Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography

Summary The influence of the co-factor pyridoxine, vitamin B6, on the activity of aromatic amino acid decarboxylase enzyme was studied by positron emission tomography, PET in the brain of the Rhesus monkey using the precursor for serotonin synthesis 5-hydroxy-L-tryptophan (5-HTP) radiola-belled with¹¹C in the -position. The rate constant for the formation of serotonin in the corpus striatum was calculated using a two tissue compartment model with reference area in the brain.In baseline investigations, the mean rate constants (±S.D:) for selective utilization of [¹¹C]5-HTP to form [¹¹C]serotonin in the corpus striatum was 0.0080 ± 0.0011 min^–1. Pretreatment with intravenous pyridoxine hydrochloride 10 mg/kg bodyweight before doing a second PET study resulted in an enhanced rate constant by a mean of 20%. The rate increase was statistically significant. The increase varied considerably in different monkeys from no effect to more than 60%. The effect of pyridoxine on aromatic amino acid decarboxylase activity supported a regulatory role of pyridoxine on the synthesis of neurotransmitter in vivo, and may be of importance in diseases with deficiencies in neurotransmitter function.     

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.     

高效液相色谱法同时测定多维生素糖浆中5种维生素和山梨酸含量

目的建立可同时测定多维生素糖浆中抗坏血酸(VitC)、烟酰胺(VitPP)、盐酸硫胺(VitB1)、核黄素-5’-磷酸钠、盐酸吡多辛(VitB6)及防腐剂山梨酸含量的高效液相色谱法。方法采用高效液相色谱-紫外分光光度法,使用Allthna C18柱(250 mm×4.6 mm,5μm),流动相A为0.01 mol/L己烷磺酸钠溶液(1 000 mL溶液加入三乙胺0.25 mL和醋酸9.5 mL),流动相B为甲醇(梯度洗脱),流速为1.0 mL/min,检测波长为280 nm。结果 VitC,VitPP,VitB1、核黄素-5’-磷酸钠、VitB6、山梨酸的质量浓度分别在0.15～2.0 g/L,0.1～1.0 g/L,0.02～0.4 g/L,0.02～0.4 g/L,0.007～0.1 g/L,0.03～0.6 g/L范围内与峰面积线性关系良好;平均回收率分别为99.9%,98.4%,99.4%,100.9%,100.4%,100.3%,RSD=0.5%,0.6%,0.4%,0.9%,1.0%,0.8%(n=9)。结论该方法快速、灵敏,色谱峰分离度良好,结果准确可靠,可作为多维生素糖浆的质量控制项目之一。     

Features of Central Neurotransmission in Animals in Conditions of Dietary Magnesium Deficiency and After Its Correction

Magnesium is important in the regulation of neurotransmitter metabolism and the modulation of receptor function in the CNS, including neurotransmitters and receptors involved in the pathogenesis of many mental disorders. The aim of the present work was to perform a pharmacological evaluation of the central mechanisms of action of magnesium salts in the clofelin, phenamine, arecoline, nicotine, apomorphine, and 5-hydroxytryptophan tests in conditions of dietary magnesium deficiency. After reaching the magnesium deficiency state, animals were given oral (via tube) magnesium L-asparaginate and magnesium chloride lone and in combination with vitamin B₆, as well as the reference agent Magne B₆. Our assessments of phenamine stereotypy in magnesium-deficient animals showed reductions in the latent period by an average of 14.89% and a significant increase in the duration of phenamine stereotypy by an average of 19.44% (from 268.23 ± 8.17 to 320.36 ± 19.90 min) as compared with intact rats. Studies of hyperkinesia induced by 5-hydroxytryptophan showed a two-fold reduction in its extent in the magnesium-deficient group (p ≤ 0.05). Administration of arecoline to magnesium-deficient animals resulted in a statistically significant increase in the latent period from a mean of 92.75 ± 19.35 to 245.17 ± 121.86 sec, with a reduction in the duration of tremor from an average of 1175.58 ± 127.87 to 703.83 ± 89.33 sec (p ≤ 0.05) as compared with intact rats. In terms of its influence on the hypothermic effects of clofelin and apomorphine and the convulsive effect of nicotine, there were no significant differences between the intact group and the magnesium-deficiency animals. Administration of magnesium salts compensated for the magnesium deficiency in plasma and erythrocytes, which was accompanied by recovery of measures in the phenamine, arecoline, and 5-HT tests to levels typical of intact controls. There was a tendency for magnesium L-asparaginate and magnesium chloride combined with pyridoxine to have greater activity, and the efficacies of these treatments was no less than that of reference agent Magne B₆. Thus, dietary magnesium deficiency led to impairment of neurotransmission in central serotoninergic, M-cholinergic, and noradrenergic structures and administration of magnesium salts reversed these changes. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 7, pp. 822–833, July, 2008.     

Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria

Espinós C, García‐Cazorla A, Martínez‐Rubio D, Martínez‐Martínez E, Vilaseca MA, Pérez‐Dueñas B, Ko?ich V, Palau F, Artuch R. Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria. Hereditary cystathioninuria is due to mutations in the CTH gene that encodes for cystathionase, a pyridoxal‐5′‐phosphate (PLP) dependent enzyme. To date, mutations in this gene have been described in 10 unrelated cystathioninuric patients. Enzyme assays have showed that mutated cystathionase exhibits lower activity than controls. As cystathioninuria is usually accompanied by a wide variety of symptoms, it has been questioned whether it is a disease or just a biochemical finding not associated with the clinical picture of these patients. This is the first report of Spanish patients with cystathioninuria and mild to severe neurological symptoms in childhood. After oral pyridoxine therapy biochemical parameters have normalized but clinical amelioration was not evident. All patients were homozygotes for the c.200C>T (p.T67I) variant which is the most prevalent inactivating mutation in the CTH gene. To further investigate the history of the alleles carrying the c.200C>T transition in Europe, we also constructed the haplotypes on the CTH locus in our Spanish patients as well as in a clinical series of cystathioninuric patients from the Czech Republic harboring the same nucleotide change. We suggest that the CTH p.T67I substitution could have an ancient common origin, which probably occurred in the Neolithic Era and spread throughout Europe.     

Changes in biochemical indices of vitamin nutrition in women using oral contraceptives during treatment with ‘Surbex 500’

Summary

A study was conducted on 10 healthy young women who had taken oral contraceptives of the combined type for several cycles. Daily treatment was instituted with a high-potency vitamin B complex with vitamin C (‘Surbex 500’). Blood specimens were collected before and after treatment with this vitamin supplement and plasma levels of ascorbic acid and vitamin B₁₂ were measured. Activity of red cell aspartate aminotransferase (AST) was determined before and after the in vitro addition of excess pyridoxal phosphate, and of glutathione reductase (GTR) before and after the in vitro addition of excess flavin adenine dinucleotide. Women taking oral contraceptives showed plasma concentrations of ascorbic acid and vitamin B₁₂ below the range seen in a matched group of untreated women, while red cell AST and GTR were less saturated by their essential co-factors. Daily treatment with ‘Surbex 500’ restored all four biochemical indices of vitamin nutrition to the normal ranges.     

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications

Background:

Pyridoxine is frequently used to treat capecitabine-induced hand–foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes.

Methods:

A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/ 35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily.

Results:

Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15–1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival.

Conclusion:

Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.     

Chemoprevention of superficial bladder cancer

The American Cancer Society estimates that 57,400 new cases of bladder cancer will be diagnosed in the USA in 2003 and that approximately 70% of these cases will be superficial bladder tumors. Due to the high risk of recurrence, patients with superficial bladder cancer represent an ideal group for chemoprevention. Intravesical chemotherapy or immunotherapy is often administered in an attempt to prevent tumor recurrence in high-risk patients, although it is not without toxicity. A large body of evidence links diet and nutrition with bladder cancer. This review summarizes the efficacy of natural and synthetic agents that have purported chemopreventive activity.