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At least 19 recordsLinked to original sources
PubMed1994

Duration of anti-implantation action of the triphenylethylene anti-oestrogen centchroman in adult female rats.

The duration of the anti-implantation action of a single oral post-coital dose (1.25 mg kg-1) of a triphenylethylene anti-oestrogen, centchroman, was determined in adult rats. The effects of centchroman were compared with those of tamoxifen. In rats undergoing delay, centchroman administered orally on day 7 post-coitum prevented the induction of implantation of delayed blastocysts by an implantation inducing dose (1 micrograms per rat, s.c.) of oestrone which was administered earlier than 120 h after centchroman treatment. In tamoxifen (0.2 mg kg-1, orally) pretreated rats, oestrone administered at 144 h or later induced implantation. In cyclic rats treated with centchroman at intervals of 168 h and mated with males of proven fertility, implantation was prevented only when the interval between centchroman treatment and nidatory oestrogen secretion was less than 120 h. None of the females conceived when treated regularly at intervals of 120 h during exposure to fertile males. Discontinuation of treatment resulted in the occurrence of normal implantations in rats that mated 48 h or later after the last dose of centchroman, since in these animals the interval between anti-oestrogen treatment and nidatory oestrogen secretion was greater than 120 h. These findings suggest that the duration of the anti-implantation action of a single oral antifertility dose of centchroman in rats is about 120 h. Recovery of normal blastocysts from rats treated continuously with this dose of centchroman at these intervals suggests lack of significant effect on follicular maturation, ovulation, fertilization, preimplantation development or mating behaviour.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Centchroman: a new non-steroidal oral contraceptive in human milk.

Centchroman, a non-steroidal oral contraceptive drug, was given to 13 nursing mothers comprising two groups. Each participant in group I (n = 8) received a single 30 mg dose, and in group II (n = 5) each participant received a 30 mg twice a week dose for twelve weeks. Simultaneous blood and milk samples were collected and analyzed for the parent drug by high performance liquid chromatography. In the single dose study (group I), the mean +/- peak centchroman concentrations in milk and serum were 78.7 +/- 28.4 and 63.6 +/- 23.6 ng/ml with milk-to-serum (M/S) ratio of 1.4 +/- 0.9. There was no significant increase in centchroman concentrations in milk after multiple dosing (group II). However, serum concentrations reached up to 112.5 ng/ml at 6 h after the 13th dose. Average M/S ratios were insignificantly different at trough (prior to next dose) and at peak (4-6 h after dose) centchroman levels. Additionally, the breast milk and serum centchroman concentrations showed a significant correlation (r = 0.64, P < 0.01), indicating that the amount of centchroman excreted into breast milk is dependent on serum concentrations. The weekly dose (% of the maternal dose) of centchroman ingested by the breast-fed infant at peak maternal serum and milk levels was in the range of 0.4 to 11.5%, assuming a weekly milk uptake of 1.05 l/kg. There was no significant difference in the dose ingested by the infants between the two dosing groups. These levels of centchroman passing into breast milk and subsequent exposure to the infants are unlikely to be of any physiological consequence.

Administration, Oral↗
PubMed1996

Tissue distribution and pharmacokinetics of centchroman. A new nonsteroidal postcoital contraceptive agent and its 7-desmethyl metabolite in female rats after a single oral dose.

This study reports assay methodology, tissue distribution, and the basic pharmacokinetic behavior of centchroman and its 7-desmethyl metabolite [7-desmethyl centchroman (DMC)] after a single 12.5 mg/kg po dose in young female rats. Plasma, liver, lung, spleen, uterus, and adipose tissue were collected at various time intervals up to 14 days after dose. Reversed-phase HPLC, coupled with fluorescence detector, was used for simultaneous determination of centchroman and DMC in biosamples. The drug and metabolite were quantitated up to 2 and 5 ng/ml in plasma and 10 and 20 ng/g in tissues, respectively. The assay method was validated in terms of accuracy, precision, interassay, and intraassay variability, and was found to be reliable and reproducible. Peak centchroman levels in all of the tissues were found between 8-12 hr, whereas DMC peaks appeared between 8 and 24 hr, except that in liver the first peak of 1.2 micrograms/g appeared in the 1-hr sample. Tissue-to-plasma concentration ratios of centchroman were > 200 times in the lung; > 100 times in the spleen, liver, and adipose tissue; and > 40 times in the uterus at maxima in each tissue. Similarly, tissue concentrations of DMC were > 350 times in the lung, > 100 times in the liver and spleen, and > 25 times in the uterus and adipose tissue than in the plasma. High tissue-to-plasma concentration ratios of metabolites than the parent drug are indicative of its greater affinity for tissues. Terminal half-life of the centchroman and DMC in plasma were 24.1 and 36.6 hr, respectively. The mean residence time of centchroman was highest in the liver (78.4 hr), followed by the uterus (72.7 hr), adipose tissue (47.5 hr), lung (46 hr), spleen (44.1 hr), and plasma (37.7 hr). The mean residence time of DMC was also highest in the liver (133.7 hr), followed by the uterus (122 hr), adipose tissue (85.2 hr), lung (62.6 hr), spleen (62.6 hr), and plasma (48.2 hr).

Administration, Oral↗
PubMed1994

An X-ray crystallographic study of the nonsteroidal contraceptive agent centchroman.

We have determined an X-ray crystal structure for the N-methyl iodide derivative of the nonsteroidal contraceptive centchroman. The pendant aromatic substituents on C-3 and C-4 of the chroman system are nearly perpendicular to the plane of the chroman system, an orientation expected in such a chroman, but perturbed to some degree by the gem dimethyl substituents at C-2. Structural superposition with other nonsteroidal antiestrogens, tamoxifen and nafoxidine, shows a similar disposition of the tertiary amine side chains responsible for antagonist activity. The aryl rings also show good superposition, but in contrast to tamoxifen and nafoxidine, which have the potential for ring double bond conjugation, the centchroman aryl rings show a larger dihedral twist. While different superpositions between the enantiomers of centchroman and the bioactive enantiomer of estradiol (d-estradiol, 8 beta,9 alpha,13 beta,14 alpha,17 beta) are possible, when the chroman ring system is positioned over the AB rings of estradiol, then (3R,4R)-centchroman makes the best fit. The aryl substituents in both enantiomers make comparable overlays with the steroidal skeleton, but the axial methyl group at C-2 in (3R,4R)-centchroman is directed downward along the C-7 alpha axis of estradiol, a site where many substituents are known to be well tolerated by the estrogen receptor, while in the 3S,4S-enantiomer, this methyl group is projected upward. Thus, we suggest that the bioactive l-enantiomer of centchroman will have the 3R,4R absolute configuration.

Centchroman↗
PubMed1995

The bone-specific estrogen centchroman inhibits osteoclastic bone resorption in vitro.

There is considerable interest in identifying bone-specific estrogen-like compounds with beneficial activities on bone and the cardiovascular system, but lacking side effects on the reproductive system. Two such compounds are currently under clinical investigation -raloxifene (Lilly) and centchroman (Novo-Nordisk). There is evidence suggesting that 17 beta-estradiol can inhibit osteoclastic bone resorption although this is somewhat controversial. Therefore, we examined the effect of centchroman and raloxifene, as well as 17 beta-estradiol, in the in vitro bone slice assay, where the direct effect of compounds on osteoclast activity can be assessed. Centchroman (0.001 - 1 microM) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 microM (p = 0.007) with an IC50 = 0.1 microM, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17 beta-estradiol (0.0001 - 1 microM) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 microM, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 microM) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17 beta-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED50 approximately 1 mg/kg in animal models) is a potent inhibitor of osteoclastic bone resorption in vitro, suggesting that bone-specific estrogen-like molecules may have different mechanisms of action.

Animals↗
PubMed1984

Ultrastructural effects of the nonsteroidal contraceptive centchroman on rat uterine luminal epithelium in early pregnancy.

Centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy) -phenyl-7-methoxychroman), a nonsteroidal contraceptive developed by the Central Drug Research Institute, Lucknow, India, was administered orally (1.25 mg/kg) to rats in a state of experimentally delayed implantation both during the progesterone treatment (preattachment stage) and in conjunction with the addition of estradiol (attachment stage). When given during preattachment, centchroman did not change the characteristic ultrastructure of the uterine epithelium significantly, except that there was an increase in the size and number of secondary lysosomes. Thus, no definite estrogenic or antiprogestational potency of centchroman was observed in this test system. However, when administered simultaneously with, before, or after estrogen during attachment, centchroman both abolished the estradiol-induced attachment reaction and produced or potentiated some changes of an estrogen type. Thus, no typical antiestrogen action but the sign of an estrogen action was observed in this test system. Further, the drug also produced certain specific changes in the lysosomal system of the epithelial cells during attachment. It is suggested that, in addition to some estrogenic effects, centchroman also possesses specific cellular effects, probably of a nonhormonal nature.

Animals↗
PubMed1973

Anti-inflammatory and some other pharmacological effects of 3,4-trans-2,2-dimethyl-3-phenyl-4-(p-(beta-pyrrolidinoethoxy)-phenyl)-7-methoxy-chroman (Centchroman).

1. Anti-inflammatory, analgesic, antipyretic and other pharmacological activities of a new chroman derivative, Centchroman, have been described.2. Centchroman was found to possess significant anti-inflammatory action in the carrageenin-induced oedema test in mice and rats. It inhibited granuloma formation in the cotton pellet test. The anti-arthritic activity was also evident in formaldehyde-induced arthritis and adjuvant-induced arthritis in rats.3. Centchroman had a lower ulcerogenic index than phenylbutazone.4. The mechanism of the anti-inflammatory action of Centchroman seemed to be independent of endogenous adrenocortical hormones or of its weak oestrogenic activity.5. Centchroman antagonized phenylquinone writhing and bradykinin-induced bronchospasm but was devoid of any antipyretic activity.

Adrenal Glands↗
PubMed1986

Prostanoid mediated effects of centchroman, a non-steroidal oral contraceptive.

The effect of centchroman, a non-steroidal oral contraceptive, has been studied on platelet aggregation and on the products of arachidonate metabolism. Centchroman inhibited platelet aggregation in vitro and ex vivo after acute as well as chronic treatment for one year in laboratory animals. It did not affect aggregation of platelets in women taking centchroman for one year. It is an inhibitor of platelet cyclooxygenase as indicated by the inhibition of malonaldehyde and thromboxane B2 but has no effect on vascular cyclooxygenase activity ex vivo or at low concentration in vitro. Thus, centchroman is a safe antifertility agent without risk of thrombotic episodes associated with hormonal oral contraceptives.

Adenosine Diphosphate↗
PubMed1985

Effect of long-term centchroman treatment on plasma steroid and peptide hormones in female rhesus monkeys (Macaca mulatta).

Effect of weekly oral administration of Centchroman (3,4-trans-2, 2-dimethyl-3-phenyl-4-(p-(beta-pyrrolidinoethoxy)-phenyl)-7-met hoxychroman) at 1 and 2.5 mg/kg for 12 months on plasma estradiol, progesterone, luteinizing hormone and follicle stimulating hormone of female rhesus monkeys was studied. Centchroman administration at both doses did not disturb the menstrual pattern of rhesus monkeys except for a prolongation of the first treatment cycle. The subsequent cycles were of normal duration. The general pattern of plasma estradiol, progesterone, luteinizing hormone and follicle stimulating hormone was not affected by Centchroman treatment. The basal and peak levels were similar in pretreatment, control and treatment cycles. The results clearly indicate that Centchroman treatment up to 1 year does not affect the hypothalamo-pituitary-ovarian axis in female rhesus monkeys.

Administration, Oral↗
PubMed1989

High performance liquid chromatographic (HPLC) determination of centchroman in human serum and application to single-dose pharmacokinetics.

A simple and sensitive (2 ng/ml) HPLC method with fluorescence detection has been developed to measure serum concentrations of centchroman, a new nonsteroidal antifertility agent. The method was sufficiently sensitive to follow the drug over 21 days in human volunteers. Pharmacokinetic parameters of centchroman were determined after a single oral dose of 60 mg (2 x 30-mg tablets) in two healthy female volunteers. Centchroman is slowly eliminated from serum, showing a biexponential disappearance curve from serum. The terminal half-life of centchroman in the two volunteers was 168 and 175 hr, respectively.

Adult↗
PubMed1996

Characterization of centchroman binding protein in plasma of rhesus monkey (Macaca mulatta).

Centchroman, a nonsteroidal antifertility agent was studied for its binding to monkey (Macaca mulatta) plasma proteins using charcoal adsorption and electrophoretic techniques. 14C-centchroman showed a low affinity binding and did not compete for 3H-cortisol or 3H-DHT binding sites in plasma. 14C-centchroman binding protein was heat stable in nature and showed the electrophoretic pattern similar to that of albumin (Rf 0.70). Thus centchroman binds to albumin in monkey plasma which can be suggested as carrier protein for this contraceptive agent.

Animals↗
PubMed1986

Effect of centchroman on tubal transport and preimplantation embryonic development in rats.

A single oral administration of centchroman (1.25 mg/kg) to adult female rats within 24 h of mating induced slight acceleration in the rate of transport of embryos through the oviducts. The compound did not seem to produce any deleterious effect on preimplantation embryonic development since well organized and apparently normal embryos were collected from the genital tract up to Day 12 of pregnancy. The recovery rate of embryos from centchroman-treated rats was, however, significantly reduced after Day 4 of pregnancy. There was some stimulation in the rate of cleavage of embryos and morula to blastocyst transformation, but retardation in the shedding of the zona pellucida. The rate of blastocyst formation was not altered when 6-8-cell embryos collected from the oviducts of control rats were transferred to the uteri of control or centchroman-treated females. A delay in zona shedding was observed in the centchroman-treated recipients.

Animals↗
PubMedDate not supplied

Effect of centchroman on the genital organs of the offspring of rats when administered during lactation or during the neonatal period: a comparative study with ethynylestradiol and diethylstilbestrol.

Lactating rats were treated with centchroman (1.25 mg/kg body wt. p.o.) or ethynylestradiol (100 micrograms/kg p.o.) daily from day 1 of parturition for 21 days and their offspring were autopsied at 60, 90 and 120 days of age. In the offspring nursed by centchroman treated mothers there was no change in ovarian weight. There was a reduction in their uterine weight; while the luminal epithelium presented a stimulated state, the stroma showed immature state in its histological features. The ovarian and uterine weights and their histology in the offspring of ethynylestradiol treated mothers showed no change. The male offspring of both the groups of rats showed an increase in the weight of genital organs and testis histology presented typical adult features. When centchroman was injected s.c. on 5th postnatal day to female rats (500 micrograms/rat), the ovary remained normal but the uterus revealed estrogen deficient state when they were 60 or 90 days old. Neonatal female rats injected with diethylstilbestrol (10 micrograms/rat) on day 5 showed normal ovary while uterus presented features typical of estrogenic stimulation with small areas of luminal epithelium showing squamous metaplastic changes. The results are discussed comparing the centchroman effects with the reported findings in rats treated with steroidal and triphenylethylene estrogenic compounds during lactation or the neonatal period.

Age Factors↗
PubMedDate not supplied

Mode of action of centchroman at vaginal and ovarian level in immature rats.

Centchroman studied at various doses did not cause ovulation in immature rats as judged by morphological, histological and biochemical parameters whereas, 20 mg/kh dose caused early opening of vagina and cornification of the vaginal epithelial cells. However, no ovulation was detected by this regimen. No stimulatory effect was observed in the glycogen and cholesterol content in the ovaries of Centchroman treated rats. The effects on vagina persisted even in ovariectomised immature rats administered with Centchroman. The mode of various doses of Centchroman in immature rats as judged morphologically, histologically and biochemically has been discussed.

Animals↗
PubMed1984

Binding of centchroman--a nonsteroidal antifertility agent to human plasma proteins.

Centchroman, a non-steroidal antifertility agent showed a low affinity (Kd = 13.19 X 10(-6) M) and nonsaturable binding to human plasma. Centchroman did not compete either with sex hormone binding globulin or corticosteroid binding globulin. Polyacrylamide gel electrophoresis and temperature dependent binding characteristics revealed that the protein responsible for centchroman binding to human plasma resembles albumin.

Benzopyrans↗
PubMed1985

Effect of long-term centchroman treatment on some estrogen-sensitive biochemical constituents in the genital organs of female rhesus monkeys (Macaca mulatta).

Effect of long-term Centchroman (3,4,-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy)-phe nyl)-7-methoxy chroman) treatment on some estrogen-sensitive biochemical parameters in the genital organs of female rhesus monkey was studied. Centchroman treatment did not demonstrate any consistent pattern of stimulation or inhibition in any of the estrogen-sensitive biochemical parameters. However, glycogen recorded a gradual decline in uterus, cervix and vagina. The results thus indicate that Centchroman evoked a mixed response probably due to manifestations of both estrogenic and antiestrogenic properties.

Alkaline Phosphatase↗
PubMed1990

Effects of centchroman, a synthetic estrogen antagonist on the fertility of female hamsters.

Centchroman (3, 4-trans-2, 2-dimethyl-3-phenyl-4-p-beta-pyrrolidinoethoxy-phenyl-7-methoxy-chroman) , a non-steroidal, estrogen antagonist, injected subcutaneously (2 mg/kg body wt) on days 1, 2 and 3 post-coitum in hamsters, prevented implantation in 70% of the animals. A significant decrease in the circulating levels of estradiol and progesterone was observed on day 4 post-coitum as compared to control animals following the treatment of centchroman. The activities of various lysosomal enzymes were also found diminished in the treated animals. This study shows that centchroman may act as an anti-implantation agent in hamsters indicating that estrogen plays a key role during the process of ovum implantation in this species.

Animals↗
PubMed1995

Pharmacokinetics of centchroman in healthy female subjects after oral administration.

The pharmacokinetics of centchroman, a non-steroidal antifertility agent, were assessed in serum of eleven healthy female subjects after a single 30 mg oral dose. Maximum serum concentration (Cmax) of 55.53 (s.d., 15.45) microgram/L was attained at 5.18 (s.d., 1.78) h after oral administration. The concentration-time profile was best described by a two-compartment open model with bi-exponential disposition functions. The mean terminal elimination half-life (t1/2) was 165 (s.d., 49) h with a clearance of 6.17 (s.d., 1.67) L/h and volume of distribution of 1420 (s.d., 478) L. Comparison of the pharmacokinetic parameters of this study with those obtained after a single 60 mg oral dose did not show statistically significant differences in the rate of absorption, distribution and elimination. The Cmax and AUC0-infinity were dose-dependent. Thus, the absorption and disposition of centchroman are of first-order, reproducible and dose-dependent.

Administration, Oral↗