M C e o d n i t ca in l u Ed in u g c at io n

The Use of Dietary Supplements in Diabetic

Peripheral Objectives 1) To examine the significant role of Neuropathy dietary supplements in the treatment of painful diabetic . 2) To understand the Dietary Sup - These products can be used to plement Health and Education Act. treat this frequent complication 3) To identify both the benefits and of diabetes. risks of specific dietary supplements when treating painful diabetic periph - eral neuropathy.

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By Robert G. Smith DPM, MSc, RPh and the intensity of investigation, results from primary lesions or dysfunc - most studies suggest that about 30- tion of the peripheral or central ner - Introduction 50% of all diabetic people are vous system (Figure 1). This pain en - Polyneuropathy is a major compli - affected. 2 Backonja 3 stated that ap - compasses a variety of sensory, motor, cation of both insulin-dependent and proximately 45% of diabetic patients and autonomic symptoms. 4,5 non-insulin-dependent diabetes melli - will experience neuropathy during the Despite its many etiologies, neuro - tus, and is the most common form of course of the disease. Backonja 3 also pathic pain is usually spontaneous, neuropathy in the developed world. stated that 4% to 5% of all diabetic pa - continuous, burning, paroxysmal, and In the United States, the American Di - tients will have painful neuropathy. evoked by various mechanical or ther - abetes Association reports that 23.6 Peripheral neuropathy is character - mal stimuli. 6 Long-term elevation of million children and adults (8% of the ized by a progressive loss of nerve fibers plasma glucose levels has been estab - population) have diabetes. 1 Although that predisposes the patient to pain or lished as the definitive cause of diabet - estimates of the prevalence of diabetic insensitivity in the extremities as well ic peripheral neuropathy. 7 Currently, peripheral neuropathy vary substan - as neuropathic ulcerations; it can also the only treatment that addresses the tially depending on diagnostic criteria result in amputation. Continued on page 196 www.podiatrym.com NOVEMBER/DECEMBER 2009 • PODIATRY MANAGEMENT 195 n g o in ti u a n c Large-scale fortification of diets plement was evidence for its safety, ti u Supplements... n d o E began in the United States with the thus grandfathering in all supplements C al ic underlying cause of painful dia - addition of iodine to table salt in 1924 on the market before the legislation. d e betic neuropathy is improved con - to prevent goiter, followed by the ad - The current level of public assurance of M trol of blood glucose levels. 5 dition of , , , the safety and quality of and iron to flour in 1941. Multivita - and minerals products is inadequate. Glucose Control and Diabetic min and multimineral products pro - Currently, manufacturers of these Neuropathy viding more than A and D products are not required to report ad - There is strong evidence for the became available in pharmacies and verse events and the FDA has no regula - importance of tight glucose control in grocery stores in the mid-1930s. tory authority to require labeling delaying, and possibly preventing dia - In the early 1940s, the first multivi - changes or to help inform the public of betic peripheral neuropathy. these issues and concerns. Tesfaye noted that the same Further, the FDA has insuffi - cannot be said for diabetic TABLE 1 cient resources and legislative peripheral neuropathic pain. 2 Mechanisms of Neuropathic Pain authority to require specific In the absence of a curative safety data from dietary sup - therapy for painful diabetic Peripheral mechanisms Central mechanisms plement manufacturers or neuropathy, pharmacologic Changes in sodium channel Central sensitization distributors before or after or nonpharmacologic tools, distribution and expression their products are made avail - or combination of both, Altered neuropeptide expression AB fibre sprouting into able to the public. These un - should be used to provide lamina II of dorsal horn regulated supplement prod - control of symptoms. Phar - ucts would be subject to pre- Sympathetic sprouting Reduced inhibition of macological interventions, as descending pathyways market approval if they were well as advances in the man - marketed as food additives. Peripheral sensitization agement of painful diabetic Notably, the ingredients peripheral neuropathy, have Altered peripheral blood flow in some cases possess biolog - been thoroughly reviewed. 2,5 Axonal atrophy, degeneration ical activities similar, if not Lack of response and or regeneration identical, to those found in unwanted side-effects of Damage to small fibers . 10 Use of nutri - conventional pharmaco - ents in foods and supple - Glycaemic flux logical treatments force ments in the United States is many suffers of painful di - Adapted from Tesfaye S. Advances in the management of diabetic peripheral changing, and the NIH is neuropathy Curr Opin Support Palliat Care 3: 136, 2009 abetic neuropathy to ex - concerned that public safety plore alternative herbal cannot be assured. 10 and dietary supplements. 8 tamin and mineral tablet was intro - Adverse events from multivita - This article reviews dietary supple - duced. Annual sales of supplements to min/multimineral supplements ap - ments currently used to manage Americans are now reported at about pear with some frequency in both painful . First, the $23 billion, a substantial share of which the reports of the American Associ - history of dietary supplements and is spent on vitamins and minerals. 9 The ation of Poison Control Centers the Health and most common type of dietary supple - and the FDA’s MedWatch system. 10 Education Act (DSHEA) legislation are ment reported in the United States is Finally, the NIH position is that the presented as a foundation. Second, the multivitamin supplement. 10 present evidence is insufficient to rec - the dietary supplement properties Dietary supplement use is in - ommend either for or against the use used to treat painful diabetic neuropa - creasingly common in the general of multivitamin/multimineral supple - thy are described. Finally, compar - population of the United States, and ments by the American public to pre - isons of these supplements with re - usage may be even more common in vent chronic disease. 10 Further, Bardia gard to the dosages, frequencies, and some subpopulations (e.g., patients et al. examined the extent to which US adverse effects described in the medi - with diabetes). 11 More than half of adults used herbal supplements in ac - cal literature are offered to help with American adults take dietary supple - cordance with evidence-based indica - selection of the most appropriate sup - ments in the belief that the supple - tions. 13 Of the 30, 617 adults surveyed, plement for each individual patient. ments will make them feel better, 5,787 (18.9%) had consumed herbal have greater energy, improve their supplements in the past 12 months. Of Supplement Use and Legislation health, and prevent and treat disease. these, 3,315 (57.3%) used herbs to treat The word “”, short for a specific health condition. vital amines, was coined in 1912 as DSHEA It was concluded that roughly an abbreviated term meant to cap - In 1994, the Dietary Supplement two-thirds of adults using common - ture the notion of important factors Health and Education Act (DSHEA) de - ly consumed herbs did not do so in in the diet. In 1913, the first vita - fined a dietary supplement as a vita - accordance with evidence-based in - min, thiamine, was isolated; defi - min, mineral, herb or other botanical, dications. For this reason, it is es - ciency of thiamine caused beriberi. amino acid, or other substance (e.g., sential that practicing podiatric Thirteen vitamins and 15 essential coenzyme, organ tissue, glandular, or physicians acutely evaluate current minerals have now been identified metabolite). 12 The DSHEA assumed medical literature on the subject of as important to human nutrition. that the history of use of a given sup - Continued on page 197

196 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2009 www.podiatrym.com M C e o d n i t ticipants than trials of conventional volving persons with dia - ca in Supplements... l u Ed in medications. Other limitations (e.g., betes or impaired glucose tol - u g 15 c botanicals and supplements to treat poorly designed clinical trials or in - erance were discovered. at io diabetic neuropathic pain. complete reports) make it difficult to These investigators present both n evaluate published studies. 14 a well-written narrative and a descrip - Challenges in Standardizing One method of resolving these tive graphic table illustrating the study Herbal and Supplemental limitations is to pool data from indi - design, sample size, intervention, con - Products vidual trials by using a meta-analysis trol group, outcomes, and adverse ef - Goldman identified several to reach an interpretation of the re - fects. 15 Two interesting points of inclu - challenges in standardizing herbal sults of a group of inconclusive trials. 14 sion in this table were the “quality of medicines. 14 The first such chal - Herbal and Dietary Supplements evidence” and “Jadad” scores. 15 Of lenge is that bioassays must be used in Diabetes Mellitus and Diabet - these 58 trials, the direction of evidence based on biological models, which ic Peripheral Neuropathy for improved glucose control was posi - are not available for the health Diabetes mellitus is a chronic con - tive in 76% (44 of 58 trials). 15 claims made for many popular dition affecting millions of Americans. It was concluded that there is still herbs. 14 Secondly, chemical analysis Podiatric physicians are very familiar insufficient evidence to draw defini - has limited value when the ingredi - with conventional medical treatments tive conclusions regarding the efficien - ents responsible for a plant’s activi - available to treat both diabetes mellitus cy of individual herbs and supple - ty have not been identified. 14 Also, and painful diabetic peripheral neu - ments for diabetes. Chromium has if the active ingredient of an herb is ropathy. Many of the podiatric physi - been the most widely studied supple - known, it remains unclear whether cian’s patients solicit a professional po - ment, but other supplements with the crude herb would be preferable diatric opinion on the use of comple - positive preliminary results include: to its purified active component. 14 mentary and alternative medicine gymnema sylvestre, aloe vera, vanadi - When the active principle ingre - therapies, including dietary supple - um, momordic charantia, and nopal. 15 dient of an herbal preparation is not ments to treat their diabetic and neu - Finally, it was noted that the avail - known and there is no accepted ropathic symptoms (Figure 2). able data suggest that several supple - method of standardization, a clini - The main motivations for patients ments may warrant further study. 15 cal trial offers an attractive ap - to use these dietary supplements are proach to evaluate the activity. 14 to improve blood glucose, manage Alpha- Two important requirements neces - their symptoms, and lessen the risk of Alpha-lipoic acid, also known as sary for successful clinical herbal tri - developing serious complications. thioctic acid, is an endogenous, sulfur- als include a consistent herbal for - Yeh, et al. conducted an electronic containing free radical scavenger mulation and a large study sample. 14 literature search as well as a follow-up found in mitochondria. 8 Treatment Although the methodology of physical search of 108 trials examin - with alpha-lipoic acid improves nerve herbal trials has improved, some ing 36 herbs and 9 vitamin and min - blood flow and distal nerve conduc - studies cited in specific herbal com - eral supplements that involved 4,565 tion and increases endoneurial glucose pendia have a specific limitation. patients with diabetes or impaired glu - uptake and energy metabolism in ani - Many results of herbal trials often do cose tolerance. 15 Upon analysis, 58 mals. 8,16,17 Alpha-lipoic acid also recy - not reach statistical significance be - controlled clinical trials (42 random - cles other antioxidants (e.g., cause these studies enroll fewer par - ized and 16 non-randomized trials) in - Continued on page 198

TABLE 2 Dietary Supplements Treating Diabetic Peripheral Neuropathy

Supplement Mechanisms Daily Dose Possible Adverse Effects Alpha-Lipoic acid Reduces oxidation throughout body 600 mg May Lower Blood Glucose Acetl-L-carnitine Uptake and oxidation of long fatty acids 1000 mg (IM) Nausea and Diarrhea Benfotiamine Increase transketolase activity 300-450 mg No reports of toxicity Capsaicin Depletes neurotransmitter stores Topical 3 to 4 times Hot sensation may cause discontinuation Vitamin B-6 Inhibits glycoslation of proteins Inconclusive Avoid doses larges dose with levodopa without taking carbidopa Vitamin B-12 Reduces homocysteine Unknown Not to used with Leber's opyic atropy L-methylfolate Methlation of homocsteine Twice a day Co-administration with certain drugs Pyridoxal 5'-phosphate Prosthetic group for enzymes will alter plasma levels Biological active Vitamin B-12 Antibiotics may alter intestinal microflora resulting decrease absorption of methycobalamine Vitamin E Powerful antioxidant reducing 900 IU Possible drug interaction with Warfarin free radicals alteration in stores Use in caution of liver failure

www.podiatrym.com NOVEMBER/DECEMBER 2009 • PODIATRY MANAGEMENT 197 n g o in ti u a 21 n c day. Those patients who received in - least five times greater than those ob - ti u Supplements... n d o E tramuscular acetyl-L-carnitine showed a served after oral administration of C al ic and ) but can chelate significant decrease in neuropathic water-soluble thiamine salts. d e transition metals, like iron and cop - symptoms as compared to the placebo Benfotiamine exerts its beneficial M per. 8 Alpha-lipoic acid reduces oxida - group, but no change in vibratory per - effects through a number of mecha - tion throughout the body because it is ception threshold was noted. 21 nisms. In the case of diabetes, benfoti - both fat-soluble and water-soluble. 8 De Grandis and Minardi assessed amine increases transketolase activity, According to Halat and Dennehy, the efficacy and tolerability of acetyl-L- and thereby blocks three of the major clinical trials have demonstrated carnitine versus placebo in the treat - molecular pathways leading to hyper - symptomatic improvements after ment of diabetic neuropathy, mainly glycemic damage. Benfotiamine pre - short-term parenteral use rather than by evaluating the effects of treatment vents the increase in UDP-N-acetylglu - long-term use of alpha-lipoic acid. 8 Be - on electrophysiological parameters and cosamine (UDP-GlcNAc), and enhances cause oral formulations are more con - pain symptoms. 22 The main efficacy pa - the hexosamine pathway activity to de - venient for patients to maintain adher - rameter was the effect of treatment on crease the buildup of detrimental glu - ence, more economical, and easier to 6- and 12-month changes from base - cose metabolites that can lead to ad - obtain, the scope of alpha-lipoic acid line in nerve conduction velocity vanced glycation end products (AGE). trials discussed here will be limited to (NCV) and amplitude in the sensory In addition, benfotiamine corrects recent trials using oral alpha lipoic (ulnar, sural and median) and motor imbalances in the polyol pathway by acid. One reported signifi - (median, ulnar and peroneal) nerves. decreasing aldose reductase activity, sor - cant improvements in nerve conduc - The effect of treatment on pain bitol concentrations, and intracellular tion velocity with oral doses of 600 to was also evaluated by means of a visu - glucose, thereby protecting endothelial 1, 200 mg per day for two years. 18 al analog scale (VAS). 22 Acetyl-L-carni - cells from glucose-induced damage. 24 Another trial observed that symp - tine was effective and well-tolerated The efficacy and safety of benfoti - toms improved using 1,800 mg per for both improving neurophysiologi - amine in the treatment of diabetic day for 21 days. 19 A final investigation cal parameters and reducing pain over polyneuropathy have been recently re - demonstrated that oral treatment with a one-year period. Therefore, it was ported. 25 Stracke, et al. utilized a ran - alpha-lipoic acid for five weeks im - concluded that acetyl-L-carnitine of - domized double blind, placebo-con - proved neuropathic symptoms and fers a promising treatment option for trolled, phase-III study of 181 patients deficits in patients with diabetic pe - patients with diabetic neuropathy. 22 with symmetrical, distal diabetic ripheral neuropathy. Further, the The podiatric clinician will obtain polyneuropathy. 25 study established that an oral dose of valuable information by reading De After six weeks of treatment with 600 mg once daily provided the opti - Grandis’s recent review on the use of 600 mg of benfotiamine per day, 300 mum risk-to-benefit ratio. 20 acetyl-L-carnitine in chemotherapy-in - mg of benfotiamine per day, or place - Currently, alpha-lipoic acid is al - duced peripheral neuropathy and ap - bo, the primary outcome parameter ready approved in Germany for dia - plying this knowledge to diabetes-in - “neuropathy symptom scored” differed betic neuropathy. 8 When more re - duced peripheral neuropathy. 23 Prelimi - significantly between the treatment search on the long-term benefits of nary results have confirmed the reason - groups. 25 The improvement was more alpha-lipoic acid become available, it ably good tolerability profile and effica - pronounced at the higher benfoti - is hoped that statements concerning cy of acetyl-L-carnitine in chemothera - amine dose and increased with treat - the long-term safety and clinical ef - py-induced peripheral neuropathy. 23 ment duration. 25 fectiveness will allow the practicing Realm Laboratories has recently podiatric physician to evaluate the De Grandis suggested that these made Neuremedy ™ available in the benefits of this supplement for treat - studies support the use of acetyl-L-car - U.S.A. The active ingredient in Neurem - ing diabetic peripheral neuropathy. nitine in cancer patients with persisting edy ™ is 150 mg of benfotiamine. There The podiatric physician may need neurotoxicity induced by paclitaxel or are no reports of benfotiamine drug in - to advise the patient who initiates cisplatin treatment. 23 Acetyl-L-carnitine teractions. 25 Benfotiamine administra - alpha-lipoic acid treatment to monitor can cause gastrointestinal symptoms tion appears to be safe with no reports their blood glucose levels frequently such as nausea and diarrhea. of toxicity in the scientific literature. 26 because lipoic acid may lower blood Based on clinical studies to date, daily glucose levels unexpectedly. Benfotiamine doses of oral benfotiamine range from The fat-soluble form of vitamin B1, 300-450 mg daily, in divided doses. 26 Acetyl-L-carnitine called benfotiamine, has been used ef - Acetyl-L-carnitine is an endogenous fectively to treat alcoholic and diabetic Capsaicin substance similar in structure to acetyl - neuropathies. Unlike that of thiamine, Capsaicin directly affects sensory choline, and is involved in the uptake the structure of benfotiamine contains fibers, especially C-fibers. 8,27 Initial ap - and oxidation of long-chain fatty acids an open thiazole ring that closes once it plication of capsaicin stimulates these in mitochondria. 8,21 One of the first is absorbed to produce biologically ac - fibers and deletes endogenous neuro - human randomized controlled trials tive thiamine. Benfotiamine is absorbed transmitter stores associated with examined 20 patients with symptomat - via passive diffusion through the intesti - pain transmission (e.g., substance P, ic neuropathy during a 15-day period. 21 nal mucosa and is rapidly converted to vasoactive intestinal peptide, chole - The subjects of this investigation re - biologically active thiamine. Peak plas - cystokinin, and somatostatin). 28 This ceived either intramuscular acetyl-L-car - ma concentrations of thiamine after can result in a burning sensation nitine or a placebo at 1000 mg per oral benfotiamine administration are at Continued on page 199

198 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2009 www.podiatrym.com M C e o d n i t improvement in all patients; however, Metanx ® include: paresthe - ca in Supplements... l u Ed in subsequent randomized, double-blind sia, somnolence, nausea and u g c within the first few weeks of use. and placebo-controlled trials failed to headaches, mild transient diar - at 8 io This sensation might affect patient demonstrate similar results. Individu - rhea, polycythemia vera, itching, n compliance, and patients should be als being treated with levodopa with - transitory exanthema and the feeling advised to continue use, since it may out taking carbidopa at the same time of swelling of the entire body. 31 When take four to six weeks before benefits should avoid daily doses of 5 mil - the podiatric physician elects to pre - are appreciated. 8 Capsaicin is available ligrams or greater of vitamin B6. scribe this combination of medica - without a prescription in strengths Neuropathy caused by vitamin tion, caution may need to be exercised ranging from 0.025% to 0.25%. Clini - B12 deficiency is successfully treated with antibiotics since alteration of the cal trials have demonstrated that ap - with supplementation to restore nor - intestinal microflora may decrease the plication of capsaicin must take place mal vitamin B12 levels. The most absorption of methylcobalamine. three to four times a day for symptom common forms of supplemental B12 The co-adminstration of Metanx ® improvement. There have been hun - are and hydrox - with either , para aminosal - dreds of studies on using capsaicin for cobalamin. The natural form of B12 icylic acid, or potassium chloride may the treatment of diabetic neuropathy. found in food is methylcobalamin. decrease the absorption of methyl - Unlike many other herbal food-based The chemical structure of B12 is cobalamin. 31 Because several drugs are products, capsaicin is regulated as an very complex, with numerous methyl associated with lowering serum folate over-the-counter product by the Food groups attached. Methyl groups are levels or reduction of active folate and Drug Administration; and there - used in beneficial methylation reac - available, monitoring of folate plasma fore, it meets manufacturing, safety, tions such as those that reduce homo - levels may be advised when a patient’s and clinical efficacy standards for cysteine. Methylcobalamin appears to includes anticonvul - over-the-counter products. 8 be the most effective form of vitamin sants, methotrexate, sulfasalazine, Zostrix ® Neuropathy Cream is B12 for protection of nerves. Patients cholestyramine, colchicine, high dose made with topical purified natural should be advised not to take NSAIDs, triamterene, trimethoprim, or capsaicin (0.25%) that is far stronger cyanocobalamin if they have Leber’s in the presence of excessive alcohol than any other capsaicin cream cur - optic atrophy. intake or smoking. 31 rently available without a prescrip - tion. The product’s unique patented L-methylfolate, Pyridoxal 5’- Vitamin E cream formulation, which includes phosphate, Methylcobalamin Vitamin E is a powerful antioxi - , improves the tolerance of combination dant that reduces levels of free radi - high strength capsaicin. L-methylfolate is the primary bio - cals and oxidative stress. The effect of Zostrix ® Neuropathy Cream can logically active isomer of folate and vitamin E on nerve function was eval - be used alone, or as a highly effective the primary form of folate in the cir - uated in a randomized, double-blind, adjunctive therapy as a systemic culation. L-methylfolate is used in the placebo-controlled trial with 21 type- pain medication to effectively relieve methylation of homocysteine to form 2 diabetic patients diagnosed with diabetic neuropathy pain. The for - methionine and tetrahydrofolate. mild-to-moderate neuropathy. 8,32 mulation has proven efficacy with Pyridoxal 5’-phosphate is the active The primary outcome evaluated continued use for the treatment of form of vitamin B6 and is used as the large doses of vitamin E (900 IU) and localized neuropathic pain and a low prosthetic group for many enzymes the ability to reduce neuropathy risk of systemic side effects, adverse that depend on this vitamin. over a six-month period. 32 There events, or drug interactions. Methylcobalamin is one of the two were no changes in glycemic indices, Clinically proven results demon - forms of biologically active vitamin but both median and tibial motor strated that Zostrix Neuropathy B12. Commercial prescription products nerve conduction velocities were sig - Cream significantly increased pain of L-methylfolate 2.8 mg, Pyridoxal 5’- nificantly improved in the vitamin E relief. Overall, 90% of Painful Dia - phosphate 25 mg, and Methylcobal - group as compared to the placebo betic Neuropathy patients reported amin 2 mg are available under the group. 32 These findings suggest that improvement and by week six pa - name Metanx ®.31 These products are in - patients with neuropathy might ex - tients’ pain was reduced by 50%.** dicated for the distinct nutritional re - perience a reduction of symptoms. 32 quirements of diabetic patients with Patients who begin to take vita - Vitamin B6 and Vitamin B12 endothelial dysfunction, who present min E should consult their primary Low levels of vitamin B6 have with loss of protective sensation as well care providers before taking the vi - been reported in patients with dia - as neuropathic pain associated with di - tamin if they are also taking war - betic neuropathy, but not in diabet - abetic peripheral neuropathy. 31 farin, or if they have a vitamin K ic patients with neuropathy. 8,29 Vita - Additionally, it is indicated for deficiency or history of liver failure. min B6 inhibits the glycosylation of the distinct nutritional requirements proteins. Jones and Gonzalez con - of patients with endothelial dys - Homeopathic Alternative ducted a small-scale, six-week trial of function and/or hyperhomocys - Neuragen PN ® is a topical homeo - 10 diabetic patients using an open- teinemia, who present with lower pathic drug designed for effective, study design to evaluate the effect of extremity ulcerations. 31 The recom - temporary relief from pain that is de - 25 mg of oral vitamin B6 on diabetic mended dose is one tablet twice scribed as shooting, burning, tingling, peripheral neuropathy. 30 daily or as directed by a physician. or stabbing, especially in the hands This trial observed symptomatic Adverse reactions reported with Continued on page 200 www.podiatrym.com NOVEMBER/DECEMBER 2009 • PODIATRY MANAGEMENT 199 n g o in ti u a n c tional treatment and risk of complications in 20 Ziegler D, Ametv A, Barnov A, et al. ti u Supplements... n d o E patients with type 2 diabetes. Lancet 352: Oral treatment with lipoic acid improves C al ic and feet. Neuragen PN is a clini - 837, 1998. symptomatic diabetic polyneuropathy: the d 5 e cally-proven treatment for nerve Smith RG: Painful Diabetic Peripheral Sydney 2 trial. Diabetes Care 3: 108, 2006. M 21 pain caused by diabetes (foot and Neuropathy. J Am Podiatr Med Assoc 97: 394, Quatraro A, Roca P, Donzella C, et al. 2007. Acetyl-L-carnitine for symptomatic diabetic hand nerve pain)** Neuragen PN’s ® 6 Attal N, Bouhassira D: Mechanisms of neuropathy. Diabetologia 38: 123, 1995. listed homeopathic ingredients in - pain in peripheral neuropathy. Acta Neurol 22 De Grandis D, Minardi C. Acetyl-L-car - clude: hypericum 12C, aconitum Scand Suppl 173: 12, 1999. nitine (levacecarnine) in the treatment of dia - napellus 12C, lycopodium 12C, phos - 7 The Diabetes Control and Complica - betic neuropathy. A long-term, randomized, phorus 12C, rhus toxicodendron 12C, tions Trial Research Group. The effect of in - double-blind, placebo-controlled study. and secale cornutum 12C. Neuragen tensive diabetes therapy on the development Drugs R D. 3: 223, 2002. PN ® is concentrated and requires ap - and progression of neuropathy, Ann Intern 23 De Grandis D. Acetyl-L-carnitine for plication of only a few drops. Med 122: 561, 1995. the treatment of chemotherapy-induced pe - Application of more than a few 8 Halat KM, Dennehy CE. Botanicals and ripheral neuropathy: a short review. CNS drops at a time may not improve ef - dietary supplements in diabetic peripheral Drugs. 21:39, 2007. 24 fectiveness. The time period of relief neuropathy. J AM Board Fam Pract. 16: 47, Berrone E, Beltramo E, Solimine C, et 2003. al. Regulation of intracellular glucose and varies from less than an hour to sever - 9 NIH State-Of-The-Science Conference polyol pathway by thiamine and benfoti - al days, depending on the type and Statement on Multivitamin/Mineral Supple - amine in vascular cells cultured in high glu - ® extent of pain. Neuragen PN does not ments and Chronic Disease Prevention. NIH cose. J Biol Chem 281: 9307, 2006. numb the area of application and can Consensus and State-of-the-Science State - 25 Stracke H, Gaus W, Achenbach U, et be applied up to four times per day. ments 23, (2): May 15-17, 2006. al. Benfotiamine in diabetic polyneuropathy Neuragen PN ® is not recommended 10 Murphy SP, White KK, Park S, et al. (BENDIP): results of a randomized, double for muscular pain or arthritis. Multivitamin-multimineral supplements’ ef - blind, placebo-controlled clinical study. Exp fect on total nutrient intake. Am J Clin Nutr Clin Endocrinol Diabetes. 116: 600, 2008. 26 Conclusion 85: 280S, 2007. Benfotiamine Monograph Altern Med 11 Pain relief is one of the most chal - Rock CL. Multivitamin-multimineral Rev 11: 238, 2006. supplements:who uses them? Am J Clin Nutr 27 Robbins WR. Clinical applications of lenging issues in diabetic neuropathy. 85: 277S, 2007. capsaicinoids. Clin J Pain 16: S86, 2000. Adequate glucose control is the main - 12 Dietary Supplement Health and Edu - 28 Markovits E, Gilhar A. Capsaicin-an ef - stay of treatment for diabetic neuropa - cation Act of 1994, P.L. 103-147. [103RD fective topical treatment in pain. Int J Derma - thy, and conventional FDA-approved Cong, 2nd Sess, Jan 25, 1994.] Washington, tol 36: 401, 1997. pharmaceuticals may be prescribed and DC: Congressional Research Service, Library 29 McCan YJ, Davis RF. Serum pyridoxal used by neuropathic patients if symp - of Congress, 1994. concentrations in patients with diabetic neu - tom relief is not adequate. The podi - 13 Bardia A, Nisly NL, Zimmerman MB, ropathy. Aust NZ J Med 8: 259, 1978. atric physician will come to realize that et al. Use of herbs among adults based on evi - 30 Jones CL, Gonzalez V. defi - the accessibility and advertising of di - dence-based indications: findings from na - ciency: a new factor in diabetic neuropathy. J etary supplement products make these tional health interview survey. Mayo Clin Am Podiatry Assoc. 68: 646, 1978. Proc 82: 561, 2007. 31 Metanax ® Tablets: Methanx ® Feel the products attractive for many sufferers. 14 Goldman P. Herbal medicines today Difference. http://www.metanx.com/HCP, Additionally, shortcomings exist in and the roots of modern pharmacology. Ann PackageInsert accessed 08/31/2009. the available dietary supplements be - Intern Med 135: 594, 2001. 32 Tutuncu NB, Bayraktar M, Varli K. Re - cause of the current governmental leg - 15 Yeh Gy, Eisenberg DM, Kaptchuk TJ, versal of defective nerve conduction with vi - islation. Specifically, there is no guar - et al. Systematic review of herbs and diatary tamin E supplementation in type 2 diabetes: antee of efficacy, safety, or product supplements for glycemic control in diabetes. a preliminary study. Diabetes Care 11: 1915, content. This article reviewed dietary Diabetes care 26: 1277, 2003. 1998. supplements currently used to manage 16 Nagamatsu M, Nickander KK, painful diabetic neuropathy. I Schmelzer JD, et al. Lipoic acid improves blood flow, reduces oxidative stress, and im - Dr. Smith com - proves distal nerve conduction in experimen - **Company will provide clinical infor - pleted his post- tal diabetic neuropathy. Diabetes Care 16: graduate training mation upon request to substantiate state - 1160, 1995. with the College ments. 17 Low PA, Nickander KK, Tritschler HJ. of Medicine at The roles of oxidative stress and antioxidant the University of References treatment in experimental diabetic neuropa - Wales, Cardiff, 1 American Diabetes Assoication: Diabet - thy. Diabetes 46: S38, 1997. Wales, UK in ic statistics. Available at 18 Reljanovic M, Reichel G, Rett K, et al. wound care and http://www.diabetes.org/utils/printpage.jsp? Treatment of diabetic polyneuropathy with tissue repair. He Page ID=STATISTICS_233187. Accessed Au - antioxidant thioctic acid (alpha-lipoic acid): a is an associate of gust 28, 2009. two-year-multi-center randomized double- the American Professional Wound Care 2 Tesfaye S: Advances in the manage - blind placebo-controlled trial (Aladin II). Association and a consultant to National ment of diabetic peripheral neuropathy. Curr Alpha Lipoic Acid in Diabetic Neuropathy. Board of Podiatric Medical Examiners. He Opin Suppot Palliat Care 3: 136, 2009. Free Radic Res 31: 171, 1999. is a contributing editor and reviewer to 3 Backonja M: Managing painful diabetic 19 Ruhnau KJ, Meissner HP, Finn JR, et al. JAPMA in the area of podiatric clinical neuropathy. Hosp Pract 34: 79, 1999. Effects of 3-week oral treatment with antioxi - pharmacology and has authored 50 refer - 4 UK Prospective Diabetes Study Group: dant thioctic acid (alpha-lipoic acid) in symp - eed journal articles in the disciplines of Intensive blood glucose control with sulpho - tomatic diabetic polyneuropathy. Diabet pharmacy, podiatry, and wound care. He nylureas or insulin compared with conven - Med 16: 1040, 1999. currently practices in Ormond Beach, FL.

200 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2009 www.podiatrym.com M C e o d n i t ca in l u Ed in EXAMINATION u g c at io n See answer sheet on page 203 .

1) Backonja stated that ___to ____ 6) Alpha-lipoic acid is an endoge - 11) The amount of purified natu - of all diabetic patients will have nous, sulfur-containing, free radi - ral capsaicin in proven Zostrix® painful neuropathy. cal scavenger found in Neuropathy Cream, the strongest A) 1%, 2% the______. available without a prescription, B) 2%, 3% A) golgi body is: C) 4%, 5% B) nucleus A) .0015 D) 6%, 10% C) ribosomal RNA B) .0025 D) mitochondria C) .25 2) All of the following are periph - D) .025 eral mechanisms of neuropathic 7) Acetyl-L-carnitine is involved in pain except: the uptake and oxidation 12) The natural form of B12 A) Damage to small fibers of______in mitochondria? found in food is______. B) Reduced inhibition of de - A) long-chain proteins A) cyanocobalamin scending pathways B) omega-3 fatty acids B) hydroxcobalamin C) Glycemic flux C) long-chain fatty acids C) methylcobalamin D) Sympathetic sprouting D) long-chain polysaccharides D) hexhydrocobalamin

3) The word “vitamin” was coined 8) The fat-soluble form of vitamin 13) According to this review, all of in 1912 as an abbreviated term for B1 is called______. the following drugs are associated ______. A) thiamine with reduction of serum folate A) vital minerals B) methylfolate levels except:______. B) vital proteins C) benfotiamine A) high doses of NSAIDs C) vital acids D) tetrahydrofolate B) L-methylfolate D) vital amines C) 9) Stracke, et al. found that im - D) colchicine 4) Annual sales of supplements to provement in diabetic polyneu - Americans are reported at ropathy symptoms was more pro - 14) According to ADA reports re - about______. nounced at ______garding US patients, 23.6 million A) $ 16 million A) a lower benfotiamine dose children and adults or ____ of the B) $ 50 thousand and decreased duration population, have diabetes. C) $ 23 billion B) a higher benfotiamine dose A) 2% D) $ 10 million and increased duration B) 5% C) a lower benfotiamine dose C) 8% 5) All of the following are challenges and increased duration D) 15% in standardizing herbal medicines D) a higher benfotiamine dose identified by Goldman except: and decreased duration 15) Select the homeopathic ingre - A) FDA safety data exists on all dient found in clinically-proven herbal products 10) Based on clinical studies to Neuragen® PN? B) chemical analysis has limited date, daily doses of oral benfoti - A) Hypericum 12C, Aconitum value for many herbs amine range from______daily, in B) Phosphorus 12C, C) whether the crude herb divided doses. C) Secale cornutum 12 C, would be preferable to its puri - A) 25 mg—50 mg D) All of the above are home - fied active component B) 100 mg—150 mg opathic ingredients D) bioassays must be based on C) 500 mg—750 mg biological models D) 300 mg—450 mg Continued on page 202 www.podiatrym.com NOVEMBER/DECEMBER 2009 • PODIATRY MANAGEMENT 201 n g o in ti u a n c ti u n d o E EXAMINATION PM ’s C al ic ed (cont’d) M CPME Program Welcome to the innovative Continuing Education 16) According to this review, several studies have Program brought to you by Podiatry Management established long-term______as the definitive Magazine . Our journal has been approved as a cause of diabetic peripheral neuropathy. sponsor of Continuing Medical Education by the A) elevation of plasma potassium Council on Podiatric Medical Education. B) elevation of plasma glucose C) elevation of plasma uric acid Now it’s even easier and more convenient D) elevation of plasma calcium to enroll in PM’s CE program! You can now enroll at any time during the year 17) The current level of public assurance of safety and submit eligible exams at any time during your and quality of multivitamin and minerals is enrollment period. ______. PM enrollees are entitled to submit ten exams A) adequate published during their consecutive, twelve–month B) acceptable enrollment period. Your enrollment period begins C) inadequate with the month payment is received. For example, D) sufficient if your payment is received on September 1, 2006, your enrollment is valid through August 31, 2007. 18) Yeh, et al. concluded that there is still ______If you’re not enrolled, you may also submit any evidence to draw definitive conclusions regard - exam(s) published in PM magazine within the past ing efficiency of herbs for diabetes. twelve months. CME articles and examination A) insufficient questions from past issues of Podiatry Man - B) sufficient agement can be found on the Internet at C) satisfactory http://www.podiatrym.com/cme. Each lesson D) enough is approved for 1.5 hours continuing education con - tact hours. Please read the testing, grading and pay - 19) According to this review, vitamin E doses of ment instructions to decide which method of partici - ______may improve both median and tibial pation is best for you. motor nerve conduction velocities when com - Please call (631) 563-1604 if you have any ques - pared to placebo. tions. A personal operator will be happy to assist you. A) 200 IU Each of the 10 lessons will count as 1.5 credits; B) 400 IU thus a maximum of 15 CME credits may be C) 900 IU earned during any 12-month period. You may se - D) 300 IU lect any 10 in a 24-month period.

20) Despite its many etiologies, neuropathic pain The Podiatry Management Magazine CME is usually______. program is approved by the Council on Podiatric A) spontaneous Education in all states where credits in instruction - B) continuous al media are accepted. This article is approved for C) burning 1.5 Continuing Education Contact Hours (or 0.15 D) all of the above are correct descriptions of CEU’s) for each examination successfully completed. neuropathic pain

Home Study CME credits now See answer sheet on page 203 . accepted in Pennsylvania

202 PODIATRY MANAGEMENT www.podiatrym.com £ M C e o d n i t ca in l u Ed in Enrollment/Testing Information u g c at io and Answer Sheet n Note: If you are mailing your answer sheet, you must complete exam during your current enrollment period. If you are not en - all info. on the front and back of this page and mail with your rolled, please send $20.00 per exam, or $139 to cover all 10 exams credit card information to: Podiatry Management , P.O. Box (thus saving $61* over the cost of 10 individual exam fees). 490, East Islip, NY 11730. Facsimile Grading To receive your CPME certificate, complete all information and TESTING, GRADING AND PAYMENT INSTRUCTIONS fax 24 hours a day to 1-631-563-1907. Your CPME certificate will (1) Each participant achieving a passing grade of 70% or be dated and mailed within 48 hours. This service is available for higher on any examination will receive an official computer form $2.50 per exam if you are currently enrolled in the annual 10-exam stating the number of CE credits earned. This form should be safe - CPME program (and this exam falls within your enrollment period), guarded and may be used as documentation of credits earned. and can be charged to your Visa, MasterCard, or American Express. (2) Participants receiving a failing grade on any exam will be If you are not enrolled in the annual 10-exam CPME pro - notified and permitted to take one re-examination at no extra cost. gram, the fee is $20 per exam. (3) All answers should be recorded on the answer form below. For each question, decide which choice is the best an - Phone-In Grading swer, and circle the letter representing your choice. You may also complete your exam by using the toll-free ser - (4) Complete all other information on the front and back of vice. Call 1-800-232-4422 from 10 a.m. to 5 p.m. EST, Monday this page. through Friday. Your CPME certificate will be dated the same day (5) Choose one out of the 3 options for testgrading: mail-in, you call and mailed within 48 hours. There is a $2.50 charge for fax, or phone. To select the type of service that best suits your this service if you are currently enrolled in the annual 10-exam needs, please read the following section, “Test Grading Options”. CPME program (and this exam falls within your enrollment peri - od), and this fee can be charged to your Visa, Mastercard, Ameri - TEST GRADING OPTIONS can Express, or Discover. If you are not currently enrolled, the fee Mail-In Grading is $20 per exam. When you call, please have ready: To receive your CME certificate, complete all information 1. Program number (Month and Year) and mail with your credit card information to: 2. The answers to the test Podiatry Management 3. Your social security number P.O. Box 490, East Islip, NY 11730 4. Credit card information There is no charge for the mail-in service if you have already In the event you require additional CPME information, enrolled in the annual exam CPME program, and we receive this please contact PMS, Inc., at 1-631-563-1604 .

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Check one: ______I am currently enrolled. (If faxing or phoning in your answer form please note that $2.50 will be charged to your credit card.) ______I am not enrolled. Enclosed is my credit card information. Please charge my credit card $20.00 for each exam submitted. (plus $2.50 for each exam if submitting by fax or phone). ______I am not enrolled and I wish to enroll for 10 courses at $139.00 (thus saving me $61 over the cost of 10 individual exam fees). I understand there will be an additional fee of $2.50 for any exam I wish to submit via fax or phone. Over, please 203 £ n i y s t t’d) h t a exam n e p con esson? l ( this o r m e www.podiatrym.com l 09 the u e p leted N ) p u l S #10/ EET h t i comp y a r e M complete N m o you t h p SH IO S ( r a t e i EXA i r e T A you D date P educational c f o the take i t its e it all LU A EV id eve e s U at d e b a SWER N indicat O achi i D e h le: N lesson? time T SS h c ir E A L Please C this exams: lesson n muc ______minutes & this ______Well 2009 ______Not future assig ______How did hours for you well well RM ______es? estions would How FO ABCD t ABCD ABCD sugg D exam rade ABCD ) a s o o ABCD g T objectiv ABCD F 11. esson? ABCD ______Very thi and l 12. ABCD 13. ABCD c i 14. erall ABCD 15. C ______Somewhat the 16. ov eted NOVEMBER/DECEMBER /09 17. 18. • 19. ete 20. #9 u q c a l i v e B B What compl comments t e b a i D M ENT al compl LLM EN d n ON you o XA t a e h t E te A n da i RO you Degree______Addition ABCD ucational ABCD he s r e g ABCD MANAGEM t ABCD TI ALUA ed o ABCD take Y ABCD 1. EN A S R ABCD t 2. i ABCD ate its 3. R ( EV ABCD

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