Swaran Nityanand

Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii☆

Coleus spp. have been used in Aurvedic medicine for heart diseases, spasmodic pain, painful micturition and convulsions. The pharmacological properties of coleonol, a diterpene, isolated from Coleus forskohlii were investigated. Its predominant effect is to lower the blood pressure of anaesthetised cat and rat as well as of the spontaneously hypertensive rat due to relaxation of the vascular smooth muscle. In small doses it has a positive inotropic effect on isolated rabbit heart as well as on cat heart in vivo. Coleonol also exhibits nonspecific spasmolytic activity on smooth muscle of the gastrointestinal tract in various species but not on bronchial musculature of guinea pig. Large doses of coleonol have a depressant action on the central nervous system. These results provide the rationale for the use of this plant in Aurvedic medicine.

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 × 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.

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.

Pharmacological studies on 2-(2-(4-(3-methylphenyl)-1-piperazinyl)ethyl) quinoline (centhaquin). I. hypotensive activity

Hypotensive activity of 2-(2-(4-(3-methylphenyl)-1-piperazinyl)ethyl) quinoline (compound 71/73; centhaquin) was studied in cat and rat. The compound lowered the blood pressure and reduced the heart rate of anaesthetized and unanaesthetized (decerebrate) cat in a dose-dependent manner (0.01-1.0 mg/kg i.v. or 1.0-2.5 mg/kg intraduodenally). The hypotensive effect was insignificant in spinal transected cat but more marked in deafferented and vagotomized animals. Localization of centhaquin to brain by intravertebral arterial injection (5-10 micrograms) or by topical application to the exposed ventral surface of medulla or floor of the fourth ventricle caused hypotension and bradycardia as well as reduced the excitability of the vasomotor loci. It was also effective in rats after single as well as multiple dosing. The compound seems to act centrally to reduce the blood pressure.

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.

Antihypertensive and central nervous system depressant properties of 3-(γ-p-fluorobenzoyl propyl) 2,3,4,4a,5,6-hexahydro-1(H)-pyrazino(1,2-a) quinoline hydrochloride (compound 69-183, centpyraquin)

Centpyraquin (3-(γ-p-fluorobenzyl propyl) 2,3,4,4a,5,6-hexahydro-1(H)-pyrazino (1,2-a) quinoline hydrochloride) zeigte hypotensive Aktivität bei narkotisierten wie auch bei wachen Katzen. Es senkt auch den Blutdruck bei Ratten mit nephrogenem Hochdurck. Die Hypotension scheint auf einem peripheren Mechanismus zu beruhen.

Pharmacokinetics of Centchroman in Nursing Women and Passage into Breast Milk

SummaryThe pharmacokinetics of centchroman (ormeloxifene), a nonsteroidal antifertility agent, was determined in 4 nursing mothers in the postpartum period after a single 30mg oral dose of the drug. The concentration-time profile of centchroman in serum and milk were not parallel. The milk/serum (M/S) area under the curve ratio of centchroman was 1.47 ± 0.56. Individual mean M/S concentration ratios of centchroman showed significant interindividual variation (range 0.38 to 1.94). A comparison of pharmacokinetic parameters in the nursing women with those reported previously in nonlactating women showed an insignificant difference; time to maximum concentration occurred later in milk than in maternal serum. The average infant dose of centchroman via breast milk, assuming a weekly milk intake of 1.05 L/kg and 100% absorption, would be 7.43 ± 3.18% per week of the maternal dose.

Pharmacokinetic Interaction of Tetracycline with Centchroman in Healthy Female Volunteers

AbstractObjective: We aimed to investigate the effect of tetracycline coadministration, with and without lactic acid bacillus spores supplementation, on the pharmacokinetics of centchroman, a nonsteroidal oral contraceptive, in healthy female volunteers. Participants and methods: The study was a single-centre, single-blinded, randomised, parallel treatment study in healthy female subjects of reproductive age randomised to two groups (11 subjects in each group). On day 1, subjects were given either a single oral dose of centchroman 30mg with tetracycline 250mg (group A) or a single dose of centchroman 30mg, tetracycline 250mg and one tablet containing 60 million lactic acid bacillus spores (group B). Tetracycline (250mg three times daily) and lactic acid bacillus spores (one tablet three times daily) were continued for 3 days. Serial blood samples were collected and analysed by high performance liquid chromatography. The pharmacokinetic parameters were compared with the control data reported previously from this laboratory. Results: Coadministration of tetracycline yielded significantly higher maximum plasma concentrations (Cmax) [35%] and a shorter time to reach Cmax (tmax) values for centchroman (42%) than those obtained in the control group of females (p < 0.05). Inclusion of lactic acid bacillus spores in the regimen resulted in similar effects with increased Cmax (47%) and area under the concentration-time curve from time zero to infinity (34%) of centchroman (p < 0.05) with a significant decrease in tmax. Other parameters such as half-life, apparent clearance, apparent volume of distribution and mean residence time of centchroman were not affected by either of the treatments. Conclusions: The apparent effects of either of the regimens on centchroman pharmacokinetics seem to be of little clinical relevance in terms of increased rate or extent of availability. It can be concluded that this tetracycline-containing regimen is unlikely to alter the contraceptive efficacy of centchroman in humans.

Simultaneous determination of centbutindole and its hydroxy metabolite in serum by high-performance liquid chromatography☆

A high-performance liquid chromatographic assay has been developed and validated for the determination of centbutindole and its hydroxy metabolite in serum. The method involves extraction of serum samples with diethyl ether at pH greater than 8, back-extraction into 0.5 M hydrochloric acid and finally again with diethyl ether after addition of 2 M potassium hydroxide. Separation was accomplished by reversed-phase high-performance liquid chromatography on a cyano column with an acetonitrile-phosphate buffer system. The recovery of centbutindole and its metabolite was always greater than 80%. Calibration curves were linear over the concentration range 0.25-5 ng/ml for centbutindole and 0.05-1 ng/ml for the hydroxy metabolite. Although the lower limit of detection was 0.1 ng/ml for centbuntindole and 0.02 ng/ml for the hydroxy metabolite, the reliable limits of quantitation were 0.25 and 0.05 ng/ml, respectively, using 4 ml of serum.

Single Oral Dose Pharmacokinetics of Centbutindole, a New Neuroleptic Agent, in Healthy Human Volunteers

SummaryCentbutindole, a butyrophenone derivative, is a new neuroleptic agent developed at the Central Drug Research Institute, Lucknow, India. The pharmacokinetics of this compound were investigated after oral administration of single 3mg tablets in 5 healthy male volunteers. Serum levels of the unchanged drug were measured by high pressure liquid chromatography (HPLC) with fluorescence detection. Mean peak serum levels (3.48 ± 1.58 mg/L) were reached at 4 hours, and the mean biological half-life was calculated as 12.45 ± 3.59 hours. The data were best fitted to a 1-compartment open model with first-order absorption and elimination kinetics. Considerable intersubject variability was noted in the absorption characteristics of centbutindole, and further study is planned to better define the pharmacokinetics of this drug.