Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.

BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

Study on the conditions of use for Caribán(R) and other antiemetics in the treatment of nausea and vomiting during pregnancy / Estudio sobre las condiciones de uso de Caribán(R) y de otros antieméticos en el tratamiento de las náuseas y vómitos en el embarazo: estudio prospectivo observacional longitudinal

Objective: We performed a prospective observational study on the conditions of use of a medication, Caribán(R), and of other antiemetics for the treatment of nausea and vomiting in pregnancy (NVP). The study was practical in design, and its main objective was to determine the frequency of use of Caribán(R) in the treatment of NVP by analyzing conditions of use in daily clinical practice. Material and methods: The study population comprised 184 pregnant women with nausea and/or vomiting during the days preceding the first study visit. The patients attended up to 4 visits, 3 of which were face-to-face, and provided clinical follow-up data and data on the treatment used by means of an app. Data on treatment and the evaluation of nausea and vomiting were obtained every 24 hours using the Pregnancy-Unique Quantification of Emesis and Nausea score (PUQE). Results: The most frequently used initial regimen was 1 capsule every 8 hours. Data were available from the baseline visit and from the daily follow-up of 158 women (ie, 4982 daily evaluations). The mean score for severity of NVP was 5.69 points (mild) (SD, 1.8; range, 3-13) and the mean cumulative dose per woman throughout the follow-up was 34.61 capsules (6-197). NVP was mild in 72.48% of evaluations, moderate in 26.57%, and severe in 0.94%. Patients did not take medication in 54% (n=1969) of the mild daily episodes and in 14% of the moderate episodes. Mean consumption per daily episode was 1.74 (0-10) capsules per episode of mild NVP and 2.14 (0-35) capsules per episode of moderate NVP. Women who had NVP took Caribán(R) according to the app on 66.7% of the days with symptoms. Conclusions: The most common initial regimen prescribed was 1 capsule every 8 hours. Most of the episodes of NVP were mild, and on 50.85% of days with mild NVP, the women did not take medication. The mean daily dose per mild episode was 1.74 capsules. The patients reported having taken medication for moderate NVP in 86% of cases. The mean dose per episode was 2.14 capsules. The patients took Caribán(R) on 66.7% of days with NVP

Objetivo: El estudio sobre las condiciones de uso de Caribán(R) y otros antieméticos en el tratamiento de las náuseas y vómitos del embarazo (NVE) es un estudio observacional prospectivo de utilización de medicamentos diseñado con criterios pragmáticos que se plantea con el objetivo principal de determinar la frecuencia de uso de Caribán(R) en el tratamiento de las náuseas y vómitos del embarazo (NVE) analizando sus condiciones de uso en la práctica clínica diaria. Material y Metodos: Han participado 184 embarazadas con náuseas y/o vómitos en los días previos a la primera visita del estudio que atendieron hasta 4 visitas, tres de ellas presenciales, y facilitaron información del seguimiento clínico y del tratamiento utilizado mediante una aplicación telefónica. Se han recogido variables de tratamiento y la valoración de náuseas y vómitos cada 24 horas mediante la escala PUQE (PregnancyUniqueQuantification of Emesis and nausea). Resultados: La pauta de inicio más frecuentemente utilizada fue una capsula cada 8 horas. Existen datos de visita basal y de seguimiento diario de 158 embarazadas que suponen 4982 valoraciones diarias. La valoración media de la gravedad de las NVE es 5,69 puntos (LEVE), (SD 1,8, rango 3-13) y la dosis acumulada media por mujer durante todo el seguimiento 34,61 cápsulas ( 6-197). En el 72,48% de todas las valoraciones las NVE fueron leves, el 26,57% moderadas y el 0,94% graves. En el 54% (n=1969) de los episodios diarios leves y en el 14% de los moderados las gestantes no tomaron medicación. El consumo medio por cada episodio diario de NVE leve fue de 1,74 (0-10) cápsulas, mientras que en cada episodio moderado se utilizaron 2,14 (0-35) cápsulas. Las mujeres que tenían NVE tomaban Caribán(R) según la aplicación en el 66,7% de los días que tenían clínica. Conclusiones: La pauta de inicio prescrita mas frecuentemente fue una capsula cada 8 horas. La mayor parte de los episodios de NVE son leves, y en el 50.85% de los días con náuseas o vómitos leves las embarazadas no tomaron medicación. La dosis media por episodio/día leve es de 1,74 cápsulas. En los episodios diarios de NVE moderados el 86% de las embarazadas señalaron tomar la medicación siendo la dosis media por episodio de 2,14. El 66,7% de los días en que las mujeres tenían NVE tomaban Caribán(R)

Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6.

Erymet is a new therapy resulting from the encapsulation of a methionine gamma-lyase (MGL; EC number 4.4.1.11) in red blood cells (RBC). The aim of this study was to evaluate erymet potential efficacy in methionine (Met)-dependent cancers. We produced a highly purified MGL using a cGMP process, determined the pharmacokinetics/pharmacodynamics (PK/PD) properties of erymet in mice, and assessed its efficacy on tumor growth prevention. Cytotoxicity of purified MGL was tested in six cancer cell lines. CD1 mice were injected with single erymet product supplemented or not with vitamin B6 vitamer pyridoxine (PN; a precursor of PLP cofactor). NMRI nude mice were xenografted in the flank with U-87 MG-luc2 glioblastoma cells for tumor growth study following five intravenous (IV) injections of erymet with daily PN oral administration. Endpoints included efficacy and event-free survival (EFS). Finally, a repeated dose toxicity study of erymet combined with PN cofactor was conducted in CD1 mice. Recombinant MGL was cytotoxic on 4/6 cell lines tested. MGL half-life was increased from <24 h to 9-12 days when encapsulated in RBC. Conversion of PN into PLP by RBC was demonstrated. Combined erymet + PN treatment led to a sustained Met depletion in plasma for several days with a 85% reduction of tumor volume after 45 days following cells implantation, and a significant EFS prolongation for treated mice. Repeated injections in mice exhibited a very good tolerability with only minor impact on clinical state (piloerection, lean aspect) and a slight decrease in hemoglobin and triglyceride concentrations. This study demonstrated that encapsulation of methioninase inside erythrocyte greatly enhanced pharmacokinetics properties of the enzyme and is efficacy against tumor growth. The perspective on these results is the clinical evaluation of the erymet product in patients with Met starvation-sensitive tumors.

Bioavailability of Cu, Zn and Mn from Mineral Chelates or Blends of Inorganic Salts in Growing Turkeys Fed with Supplemental Riboflavin and/or Pyridoxine.

An 84-day feeding trial was conducted in growing turkeys to measure the bioavailability of Cu, Zn and Mn from a commercial mineral chelate and corresponding inorganic salts in composite feeds containing supplemental riboflavin (B2) and/or pyridoxine (B6). A total of 320, 28-day-old British United Turkeys (BUT) were assigned to eight dietary treatments in a 2 × 4 factorial arrangement comprising two trace mineral sources: chelated trace mineral blend (CTMB) and its corresponding inorganic trace minerals blend (ITMB) fed solely or with supplements of vitamin B2 (8 ppm) or B6 (7 ppm) or 8 ppm B2 + 7 ppm B6. Each treatment was replicated four times with 10 turkeys each. It was observed that turkeys fed with diets supplemented solely with ITMB elicited higher (P < 0.05) Zn excretion than their counterparts fed with diets containing ITMB with supplements of vitamins B2 and/or B6. Manganese retention was lower (P < 0.05) in turkeys fed with diets supplemented solely with ITMB than those fed with diets containing vitamins B2 and/or B6 additives. Combination of CTMB or ITMB with B6 improved (P < 0.05) the concentration of Mn in the liver and Cu in the bone. It was concluded that the minerals in CTMB were more available to the animals than ITMB. Furthermore, vitamins B2 and/or B6 supplementation improved the bioavailability of the inorganic Cu, Zn and Mn in growing turkeys and tended to reduce the concentration of these trace elements in birds' excreta.

Linezolid-induced haematological toxicity / Toxicidad hematológica inducida por linezolid

Objective: to determine the incidence of linezolid-induced haematological toxicity and study the influence of renal clearance on its appearance and the preventive effect of pyridoxine. Methods: a retrospective observational study was conducted. Every patient treated with linezolid in a university hospital during 6 months was included. Haematological toxicity was defined as a decrease of 25% in hemoglobin, of 25% in platelets and/or 50% in neutrophils from baseline. The incidence of haematological toxicity and the percentage decrease in analytical variables were compared in patients with and without renal failure (creatinine clearance lower than 50 mL/min), using the 30 mL/min threshold, and with or without pyridoxine; using Chi -Square and U Mann-Whitney tests, respectively. Results: thirty-eight patients were evaluated. Sixteen (42%) presented haematological toxicity (2 due to a decrease in haemoglobin, 9 in platelets and 8 in neutrophils). Two patients (5%) discontinued treatment due to thrombocytopenia. Toxicity incidence was similar in patients with and without renal failure, 42% vs 42%, p = 0.970, with more or less than 30 ml/min, 67% vs 40%, p = 0.369, or with or without pyridoxine, 47.8% vs 33%, p = 0.376. Patients with renal failure had a significantly greater reduction in platelet count, p = 0.0185. Conclusion: forty-two percent of patients had haematological toxicity, being more frequent platelets and neutrophils reduction. This was not significantly higher in patients with renal failure or in those without pyridoxine. Greater reduction in platelet count was observed in patients with renal failure (AU)

Objetivo: determinar la incidencia de toxicidad hematológica por linezolid. Estudiar la influencia del aclaramiento renal en su aparición y la efectividad de la piridoxina en su prevención. Método: estudio observacional retrospectivo de todos los pacientes tratados con linezolid en un hospital universitario en seis meses. Se consideró toxicidad hematológica a la disminución del 25% de la hemoglobina, del 25% de las plaquetas y/o del 50% de neutrófilos al final respecto al inicio del tratamiento. Se comparó en los pacientes con y sin fallo renal (aclaramiento de creatinina inferior a 50 mL/min), con más o menos de 30 mL/min, y con o sin piridoxina, la incidencia de toxicidad hematológica mediante Chi-Cuadrado y la disminución en el porcentaje de variables analíticas hematológicas mediante U Mann-Whitney. Resultados: se evaluaron 38 pacientes. Dieciséis (42%) presentaron toxicidad hematológica (2 por disminución de hemoglobina, 9 de plaquetas y 8 de neutrófilos). En 2 pacientes (5%) se suspendió el tratamiento por plaquetopenia. La incidencia de toxicidad fue similar en pacientes con y sin insuficiencia renal, 42% vs. 42%, p = 0,970, con más o menos de 30 mL/min, 67% vs. 40%, p = 0,369, con piridoxina o sin ella, 47,8% vs. 33%, p = 0,376. Los pacientes con fallo renal presentaron una reducción significativamente mayor de plaquetas, p = 0,0185. Conclusiones: un 42% de los pacientes presentó toxicidad hematológica, más frecuentemente disminución de plaquetas y neutrófilos. Esta no fue significativamente mayor en los pacientes con fallo renal, ni en aquellos sin piridoxina. Se halló mayor reducción de plaquetas en los pacientes con insuficiencia renal (AU)

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.

Comparing the pharmacokinetics of doxylamine/pyridoxine delayed-release combination in nonpregnant women of reproductive age and women in the first trimester of pregnancy.

Although Diclectin (doxylamine/pyridoxine delayed-released combination) is widely used in Canada, its pharmacokinetics (PK) during pregnancy has never been described. The objective of this study was to compare the PK of doxylamine/pyridoxine delayed-released combination in pregnant versus nonpregnant women. The apparent clearances (CL) of doxylamine and pyridoxal 5'-phosphate (PLP; the active metabolite of vitamin B(6) ) during the first-trimester pregnancy in women who participated in a Diclectin randomized trial were compared with those of healthy, adult, nonpregnant women who participated in a voluntary PK trial. Eighteen nonpregnant women were compared with 50 pregnant women who were treated with Diclectin. There was no difference in the apparent CL of doxylamine in women in their first trimester of pregnancy when compared with nonpregnant women on day 4 (median = 196.7 vs 249.5 mL/h/kg, respectively, P = .065), day 8 (median = 248.4 vs 249.5 mL/h/kg, respectively, P = .82), and day 15 (median = 200.9 vs 249.5 mL/h/kg, respectively, P = .55). No difference was found in the apparent CL of PLP on day 15 (median = 342.3 vs 314.7 mL/h/kg, respectively, P = .92). There was no pregnancy-induced effect in the apparent CL of either doxylamine or PLP in women during the first trimester of pregnancy despite the existence of morning sickness.

Systemic bioavailability and pharmacokinetics of the doxylamine-pyridoxine delayed-release combination (Diclectin).

BACKGROUND: Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied. OBJECTIVES: To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population. METHODS: Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight. RESULTS: The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%. CONCLUSION: There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.

Negligible effect of oral garlic oil on the oral absorption of pyridoxine in metadoxine in rats.

Metadoxine [an ion-pair between pyridoxine and pyrrolidone carboxylate (PCA)] plus garlic oil treatment synergistically reduces alcoholic steatosis compared to each agent alone. We evaluated the effect of garlic oil on the pharmacokinetics of pyridoxine. After the oral administration of metadoxine, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and the peak plasma concentration (C(max)) of pyridoxine were significantly greater (by 40.6%) and higher (by 63.9%), respectively, than after oral administration of pyridoxine plus PCA. Oral metadoxine plus garlic oil also gave larger AUC (31.8%) and higher C(max) (64.9%) than pyridoxine plus PCA. However, garlic oil did not change the AUC or C(max) of pyridoxine in metadoxine. Thus, garlic oil does not enhance the metadoxine activity by affecting the absorption of pyridoxine.

[Comparative pharmacokinetics and relative bioavailability of magnesium-containing drugs].

Pharmacokinetics of magnesium ions after single peroral administration of Magnelis B6 and Magne B6 coated tablets (magnesium dose, 48 mg) was studied in rabbits. In the blood plasma, the level of magnesium ions was very low compared to the endogenous level, which did not allow the drug bioavailability to be reliable evaluated. At the same time, the level of magnesium ions was reliable determined in the daily urine of test animals. The relative bioavailability of magnesium for Magnelis B6 versus Magne B6 was estimated at 98.93 +/- 12.45% (average +/- SD).

Pharmacokinetic comparison of a delayed-release combination of doxylamine succinate and pyridoxine hydrocholoride (Diclectin) and oral solutions of these drugs in healthy women of childbearing age.

BACKGROUND: The delayed-release combination of doxylamine succinate and pyridoxine hydrochloride was the most commonly used antiemetic (Bendectin) approved by FDA for nausea and vomiting of pregnancy (NVP) until its removal of the market in 1983. The drug is widely used today in Canada (Diclectin). The pharmacokinetics of Diclectin has never been described in humans. OBJECTIVES: To compare the pharmacokinetics of Diclectin to oral solutions of its two components. SUBJECTS AND METHODS: A randomized, cross over, open label design, comparing the pharmacokinetics of Diclectin to those of the oral solutions of the two components in 18 healthy adult, non pregnant women of childbearing age. RESULTS: Diclectin exhibited similar oral bioavailability to those of the oral solutions. In contrast, the time-to-peak, (Tmax), reflecting the rate of absorption, was 3-6 times longer for the two components of the delayed-release drug confirming its delayed-release characteristics. CONCLUSION: The pharmacokinetic profile of Diclectin well explains its documented delayed efficacy.

Transport of high concentration of thiamin, riboflavin and pyridoxine across intestinal epithelial cells Caco-2.

In this study, we examined the intestinal uptake of thiamin (vitamin B(1)), riboflavin (vitamin B(2)) and pyridoxine (vitamin B(6)) administered at high concentration using intestinal epithelial Caco-2 cells as an in vitro model of drugs and food absorption. The effect of vitamin concentration, culture age, transport direction and incubation temperature on vitamin transport was determined. The vitamin transport was expressed as an apparent permeability coefficient and changes in cumulative fraction transported across epithelial membrane in time. It was found that transepithelial transport of these vitamins is dependent on the experimental factors. At low concentrations an active transport mechanism was observed, whereas at high vitamin concentration a passive transport dominated. At high vitamin concentration the transepithelial flux of vitamins in both directions was similar, which proves the mechanism of passive transport.

Uptake, hydrolysis, and metabolism of pyridoxine-5'-beta-D-glucoside in Caco-2 cells.

An important dietary source of vitamin B-6, pyridoxine-5'-beta-D-glucoside (PNG), exhibits only partial bioavailability, which is limited by the extent of enzymatic cleavage of the beta-glucosidic bond to release metabolically available pyridoxine (PN). This laboratory showed that the intestinal hydrolysis of PNG is catalyzed by cytosolic PNG hydrolase (PNGH) and brush border lactase-phlorizin hydrolase (LPH). LPH-catalyzed PNG hydrolysis in vitro is competitively inhibited by lactose. In the present study, the uptake and hydrolysis of PNG were examined in Caco-2 human colon carcinoma cells, which express a functional LPH but exhibit no PNGH activity. PNG uptake at 37 degrees C was linear over 5-500 micromol/L PNG. Uptake was not significantly reduced when Na(+) was substituted with K(+), Li(+), or Tris in the medium. Increasing PNG concentration in the medium did not change intracellular concentrations of PN, pyridoxamine (PM), pyridoxamine 5'-phosphate (PMP), or pyridoxal 5'-phosphate (PLP); however, intracellular pyridoxal (PL) concentration increased. Intracellular PNG concentration was not significantly reduced in the presence of lactose, but the concentration of PL declined in proportion to extracellular lactose (P = 0.01). These results indicate that PNG can be absorbed intact in a Na(+)-independent process and is taken up by passive diffusion. The presence of lactose in this in vitro model of intestinal uptake reduced the enzymatic hydrolysis of PNG by lactase.

Metadoxine in the treatment of acute and chronic alcoholism: a review.

Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmaco-therapeutic aspect of alcoholism includes the use of drugs, with different actions and objectives. Among them, metadoxine seems to be of interest. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, to help restore the functional structure of the liver and to relieve neuro-psychological disorders associated with alcohol intoxication. Metadoxine also seems to be safe; in more than 15 years of post-marketing surveillance only minor aspecific and reversible events were monitored in patients exposed to the treatment. In this review the preclinical and clinical results obtained using metadoxine in acute and chronic alcohol intoxication are reported.

Bendectin and birth defects. II: Ecological analyses.

BACKGROUND: Bendectin was the primary pharmaceutical treatment of nausea and vomiting of pregnancy (NVP) in the United States until the early 1980s. Its manufacture was then discontinued after public allegations that it was causing birth defects. Subsequently, meta-analyses of the many epidemiological cohort and case/control studies used to examine that hypothesis have demonstrated the absence of a detectable teratogenic effect. This study presents an ecological analysis of the same hypothesis that examines specific malformations. METHODS: Annual birth defect prevalence data for the 1970s to the 1990s have been obtained for specific birth defects from the Center for Disease Control's nationwide Birth Defect Monitoring Program. These data for the US have been compared graphically to the annual US Bendectin sales for the treatment of NVP. Data have also been obtained for annual US rates for hospitalization for NVP. The three data sets have been temporally compared in graphic analysis. RESULTS: The temporal trends in prevalence rates for specific birth defects examined from 1970 through 1992 did not show changes that reflected the cessation of Bendectin use over the 1980-84 period. Further, the NVP hospitalization rate doubled when Bendectin use ceased. CONCLUSIONS: The population results of the ecological analyses complement the person-specific results of the epidemiological analyses in finding no evidence of a teratogenic effect from the use of Bendectin.

Hydrolytic activity toward pyridoxine-5'-beta-D-glucoside in rat intestinal mucosa is not increased by vitamin B-6 deficiency: effect of basal diet composition and pyridoxine intake.

Pyridoxine-5'-beta-D-glucoside (PNG), a glycosylated form of dietary vitamin B-6, is partially hydrolyzed in the small intestine by the cytosolic enzyme pyridoxine-5'-beta-D-glucoside hydrolase (PNG hydrolase) and by the brush border enzyme lactase phlorizin hydrolase (LPH) to release free pyridoxine (PN). This laboratory has previously shown that PNG hydrolase activity is inversely related to dietary vitamin B-6 in rats and guinea pigs. The current investigation was done to examine the effect of dietary PN on PNG hydrolytic activity and its distribution. Nutrient compositional differences between the AIN-76A and AIN-93G purified diets that were unrelated to vitamin B-6 were also examined in relation to PNG hydrolysis in rat small intestinal mucosa. Study one included rats (n = 29) that were fed the AIN-93G diet providing a range of PN concentrations for 5 wk. Rats (n = 49) in study two were fed either AIN-76A or AIN-93G each with graded concentrations of PN. In both studies, rat growth and plasma and liver pyridoxal 5'-phosphate (PLP) concentrations increased (P < 0.05) with increasing concentrations of dietary PN. PNG hydrolytic activity localized to the brush border membrane was five times that measured in the cytosol. Cytosolic PNG hydrolytic activity increased significantly with increasing dietary PN concentration in rats fed the AIN-76A, but not AIN-93G diet. Activity in the mucosal total membrane fraction did not increase in proportion to dietary PN concentration for either diet. Regardless of dietary PN concentration, the basal nutrient composition of the diets affected growth and PNG hydrolytic activity in intestinal mucosa. In contrast to previous results from this laboratory, intestinal hydrolytic activity toward PNG did not increase in vitamin B-6-deficient rats.