The Role of Pyridoxine in the Prevention and Treatment of Neuropathy and Neurotoxicity Associated with Rifampicin-Resistant Tuberculosis Treatment Regimens: A Topic Review

Rifampicin-resistant tuberculosis (RR-TB) is a global public health problem caused by mycobacterium tuberculosis resistant to Rifampicin. Drug-induced peripheral neuropathy and neurotoxicity are well-known adverse effects of treatment regimens that cause significant morbidity. Pyridoxine is often added to treatment regimens for the prevention and/or treatment of these side effects. The basis and effectiveness of this practice are unclear. We conducted a systematic review to evaluate the effectiveness of pyridoxine in preventing and/or treating neuropathy and neurotoxicity associated with RR-TB treatment. We included studies with patients with RR-TB who experienced neuropathy or neurotoxicity attributed to RR-TB regimens and were given pyridoxine. Our findings showed contradicting evidence on the use of pyridoxine for preventing or treating neurotoxicity due to cycloserine in the treatment of RR-TB. Moreover, pyridoxine did not have a protective effect against neuropathy and/or neurotoxicity caused by other RR-TB regimens that do not contain isoniazid. In conclusion, we found that withdrawing or withholding medications such as linezolid, cycloserine, thioamides, fluoroquinolones, and ethambutol, implicated in causing neuropathy or neurotoxicity was more effective than using pyridoxine to stop the progression of symptoms, and in some instances, led to their reversal over time.

Beta-nerve growth factor gene therapy alleviates pyridoxine-induced neuropathic damage by increasing doublecortin and tyrosine kinase A in the dorsal root ganglion

Beta-nerve growth factor(β-NGF)is known to be a major leading cause of neuronal plasticity.To identify the possible action mechanisms ofβ-NGF gene therapy for sciatic nerve recovery,experimental dogs were randomly divided into control,pyridoxine,and pyridoxine+β-NGF groups.We observed chronological changes of morphology in the dorsal root ganglia in response to pyridoxine toxicity based on cresyl violet staining.The number of large neurons positive for cresyl violet was dramatically decreased after pyridoxine intoxication for 7 days in the dorsal root ganglia and the neuron number was gradually increased after pyridoxine withdrawal.In addition,we also investigated the effects ofβ-NGF gene therapy on neuronal plasticity in pyridoxine-induced neuropathic dogs.To accomplish this,tyrosine kinase receptor A(TrkA),βIII-tubulin and doublecortin(DCX)immunohistochemical staining was performed at 3 days after the last pyridoxine treatment.TrkA-immunoreactive neurons were dramatically decreased in the pyridoxine group compared to the control group,but strong TrkA immunoreactivity was observed in the small-sized dorsal root ganglia in this group.TrkA immunoreactivity in the dorsal root ganglia was similar betweenβ-NGF and control groups.The numbers ofβⅢ-tubulin-and DCX-immunoreactive cells decreased significantly in the pyridoxine group compared to the control group.However,the reduction ofβⅢ-tubulin-and DCX-immunoreactive cells in the dorsal root ganglia in theβ-NGF group was significantly ameliorated than that in the pyridoxine group.These results indicate thatβ-NGF gene therapy is a powerful treatment of pyridoxine-induced neuropathic damage by increasing the TrkA and DCX levels in the dorsal root ganglia.The experimental protocol was approved by the Institutional Animal Care and Use Committee(IACUC)of Seoul National University,South Korea(approval No.SNU-060623-1,SNU-091009-1)on June 23,2006 and October 9,2009,respectively.

Effects of Pyridoxine on Selected Appetite Regulating Peptides mRNA Expression in Hypothalamic PVN/ARC Nuclei and Gastrointestinal Tract Tissues

An experiment was conducted to investigate the effect of dietary pyridoxine on the gene expression of appetite-regulating peptides in the hypothalamus and gastrointestinal tract of rabbits. Thirty-two rabbits were randomly divided into 2 treatments for 8 weeks (16 replicates/group and 1 rabbit/replicate). The treatments were fed a basal diet (control, measured pyridoxine content is 4.51 mg/kg) and the basal diet with a pyridoxine supplementation at 10 mg/kg (pyridoxine, measured pyridoxine content is 14.64 mg/kg). The results showed that dietary pyridoxine did not significantly alter the mRNA levels of neuropeptide Y, agouti related peptide, pro-opiomelanocortin and cocaine, amphetamine regulated transcript, peptide YY and cholecystokinin in arcuate nucleus, peptide YY in jejunum and ileum, and cholecystokinin in duodenum, jejunum and ileum (P > 0.05). Compared with the control, the mRNA levels of corticotropin-releasing hormone and melanocortin 4 receptor in paraventricular nuclei and peptide YY in duodenum were significantly decreased after pyridoxine treatment (P 0.05). In conclusion, the appetite genes of melanocortin 4 receptor and corticotropin-releasing hormone in paraventricular nuclei and peptide YY in duodenum are involved in the pyridoxine-caused hyperphagia.

Should pyridoxine be given to breastfed infants whose mothers are on isoniazid?

A mother was recently started on isoniazid and rifampicin for latent tuberculosis infection.She was breastfeeding her 1-monthold infant.There was no indication to treat the child with antituberculous therapy.As isoniazid can be present in breast milk,question was raised whether the baby should receive pyridoxine supplementation to prevent peripheral neuropathy or seizures.There were variable views in the management approach due to uncertainties of evidence in this topic.

Clinical characteristics of two cohorts of infantile spasms: response to pyridoxine or topiramate monotherapy

Background Infantile spasms (IS) was an epileptic disease with varied treatment widely among clinicians. Here, we aimed to compare and analyze the clinical characteristics of IS response to pyridoxine or topiramate monotherapy (TPM control IS). Methods The clinical manifestations, treatment processes and outcomes were analyzed in 11 pyridoxine responsive IS and 17 TPM-control IS. Results Of the 11 patients with pyridoxine responsive IS, nine were cryptogenic/idiopathic. Age of seizure onset was 5.36 ± 1.48 months. Spasms were controlled within a week in most of the patients. At the last follow-up, EEG returned to normal in 8. Psychomotor development was normal in 6, mild delay in 3, severe delay in 2. Of the 17 patients with TPM-control IS, 10 were cryptogenic/idiopathic. The age of seizure onset was 5.58 ± 2.09 months. All patients were controlled within a month. At the last follow-up, EEG was normal in 10. Psychomotor development was normal in 8, mild delay in 5, severe delay in 4. Genetic analysis did not show any meaningful results. Conclusions The clinical characteristics and disease courses of pyridoxine responsive IS and TPM-control IS were similar, which possibly clued for a same pathogenic mechanism. Pyridoxine should be tried first in all IS patients, even in sympto-matic cases. If patients were not responsive to pyridoxine, TPM could be tried.

Pyridoxine regulates hair follicle development via the PI3K/Akt, Wnt and Notch signalling pathways in rex rabbits

This study was conducted to evaluate the effect of pyridoxine on the development of hair follicles in Rex rabbits and the underlying molecular mechanism.Two hundred 3-month-old Rex rabbits were randomly divided into 5 groups and fed diets supplemented with 0,5,10,20,or 40 mg/kg pyridoxine.The hair follicle density on the dorsal skin and the gene and protein expression levels of components of the phosphoinositide 3-kinase(PI3 K)/protein kinase B(PKB or Akt),Wnt,Notch and bone morphogenetic protein(BMP)signalling pathways were measured.In addition,free hair follicles were isolated from Rex rabbits and cultured with pyridoxine in vitro to measure hair shaft growth.Furthermore,dermal papilla cells(DPC)were isolated from the skin of Rex rabbits and cultured with pyridoxine in vitro to measure the gene and protein expression levels of components of the PI3 K/Akt,Wnt,Notch and BMP signalling pathways.The results showed that the addition of dietary pyridoxine significantly increased the total follicle density,secondary follicle density,and secondary-to-primary ratio(S/P,P<0.05),that the growth ratio of hair stems was promoted by pyridoxine in basic culture medium,and that the growth length of tentacle hair follicles cultured in the pyridoxine group was longer than that in the control group(P<0.05).In addition,pyridoxine changed the DPC cycle progression and promoted cell proliferation,and appropriate concentrations of pyridoxine(10 and 20μmol/L)significantly inhibited cell apoptosis(P<0.05).Pyridoxine significantly affected the gene expression of components of the PI3 K/Akt,Wnt and Notch signalling pathways in the skin and DPC of Rex rabbits(P<0.05),increased the levels of phosphorylated catenin beta 1(CTNNB1)and Akt,and decreased the level of phosphorylated glycogen synthase kinase 3 beta(GSK-3β)(P<0.05).Therefore,the molecular mechanism by which pyridoxine promotes hair follicle density in Rex rabbits probably occurs through activation of the PI3 K/Akt,Wnt and Notch signalling pathways,prolonging hair follicle growth and delaying the onset of telogen.

Electrochemical Preparation of Poly(arginine)-Modified Carbon Nanotube Paste Electrode and its Application for the Determination of Pyridoxine in the Presence of Riboflavin: An Electroanalytical Approach

A simple poly(arginine)film-modified carbon nanotube paste electrode(PAMCNTPE)was prepared using cyclic voltam-metry(CV).The devised sensor was subjected to field-emission scanning electron microscope(FESEM)and CV charac-terization.The sensing of 0.1 mM pyridoxine(PY)was upgraded at PAMCNTPE as compared to the bare carbon nanotube paste electrode(BCNTPE).The PAMCNTPE detects the 0.1 mM PY at a specific potential 0.727 V with a current response of 10.68μA.In the case of BCNTPE,the PY appeared at 0.798 V with a current 2.90μA.The proposed analytical method was optimized by prime parameters such as the impact scan rate,pH and PY concentration.Under optimal conditions,the concentration of PY is directly proportional to oxidation current(I_(pa))in linear range 2-10μM,and 10-80μM with a detection limit(LOD)of 9.6×10^(−7) M and limit of quantification(LOQ)of 3.21×10^(−6) M.The simultaneous determination,concen-tration variation analysis of PY is performed with riboflavin(RF)and interference analysis in detecting PY also examined.The proposed sensor was effectively applied for the determination of PY in natural food supplement with excellent recovery.

Regioselective acylation of pyridoxine catalyzed by immobilized lipase in ionic liquid

The regioselective acylation of pyridoxine catalyzed by immobilized lipase(Candida Antarctica)in 1-butyl-3-methylimidazolium hexafluorophosphate([BMIM]PF_(6))has been investigated,and compared with that in acetonitrile(ACN).The acetylation of pyridoxine using acetic anhydride in[BMIM]PF6 gave comparable conversion of pyridoxine to 5-monoacetyl pyridoxine with considerably higher regioselectivity(93%-95%)than that in ACN(70%-73%).Among the tested parameters,water activity(aw)and temperature have profound effects on the reaction performances in either[BMIM]PF6 or ACN.For the reaction in[BMIM]PF6,higher temperature(50℃-55℃)and lower aw(<0.01)are preferable conditions to obtain better conversion and regioselectivity.Mass transfer limitation and intrinsic kinetic from the ionic nature of ionic liquids(ILs)may account for a different rate-temperature profile and a lower velocity at lower temperature in[BMIM]PF_(6)-mediated reaction.Moreover,consecutive batch reactions for enzyme reuse also show that lipase exhibited a much higher thermal stability and better reusability in[BMIM]PF_(6)than in ACN,which represents another advantage of ILs as an alternative to traditional solvents beyond green technology.

Effects of a rumen protected B vitamin blend upon milk production and component yield in lactating dairy cows

Results from 12 switchback field trials involving 1216 cows were combined to assess the effects of a protected B vitamin blend (BVB) upon milk yield (kg), fat percentage (%), protein %, fat yield (kg) and protein yield (kg) in primiparous and multiparous cows. Trials consisted of 3 test periods executed in the order control-test-control. No diet changes other than the inclusion of 3 grams/cow/ day of the BVB during the test period occurred. Means from the two control periods were compared to results obtained during the test period using a paired T test. Cows include in the analysis were between 45 and 300 days in milk (DIM) at the start of the experiment and were continuously available for all periods. The provision of the BVB resulted in increased (P < 0.05) milk, fat %, protein %, fat yield and protein yield. Regression models showed that the amount of milk produced had no effect upon the magnitude of the increase in milk components. The increase in milk was greatest in early lactation and declined with DIM. Protein and fat % increased with DIM in mature cows, but not in first lactation cows. Differences in fat yields between test and control feeding periods did not change with DIM, but the improvement in protein yield in mature cows declined with DIM. These results indicate that the BVB provided economically important advantages throughout lactation, but expected results would vary with cow age and stage of lactation.

Impact of Low Back Pain on Quality of Life: Assessment by Patient Functionality Questionnaire and Treatment Results Using a Combination of Diclofenac plus B Vitamins or Diclofenac Monotherapy

Objective: To analyze the Patient Functionality Questionnaire (PFQ) scores of the patients treated with either Diclofenac + B vitamins (Group DB) or Diclofenac monotherapy (Group D) in order to better understand the impact of the combination of diclofenac with vitamins B1, B6, and B12 on quality of life. Research Design/Methods: We performed a post-hoc analysis of tabulated data generated during the DOLOR study (Diclofenac plus B vitamins versus diclofenac monotherapy in lumbago: the DOLOR study), using the software GraphPad Prism 5 for Windows, v5.04. The absolute number or percentage of “True”/“False” respondents for each questionnaire item at each study visit, together with the absolute number and percentage of subjects with no change, improvement, or worsening of each PFQ item at each study visit, within and between treatment groups were arranged on contingency tables and analyzed with the Chi-squared or Fisher’s Exact test. Results: At pretreatment there were no statistically significant differences between treatment groups (p > 0.05 for all items). At Visit 2 in both treatment groups, there were statistically significant improvements in individual question responses in each of the 12 items of the questionnaire (p < 0.05 for all items). At Visit 2, comparing the distribution of patients in each treatment group with “improvement”, “no change”, or “worsening”, there was a statistically significant superiority among subjects of group DB in response to items 1, 6, 8, and 10. At Visit 3, both groups had statistically significant (p < 0.001) improvements in each individual item of the PFQ in relation to pretreatment values. The distribution of subjects in each treatment group presenting with “improvement”, “no change”, or “worsening” at Visit 3 varied significantly in favor of group DB in the responses to item 4. At Visit 4, the subjects remaining in treatment in both groups showed statistically significant improvement in PFQ responses in relation to pretreatment values (p < 0.05). The distribution of subjects in each treatment group presenting with “improvement” or “no change” at Visit 4 varied significantly in favor of group D in the responses to items 5, 8, and 12. Conclusion: Improvement in overall PFQ scores was observed in both treatment groups, though the specific items of the questionnaire of the subjects in group DB at Visit 2 showed greater improvement in areas related to sleep quality, mobility, ability to wash and dry, ability to walk distances, and posture comfort. These results serve to corroborate the previously published data, which indicates a benefit of combining the B vitamins with diclofenac in the treatment of patients with low back pain, yielding shorter treatment time to resolution of the lumbago in the treated patients.

Nitric oxide regulation of plant metabolism

Nitric oxide(NO)has emerged as an important signal molecule in plants,having myriad roles in plant devel-opment.In addition,NO also orchestrates both biotic and abiotic stress responses,during which intensive cellular metabolic reprogramming occurs.Integral to these responses is the location of NO biosynthetic and scavenging pathways in diverse cellular compartments,enabling plants to effectively organize signal transduction pathways.NO regulates plant metabolism and,in turn,metabolic pathways reciprocally regu-late NO accumulation and function.Thus,these diverse cellular processes are inextricably linked.This re-view addresses the numerous redox pathways,located in the various subcellular compartments that pro-duce NO,in addition to the mechanisms underpinning NO scavenging.We focus on how this molecular dance is integrated into the metabolic state of the cell.Within this context,a reciprocal relationship be-tween NO accumulation and metabolite production is often apparent.We also showcase cellular pathways,including those associated with nitrate reduction,that provide evidence for this integration of NO function and metabolism.Finally,we discuss the potential importance of the biochemical reactions governing NO levels in determining plant responses to a changing environment.

PDX1.1-dependent biosynthesis of vitamin B6 protects roots from ammonium-induced oxidative stress

Despite serving as a major inorganic nitrogen source for plants,ammonium causes toxicity at elevated con-centrations,inhibiting root elongation early on.While previous studies have shown that ammonium-inhibited root development relates to ammonium uptake and formation of reactive oxygen species(ROS)in roots,it remains unclear about the mechanisms underlying the repression of root growth and how plants cope with this inhibitory effect of ammonium.In this study,we demonstrate that ammonium-induced apo-plastic acidification co-localizes with Fe precipitation and hydrogen peroxide(H_(2)O_(2))accumulation along the stele of the elongation and differentiation zone in root tips,indicating Fe-dependent ROS formation.By screening ammonium sensitivity in T-DNA insertion lines of ammonium-responsive genes,we identified PDX1.1,which is upregulated by ammonium in the root stele and whose product catalyzes de novo biosyn-thesis of vitamin B6.Root growth of pdx1.1 mutants is hypersensitive to ammonium,while chemical complementation or overexpression of PDX1.1 restores root elongation.This salvage strategy requires non-phosphorylated forms of vitamin B6 that are able to quench ROS and rescue root growth from ammo-nium inhibition.Collectively,these results suggest that PDX1.1-mediated synthesis of non-phosphorylated B6 vitamers acts as a primary strategy to protect roots from ammonium-dependent ROS formation.