Studying the antiemetic effect of vitamin B6 for morning sickness: pyridoxine and pyridoxal are prodrugs.

Vitamin B6 has been known to possess antiemetic effects since 1942. This water soluble compound has several forms in the circulation including pyridoxine, pyridoxal, and pyridoxal phosphate. The active antiemetic form of vitamin B6 is unknown. This was a pre-specified substudy of a randomized, placebo-controlled trial comparing the antiemetic effect of the doxylamine-vitamin B6 combination (Diclectin®) (n = 131) to placebo (n = 126) in women with nausea and vomiting of pregnancy. Serum concentrations of pyridoxine, pyridoxal, and pyridoxal 5' phosphate (PLP) and doxylamine were measured on Days 4, 8, and 15. With Diclectin® exhibiting a significant antiemetic effect in pregnancy, serum concentrations of pyridoxine were unmeasurable in almost all patients and those of pyridoxal were undetectable in half of patients. In contrast, PLP was measurable at sustained, stable steady-state levels in all patients. Our data suggest that there is a correlation between PLP levels and PUQE score of morning sickness symptoms when pyridoxine and pyridoxal levels are undetectable, and hence they might be prodrugs of PLP, which may be the active antiemetic form of vitamin B6.

Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride; implications for pharmacotherapy in pregnancy.

Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single-center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine-pyridoxine 10 mg-10 mg delayed-release tablets. Healthy males (n = 12) and non-pregnant females (n = 12) were administered two tablets, and blood sampling was conducted from 1 hour pre-dose until 72 hours post-dose. After 21 days, dose administration and blood sampling were re-conducted. All analytes were measured using liquid chromatography-tandem mass-spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non-compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0-t for each analyte. Females had significantly larger AUC0-t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV = 19%]) versus 1,272 ng h/mL (CV = 21%; P ≤ .05), and pyridoxine, 35 ng h/mL, (CV = 43%) versus 25 ng h/mL (CV = 31%; P ≤ .05) compared to males. A higher Cmax for doxylamine was observed in females, 107 ng/mL (CV = 16%), compared to males, 86 ng/mL (CV = 15%) (P ≤ .05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine-pyridoxine.

Quantitative determination of pharmaceuticals using nano-electrospray ionization mass spectrometry after reversed phase mini-solid phase extraction.

The pre-concentration effect of solid phase microextraction (SPE) with nano-electrospray ionization mass spectrometry (nano-ESI MS) for selected pharmaceuticals is presented. An analytical method is developed for the quantitative determination of dicyclomine in serum with cyclopentolate as the internal standard by off-line nano-ESI ion-trap MS with reversed phase mini-SPE. Homemade C18 and C4 mini-SPE cartridges of 0.5 and 1cm in length and 1.55 mm i.d. have been tested for pre-concentration of samples originally 30 microL in volume. After SPE, the volume of the sample in methanol is about 1-2 microL and 0.5 microL can be injected into the nano-ESI MS instrument. Use of a 1cm C18 cartridge lowered the detection limit of dicyclomine 100 times to 16.1 fmole. Dicyclomine spiked in serum can be determined by nano-ESI MS after protein precipitation and further clean-up on the 1cm C18 cartridge. However, the slope of a calibration curve of dicyclomine standards spiked in serum is more than a factor of 10 less than that for a calibration curve of dicyclomine standards prepared in water indicating pre-concentration of pharmaceuticals could be compromised by a complex biological matrix.

Dicyclomine in the sudden infant death syndrome (SIDS)--a cause of death or an incidental finding?

We report a case of a small infant apparently dying of the Sudden Infant Death Syndrome (SIDS) with a postmortem blood dicyclomine level of 200 ng/mL. Review of the literature and the comparison with blood dicyclomine values from four rabbits given equivalent doses suggests that a blood dicyclomine value of 200 ng/mL probably is in the therapeutic range for infants. Although safely used for years for infantile colic, recently, the administration of dicyclomine has been related to acute episodes of apnea, seizures, and coma. In the absence of those acute reactions, we feel that a 200-ng/mL blood dicyclomine level in a child dying of apparent SIDS should not prevent categorization of the death as SIDS.

Two cases of death involving dicyclomine in infants. Measurement of therapeutic and toxic concentrations in blood.

In two deaths of infants investigated by the Medical Examiner, high levels of dicyclomine were detected in blood. In one of the cases, a level of 0.505 micrograms/ml was found, nearly 10 times reported adult therapeutic blood concentrations, and death was ascribed to an overdose of dicyclomine. Gas chromatography/mass spectrometry was used for the analysis of biological specimens.