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.

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.

Effect of early childhood undernutrition and child labour on growth and adult nutritional status of rural Indian boys around Hyderabad.

A longitudinal study of rural Hyderabad children has been in progress from 1965. About 700 boys who are under follow-up are now in late adolescence and young adult stage. Of them, 410 had completed linear growth by the 1983-84 annual round. Severe growth retardation was observed among one-sixth at their 5th year of life. The severely undernourished group grew up as the shortest and lightest young adults. One-fifth of the boys under study worked for wages in their childhood. Their work experience ranged from 4 to 8 years at 14 years of age (child labourers or working children). Growth and development of working children was compared with students, who were matched for nutritional status at age 5. Working children lost considerable ground and suffered significant growth deficits.

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.

Effect of fluoride, silicon, and magnesium on the mineralizing capacity of an inorganic medium and stone formers urine tested by a modified in vitro method.

An in vitro mineralizing system using bovine achilles tendon developed by Thomas and Tomita (3) was modified to enable quantitative evaluation of mineralization. Using this modified method, the potential effect of various ions on the rate of calcium uptake from inorganic mineralization medium was measured. Of the elements tested, only silicon and fluoride accelerated calcium uptake, whereas magnesium had an inhibitory effect. The simultaneous presence of silicon and fluoride in the medium had a synergistic action on calcium uptake. Urine of stone formers showed high propensity to mineralize tendon collagen, but not the urine of non-stone formers. Total content, and concentration of silicon in urine of stone formers was significantly higher than in normal urine. Addition of silicon to non-stone formers urine enhanced its capacity to mineralize collagen in vitro. These results strongly suggest the possible involvement of silicon and fluoride in the genesis of urinary calculi in man.

Pharmacokinetics of levonorgestrel in Indian women.

A low dose combination pill containing levonorgestrel 150 micrograms and ethynylestradiol 50 micrograms was administered orally to 13 women. Based on their anthropometric index they were classed as well-nourished (Group A) or undernourished (Group B). Plasma levels of levonorgestrel at various intervals after dosing were analysed by a specific radioimmunoassay and its pharmacokinetic parameters were computed. Peak plasma levels in both groups occurred within 2 h and the absorption half-lives were also similar. The decline in plasma levonorgestrel showed a tri-exponential decline in all Group A women, whereas it was biphasic in most of Group B. The pi t1/2 was lower in Group A women and the alpha-phase was found to be negligible in Group B. A significant positive correlation between elimination half-life (beta t1/2) and some of the anthropometric indices suggests a possible role of nutritional status in the metabolic handling of levonorgestrel.

Long-term nitrogen balance in preschool children fed the safe level of protein from a cereal-legume-milk diet and adequate energy.

A long-term N balance study was carried out in five preschool children 3-4 years of age fed a cereal-legume-milk diet providing 1.75 g protein and 100 kcal (418 kJ) energy/kg body weight. This level of protein was found to be safe for preschool children in an earlier short-term N balance study. Continuous N balance was determined for 70 d in three subjects and 45 d in two subjects. All the subjects were found to be in steady positive N balance throughout the experimental period, the mean daily N retention varying between 54.5 and 87.5 mg/d. All the children increased their body weight steadily over the experimental period. No tendency of N balance to decrease with time was observed. It is concluded that the safe level of protein for preschool children estimated from a short-term N balance study is quite adequate when tested by a long-term feeding trial.

Effects of iron deficiency on serotonin uptake in vitro by rat brain synaptic vesicles.

The effects of moderate and severe degrees of iron deficiency on brain and liver nonhaem iron levels and 5-hydroxytryptamine (serotonin; 5-HT) uptake by synaptic vesicles in vitro were investigated in experimental rats. Data obtained suggested that in both moderate and severe forms of iron deficiency, 5-HT uptake by brain synaptic vesicles is decreased and is accompanied by a reduction in brain and liver nonhaem iron levels. On repletion with iron for 4 weeks, the deficient group of rats showed a normalisation of 5-HT uptake by synaptic vesicles and liver nonhaem iron content, whereas the brain nonhaem iron concentration still showed a significant deficit. The data thus suggest that changes in the uptake of 5-HT by brain synaptic vesicles that accompany iron depletion and repletion are more rapid than changes in the total nonhaem iron concentration in the brain. The observation that 5-HT uptake by brain synaptic vesicles is decreased in iron deficiency suggests a probable role for iron in 5-HT storage in rat brain.

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.

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.

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.

Adolescent growth spurt among rural Indian boys in relation to their nutritional status in early childhood.

The growth pattern of 677 rural Hyderabad boys aged between 13 and 18 years was studied over a year (1977-78) to obtain annual increments. These boys had earlier been studied over a four-year period (1965-69). Height for age at 5 years in relation to Boston standards was used to classify these subjects into four nutritional categories. The group that had experienced severe growth retardation in early life achieved a peak height velocity (6.9 cm/yr) similar to that of British boys (7.3 cm/yr), though the event was postponed by 2 years--from 14 years to 16 years. Height growth from 5 years to 17.5 years (62 cm) was comparable with that of Western boys (63 to 66 cm). However, increase in weight was lower (29 kg) than in Western boys (44 to 48 kg). Height deficits observed at age 5 continued into adolescence and weight deficits increased. As a consequence, the group that was shortest at age 5 continued to be shorter and lighter at 17-18 years of age.

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.