B. Sivakumar

Vitamin A deficiency in infants: Effects of postnatal maternal vitamin A supplementation on the growth and vitamin A status

Abstract The effects of early postpartum maternal vitamin A supplementation (200,000 IU) on vitamin A status and growth of healthy breastfed infants were examined using a double blind controlled prospective study design. Vitamin A status during infancy was determined using a cross sectional study in infants. A retrospective analysis of case records of hospitalised children was used to define the extent of corneal lesions in infants. Serum vitamin A, retinol binding protein (RBP) and molar ratio of retinol to RBP in infants at birth, 6 wk, 3,6,9 & 12 months of age and vitamin A levels in breast milk were determined. Vitamin A status of infants at birth was low with mean serum retinol and RBP being 0.51 and 0.83 μmoles/L, respectively with a molar ratio of 0.59. Mean serum retinol was significantly increased in both the groups of infants by 6 wk of age (0.91 in the control and 0.82 μmoles L in the experimental group). Nevertheless, nearly 30% of infants continued to have serum retinol 1.05 μmoles/L upto 1 year of lactation in unsupplemented women. Supplemented mothers had significantly higher retinol content during the first 30 days of lactation. However, no impact of increased vitamin A intake could be observed on serum retinol levels and growth of their infants. In view of these data, the functional significance of low retinol levels among young infants and justification of supplementing lactating women with vitamin A to improve the vitamin A status of their newborns and young infants needs to be critically re-examined.

Pharmacokinetics of levonorgestkel in Indian women belonging to low socio-economic group

This study attempted to evaluate the effect of nutritional factors on the disposition of levonorgestrel (LN), as administered in a combination oral pill. Plasma samples from 11 low socioeconomic women were measured by radioimmunoassay after oral doses of 2 types of combination oral formulations, Primovlar-30 (500 mcg of LN and 30 mcg of ethinyl estradiol) and WHO-LNB (150 mcg of LN and 50 mcg of ethinyl estradiol). The following data suggest that nutritional status as reflected by anthropometry can modify the disposition of LN in women. With both preparations, plasma levels of LN reached a peak from 1-2 hours after administration and ranged from 4.6-16.2 ng/ml with Primovlar-30 and 2.8-14.4 ng/ml with LNB. The amount of LN in circulation at 48 hours was found to be more than .5 ng/ml. A triphasic decline in plasma levels of the steroid was established. Pharmacokinetic parameters calculated by graphical and regression analyses showed that the elimination half-life of the LN had a positive correlation and the peak plasma concentration a negative correlation with the 2 anthropometric indexes: weight/height sq. times 100 and skin-fold at triceps.

Effect of iron and vitamin A deficiencies on macrophage function in children

Abstract Macrophages obtained from activated peripheral blood monocytes of preschool children suffering from marginal vitamin A deficiency and iron deficiency anemia were investigated. Nonspecific or spontaneous cytotoxic function and Interleukin1 (IL1) production by appropriately activated macrophages were determined initially and one month after administration of 100,000 IU of oral vitamin A as a single dose. Macrophage functions appeared normal in children with iron deficiency anemia as well as in children with marginal vitamin A deficiency. However, there was a significant potentiation of IL1 production after the administration of vitamin A as a large dose while there was no change in cytotoxic function. The public health implications of these observations are discussed.

A new method for purification of human plasma retinol-binding protein and transthyretin.

Retinol is transported in the blood bound to a specific carrier protein called retinol‐binding protein (RBP), which in turn binds to another protein, transthyretin (TTR), a homotetrameric, thyroid‐hormone‐transporting protein. Binding of TTR increases the apparent molecular mass of RBP and thereby prevents glomerular filtration of RBP. Owing to their rapid turnover rates, plasma concentrations of these proteins are sensitive indicators and valuable diagnostic markers of vitamin A nutrition, protein energy malnutrition, infection and renal‐tubule function. Previously RBP and TTR were purified by using different procedures, either from plasma or from pathological urine of humans. In general the procedure for purification of RBP and TTR is laborious, and extensive sample recycling is necessary for purification in appreciable amounts. In the present study, we have purified RBP using a simple method, which involves (NH4)2SO4 fractionation followed by sequential gel filtration under native conditions and 6 M urea. TTR, which was eluted in 60 kDa fractions during urea/Sephadex G‐100 chromatography, was further purified to homogeneity using a combination of two dye‐affinity chromatographic steps on Reactive Yellow and Cibacron Blue coupled to agarose columns. SDS/PAGE and immunoblotting, apart from typical UV absorption and fluorescent properties of RBP, were used for characterizing the purified RBP and TTR. Furthermore, the purified RBP and TTR were found to be functional from mutual binding monitored by fluorescence quenching.

Plasma levels of norethindrone in indian women receiving norethindrone enanthate (20 mg) injectable

Plasma norethindrone (NET) and progesterone were estimated by radioimmunoassay in seven Indian women after intramuscular administration of 20 mg NET enanthate. One subject had intermenstrual bleeding throughout the cycle. Out of the six subjects considered for analysis, three subjects showed ovulation suppression, two had delayed ovulation and the remaining one exhibited normal ovulatory pattern. Post-peak average plasma NET values ranged from 1.0 to 2.1 ng/ml. These values showed a significant positive correlation with the anthropometric indices such as body weight and mid-arm-circumference. The subjects with lower anthropometry showed exponential decline of plasma NET. A possible role for nutritional status of an individual in drug disposition is indicated from this study.

Effect of food restriction (undernutrition) on pharmacokinetics of levonorgestrel in rabbits.

Twelve female rabbits aged about 3-4 months were randomly divided into two groups (group A and group B) and were individually matched for their initial body weights. Animals of group A received a stock diet ad libitum while each of the animals in group B were fed 50% of the diet consumed by the corresponding matched control from group A. Pharmacokinetics of levonorgestrel were determined in all animals between 1 1/2-2 months after these diets were started, using an intravenous dose of 8-20 /uCi of 3H-levonorgestrel and 15-20 /ug of levonorgestrel per kg body weight. Urinary excretion of radioactivity was also measured in all the animals for a period of 5 days following the dose. The body weights of animals on the restricted diet were 17% lower than those of the ad lib fed animals. Haemoglobin levels and plasma albumin concentration were found to be in the normal range in both groups. There was a significant increase in Metabolic Clearance Rate (MCR) and t 1/2 pi and a decrease in elimination half-life in animals of group B as compared to those seen in animals of group A. The urinary excretion of label was found to be slightly increased in group B animals as compared to that in group A controls.

The rabbit as an animal model to study pharmacokinetics of levonorgestrel in women

In an attempt to develop an animal model to facilitate investigations on the effects of various nutritional and environmental factors on the metabolism of the contraceptive steroid levonorgestrel, the pharmacokinetics of levonorgestrel were investigated in rabbits. Six adult female rabbits received an intravenous bolus dose of 3H-levonorgestrel, 8-20 microCi, with 15-20 micrograms of carrier cold levonorgestrel per kg body weight. Blood samples were drawn at different intervals of time after the dose and the plasma drug concentration was determined both by radioisotopic dilution method and by radioimmunoassay. Plasma concentrations of levonorgestrel as assayed by radioimmunoassay agreed very closely with those obtained by isotope counting. The decline in plasma radioactivity attributable to unchanged levonorgestrel followed a triexponential pattern. Plasma radioactivity data were therefore analysed according to a three-compartment open model by graphical and regression analysis. The half-lives of the three phases pi, alpha and beta representing the shallow, deep peripheral and the terminal elimination compartment, respectively, were in close agreement with those reported in women. The metabolic clearance rate (MCR) and volume of distribution (VB) of levonorgestrel expressed per unit of body weight were comparable to values reported in women. The overall observed trend of pharmacokinetics of levonorgestrel in rabbits resemble closely those seen in women. It would therefore appear that the rabbit is a suitable animal model for studying the effects of nutritional factors on the pharmacokinetics of the drug.

Pharmacokinetics of orally administered norethisterone enanthate in rabbit, monkey, and women

Norethisterone enanthate (NET-En), an established intramuscular long-acting contraceptive agent, has previously been shown to be effective in inhibiting fertility in two rodent species even 4 days after oral ingestion. Pharmacokinetics of NET and NET-En were studied after oral and intramuscular doses in two animal species and a few women. The results suggest that the NET-En was absorbed within a day in all the species after oral dose. The estimates of relative bioavailability ranged from 13 to 51% in rabbits, monkeys, and women. The elimination half-life was 5-10 days. The presence of the active component, NET, in the circulation over the experimental period of 15 days suggests that NET-En could be useful as a long-acting oral pill. The suppression of progesterone levels during the luteal phase of menstrual cycle in women also supports this finding.

Effect of food restriction (undernutrition) on pharmacokinetics of norethindrone in rabbits

Our previous studies have shown that the plasma norethindrone (NET) elimination is faster in women of low socio-economic group as compared to those of high socio-economic group. Undernutrition being very common in low socio-economic group, using an animal model, efforts were made to determine whether these differences were due to differences in the nutritional status of these two group of women. The experimental animals consisted of a set of twelve female rabbits, divided equally into two groups. One group (A) was fed on a stock diet ad libitum while the second group (B) received the diet in restricted amounts (half of that consumed by animals of group A). At the end of three months, radiolabelled NET was administered intravenously and plasma drug levels were determined at frequent intervals up to 24 hours. The plasma values were subjected to pharmacokinetic analysis. Food restriction to the extent of 50% resulted in a 20% deficit of body weight as compared to controls. The half-lives of alpha and beta phases were shortened in the restricted group resulting in an enhanced metabolic clearance rate of NET in this group. Though the differences were not statistically significant, the volume of distribution tended to be lower and the dose excreted in urine higher when food restriction was imposed.

Effect of vitamin a deficiency on circulating levels of amino acids and urea in children

Abstract Free amino nitrogen (AN) and urea nitrogen (UN) were estimated in the plasma samples of apparently normal and vitamin A deficient children, before and after treatment. The results indicate that the deficient children had significantly reduced plasma amino and urea nitrogen levels as compared to controls. Rehabilitation of these children with vitamin A for 10 days on an out-patient basis, had significantly increased the levels of UN and AN. Representative plasma aminograms showed no significant alteration except for an increase in the levels of methionine and glycine in deficient children, indicating that the decrease was generalized in deficiency. When a massive dose of vitamin A was administered, there was a significant increase in the plasma AN just after 24 h suggesting a mobilizing effect of the vitamin. The overall correlation obtained between basal vitamin A and plasma AN was found to be significant. The results suggest that vitamin A could modify protein metabolism.