Biomedical subjects
Publications and source records attributed to B N Saxena.
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OBJECTIVE: Levonorgestrel (LNG), a low-dose progestin, does not affect lactation but like all drugs taken by breastfeeding mothers, it can be transferred to the infant via breast milk. How infants of various ages cope with this unwanted maternal drug would help in deciding when to recommend this method of contraception to breastfeeding mothers. METHODS: The study was conducted in 30 exclusively breastfeeding mothers and their 4-, 12- and 24-week-old infants. The mothers daily received 30 micrograms LNG over a five-week period, thus exposing their infants to maternal LNG for that period. RESULTS: Four-week-old infants could neither absorb nor metabolize LNG efficiently. Twelve-week-old infants could metabolize LNG more efficiently than absorb. Twenty-four-week-old infants could do both efficiently. CONCLUSION: It is safe to introduce LNG to breastfeeding mothers at 12 weeks postpartum.
Handigodu disease is a new syndrome of familial spondyloepi(meta)physeal dysplasia. It is inherited as an autosomal dominant trait. The disease is prevalent in a localised area of South India. On the basis of detailed clinical, anthropometric and radiological investigations of 234 affected individuals, it has been observed that different clinical presentations reflect variation in the severity of the disease. All of them could be explained as being caused by defective development of bones as a result of monogenic disorder.
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A study was undertaken to compare the effects of exposure to the toxic gas in pregnant women in Bhopal with pregnant women in a similar, unexposed area. A high incidence of spontaneous abortions (24.2%) in the pregnant women exposed to the toxic gas was observed as compared to those in the control area (5.6%). Other indices of adverse reproductive outcome, such as the rate of still birth and congenital malformation were not found to be different. The perinatal and neonatal mortalities were significantly higher in the affected area (6.9 and 6.1% respectively), as compared to the control area (5.0 and 4.5% respectively).
A study on the bioenvironmental control of malaria was launched in Bizadandi block (Mandla district, M.P.) in May 1986. Besides intervention, using environmental management methods and larvivorous fishes, weekly surveillance and chloroquine administration at 25 mg/kg body weight was practiced. Studies during 1987 revealed that a large number of P. falciparum cases did not respond to the standard anti-malarial treatment. Therefore, systematic 28 day in vivo studies were taken up on the follow-up of P. falciparum cases after administration of 3 day course of 25 mg/kg body weight as per the WHO procedure. Results revealed a high proportion of drug resistant cases belonging to RI (237), RII and RIII (182) category. In vivo studies on the sensitivity to metakelfin showed that some cases were resistant to this drug. There is an urgent need to eradicate this focus before it starts spreading to other areas.
The transfer of levonorgestrel (LNG) from the maternal plasma via breast milk to the infant was studied in 38 fully lactating and breast-feeding women at 4-6 weeks postpartum, for a duration of 28 days. These volunteers were provided with LNG contraceptive treatment delivered through three, different routes of drug delivery system: (i) intrauterine devices impregnated with LNG (LNG-IUD); (ii) subdermal implant (Norplant (R)-2); and (iii) minipills (LNG 30 micrograms daily). On the first day after either the LNG-IUD (n = 14 women) or Norplant (R)-2 (n = 14 women) insertion, the maternal blood and breast milk samples were collected at 2, 4 and 8 hourly intervals. This was followed by daily collection of these samples as well as infant's blood from days 2 to 4 and thereafter on days 7, 14 and 28. For infant's blood samples from LNG minipill users (n = 10 women), only a single 4-hour sample was collected on the first day and no samples were collected on days 3 and 4. The rest of the schedule for collection of maternal blood and breast milk as well as infant's blood samples were the same in minipill users as for the other two treatment groups. The study revealed a lower LNG percentage transfer from maternal sera to breast milk--11.8 +/- 2, 7 +/- 2 and 8 +/- 1 and relatively higher percentage LNG transfer from breast milk to infant's sera--75 +/- 17, 68 +/- 20 and 32 +/- 3, in LNG-IUD, Norplant (R)-2 and minipill users, respectively. Therefore, LNG contraceptive steroid is transferred into the infant's circulation, the biological significance of which remains to be established.
A single tablet of either of the three different types of oral contraceptive preparations, viz. "Gynovlar" containing 3000 micrograms norethisterone (NET) and 50 micrograms ethinyl estradiol (EE2) or "Ovral" containing 250 micrograms levonorgestrel (LNG) and 50 micrograms EE2, or a daily progestogen only type--"Minipill" containing 30 micrograms of LNG only, were administered to 40 normal lactating women on a random basis. The sampling schedule in all the three body fluids, i.e. the maternal sera, breast milk and the infant's sera, was kept in such a manner that the peak levels of the contraceptive steroids would be expected to be present in these fluids. The results of this study indicate that the transfer ratio of LNG or NET from the maternal sera to her breast milk was approximately 10% (6-34%) for Gynovlar, 9% (5-18%) for Ovral and 6% (2-34%) for Minipill. However, it was interesting to observe that whereas the transfer ratio of NET or LNG from breast milk to infant's sera was similar for combination pills--8% (3-23%) for Gynovlar and 12% (3-42%) for Ovral, it was significantly higher for progestogen only Minipills--38% (13-92%) for LNG. The precise reason for the higher transfer ratio of LNG from breast milk to infant's serum in Minipill users cannot be explained.
In a randomized clinical study, contraceptive efficacy and bleeding patterns were studied in a group of healthy, regularly menstruating, non-lactating women (n = 84) using two 4.4 cm covered silastic rods containing levonorgestrel, Norplant(R)-2, and compared with another group of women (n = 88) using six 3.4 cm capsules also containing levonorgestrel, Norplant(R). The silastic rods or capsules were placed subdermally in the medial aspect of the upper arm. No method failure was reported up to 24 months of use in this study with either of the device. The bleeding pattern was also similar for both devices as indicated by average episode length, number of bleeding runs and number of spotting days. The continuation rates with both devices were over 80 per 100 users at the end of 12 months and over 65 per 100 users at the end of 24 months. Discontinuations due to expulsion of the device, bleeding problems or personal reasons were few and similar for both devices. The results suggest that silastic-covered rods, Norplant(R)-2, which are comparatively easier to insert and remove and have similar clinical effect, could replace capsules, Norplant(R), as a long-term reversible subdermal contraceptive.
A study was conducted to compare the biological activity of the estrogenic component of the endogenous steroids in breast milk samples collected during various phases of lactation with those milk samples collected from women who were on estrogen therapy. The estrogenic biological activity in the milk sample was assessed by the immature mouse uterine weight gain assay. Milk samples collected during postpartum period from six different study groups, viz., control colostrum of 1-3 days and 4-6 days, transitional milk (10-20 days) and mature milk (1-3 months) were compared with colostrum and mature milk of women treated with Lynoral (ethinyl estradiol 0.1 mg) three times a day for three days. Estrogenic activity was observed only in animals injected with milk extracts of colostrum samples from both control and Lynoral-treated women; however, they were not significantly different from each other. Therefore it is not the exogenous estrogens, but the endogenous estrogen present in large quantities in the colostrum that is responsible for the biological activity.
Pharmacodynamic effect of levonorgestrel (LNG) present in small amounts in infant's circulation has not yet been studied adequately. In our present study, nine women were taking oral minipills (LNG 30 micrograms daily) and 10 were using subdermal implants, Norplant(R)-2, during early postpartum period from four weeks to 15 weeks. These were healthy lactating women in age group 20 to 35 yrs, who had full-term normal delivery of male infants. Daily 4-hour urine samples (from 8 AM to 12 noon) were collected from four weeks onwards to 15 weeks for estimations by radioimmunoassays of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) levels. No significant differences (P greater than 0.05) were found between geometric means of the total area under curve at weekly intervals for FSH, LH and T hormones between the male infants from control group (n=10) when compared with oral minipill or Norplant(R)-2 users. These results are reassuring for future sexual growth and development of children who are exposed to contraceptive steroids during their infancy; however, they do require further confirmation by long-term epidemiological studies incorporating monitoring and surveillance of such children.
The potential for antifertility effect of two bioabsorable pellets, one containing norethisterone (NET) and the other containing levonorgestrel (LNG) fused with cholesterol, was studied in a group of healthy, menstruating but sterilised women. The pellets weighed approximately 30 mg and contain 85% steroid and 15% cholesterol. A single NET pellet was inserted in 4 subjects, out of which 2 were also studied for steroid pattern in blood. After reaching peak levels within 48 hours, the plasma NET levels declined gradually within a fortnight's time, and thereafter, ranged between 200 to 700 mg/ml up to 90 days post-insertion. After this period, occassional spurts of NET release were seen. Bleeding pattern was studied in 37 cycles; mid-luteal progesterone (P) estimation was done in 16 cycles, mid-cycle cervical mucus was studied in 27 cycles and post-coital test (PCT) in 7 cycles. Cycle length with pellet insertion was of 25 to 37 days duration except one cycle of 55 days duration. All cycles studied during the treatment were ovulatory (P greater than 5 ng/ml) and no consistent effect was observed on cervical mucus as well as on PCT. Thus, a single NET pellet does not seem to have a reliable contraceptive potential. A single LNG pellet was inserted in 8 subjects, and steroid patterns were studied in 6 women. Peak levels of LNG were reached within 24 hours of pellet insertion and the levels fell gradually in a week's time. Thereafter, LNG levels ranged between 100-400 pg/ml up to 8 months. In contrast to the observation with NET pellets, only one subject showed frequent spurts of LNG release until the 4th month of treatment. Bleeding pattern was studied in 90 cycles, P was estimated in 52 cycles, mid-cycle cervical mucus studied in 55 cycles and PCT done in 26 cycles. Breakthrough bleeding (BTB) occurred on 15 occasions, 11 episodes being in 2 subjects. Cycle length varied between 21 to 42 days. The LNG pellet did not exert a consistent effect either on ovulation inhibition or cervical mucus or PCT. In their present form, therefore, a single LNG pellet also does not appear to have a reliable contraceptive effect.
Contraceptive vaginal rings (CVRs) impregnated with a combination of estradiol and d-norgestrel were studied in 39 women. The rings were inserted as three weeks "in" and one week "out" schedule to allow withdrawal bleeding. Ovulation was inhibited in all cycles and promptly resumed on completion of the treatment cycles. Bleeding control was excellent. Incidence of breakthrough bleeding was 2.11 per cent in 273 cycles studied, with 89 per cent of the cycles within the acceptable range (25 - 35 days). Levels of estradiol after an initial rise were maintained between 50-100 pg/ml and, d-norgestrel levels were relatively constant between 1.8-3 ng/ml during the period while the ring remained in situ. Clinical acceptance was good. The main problem encountered was of spontaneous expulsion of the ring in the toilet, which might be due to the squatting toilet habits of Indian women and laxity of vaginal wall.
The release of contraceptive steroids through different drug delivery systems into serum and breast milk was investigated in a group of lactating women. Four women in each group were taking either a low dosage progestogen compound like norethisterone (NET) 350 micrograms or d-norgestrel (d-Ng) 50 micrograms alone or low dosage combination pills containing NET 1 mg or d-Ng 150 micrograms with 30 micrograms ethinyl estradiol (EE2) or a biodegradable implant containing 25 mg NET or d-Ng. Peak levels in plasma and milk were seen in oral contraceptive users around 2 hours. Of the two low dosage progestogen compounds, d-Ng was below the detection limit in milk within 4 hours whereas NET was still detectable at the 24-hour interval. In contrast to this, because of the larger quantity of steroids in the combination pills, the NET/d-Ng levels in serum as well as in milk were high throughout the 24-hour period. With the subdermal route because of the sustained low release of the drug from the biodegradable implants, the levels in milk were below the detection limit within a day with d-Ng and within a week with NET.
Low-dose combination contraceptive (containing norethisterone acetate 1 mg and ethinyl estradiol 30 micrograms) was administered to women receiving concurrent therapy with either Rifampicin or "triple" antitubercular treatment consisting of paraaminosalicylic acid (PAS), isonicotinic acid hydrazide (INH) and streptomycin. Plasma levels of norethisterone (NET) and ethinyl estradiol (EE), PAS and INH were measured and the area under curve (AUC) was calculated for NET and EE. Rifampicin treatment (9 women) caused a statistically significant reduction of the plasma NET levels as well as the AUC of NET. In this group of women, though a trend for reduction in EE levels was observed in individual subjects, it was not statistically significant. Out of 7 regularly menstruating women on Rifampicin therapy, 2 showed a premenstrual rise of plasma progesterone (P) levels (> 4 ng/ml) suggesting an ovulatory cycle and 3 experienced menstrual irregularities. In contrast, plasma levels of NET and EE as well as their AUCs were not altered in 8 women receiving "triple" antitubercular therapy. Only one woman out of 8, had menstrual irregularity and all women had P levels in the anovulatory range. Furthermore, oral contraceptive treatment did not alter the plasma levels of PAS and INH.
Plasma levels of norethisterone (NET), ethinyl estradiol (EE), Ampicillin or Metronidazole were estimated in 16 women, who were taking low-dose oral combination contraceptive pills (containing norethisterone acetate 1 mg and ethinyl estradiol 30 microgram) and in whom concurrently, either Ampicillin (6 women) or Metronidazole therapy (10 women) was given. Neither Ampicillin nor Metronidazole therapy altered the 'peak' or 24-hour plasma levels and area under the curve, for NET and EE. Furthermore, oral contraceptive treatment did not alter the 'peak' levels of Ampicillin or Metronidazole. Progesterone (P) levels were in the anovulatory range in all Ampicillin treated cycles. However, in Metronidazole treated group, two out of 10 women showed a P rise of more than 4 ng/ml. The study was expanded to include another group of 15 women treated with Metronidazole, where only one women showed a P rise of more than 4 ng/ml. The occurrence of 'escape ovulation' as suggested by P rise of more than 4 ng/ml in three out of 25 Metronidazole treated women is either a chance incidence due to a different pharmacological response in them, or most probably due to the default in the regular intake of pills in these women. This is supported by the observation that one out of three women showing a P rise (greater than 4 ng/ml( during concurrent Metronidazole therapy, also showed ovulatory P values in oral contraceptive-only treated cycles. Furthermore, in the control group also, one out of 10 women had ovulatory P levels (greater than 4 ng/ml) in oral contraceptive-only treated cycles.
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