Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Complex B vitamins: Physiology and Therapeutic Effect on Pain

Alberto Mimenza Alvarado*, Sara Aguilar Navarro

Geriatric Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México

Abstract: Complex B vitamins (B1, B6, and B12) have shown affect several metabolic routes in the organism. Vitamin B1, or thiamine, has anti-oxidative properties and significant effects on the nitric oxide-cGMP pathway, giving it anti-hyperalgesic and anti-allodynic properties. Vitamin B6, or pyridoxine, has modulatory effects on calcium channels, inhibiting glutamate synthesis and intervening in the metabolism of carbohydrates. Vitamin B12 shows reconstructive effects and increases epidermal growth factor synthesis. Combining them produces an additive effect that, apart from participating in vital body functions, can help treat diseases such as pain. It is important to know about the mechanisms that explain their analgesic and anti-allodynic effects, in order to understand the physiologic mechanisms involved in these actions. This article summarizes Vitamins B1, B6 and B12 actions, focusing in pain treatment.

Keywords: thiamine, cobalamine, pyridoxine, pain nitric oxide, oxidative

Citation: Alberto Mimenza Alvarado, Sara Aguilar Navarro, Complex B vitamins: Physiology and Therapeutic Effect on Pain. American Journal of Pharmacological Sciences, 4 (2). 20-27. January 2016. doi:10.12691/ajps-4-2-2

1. Introduction

Complex B is constituted by 8 vitamins, essential for cells to function, since they help the body to transform food into energy. [1] They are water-soluble and, therefore, they may get lost in cooking-water and, if taken excessively, eliminated in urine. These vitamins are B1 (thiamine); B2 (riboflavin); B3 (niacin), B5 (pantothenic acid); B6 (pyridoxine); B7 (biotin), also known as vitamin H; B9 (folic acid) and B12 (cobalamin). Other substances, such as B10, B11 and B4, are not really vitamins. In addition to their nutritional contents, they have effects on other pathologies, such as pain treatment [2].

2. Chemical Structure

Thiamine or B1 has a thiazole ring and a pyrimidine group, creating together a structure containing sulfur within two rings bonded by a methylene group. It is water-soluble and has an organic cation that, at neutral pH, allows thiamine to go through cellular membranes at normal physiological concentrations, through a specific mechanism called high affinity thiamine transportation. [3] The Figure 1, show the chemical structure of the thiamine.

Pyridoxine or vitamin B6 is water-soluble and stable in both heat and acidic media. The chemical structure of vitamin B6 main compounds (pyridoxine, pyridoxal and pyridoxamine) share a pyridine, hydroxyl and aminophenyl ring, with hydroxymethyl substituents on position 4. In pyridoxine, an alcohol group substitutes the aldehyde group in position 4 of pyridoxal. In pyridoxamine, an amine group replaces the same aldehyde group, see Figure 2. Summarizing, position 5 substitutions are: pyridoxine: -CH₂OH, pyridoxal: -CHO and pyridoxamine: -CH₂NH2. PLP (pyridoxal 5´-phosphate) acts as coenzyme in all transamination reactions and, in some of them, in decarboxylation and deamination of amino acids [4,5].

Figure 1. Chemical structure of thiamine

Figure 2. Chemical structure of pyridoxine

Figure 3. Chemical structure of cobalamin

Cobalamin or vitamin B12 is a cobalamin that belong to the family of complex molecules, formed by the asymmetrical bond of two pyrrolic rings, creating an almost-planar macrocyclic group (corrin nucleus), surrounding a central cobalt atom (Co), see Figure 3 [6].

Cobalamin is an essential co-factor for 2 enzymes: methionine synthase and methylmalonyl coenzyme A mutase (MMCoA). High cobalamin doses can help to maintain low homocysteine and methylmalonic acid (MMA) levels.

3. Thiamine Deficiency: Diagnosis and Clinical Manifestations

Thiamine is necessary for carbohydrate use as an energy source, as well as for amino acid metabolism [7].

Human beings are not capable of synthesizing thiamine and can only store it in small quantities. It is synthesized in bacteria, fungi and plants; it is essential for all mammal diets. Thiamine is found in whole, enriched and fortified products such as bread, cereal, rice, pasta and flour, beef liver and pork meat, milk powder, eggs, legumes, nuts and seed. Dairy products, fruits and vegetables do not contain much thiamine, but, if ingested in large quantities, they can become an important source of this vitamin [8].

Thiamine requirements are related to energy metabolism; it is estimated that a human requires thiamine 0.33 mg per 1000 Kcal of energy. For adults, the recommended daily thiamine dosage is between 1.1 and 1.4 mg per day. Usually, thiamine deficiency develops within 12 months after deficient ingestion [9,10].

Deficient ingestion results from situation restricting its ingestion, requirements increasing (fever, pregnancy), excessive renal loss, anti-thiamine factor consumption (coffee, raw shellfish) or absorption alterations. [11] However, the most common cause of thiamine deficiency worldwide is alcoholism. Causes for deficiency can be predisposing factors (washed rice/malnutrition, GI surgery; gastrostomy, colectomy, gastrojejunostomy, others), psychiatric disorders: nervous anorexia, bulimia, chronic use of alcohol), medical disorders: gastric cancer, colon cancer, severe obesity, chronic diarrhea, pancreatitis, hyperemesis gravidarum, among other cancers, such as lymphoma, leukemia, others), and systemic diseases: renal diseases, acquired immunodeficiency, chronic infectious febrile illness, thyrotoxicosis) [10].

Thiamine deficiency and diabetes mellitus have been shown to be related, since up to 76% of type I diabetics and 75% of type 2 diabetics have low plasma thiamine levels. The polyol pathway increases through hyperglycemia, resulting in the final products of protein glycosylation (AGE), kinase-C protein activation (PKC) and increased flow through the hexosamine pathway [12].

Other cause for deficiency is age. A UK-based study showed that thiamine deficiency prevalence in elders was 8 to 31%, and 23 to 40% in elders from nursing homes. Thiamine biochemical deficiency is 48% in geriatric units [13,14].

B1 deficiency main symptom is heart failure with peripheral edema (wet beriberi) [15], peripheral neuropathy (dry beriberi), and acute (Korsakoff) and chronic (Wernicke) encephalopathy. Heart failure, peripheral neuropathy and cognitive impairment are more frequent in elders [13].

Laboratory diagnosis is complicated, but it can be determined through thiamine blood levels or functional measurement of erythrocyte transketolase activity, [11] as well as measuring metabolites due to alterations on the metabolism of carbohydrates, such as pyruvate or lactate. [10] Thiamine excretion in urine is other option. Thiamine diphosphate-measuring chromatography seems a simple and accurate method to evaluate thiamine status [16].

Nervous system: the best example for thiamine deficiency is Wernicke' syndrome, since this pathology presents with lesions in the cerebral stem, hypothalamus, thalamus and mammillary bodies with glial proliferation, capillary dilation and perivascular hemorrhage, in addition to neurodegeneration, consequence of increased production of nitric oxide synthase, intracellular adhesion molecules-1 (ICAM-1) and oxygen reactive species. [17] Thiamine participates in the metabolism of carbohydrates, both in euglycemic and hyperglycemic environments, with the latter being capable of increasing thiamine consumption. [18] An interesting aspect related to thiamine deficiency in diabetics is that supplements (>4 mg per day) have shown to normalize thiamine levels in red cells, while increased dietary thiamine consumption at the recommended dose (1-1.4 mg/day) does not increase thiamine levels, suggesting the need for higher levels than recommended in diabetic patients, compared to normal individuals [19].

The brain uses glucose as substrate to produce energy. [20] Glucose enters the brain by means of facilitated diffusion through the blood-brain barrier (BHE), when B1 blood-levels are high and through active transport when low. [10] Approximately 30% of glucose absorbed by the brain suffers oxidation, through the tricarboxylic acid cycle. Three enzymatic systems, essential for glucose metabolism in the brain, depend on B1: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and cytosolic transketolase. These three enzymes are used as cofactors for thiamine pyrophosphate (TPP), which represents 80% of total thiamine in nervous tissues 21. Other important aspect is the fact that thiamine deficiency alters the blood-brain barrier (BHE), which lead to rupture of the latter, generating endothelial impairment and decreased brain energy; all of this from decreased alpha-ketoglutarate dehydrogenase activity [11].

Cholinergic neurons synthesize acetylcholine (Ach) and are especially sensitive to cellular death due to thiamine deficiency. [17] Studies conducted in Wernicke encephalopathy show that neurodegeneration is related to increase production of endothelial nitric oxide synthase (SONe), intracellular adhesion molecules-1 (ICAM-1) and oxygen reactive species [22].

There is a possible sub-diagnosis of B1 deficiency, which can be a factor contributing to cardiac or neurological function degeneration. There is also evidence of thiamine deficiency contributing to non-specific symptoms, very common in elderly patients, such as weakness, mobility impairment and anorexia. Diagnosis can be established by measuring erythrocyte transketolase.

4. Pyridoxine Deficiency: Diagnosis and Clinical Manifestations

Vitamin B6 has an important role in the human nervous system. It can be found in animal tissue as pyridoxal 5-phosphate (most common form) and pyridoxamine 5-phosphate; [5] in vegetables it can be found as pyridoxine and is less bioavailable than in animal tissues. Main sources of vitamin B6 are legumes, nuts, whole bread and beef, although it can be found in all food groups.

All living beings depend on vitamin B6 to exist, however, only microorganisms and plants are capable of synthesizing it de novo. All other organisms acquire vitamin B6 through nutrients and interconvert it to its different forms, and adjust it to their needs. The daily dose recommended is 2 mg/d for men and 1.5 mg/d for women.

Total body reserves of B6 are small, approximately 167mg, [23] of which, 80% is in muscular tissue [24].

Although nowadays evident B6 clinical deficiency is rare, at least in the general population. However, there can be a subclinical deficiency (non-diagnosed) in some individuals, especially in the elderly. [24] Hermann and Cols found B6 deficiency in 23% of subjects between 65 and 75 years old, and 40% in of more than 85. [25] In the SENECA study, 23.3% of elder European population presented deficiency in B6 levels (pyridoxal 5-phosphate, PLP < 20 mmol/L) [26].

Vitamin B6 main function is to act as a coenzyme for amino acid transamination and synthesis. It participates in HEM synthesis and metabolism of homocysteine, glucose, lipids, steroids, production of neurotransmitters and synthesis of DNA/RNA. It can also act as a genetic expression modulator.

The most characteristic symptoms of pyridoxine deficiency are in the nervous system and include irritability, alertness impairment, abnormal movement and seizures. Corticosteroids and thyroid hormones can increase pyridoxine requirements and affect the metabolic process dependant on pyridoxal 5-phosphate. Hydroxitryptamine and dopamine synthesis requires pyridoxal 5-phosphate; therefore, its deficiency has been associated to decreased serotonin synthesis. [27,28] Deficiency of biologically active vitamin B6 (pyridoxal 5-phosphate) has been associated to Alzheimer' and Parkinson' disease. Risk factors are advanced age, malnutrition, hospitalization, chronic renal impairment, renal transplant, catabolic status, hemodialysis, peritoneal dialysis, celiac disease, alcoholism, sideroblastic anemia, pregnancy, physical exercise, among others. [24] It has also been associated to oxidative stress inhibition due to amyloid beta Cu (II) [29].

Diagnosis is established by measuring vitamin B6 direct concentration, in plasma or erythrocytes, although it can also be done by determining pyridoxal 5-phosphate metabolite in urine, 4-pyridoxic acid.

Vitamin B6 clinical deficiency treatment requires a mega dose of this vitamin via oral route, usually 50 mg/day, administered depending on the cause of the deficiency. It is important to take into account the subclinical deficiency status, since it has been associated to chronic illness, especially in the elderly, and therefore supplementation of this group is indicated [24].

5. Cobalamin Deficiency

The definition of vitamin B12 deficiency varies greatly; therefore, values obtained in population studies are used to obtain normal serum values. [6] Prevalence of B12 deficiency is unknown in general population; however, incidence seems to increase with age. [30] Framingham study reported a prevalence of B12 deficiency (defined as a serum level under 200 pg/mL and increased levels of homocysteine, methylmalonic acid or both) in 12% of 548 elders of the community. [31] Another study reported 15% of adults more than 65 years old had evidence of vitamin B12 deficiency. [30] Among risk factors for vitamin B12 deficiency are decreased ileum absorption (Crohn disease, ileum resection), decreased intrinsic factor (atrophic gastritis, pernicious anemia, postgastrectomy syndrome), genetics (transcobalamin II deficiency), inadequate ingestion (alcohol abuse, elderly, vegetarians) and chronic drug use (H2 blockers, metformin, proton pump inhibitors) [32].

Vitamin B12 is found in a wide variety of foods of animal origin. The plant foods do not contain B12, unless they are fortified. Entrails (beef liver), shellfish (clams), beef and bird meat, eggs, milk and other dairy products, some cereals and nutritional yeast contain B12 [33].

B12 minimum plasma level must be over 200 pg/mL, however, clinical manifestations have been observed with levels between 200 and 300 pg/mL. [34] Van Goor et al [35] suggests measuring methylmalonic acid (AMM) and homocysteine (Hcy) in case of high suspicion of cobalamin deficiency.

Total body reserves of cobalamin are 2-5 mg, of which half is stored in the liver. Daily recommended dose is 2 µg/day in adults, 2.6 µg/d in pregnant and breastfeeding women, and 2 µg/d in teenagers. Neurological disorders due to vitamin B12 deficiency typically occur in both sexes between 40 and 90 years old, with a peak between 60-70 years [36].

B12 deficiency is associated with skin (hyperpigmentation, vitiligo), gastrointestinal (glositis, jaundice), hematological (macrocytic and megaloblastic anemia), and neuropsychiatric (cognitive impairment, gait disorder, peripheral neuropathy, depression) manifestations. [32] It is important to mention that the liver stores large quantities of B12, reason why it can be a delay of 5 to 10 years between the deficiency starting and the clinical symptoms appearing [37].

Pernicious anemia is characterized by autoimmune atrophic chronic gastritis and represents a common cause of B12 deficiency.

Neurological deficiencies include paresthesia, peripheral neuropathy, demyelination of the corticospinal tract and dorsal column (subacute combined degeneration). Both glial cells, myelin and interstitium are the main structures affected by B12 deficiency. Specifically, astrocytes and microglia are responsible for increasing cell numbers for glial fibrillary acidic protein, and production and secretion of growth and cytokine factors. Damage to myelin affects particularly the lamellae, which disorganizes due to edema. [38] In the deficiency status there is a decrease in epidermal growth factor production, which is a myelotrophic factor [39].

A key interaction between B12 and folate exists in methionine synthesis from homocysteine, via methionine synthase, in which 5-methylhydrofolate and methyl-vitamin B12 are cofactors in a reaction that can be inhibited by nitric oxide. The folate cycle, whose function is to synthesize methyl groups, is essential for many genomic and non-genomic methylation reactions via the S-adenosylmethionine pathway and indirectly for synthesizing purine and thymidine, and therefore, DNA and RNA nucleotide.

Subacute combined degeneration (DCS): includes paresthesia, ataxia, loss of vibration and proprioception, abnormal reflexes, urinary and bowel incontinence, optic atrophy, orthostatic hypotension and autonomic disorders [6].

Neuropathy: most series evaluating complications of cobalamin deficiency cannot distinguish between myelopathy and neuropathy, since from a clinical point of view; both cases can have paresthesia, weakness and numbing. However, findings of superior motor neuron syndrome: Babinski and sensitive spinal level indicate myelopathy, and decreased or absent muscular stretch reflex suggest peripheral neuropathy. Appearance of symptoms in the hands, as well as involvement of both upper and lower limbs and sudden appearance of symptoms are manifestations suggesting peripheral neuropathy due to cobalamin deficiency [41].

Dementia: cobalamin deficiency has been associated to neuropsychiatric symptoms and Alzheimer disease. It is estimated that more than 40% of the elderly have B12 deficiency (cobalamin), most due to cobalamin malabsorption.

Complex B effects on pain treatment.

Each one of complex B vitamins (B1, B6, and B12) have individual effects on several pain pathways, although they have shown to be beneficial when combined. The benefits of these vitamins in neuropathic pain treatment, for example, can be divided in two aspects: those decreasing damage effects on the nervous fiber and those that are antinociceptive and antihyperalgesic [18].

Thiamine (B1). Song SX and cols, showed in animal models that B1 modulates neural excitability and sodium currents in damaged neurons in the dorsal root ganglion (GRD), suppressing therefore thermal hyperalgesia and contributing to pain control. [42] Likewise, it has effects on neuronal conduction and excitability [43].

Synthesis and secretion of serotonin are also increased in various areas of the brain; in addition to reducing thalamic neuron response to nociceptive stimulation [44].

Intratecal administration of B1 induces hyperalgesia inhibition, which can be reverted by blockers via cyclic guanosine monophosphate (GMPc)-protein kinase G (PKG) signaling. [45] This route has antinociceptive activity in pain processing [46].

An important effect is through activation of the nitric oxide (ON)-cyclic GMP (GMPc) pathway. ON activates soluble guanylate cyclase (Gcs), which generates GMPc, activating in turn type G protein kinase (PKG), hyperpolarizing nociceptor potassium channels, [44] See Figure 4.

Figure 4. Action of thiamine on the ON-cyclic GMP pathway for pain treatment

Pyridoxine (B6). It can interact with intra - supraspinal receptors, with both endogenous opioids tonically discharged and non-opioid inhibitory neurotransmitters, such as serotoninergic systems and gamma aminobutyric acid (GABA). [47,49] Pyridoxal 5-phosphate participates in dopa to dopamine conversion and allows conversion of glutamate to the inhibitory GABA neurotransmitter, preventing neurotoxicity-related damage [5,50].

It can alter intracellular glutamate levels and cell surface calcium channels, [47,51] inducing hyperalgesia inhibition.

Cobalamin (B12).

Cobalamin effects are based in remyelination. The mechanism of damage to the nerve is related to B12 deficiency itself, as well as with production of metabolites related to the latter (increased methylmalonic acid) and decreased S-adenosylmethionine (SAM), which participates in Hcy conversion to useful metabolites. In addition, B12 is necessary as methyl donor in polyamine synthesis and transmethylation reactions. [52] Figure 5 shows mechanisms related to the damage process to the nervous fiber.

Figure 5. Effects on the nervous system, related to B12 deficiency

Figure 6. Physiologic effects summary of complex B vitamins on pain treatment

Likewise, cobalamin deficiency is associated with increased nuclear factor kappa-Beta (FN-kB), which increased inflammation, since this factor increases tumor necrosis factor alpha (FNT- α) levels, immune reactions and apoptosis [38].

Mechanisms to decrease nervous fiber damage are based on decreasing the final products of advanced protein glycosylation, [53] inhibition of the diacylglycerol (DAG) pathway, which is a potent protein kinase (PKC) activation pathway. [54] Likewise, it also regulated the hexosamine pathway, regulating and improving the pentose pathway through alternate metabolism pathways [18].

Global effects of combining thiamine and cobalamin.

The analgesic action of vitamins B1, B6 and B12 is based on:

* Improving axonal conduction, which might contribute to analgesia. [43]

* Activation of soluble guanylate cyclase (Gcs) through ON and therefore increasing GMPc synthesis in various tissues. [44]

* Inhibition of thermal hyperalgesia (not mechanical). [47]

* Reconstructive activation in damaged nerves, contributing to nerve function recovery. [55]

* Decreased intracellular glutamate levels and cellular surface of calcium channels. [51]

* Regulation of FN-kB. [38]

* Decreased nervous fiber damage due to a metabolic disorder: decreased oxidative stress, decreased activation of both the DAG-PKG pathway and hexosamine pathway. [12]

* Regulation of carbohydrate metabolism. [18]

Figure 6 shows the global effects of complex B vitamins and Figure 4 shows individual effects of each vitamin on several physiopathological pain mechanisms.

6. Conclusions

Complex B vitamins have a vital role in human beings, since they participate in the metabolism of carbohydrates and amino acids, acting as enzymatic cofactors in multiple synthesis reactions.

Although traditionally it has been considered that only severe deficiencies cause symptoms, many common diseases, such as diabetes mellitus, surgical procedures, among others, can produce subclinical deficiency of vitamin B1, B6 or B12, so it is important to consider these deficiencies as possible factors that could contribute to or exacerbate certain complications of these diseases. Also, aging is a factor that may alter the absorption of these vitamins, through use of multiple drugs or decreased specific factors necessary for the absorption of these. Therefore, they should be considered clinical and subclinical deficiencies as possible manifestations neurological disorders, such as painful neuropathy.

Today, it is possible to explain the analgesic effect of B vitamins through their effects on activation of the nitric oxide (ON)-cyclic GMP (GMPc) pathway, decreasing the levels of intracellular glutamate and NF-kB, improving axonal conduction (which contributes to analgesia), restoring the nerve fiber and inhibiting thermal hyperalgesia.

Therefore, it is necessary to know the effects that these vitamins because they have further shown to be an adjunct treatment option for neuropathic pain, in combination with gabapentin or in nociceptive pain in combination with diclofenac. Undoubtedly, more clinical studies to demonstrate the effect on pain management are needed to extend its recommendation in this pathology

References

[1]   | Hasan Nazmul, Akhtaruzzaman M, Zakir Sultan. Estimation of Vitamins B-Complex (B2, B3, B5 and B6) of Some Leafy Vegetables Indigenous to Bangladesh by HPLC Method. Journal of Analytical Sciences, Methods and Instrumentation 2013; 3:24-29.
[2]   | Mollinedo PM, Carrillo LK. Absorción, excreción y metabolismo de las vitaminas hidrosolubles. Revista de Actualización Clínica 2014;41:2146-2150.
[3]   | Manzetti S, Zhang J, van der Spoel D. Thiamine function, metabolism, uptake and transport. Biochemistry 2014,53:821-835.
[4]   | Luigi di Salvo M, Contestabile R, Safo Mk. Vitamin B6 salvage enzymes: mechanism, structure and regulation. Biochimica et Biophfysica Acta 2011; 1814: 1597-1608.
[5]   | Bowling FG. Pyridoxine supply in human development. Seminars in Cell & Development Biology 2011;22: 611-618.
[6]   | Lachner C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B12 deficiency elderly patients. J Neuropsychiatry Clin Neurosci 2012;24: 5-15.
[7]   | Rakesh KG, Santosh KY, Saraswat VA, et al. Thiamine deficiency realted microstructural brain changes in acute and acute on chornic liver failure of non alcoholic etiology. Clinical Nutrition 2012;31: 422-428.
[8]   | Guéant JL, Gasten J, Vidailhet M. Méthodes biologiques de diagnostique positif et etiologique des carence vitaminiques- Nutr Clin Métabol 1995;9: 29-42.
[9]   | Smithline H, Donnino M, Greenblatt Dj. Pharmacokinetics of high dose oral thimine hydrochloride in healthy subjects. BMC clinical pharmacology 2012;12(4): 1-10.
[10]   | Osiezagha K, Ali S, Freeman C, et al. Thiamine deficiency and delirium. Innov Clin Neurosci 2013;10(4): 26-32.
[11]   | Page G, Laight D, Cummings M. Thiamine deficiency in diabetes mellitus and the impact of thiamine on glucose metabolism and vascular disease. International Journal of Clinical Practice 2011;65(6): 1-17.
[12]   | Vin ouc Luong K, Thi Hoang L. The impact of the thiamine treatment in the diabetes mellitus. J Clin Med Res 2012;4(3): 153-160.
[13]   | O´Keeffe ST. Thiamine deficiency in elderly people. Age and Ageing 2000;29: 99-101
[14]   | O´Keeffe ST, Tormey WP, Glasgow R, et al. The relationship between erythrocyte transketolase activity and the “TPP effect” in Wernicke´s encephalopathy and other thiamine deficiency states. Clin Chim Acta 1990;192: 89-98.
[15]   | Roman Campos D, Santos Cruz J. Current aspects of thiamine deficiency on heart function. Life Sci 2014; 98: 1–5.
[16]   | Lu J, Frank EL, Rapid HPLC. Measurement of thiamine and its phosphate esters in whole blood. Clinical Chemistry 2008;54(5): 901-906.
[17]   | Nardone R, Höler Y, Storti M, et al. Thiamine deficiency induced neurochemical, neuroanatomical and neuropsycological alterations: a reappraisal. The Scientific World Journal 2013; 1-8.
[18]   | Mimenza AJ, Aguilar SG. Comparative Clinical Trial of Safety and Tolerability of Gabapentin Plus Vitamin B1/B12 versus Pregabalin in the Treatment of Painful Peripheral. J Pain Relief 2014, S3: 1-6. Diabetic Neuropathy.
[19]   | Vindedzis SA, Stanton KG, Sherriff JL, et al. Thimine deficiency in diabetes – is diet relevant?. Diab Vasc Dis Res 2008;5(3): 215.
[20]   | Rao J, Oz G, Seaquist ER. Regulation of cerebral glucose metabolism. Minerva Endocrinol 2000; 31: 149-158.
[21]   | Abdoulaye Bá. Metabolic and structural role of thiamine in nervous tissues. Cell Mol Neurobiol 2008;28: 923-931.
[22]   | De Palma C, Falcone S, Panzeri C, et al. Endotelial nitric oxide sinthase overexpression by neuronal cells in neurodegenration: a link between inflammation and neuroprotection. Journal of Neurochemistry 2008;106(1): 193-204.
[23]   | Lui A, Lumeng L, Aronoff Gr, et al. Relationship between body stores of vitamin B6 and plasma pyridoxal-P clearence: metabolic balance studies in humans. J Lab Clin Med 1983;106: 491-497.
[24]   | Spinneker A, sola R, Lemmen V, et al. Vitamin B6 status, deficiency and its consequences –an overview. Nutr Hosp 2007;22(1): 7-24.
[25]   | Herrmann W, Knapp JP. Hyperhomocysteinemia: a new risk factor for degenerative diseases. Clin Lab 2002;48: 471-481.
[26]   | Haller J, Lowik MR, Ferry M, et al. Nutritional status: blood vitamins A, E, B6, B12, folic acid and carotene. Euronut SENECA investigators. Eur J Clin Nutr 1991;45(supl.3):63-82.
[27]   | Siow YL. Dakshinamurti K. Neuronal DOPA decarboxylase. Ann N. Y. Acad Sci 1990;585: 173-188.
[28]   | Ahmad I, Mirza T, Qadeer K, et al. Vitamin B₆: deficiency diseases and methods of analysis. Pak J Pharm Sci 2013;26(5): 1057-1069.
[29]   | Hashmi A, Wang L, Juneja KY, et al. Vitamin B6 inhibits oxidative stress caused by Alzheiemer´s disease-related Cu (II)-β-amyloid complexes-cooperative action of phosphor-moiety. Bioorg Med Chem Lett 2011;21: 6430-6432.
[30]   | Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin deficeincy in elderly outpatients. J AM Ger Soc 1992;40: 1197-1204.
[31]   | Lindenbaum J, Rosenberg IH, Wilson PW, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994;60(1): 2-11.
[32]   | Langan RC, Zawitoski KJ. Update on vitamin B12 deficiency. Am Fam Physician 2011; 83(12): 1425-1430.
[33]   | Watanabe F. Vitamin B12 Sources and Bioavailability. Exp Biol Med 2007; 232:1266-1274.
[34]   | Goebels N, Soyka M. Dementia associated with vitamin B12 deficiency: presentation of two cases and review of the literature. Jneuropsychiatry Clin Neurosci 2000;12: 389-394.
[35]   | van Goor L, Woiski MD, Lagaay AM, et al. Review: cobalamin deficiency and mental impairment in elderly people. Age Ageing 1995;24: 536-542.
[36]   | Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol 2006;5: 949-960.
[37]   | Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med 2000;51: 357-375.
[38]   | Scalabrino G. The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: lessons learned from its deficiency. Progress in Neurobiology 2009;88: 203-220.
[39]   | Mutti E, Magnaghi V, Veber D, et al. Cobalamin dfeficiency-induced changes of epidermal growth factor (EGF)-receptor expression and EGF levels in rat spinal cord. Brain Res 2011;1376: 23-30.
[40]   | Saperstein DS, Barohn RJ. Peripheral neuropathy due to cobalamin deficiency. Current Treatment Options in Neurology 2002;4: 197-201.
[41]   | Nations SP, Saperstein DS, Wolfe GI, et al. Clinical profile of vitamin B12 neuropathy. Neurology 1998, 50(suppl): A208-A209.
[42]   | Song SX, Huang ZJ, Jun SX. Thiamine supresses thermal hipralgesia, inhibitis hiperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology 2009;110: 387-400.
[43]   | Itokawa Y, Cooper JR. Ion movements and thiamine. II: The release of the vitamin from membrane fragments. Bioch Biophys Acta 1970;196(2): 274-284.
[44]   | Reyes GG, Medina SR, Rocha GH, et al. Synergistic interaction between spinal gabapentin and oral B vitamins in a neuropathic pain model. Proc West Pharmacol Soc 2003;46: 91-94.
[45]   | Song XJ, Wang ZB. Activation of cGMP-PKG signaling pathway mediates thiamine induced-inhibition of thermal hiperalgesia in rats with primary sensory neuron injury. FASEB J 2003;439:7.
[46]   | Vocci FJ, Petty SK, Dewey WL. Antinociceptive action of the butyryl derivatives of cyclic guanosine 3´:5´-monophosphate. J Pharmacol Exp Ther 1978;207(3): 892-898.
[47]   | Wang ZB, Gan Q, Rupert RL, et al. Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. Pain 2005;114: 266-277.
[48]   | Bernstein AL. Vitamin B6 in clinical neurology. Ann NY Acad Sci 1990;585: 250-260.
[49]   | Plaitakis A, Nicklas WJ, Berl S. Thiamine deficiency: selective impairment of the cerebellar serotoninergic system. Neurology 1978;28(7): 691-698.
[50]   | Büyükokuroglu ME, Gepdiremen A, Tyastekin A, et al. Pyridoxine may protect the cerebellar granular cells against glutamate-induced toxixity. Int J Vitam Nutr Res 2007;77(5): 336-340.
[51]   | Dakshinamurti K, Sharma SK, Geiger JD. Neuroprotective actions of pyridoxine. Biochim Biophys Acta 2003;1647: (1-2): 225-229.
[52]   | Solomon LR. Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood Review 2007; 21(3): 113-130.
[53]   | Mixcoatl ZT, Quiñones BG, Carma SN, et al. Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats. Methods Find Exp Clin Pharmacol 2008; 30: 431-441.
[54]   | Jermendy G. Evaluating thiamine deficiency in patients with diabetes. Diab Vasc Dis Res 2006; 3: 120-121.
[55]   | Fukii A, Matsumoto H, Yamamoto H. Effect of vitamin B complex on neurotransmission and neurite outgrowth. Gen Pharmacol 1996;27(6): 995-1000.