [Article in signi!cantly. "e low end of dosing has Nutrient adequacy and diet quality in Russian] generally been 100 mg/d. "e high end non-overweight and overweight 24. Böhmer BM, Roth-Maier DA. E$ects of has been 10 g/d. At higher doses, the Hispanic children of low socioeconomic high-level dietary B-vitamins on existing studies have often used 3-4 status: the Viva la Familia Study. J Am performance, body composition and divided doses a day. High potency Diet Assoc 2009;109:1012-1021. tissue vitamin contents of growing/ pantothenic acid supplements are 12. Walsh JH, Wyse BW, Hansen RG. !nishing pigs. J Anim Physiol Anim Nutr generally in the range of 250-1,000 mg Pantothenic acid content of a nursing (Berl) 2007;91:6-10. per capsule/tablet. Dosing at the home diet 1,2. Ann Nutr Metab 25. Gurinovich VA, Moiseenok AG. highest levels – 10 g/d – can present 1981;25:178-181. Metabolism of pantothenic acid and its adherence issues, because of the number 13. Wendland BE, Greenwood CE, derivatives in animals de!cient in this of tablets or capsules required to Weinberg I, Young KW. Malnutrition in enzyme. Ukr Biokhim Zh 1987;59:60-66. achieve the dose. institutionalized seniors: the iatrogenic [Article in Russian] component. J Am Geriatr Soc 26. Spector R. Pantothenic acid transport References 2003;51:85-90. and metabolism in the central nervous 1. Williams RJ. Pantothenic acid – a 14. Grammatikopoulou MG, Papadopoulou system. Am J Physiol vitamin. Science 1939;89:486. SK, Zakas A, et al. Dietary intake of 1986;250:R292-R297. 2. Rucker RB, Bauerly K. Pantothenic acid. free-living elderly in northern Greece. J 27. Tsuji T, Fukuwatari T, Sasaki S, Shibata In: Zempleni J, Rucker RB, McCormick Nutr Elder 2006;26:131-146. K. Urinary excretion of vitamin B1, B2, DB, Suttie JW, eds. Handbook of 15. Lewis CM, King JC. E$ect of oral B6, niacin, pantothenic acid, folate, and Vitamins. New York, NY: CRC Press; contraceptives agents on thiamin, vitamin C correlates with dietary 2007:289-305. ribo%avin, and pantothenic acid status intakes of free-living elderly, female 3. Webb ME, Smith AG, Abell C. in young women. Am J Clin Nutr Japanese. Nutr Res 2010;30:171-178. Biosynthesis of pantothenate. Nat Prod 1980;33:832-838. 28. Bender DA. Optimum nutrition: Rep 2004;21:695-721. 16. Song WO, Wyse BW, Hansen RG. thiamin, biotin and pantothenate. Proc 4. Khomich TI . Pantethine and the Pantothenic acid status of pregnant and Nutr Soc 1999;58:427-433. biosynthetic regulation of the coen- lactating women. J Am Diet Assoc 29. Hurley LS, Morgan AF. Carbohydrate zyme of acetylation. Eksp Med (Riga) 1985;85:192-198 metabolism and adrenal cortical 1991;27:112-118. [Article in Russian] 17. Johnston L, Vaughan L, Fox HM. function in the pantothenic acid-de!- 5. No authors listed. Pantethine: Pantothenic acid content of human cient rat. J Biol Chem 1952;195:583-590. Monograph. Altern Med Rev milk. Am J Clin Nutr 30. Kuo YM, Hay%ick SJ, Gitschier J. 2010;15:279-282. 1981;34:2205-2209. Deprivation of pantothenic acid elicits a 6. http://www.drugs.com/npp/panto- 18. Stein ED, Diamond JM. Do dietary movement disorder and azoospermia in thenic-acid.html [Accessed August 1, levels of pantothenic acid regulate its a mouse model of pantothenate 2011] intestinal uptake in mice? J Nutr kinase-associated neurodegeneration. J 7. http://iom.edu/Activities/Nutrition/ 1989;119:1973-1983. Inherit Metab Dis 2007;30:310-317. SummaryDRIs/~/media/Files/ 19. Fisher MN, Robishaw JD, Neely JR. "e 31. Melampy RM, Cheng DW, Northrop LC. Activity%20Files/Nutrition/DRIs/ properties and regulation of pantothe- E$ect of pantothenic acid de!ciency RDA%20and%20AIs_Vitamin%20 nate kinase from rat heart. J Biol Chem upon adrenal cortex, thymus, spleen, and%20Elements.pdf [Accessed July 29, 1985;260:15745-15751. and circulating lymphocytes in mice. 2011] 20. Scandura R, Barboni E, Granata F, et al. Proc Soc Exp Biol Med 1951;76:24-27. 8. Tarr JB, Tamura T, Stokstad EL. Pantothenoylcysteine-4’-phospate 32. Deane HW, McKibbin JM. "e chemical Availability of vitamin B6 and pantothe- decarboxylase from horse liver. Eur J cytology of the rat’s adrenal cortex in nate in an average American diet in Biochem 1974;49:1-9. pantothenic acid de!ciency. man. Am J Clin Nutr 21. Tahiliani AG, Beinlich CJ. Pantothenic Endocrinology 1946;38:385-400. 1981;34:1328-1337. acid in health and disease. Vitam Horm 33. Ashburn LL, Daft FS, Faulkner RR. 9. Watanabe T, Suemura K, Taniguchi A, et 1991;46:165-228. Hematopoiesis in pantothenic acid- al. Dietary intake of seven B vitamins 22. Fry PC, Fox HM, Tao HG. Metabolic de!cient rats. Blood 1947;2:451-462. based on a total diet study in Japan. J response to a pantothenic acid de!cient 34. Taylor DW. E$ects of de!ciency of Nutr Sci Vitaminol (Tokyo) diet in humans. J Nutr Sci Vitaminol pantothenic acid on oxygen poisoning 2010;56:279-286. (Tokyo) 1976;22:339-346. in the rat. Nature 1959;183:257.

35. Morgan AF, Simms HD. Adrenal atrophy 48. Brzezińska-Wcisło L. Evaluation of 58. Komar VI. "e use of pantothenic acid and senescence produced by a vitamin vitamin B6 and calcium pantothenate preparations in treating patients with de!ciency. Science 1939;89:565-566. e$ectiveness on hair growth from viral hepatitis A. Ter Arkh 1991;63:58- 36. Mahboob S. "ymic weight in panto- clinical and trichographic aspects for 60. [Article in Russian] thenic acid de!ciency. Nutr Metab treatment of di$use alopecia in women. 59. McRae MP. Treatment of hyperlipopro- 1976;20:272-277. Wiad Lek 2001;54:11-18. [Article in teinemia with pantethine: a review and 37. Yamamoto T, Jaroenporn S, Pan L, et al. Polish] analysis of e#cacy and tolerability. Nutr E$ects of pantothenic acid on testicular 49. Petri H, Pierchalla P, Tronnier H. "e Res 2005;25:319-333. function in male rats. J Vet Med Sci e#cacy of drug therapy in structural 60. Loftus EV Jr, Tremaine WJ, Nelson RA, 2009;71:1427-1432. lesions of the hair and in di$use et al. Dexpanthenol enemas in 38. Wittwer CT, Beck S, Peterson M, et al. e&uvium – comparative double blind ulcerative colitis: a pilot study. Mayo Mild pantothenate de!ciency in rats study. Schweiz Rundsch Med Prax Clin Proc 1997;72:616-620. elevates serum triglyceride and free 1990;79:1457-1462. [Article in 61. Gardner TS. "e use of Drosophila fatty acid levels. J Nutr German] melanogaster as a screening agent for 1990;120:719-725. 50. Budde J, Tronnier H, Rahlfs VW, longevity factors; pantothenic acid as a 39. Davenport RE, Spaide J, Hodges RE. An Frei-Kleiner S. Systemic therapy of longevity factor in royal jelly. J Gerontol evaluation of various survival rations. di$use e&uvium and hair structure 1948;3:1-8. Am J Clin Nutr 1971;24:513-523. damage. Hautarzt 1993;44:380-384. 62. Gardner TS. "e use of Drosophila 40. Hodges RE, Ohlson MA, Bean WB. [Article in German] melanogaster as a screening agent for Pantothenic acid de!ciency in man. J 51. Monro J. Pantothenic acid and coeliac longevity factors; the e$ects of biotin, Clin Invest 1958;37:1642-1657. disease. Br Med J 1972;4:112-113. pyridoxine, sodium yeast nucleate, and 41. Hodges RE, Bean WB , Ohlson MA, 52. Moiseenok AG, Dorofeev BF, pantothenic acid on the life span of the Bleiler R. Human pantothenic acid Omel’ianchik SN. "e protective e$ect fruit %y. J Gerontol 1948;3:9-13. de!ciency produced by omega-methyl of pantothenic acid derivatives and 63. Pelton RB, Williams RJ. E$ect of pantothenic acid. J Clin Invest changes in the system of acetyl CoA pantothenic acid on the longevity of 1959;38:1421-1425. metabolism in acute ethanol poisoning. mice. Proc Soc Exp Biol Med 42. "ornton GH, Bean WB, Hodges RE. Farmakol Toksikol 1988;51:82-86. 1958;99:632-633. "e e$ect of pantothenic acid de!ciency [Article in Russian] 64. Welsh AL. Lupus erythematosus: of gastric secretion and motility. J Clin 53. Skvortsova RI, Pozniakovski! VM, treatment by combined use of massive Invest 1955;34:1085-1091. Agarkova IA. Role of the vitamin factor amounts of pantothenic acid and 43. Bean WB, Hodges RE, Daum K. in preventing phenol poisoning. Vopr vitamin E. AMA Arch Derm Syphilol Pantothenic acid de!ciency induced in Pitan 1981:32-35. [Article in Russian] 1954;70:181-198. human subjects. J Clin Invest 54. Skvortsova RI, Pozniakovski! VM. E$ect 65. Cochrane T, Leslie G. "e treatment of 1955;34:1073-1084. of a therapeutic and prophylactic diet lupus erythematosus with calcium 44. Noda S, Umezaki H, Yamamoto K, et al. enriched with thiamine and calcium pantothenate and panthenol. J Invest Reye-like syndrome following treat- pantothenate on the acetylating Dermatol 1952;18:365-367. ment with the pantothenic acid capacity of the body of workers engaged 66. Naruta E, Buko V. Hypolipidemic e$ect antagonist, calcium hopantenate. J in the manufacture of phenol-formalde- of pantothenic acid derivatives in mice Neurol Neurosurg Psychiatry hyde resins. Vopr Pitan 1977:40-42. with hypothalamic obesity induced by 1988;51:582-585. [Article in Russian] aurothioglucose. Exp Toxicol Pathol 45. Leung LH. Pantothenic acid de!ciency 55. Lito$ D, Scherzer H, Harrison J. E$ects 2001;53:393-398. as the pathogenesis of acne vulgaris. of pantothenic acid supplementation 67. Leung LH. Pantothenic acid as a Med Hypotheses 1995;44:490-492. on human exercise. Med Sci Sports Exerc weight-reducing agent: fasting without 46. Romiti R, Romiti N. Dexpanthenol 1985;17:287. hunger, weakness and ketosis. Med cream signi!cantly improves mucocuta- 56. Nice C, Reeves AG, Brinck-Johnsen T, Hypotheses 1995;44:403-405. neous side e$ects associated with Noll W. "e e$ects of pantothenic acid 68. Toromanyan E, Aslanyan G, Amroyan E, isotretinoin therapy. Pediatr Dermatol on human exercise capacity. J Sports et al. E#cacy of Slim339 in reducing 2002;19:368. Med 1984;24:26-29. body weight of overweight and obese 47. Abirached IA. Case of baldness treated 57. Webster MJ. Physiological and human subjects. Phytother Res with pantothenic acid alcohol. Folha performance responses to supplemen- 2007;21:1177-1181. Med 1951;32:121-122. tation with thiamin and pantothenic 69. Haslock DI, Wright V. Pantothenic acid acid derivatives. Eur J Appl Physiol in the treatment of osteoarthrosis. Occup Physiol 1998;77:486-491. Rheumatol Phys Med 1971;11:10-13.

70. Tufts M, Bunde CA. "erapeutic advantages 84. Ciges M, Fernández-Cervilla F, Crespo 95. Clifton G, Bryant SR, Skinner CG. of the addition of calcium pantothenate to PV, Campos A. Pantothenic acid and N"-(substituted) pantothenamides, salicylates in the oral treatment of coenzyme A in experimental cisplatin- antimetabolites of pantothenic acid. rheumatoid arthritis. Am Pract Dig Treat induced ototoxia. Acta Otolaryngol Arch Biochem Biophys 1970;137:523-528. 1953;4:755-756. 1996;116:263-268. 96. Strauss E, Begley TP. "e antibiotic 71. Jaroenporn S, Yamamoto T, Itabashi A, et al. 85. Dawson JE, Raymond AM, Winn LM. activity of N-pentylpantothenamide E$ects of pantothenic acid supplementa- Folic acid and pantothenic acid results from its conversion to ethylde- tion on adrenal steroid secretion from male protection against valproic acid-induced thia-coenzyme A, a coenzyme A rats. Biol Pharm Bull 2008;31:1205-1208. neural tube defects in CD-1 mice. antimetabolite. J Biol Chem 72. Fidanza A. "erapeutic action of panto- Toxicol Appl Pharmacol 2002;277:48205-48209. thenic acid. Int J Vitam Nutr Res Suppl 2006;211:124-132. 97. "omas J, Cronan JE. Antibacterial 1983;24:53-67. 86. "urston JH, Hauhart RE. Amelioration activity of N-pentylpantothenamide is 73. Dumm ME, Laken B, Ralli EP. Factors of adverse e$ects of valproic acid on due to inhibition of coenzyme A in%uencing adrenal weight and adrenal ketogenesis and liver coenzyme A synthesis. Antimicrob Agents Chemother cholesterol in rats following stress. J Nutr metabolism by cotreatment with 2010;54:1374-1377. 1955;56:517-531. pantothenate and carnitine in develop- 98. Virga KG, Zhang YM, Leonardi R, et al. 74. Selye H. "e general-adaptation-syndrome. ing mice: possible clinical signi!cance. Structure-activity relationships and Annu Rev Med 1951;2:327-342. Pediatr Res 1992;31:419-423. enzyme inhibition of pantothenamide- 75. Slyshenkov VS, Omelyanchik SN, 87. http://www.accessdata.fda.gov/scripts/ type pantothenate kinase inhibitors. Moiseenok AG, et al. Pantothenol protects cder/drugsatfda/index.cfm [Accessed Bioorg Med Chem 2006;14:1007-1020. rats against some deleterious e$ects of August 5, 2011] 99. Zhang YM, Frank MW, Virga KG, et al. gamma radiation. Free Radic Biol Med 88. Sharaf A, Gomaa N. Interrelationship Acyl carrier protein is a cellular target 1998;24:894-899. between vitamins of the B-complex for the antibacterial action of the 76. Weiss B. "ermal behavior of the sub- group and oestradiol. J Endocrinol pantothenamide class of pantothenate nourished and pantothenic-acid-deprived 1974;62:241-244. antimetabolites. J Biol Chem rat. J Comp Physiol Psychol 1957;50:481-485. 89. Foster JW, Pittillo RF. Metabolite 2004;279:50969-50975. 77. Ersho$ BF. Comparative e$ects of reversal of antibiotic inhibition, 100. Wright LD, Skeggs HR. pantothenic acid de!ciency and inanition especially reversal of aureomycin Succinylsulfathiazole in the nutrition of on resistance to cold stress in the rat. J Nutr inhibition by ribo%avin. J Bacteriol the rat. Am J Med Sci 1946;212:312-314. 1953;49:373-385. 1953;66:478-486. 101. Grundy WE, Freed M, Johnson HC, et 78. De Bias DA, Paschkis KE, Cantarow A, 90. Brown RG, Emerson GA. In vitro al. "e e$ect of phthalylsulfathiazole Friedler G. "e e$ects of various metabo- antagonism of pantothenic acid, (sulfathalidine) on the excretion of lites and autonomic blocking agents in ß-alanine and l-carnosine to inhibitory B-vitamins by normal adults. Arch combating stress. Exp Med Surg e$ects of erythromycin on growth of Biochem 1947;15:187-194. 1957;15:30-46. Corynebacterium diphtheriae. Fed Proc 102. Daft FS. E$ect of vitamin C on 79. Dumm ME, Ralli EP. Factors in%uencing the 1953;12:304-305. pantothenic-de!cient rats. Fed Proc response of adrenalectomized rats to stress. 91. Lichstein HC, Gil!llan RF. Inhibition of 1951;10:380. Metabolism 1953;2:153-164. pantothenate synthesis by streptomy- 103. Daft FS, Schwarz K. Prevention of 80. Ralli EP, Dumm ME. Relation of panto- cin. Proc Soc Exp Biol Med certain B vitamin de!ciencies with thenic acid to adrenal cortical function. 1951;77:459-461. ascorbic acid or antibiotics. Fed Proc Vitam Horm 1953;11:133-158. 92. Johnston RN, Smith DH, Ritchie RT, 1952;11:200. 81. Ralli EP, Kuhk WJ Jr, Gershberg H, et al. Lockhart W. Prolonged streptomycin 104. Everson G, Northrop L, Chung NY, E$ects of vitamin supplementation of the and isoniazid for pulmonary tuberculo- Getty R. E$ect of ascorbic acid on rats diet on reaction to short-term cold stress in sis. Brit Med J 1964;1:1679-1683. deprived of pantothenic acid during normal young male adults. Metabolism 93. LaCaille RA, Prigot A. "e clinical trial pregnancy. J Nutr 1954;54:305-311. 1956;5:170-196. of streptomycin pantothenate in the 105. Said HM, Ortiz A, McCloud E, et al. 82. Monro J. Pantothenic acid in schizophrenia. treatment of soft tissue infections. Am Biotin uptake by human colonic Lancet 1973;1:262-263. J Surg 1958;95:963-966. epithelial NCM460 cells: a carrier- 83. Vaxman F, Olender S, Lambert A, et al. 94. Penman AC, Dickson I, Miller JS. mediated process shared with panto- E$ect of pantothenic acid and ascorbic acid Neurotoxic symptoms in streptomycin thenic acid. Am J Physiol supplementation on human skin wound therapy: a pilot trial of treatment with 1998;275:C1365-C1371. healing process. A double-blind, prospective pantothenic acid. Tubercle and randomized trial. Eur Surg Res 1957;38:422-424. 1995;27:158-166.

106. Scienti!c Committee on Food: Opinion 108. Institute of Medicine. Dietary Reference 112. Debourdeau PM, Djezzar S, Estival JL, of the Scienti!c Committee on Food on Intakes for "iamin, Ribo#avin, Niacin, et al. Life-threatening eosinophilic the tolerable upper intake level of Vitamin B6, Folate, Vitamin B12, pleuropericardial e$usion related to pantothenic acid. Report of the Pantothenic Acid, Biotin, and Choline. vitamins B5 and H. Ann Pharmacother European Commission: Health and Washington, DC: National Academy 2001;35:424-426. consumer protection directorate- Press; 1998:367-368. 113. Schalock PC, Storrs FJ, Morrison L. general 2002SCF/CS/NUT/UPPLEV/61 109. Cosmetic Ingredient Review. Final Contact urticaria from panthenol in Final:1-6 (http://ec.europa.eu/food/fs/ report on the safety assessment of hair conditioner. Contact Dermatitis sc/scf/out80k_en.pdf) [Accessed July panthenol and pantothenic acid. J Am 2000;43:223. 27, 2011] Coll Toxicol 1987;6:139-162. 114. van Ketel WG. Hair lotion dermatitis 107. Shibata K, Takahashi C, Fukuwatari T, 110. Fox HM. Pantothenic acid. In: Machlin with sensitization to d-panthenyl ethyl Sasaki R. E$ects of excess pantothenic LJ, ed. Handbook of Vitamins, Nutritional, ether. Contact Dermatitis 1984;10:48. acid administration on the other Biochemical and Clinical Aspects. New water-soluble vitamin metabolisms in York, NY: Dekker; 1984:437-458. rats. J Nutr Sci Vitaminol (Tokyo) 111. Unna K, Greslin JG. Studies on the 2005;51:385-391. toxicity and pharmacology of pantothenic acid. J Pharmacol Exp "er 1941;73:85-90.

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