Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors.

The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.

An in vitro method for predicting the bioavailability of iron from foods.

An in vitro method for the determination of availability of nonheme iron from foods and diets was investigated. Food was extracted with pepsin-HCl at pH 1.35 and subsequently the pH was adjusted to pH 7.5 and filtered. Ionizable iron was determined in the pH 7.5 filterate by the alpha, alpha-dipyridyl method. The percent iron absorption from the same diets observed in the adult males. Ionizable iron at pH 7.5 was shown to increase in presence of ascorbic acid and meat extract while it decreased in presence of phytate and tannins, similar to the effects of these factors on iron absorption in human subjects. Based on these observations it is proposed that ionizable iron at pH 7.5 determined as described in this study can be used as a reliable measure of bioavailability of nonheme iron in foods.

Studies on 3-methylhistidine metabolism in children with protein-energy malnutrition.

Twenty-four hour urinary excretion of 3-methylhistidine (3-MeHis) was determined in children suffering from severe and moderate degrees of protein-energy malnutrition before and after treatment. Excretion of 3-MeHis was decreased both in children with severe protein-energy malnutrition and during undernutrition and increased considerably after treatment. The results suggest that there is a quantitative as well as a qualitative change in 3-MeHis metabolism in protein-energy malnutrition. A sensitive index for studying muscle protein metabolism is not available so far. Studies reported herein seem to suggest that 3-MeHis may fulfill such a requirement.

Effect of varying energy and protein intakes on some biochemical parameters of protein metabolism.

Three biochemical parameters of protein metabolism, i.e., urea index, urinary 3-methyl histidine, and urinary hydroxyproline, were studied in preschool children fed varying levels of protein and energy. The effect of varying protein and energy intakes on urinary 3-methyl histidine was also studied in adults. Varying protein and energy intakes had no significant effect on urea index and urinary 3-methyl histidine excretion as long as positive nitrogen balance was maintained. However, these two parameters decreased only when intakes of protein and energy were below maintenance levels, which resulted in a negative nitrogen balance. Urea index and urinary 3-methyl histidine excretion can be used therefore as an index to identify those malnourished children whose protein and/or energy intakes are grossly inadequate, resulting in negative nitrogen balance. Hydroxyproline excretion was responsive to alterations in protein intakes rather than to changes in energy intakes and the alteration in its excretion was small for large changes in protein intakes.

Nutritional deprivation in childhood and the body size, activity, and physical work capacity of young boys.

Clinical nutritional status and physical work capacity at submaximal level were assessed in 96 rural Hyderbad boys, 14 to 17 years of age. Data available on the previous nutritional status of these children when they were 5 years of age were used for classifying them into different nutritional grades. Factors responsible for undernutrition childhood continued to operate on later growth. Both height and weight at 5 years correlated well (P less than 0.001) with current height and weight. About 64% (P less than 0.001) of the variation in physical work capacity at a heart rate of 170/min (physical work capacity 170 kpm/min) could be explained by the differences in current body weight; habitual physical activity explained another 10% (P less than 0.001) of the variation. Malnutrition in early childhood continuing into adolescence could be considered to have adversely affected their work capacity by influencing their body weight. However, even severe undernutrition during childhood had no effect on work performance, when expressed in terms of unit weight. But for the same work load, undernourished subjects had to use significantly higher heart rate at moderate work level as compared to their counterparts.

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.

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

The pharmacokinetics of norethindrone (NET) were studied in adult female rabbits and rhesus monkeys with a view to developing an animal model closely resembling humans in the handling of NET. Plasma levels of NET were determined in rabbits and monkeys after administering either labelled NET or a NET minipill. Pharmacokinetic parameters were evaluated by using a two-compartment open model and by graphical and regression analysis of plasma NET data. In rabbits, the drug absorption was found to be rapid and NET peak levels were attained within 0.5 to 1.0 hour. The clearance half-lives were 1.3 hours for 'alpha' and 10.0 hours for 'beta'. In monkeys, plasma NET values showed an inconsistent pattern and the approximate t 1/2 was found to lie between 4 and 6 hours. The observed pharmacokinetics of NET in rabbits rather than in monkeys were closer to those in humans. On this basis, it would appear that the rabbit is a suitable animal model for studying effects of nutritional factors on the pharmacokinetics of NET.

Bioavailability of levonorgestrel from intravaginal rings in women of low income groups.

Two types of intravaginal rings (IVR) containing 50-128 mg of levonorgestrel (LNOG) and 28-60 mg of estradiol were inserted in 18 apparently normal subjects belonging to the low socioeconomic group on day 5 of the cycle. A total of 120 cycles were studied with cyclic insertion and withdrawal. Data on menstrual cycle changes were noted. For bioavailability study, blood samples were collected twice weekly for a period of one month in the first cycle in 8 women. All the plasma samples were analysed for LNOG and progestrone by RIA. Cycle control was excellent in IVR users. Expulsion of the ring was noted in 4 instances. The plasma LNOG levels were found to reach a peak level ranging from 2.7-7.5 ng/ml within 4 days after the IVR insertion. In between day 9 to 24, the plasma levels appeared to be almost steady, and once the ring was removed, the levels dropped off rapidly. The mean plasma LNOG calculated during the steady-state period of the cycle ranged from 1.6-5.1 ng/ml. These mean LNOG levels were found to be inversely correlated with skin-fold at triceps. In all the subjects ovulation was found to be inhibited, as reflected by plasma progesterone values. The range of release rates calculated from plasma steady-state values was 51-119 micrograms/day. The average release rates over the entire period of observation based on area under curve were 102-200 micrograms/day. On the other hand, the release rates obtained from the residual drug in the ring after a period of use ranged from 184-259 micrograms/day.

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 norethisterone from two different combination contraceptive pills in Indian women.

In view of our previous studies that the plasma elimination of norethisterone (NET) from mini pill is faster in low socio-economic group Indian women, the present studies were contemplated to find the least effective dosage of NET from combination pills. Pharmacokinetics of NET were evaluated in a total of twenty women of low socio-economic group taking pills containing NET-acetate (500 micrograms or 1 mg) and ethinyl estradiol (30 or 50 micrograms respectively) on empty stomach. Blood samples were drawn at different time intervals from 0.5 to 24 hr and plasma NET was estimated by a specific radio-immunoassay. In the women taking 1 mg NET-acetate containing pills peak plasma levels ranging from 6.2 to 20.8 ng/ml were observed at 1 hr whereas with 500 micrograms pill they ranged from 2.0 to 6.5 ng/ml and the peak was noted at 4 hr. Pharmacokinetic parameters of NET were more or less comparable between the two pills. The results suggest that pills containing 500 micrograms NET-acetate and 30 micrograms ethinyl estradiol provide adequate levels of NET even in low-socio-economic group women.

PIP: In view of the previous studies that determined that the plasma elimination of norethisterone (NET) from the minipill is faster in low socioeconomic bracket Indian women, the present studies were undertaken to find the least effective dosage of NET from combination pills. Pharmacokinetics of NET were evaluated in a total of 20 low socioeconomic women who were taking pills containing NET-acetate (500 mcg or 1 mg) and ethinyl estradiol (30 or 50 mcg respectively) on empty stomachs. Blood samples were drawn at different time intervals from 0.5-24 hours and plasma NET was estimated by a specific radioimmunoassay. In the women taking 1 mg NET-acetate containing pills peak plasma levels ranging from 6.2-20.8 ng/ml were observed at 1 hour whereas with the 500 mcg pills, they ranged from 2.0-6.5 ng/ml and the peak was noted at 4 hours. Pharmacokinetic parameters of NET were more or less comparable between the 2 pills. The results suggest that pills containing 500 mcg NET-acetate and 30 mcg ethinyl estradiol provide adequate levels of NET even among low socioeconomic women.