P5P Abstracts 4


Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism.
            (Chang et al., 2013) Download
BACKGROUND:  A low circulating vitamin B-6 concentration, which is an independent risk factor for cardiovascular disease, is commonly seen in human inflammation. OBJECTIVE:  We investigated whether cyclooxygenase inhibitors alter vitamin B-6 metabolism. DESIGN:  To investigate whether subjects taking a cyclooxygenase inhibitor had an altered vitamin B-6 profile, we conducted a cross-sectional study that involved 150 rheumatoid arthritis patients, with and without cyclooxygenase inhibitor treatments. C57BL/6J mice and hyperlipidemic Syrian hamsters received drug regimens that reflected clinical nonsteroidal antiinflammatory drug (NSAID) uses in treating human inflammation. The impact of long-term physiologic use of selective and nonselective cyclooxygenase inhibitors on vitamin B-6 metabolism was systematically investigated in these independent in vivo models. RESULTS:  Patients who were taking cyclooxygenase inhibitors had lower circulating pyridoxal-5'-phosphate, especially those taking NSAIDs >6 mo. Long-term celecoxib and naproxen use reduced hepatic pyridoxal-5'-phosphate in mice. Nonselective cyclooxygenase inhibitor naproxen significantly decreased vitamin B-6 vitamers in the kidney. CONCLUSIONS:  To our knowledge, we show novel findings that long-term physiologic doses of cyclooxygenase inhibitor may impede the synthesis of the coenzymatically active form of vitamin B-6. Because the cause of vitamin B-6 depletion in inflammation remains unknown, this study provides a potential mechanism that could account for the poor vitamin B-6 status in human inflammation. Moreover, this study further raises concerns about the long-term clinical use of antiinflammatory NSAIDs in humans. Vitamin B-6 status should be carefully monitored in long-term NSAID users. Future randomized placebo-controlled studies are needed to determine the impacts of antiinflammatory cyclooxygenase inhibitor use on vitamin B-6 metabolism in humans.


Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements.
            (Adams et al., 2006) Download
BACKGROUND:  There have been many studies of the effect of high-dose supplementation of vitamin B6 on children and adults with autism, with all but one reporting benefits. OBJECTIVE:  The aim of this study was to investigate the biochemical basis for vitamin B6 therapy by measuring the level of total vitamin B6 in the plasma of unsupplemented children with autism spectrum disorder compared to unsupplemented control subjects. PARTICIPANTS:  Children with autism spectrum disorders (n = 35, age 3-9 years) and unrelated typical children (n = 11, age 6-9 years), all from Arizona, were studied. (This includes the data from 24 children with autism from our previous study.) METHODOLOGY:  A microbiologic assay was used to measure the level of total vitamin B6 (including phosphorylated and unphosphorylated forms), in a blinded fashion. RESULTS:  Children with autism had a 75% higher level of total vitamin B6 than the controls (medians of 56 versus 32 ng/mL, respectively, p = 0.00002). Most of the autistic children (77%) had levels that were more than 2 standard deviations above the median value of the controls. The autistic girls (n = 5) also had elevated levels (mean of 54.6 ng/mL, median of 60 ng/mL). DISCUSSION:  These results are consistent with previous studies that found that: (1) pyridoxal kinase had a very low activity in children with autism and (2) pyridoxal 5 phosphate (PLP) levels are unusually low in children with autism. Thus, it appears that the low conversion of pyridoxal and pyridoxine to PLP results in low levels of PLP, which is the active cofactor for 113 known enzymatic reactions, including the formation of many key neurotransmitters. CONCLUSIONS:  Total vitamin B6 is abnormally high in autism, consistent with previous reports of an impaired pyridoxal kinase for the conversion of pyridoxine and pyridoxal to PLP. This may explain the many published studies of benefits of high-dose vitamin B6 supplementation in some children and adults with autism.

High-dose pyridoxine and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study.
            (Findling et al., 1997) Download
Several reports have described salutary effects such as decreased physical aggression and improved social responsiveness being associated with the administration of high doses of pyridoxine and magnesium (HDPM) in open-labeled and controlled studies of patients with autism. Despite this fact, this intervention remains controversial. A 10-week double-blind, placebo-controlled trial was undertaken to examine both the efficacy and safety of HDPM in autism. Twelve patients were enrolled, and 10 patients (mean age 6 years 3 months) were able to complete the study. HDPM at an average dose of 638.9 mg of pyridoxine and 216.3 mg of magnesium oxide was ineffective in ameliorating autistic behaviors as assessed by the Children's Psychiatric Rating Scale (CPRS), the Clinical Global Impression Scale, and the NIMH Global Obsessive Compulsive Scale. Furthermore, no clinically significant side effects were noted during HDPM administration. A trend for a transient change on the CPRS was found that was possibly due to a placebo response. This study raises doubts about the clinical effectiveness of HDPM in autistic disorder.

The effect of high doses of vitamin B6 on autistic children: a double-blind crossover study.
            (Rimland et al., 1978) Download
The authors used data from an earlier nonblind study to identify 16 autistic-type child outpatients who had apparently improved when given vitamin B6 (pyridoxine). In a double-blind study each child's B6 supplement was replaced during two separate experimental trial periods with either a B6 supplement or a matched placebo. Behavior was rated as deteriorating significantly during the B6 withdrawal.

High dose vitamin B6 and magnesium in treating autism: response to study by Findling et al.
            (Rimland, 1998) Download

Association of maternal diabetes with autism in offspring.
            (Xiang et al., 2015) Download
IMPORTANCE: Information about the association of maternal diabetes and autism spectrum disorders (ASDs) in offspring is limited, with no report on the importance of timing of exposure during gestation. OBJECTIVE: To assess ASD risk associated with intrauterine exposure to preexisting type 2 diabetes and gestational diabetes mellitus (GDM) by gestational age at GDM diagnosis. DESIGN, SETTING, AND PATIENTS: Retrospective longitudinal cohort study including 322 323 singleton children born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012. Relative risks of ASD were estimated by hazard ratios (HRs) using Cox regression models adjusted for birth year. EXPOSURES: Maternal preexisting type 2 diabetes (n = 6496), GDM diagnosed at 26 weeks' gestation or earlier (n = 7456) or after 26 weeks' gestation (n = 17 579), or no diabetes (n = 290 792) during the index pregnancy. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of ASD in offspring. RESULTS: During follow-up, 3388 children were diagnosed as having ASD (115 exposed to preexisting type 2 diabetes, 130 exposed to GDM at </=26 weeks, 180 exposed to GDM at >26 weeks, and 2963 unexposed). Unadjusted annual ASD incidences were 3.26, 3.02, 1.77, and 1.77 per 1000 among children of mothers with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM diagnosed after 26 weeks, and no diabetes, respectively. The birth year-adjusted HRs were 1.59 (95% CI, 1.29-1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 1.35-1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84-1.15) for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI, 0.97-1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95% CI, 1.15-1.74). Antidiabetic medication exposure was not independently associated with ASD risk. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68 512) did not affect the results. CONCLUSIONS AND RELEVANCE: In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks' gestation, exposure to maternal GDM diagnosed by 26 weeks' gestation was associated with risk of ASD in offspring.



Adams, JB, F George, and T Audhya (2006), ‘Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements.’, J Altern Complement Med, 12 (1), 59-63. PubMed: 16494569
Chang, HY, et al. (2013), ‘Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism.’, Am J Clin Nutr, 98 (6), 1440-49. PubMed: 24153347
Findling, RL, et al. (1997), ‘High-dose pyridoxine and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study.’, J Autism Dev Disord, 27 (4), 467-78. PubMed: 9261669
Rimland, B, E Callaway, and P Dreyfus (1978), ‘The effect of high doses of vitamin B6 on autistic children: a double-blind crossover study.’, Am J Psychiatry, 135 (4), 472-75. PubMed: 345827
Rimland, B (1998), ‘High dose vitamin B6 and magnesium in treating autism: response to study by Findling et al.’, J Autism Dev Disord, 28 (6), 581-82. PubMed: 9932247
Xiang, AH, et al. (2015), ‘Association of maternal diabetes with autism in offspring.’, JAMA, 313 (14), 1425-34. PubMed: 25871668