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Ram Chandra Gupta - One of the best experts on this subject based on the ideXlab platform.
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effect of concurrently coadministered drugs on the pharmacokinetic pharmacodynamic profile of Centchroman a nonsteroidal oral contraceptive in rats
Contraception, 2006Co-Authors: Vipul Kumar, Jawahar Lal, M M Singh, Ram Chandra GuptaAbstract:Abstract Introduction Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of Centchroman in female Sprague���Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide. Materials and Methods The pharmacological activity of Centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of Centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of Centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared. Results In pharmacological interaction studies, Centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of Centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of Centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability ( F ) and volume of distribution ( V d ) in some situations. Conclusions The results indicate that there is no direct link between the altered pharmacokinetics of Centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of Centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with Centchroman and that caution should be taken in clinical practice.
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Effect of concurrently coadministered drugs on the pharmacokinetic/pharmacodynamic profile of Centchroman, a nonsteroidal oral contraceptive, in rats.
Contraception, 2006Co-Authors: Vipul Kumar, Jawahar Lal, Man Mohan Singh, Ram Chandra GuptaAbstract:Abstract Introduction Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of Centchroman in female Sprague���Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide. Materials and Methods The pharmacological activity of Centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of Centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of Centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared. Results In pharmacological interaction studies, Centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of Centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of Centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability ( F ) and volume of distribution ( V d ) in some situations. Conclusions The results indicate that there is no direct link between the altered pharmacokinetics of Centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of Centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with Centchroman and that caution should be taken in clinical practice.
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Pharmacokinetic Interaction of Tetracycline with Centchroman in Healthy Female Volunteers
Drugs in R&D, 2003Co-Authors: Manoj Khurana, Jawahar Lal, Swaran Nityanand, Ram Chandra GuptaAbstract:Objective: 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.
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Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of Centchroman in rats
Contraception, 2002Co-Authors: Manoj Khurana, Jawahar Lal, M M Singh, Jyoti Paliwal, Ram Chandra GuptaAbstract:Centchroman (Ormeloxifene) is a nonsteroidal, selective estrogen receptor modulator, oral contraceptive and anticancer agent, and is intended for long-term use by women. In view of its vast clinical application and the interaction of steroidal oral contraceptives with certain commonly used therapeutic agents, evaluation of interaction of certain concomitantly administered therapeutic agents (ibuprofen, rifampicin, diazepam, salbutamol, nifedipine, paracetamol, haloperidol, and tetracycline), in terms of both the postcoital contraceptive efficacy and pharmacokinetic profile, with Centchroman was undertaken in female Sprague-Dawley rats. Among the representatives from each commonly used therapeutic category, interaction (pharmacokinetic) was observed with ibuprofen (60 mg/kg, twice daily), haloperidol (0.7 mg/kg, twice daily), and tetracycline (140 mg/kg, twice daily) coadministration on Days 1 through 5 postcoitum. Of these three therapeutic agents, only tetracycline interfered with the contraceptive efficacy of Centchroman. It reduced the bioavailability of Centchroman and its active metabolite by increasing their excretion through bile and feces. Increased metabolite excretion on tetracycline coadministration indicates the enterohepatic recirculation of the metabolite, not the parent drug. However, the effect of tetracycline was negated by the inclusion of lactic acid bacillus spores in the regimen.
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Original research article Optimization of contraceptive dosage regimen of Centchroman
2001Co-Authors: Jawahar Lal, Op Asthana, Swaran Nitynand, N.v. Nagaraja, Ram Chandra GuptaAbstract:Centchroman (Ormeloxifene), a non-steroidal oral contraceptive, is used at a dose of 30 mg once a week. To prevent failures in the beginning of the therapy, it is recommended that a dose of 30 mg twice a week for 12 weeks be administered to build up adequate blood levels. The present study was undertaken to simplify the dosing schedule without sacrificing the purpose of twice a week dosing regimen, using modeling and measurement approaches. The drug was given to 60 female volunteers who were divided into seven groups: group I, 30 mg weekly; group II, 30 mg twice a week; group III, 30 mg twice a week for 12 weeks followed by 30 mg weekly; group IV, 30 mg twice a week for 6 weeks followed by 30 mg weekly; group V, 60 mg weekly; and groups VI and VII, single 60 mg loading dose followed by 30 mg weekly doses. The blood samples were collected and analyzed by HPLC. In group I, mean trough concentrations of Centchroman and its active metabolite, 7-desmethyl Centchroman, were comparable to the steady-state trough concentrations in groups III, IV, VI, and VII. The metabolite to parent drug ratio remained constant in all the groups. The pharmacokinetic parameters in group VII were comparable to those reported after a single 30 mg dose. Dosage regimen VI was more convenient and provided better pregnancy protection (Pearl index 1.18; unpublished report) than regimen III, which is currently on the market and, thus, could be effectively used for contraception. © 2001 Elsevier Science Inc. All rights reserved.
Jawahar Lal - One of the best experts on this subject based on the ideXlab platform.
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pk pd interaction study of angiotensin ii antagonist losartan with selective estrogen receptor modulator Centchroman
International Journal of Pharmacokinetics, 2016Co-Authors: Abhisheak Sharma, Swati Jaiswal, Mahendra Shukla, Jitendra Kumar Singh, Ganesh Haranadh Narisipuram, Jawahar LalAbstract:Aim: The effect on pharmacokinetics and postcoital contraceptive efficacy of Centchroman was investigated after concomitant administration of losartan. Materials & methods: An LC-MS/MS method was employed for quantification of Centchroman in blood of female rats treated with Centchroman (1.5 mg/kg) only and Centchroman plus losartan (5 mg/kg, once daily up to day 7). The effect of losartan on the postcoital contraceptive activity of Centchroman was evaluated in sperm-positive female rats. Results: The area under the curve and mean residence time values were decreased in losartan concomitant group, however, sperm-positive female rats did not exhibit any implantations in either Centchroman only or losartan co-administered group of female rats. Conclusion: The study evidenced no pharmacological interaction of losartan with Centchroman.
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coadministration of hmg coa reductase inhibitors atorvastatin and rosuvastatin does not affect contraceptive efficacy of Centchroman
The European Journal of Contraception & Reproductive Health Care, 2015Co-Authors: Abhisheak Sharma, Swati Jaiswal, Mahendra Shukla, Kondagudur Ravindrachary, Jawahar LalAbstract:Objective The study aimed to investigate the effect of concomitant use of atorvastatin or rosuvastatin on the pharmacokinetic and pharmacodynamic profile of Centchroman, a non-steroidal female oral...
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Coadministration of HMG-CoA reductase inhibitors, atorvastatin and rosuvastatin, does not affect contraceptive efficacy of Centchroman.
The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception, 2015Co-Authors: Abhisheak Sharma, Swati Jaiswal, Mahendra Shukla, Kondagudur Ravindrachary, Jawahar LalAbstract:AbstractObjective The study aimed to investigate the effect of concomitant use of atorvastatin or rosuvastatin on the pharmacokinetic and pharmacodynamic profile of Centchroman, a non-steroidal female oral contraceptive.Methods A rat model was used to predict pharmacokinetic drug–drug interactions between Centchroman and atorvastatin or rosuvastatin. A dried blood spot sampling technique followed by liquid chromatography–tandem mass spectrometry detection was employed for analysis of the pharmacokinetic interaction study samples. Sperm-positive female rats were investigated for postcoital contraceptive activity of Centchroman with or without coadministration of atorvastatin or rosuvastatin.Results Coadministration of atorvastatin or rosuvastatin may increase the systemic availability of Centchroman in blood, but it does not affect the pharmacodynamic profile of Centchroman.Conclusion Atorvastatin or rosuvastatin may be prescribed with Centchroman without compromising the contraceptive efficacy of centchro...
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simultaneous quantification of Centchroman and its 7 demethylated metabolite in rat dried blood spot samples using lc ms ms
Biomedical Chromatography, 2012Co-Authors: Jawahar Lal, Nidhi SharmaAbstract:ABSTRACT: An approach has been developed for the quantitative determination of concentrations of Centchroman (I), anonsteroidal once-a-week oral contraceptive, and its major metabolite (7-desmethyl Centchroman, II) using dried blood spots(DBS) on paper, rather than conventional plasma samples. The assay employed simple solvent extraction of the DBS samplecircle (6mm) requiring small blood volumes (30 mL) followed by reversed-phase HPLC separation, combined with multiplereaction monitoring mass spectrometric detection. The calibration plot in matrix using D -trans-hydroxy chroman as internalstandard (IS) was linear (r 2 =0.998) over ranges of 1.5–240 and 4.5–720ng/mL for I and II, respectively. The recoveries of bothI and II were always >60% with quantification limits (signal-to-noise ratio=10) of 1.5 and 4.5ng/mL for I and II, respectively.The intra-day and inter-day precision (%RSD) and accuracy (%bias) variations in blood spots for both I and II were better than13%. Moreover, both I and II were stable in DBS for at least 3months when stored at room temperature. The developedmethod was successfully applied to the pharmacokinetic interaction study after oral administration of Centchroman withand without co-administration of carbamazepine in female Sprague–Dawley rats using serial sampling and results werecomparable with the plasma concentrations reported earlier. Copyright © 2011 John Wiley & Sons, Ltd.Keywords: Centchroman; 7-desmethyl Centchroman; oral contraceptive; dried blood spot; LC-MS/MS; pharmacokinetics
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Simultaneous quantification of Centchroman and its 7-demethylated metabolite in rat dried blood spot samples using LC-MS/MS.
Biomedical chromatography : BMC, 2011Co-Authors: Jawahar Lal, Nidhi SharmaAbstract:ABSTRACT: An approach has been developed for the quantitative determination of concentrations of Centchroman (I), anonsteroidal once-a-week oral contraceptive, and its major metabolite (7-desmethyl Centchroman, II) using dried blood spots(DBS) on paper, rather than conventional plasma samples. The assay employed simple solvent extraction of the DBS samplecircle (6mm) requiring small blood volumes (30 mL) followed by reversed-phase HPLC separation, combined with multiplereaction monitoring mass spectrometric detection. The calibration plot in matrix using D -trans-hydroxy chroman as internalstandard (IS) was linear (r 2 =0.998) over ranges of 1.5–240 and 4.5–720ng/mL for I and II, respectively. The recoveries of bothI and II were always >60% with quantification limits (signal-to-noise ratio=10) of 1.5 and 4.5ng/mL for I and II, respectively.The intra-day and inter-day precision (%RSD) and accuracy (%bias) variations in blood spots for both I and II were better than13%. Moreover, both I and II were stable in DBS for at least 3months when stored at room temperature. The developedmethod was successfully applied to the pharmacokinetic interaction study after oral administration of Centchroman withand without co-administration of carbamazepine in female Sprague–Dawley rats using serial sampling and results werecomparable with the plasma concentrations reported earlier. Copyright © 2011 John Wiley & Sons, Ltd.Keywords: Centchroman; 7-desmethyl Centchroman; oral contraceptive; dried blood spot; LC-MS/MS; pharmacokinetics
Suprabhat Ray - One of the best experts on this subject based on the ideXlab platform.
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Centchroman: A safe reversible postcoital contraceptive with curative and prophylactic activity in many disorders.
Frontiers in bioscience (Elite edition), 2018Co-Authors: Suprabhat Ray, Nitya AnandAbstract:Centchroman (INN: Ormeloxifene), a reversible post-coital/weekly oral contraceptive (half-life of about 168 hours), designed and developed at CDRI, Lucknow is the only non-steroidal oral contraceptive in clinical use in the world today. Synthesized in 1967 and completing pre-clinical and clinical studies in 1989, this drug was approved for marketing in 1991, social marketing in 1995 and NFPW in April 2016. It acts by preventing implantation of blastocyst in endometrium. It is the only contraceptive which neither suppresses ovulation nor interferes with the hypothalamic-pituitary-ovarian axis. It has high level of safety and is virtually free from side effects except for a delay in about 8% menstrual cycles which is not confined to any women/cycle. Besides contraception, this SERM is also clinically useful in the management of DUB, mastalgia and fibroadenoma and has promising therapeutic efficacy in a variety of cancers including breast cancer. Due to estrogenic activity, this drug also has anti-osteoporotic and cardioprotective activity. Thus, Centchroman is likely to show other curative and prophylactic activity in a wide range of other disorders.
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Effect of side-chain alteration on hormonal activity of nonsteroidal estrogen antagonists
Medicinal Chemistry Research, 2009Co-Authors: Sangita, Anila Dwivedi, Philip Prathipati, Suprabhat RayAbstract:Incorporation of novel side-chains in 3,4-diaryl chromans, an established nucleus present in the nonsteroidal estrogen antagonist Centchroman, has been carried out. The effect of variation in the nature of the chain on relative binding affinity (RBA) to estrogen receptor, estrogenicity, and antiestrogenicity has been studied. Presence of hydrazide residue on cis- and trans-3,4-diaryl chromans led to relatively higher RBA and estrogenicity as compared with corresponding acids and esters.
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Anticlastogenic effects of d- and l-Centchroman in Swiss albino mice. 2. Subacute study in vivo and comparison with tamoxifen.
Cytobios, 2001Co-Authors: Amitabha Mukhopadhyay, Suprabhat RayAbstract:The antimutagenic effects of the two enantiomers of Centchroman, a nonsteroidal oral contraceptive, were evaluated and compared with tamoxifen, a known breast cancer drug. Anticlastogenic assays in subacute in vivo studies in Swiss albino mice were used. They revealed that both d-Centchroman and I-Centchroman reduced the chromosome aberrations produced by dimethylbenz(a)anthracene and cyclophosphamide, when compared with the group treated only with the former mutagen. Tamoxifen also reduced the chromosome aberrations produced by the two mutagens. Overall the results showed that l-Centchroman alone was more effective in reducing cyclophosphamide-induced aberrations than d-Centchroman, and for toxicity reasons may be an alternative to tamoxifen in breast cancer therapy.
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Anticlastogenic effects of Centchroman and its enantiomers in Swiss albino mice. I. Acute study and their comparison with tamoxifen.
Cancer letters, 1999Co-Authors: Amitabha Mukhopadhyay, Suprabhat Ray, Sutapa Gupta, A K GiriAbstract:Abstract Centchroman (CC), a non steroidal oral contraceptive and a candidate drug for breast cancer, has been reported to exhibit partial to complete remission of lesions in 40.5% of breast cancer patients. Recently, we have reported the antimutagenic effects of CC in multiple mutational assays. The potent antioestrogenic activity, negligible side effects, anti-breast cancer activity and antimutagenic effects of CC prompted us to evaluate the anticlastogenic effects of CC and two of its enantiomers. i.e. d -Centchroman (DC) and l -Centchroman (LC) in the acute in vivo studies in female Swiss albino mice as measured by chromosome aberrations (CA) and sister chromatid exchange (SCE) assays against two known positive mutagen compounds, i.e. dimethylbenz[ a ]anthracene (DMBA) and cyclophosphamide (CP). The results of anti-mutagenicity assays of CC and its enantiomers have been compared to the known breast cancer drug tamoxifen (TM). CC and LC reduced both DMBA and CP induced CA when compared with the group treated with only DMBA and CP. DC did not reduce the DMBA-induced CA when compared with the DMBA-treated group alone. It reduces only the CP induced CA. TM also reduces both DMBA and CP induced CA when compared with group received only DMBA or CP. SCE were carried out only for LC. A weak but significant decrease in SCE was observed in both LC plus DMBA- and LC plus CP-treated groups when compared with respective positive controls alone. Thus the overall results indicate that both CC and LC are more effective in reducing the genotoxic effects of DMBA and CP than DC.
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Comparative antimutagenic effects of D- and L-Centchroman and their comparison with tamoxifen in Salmonella assay.
Mutation research, 1999Co-Authors: Sutapa Gupta, Suprabhat Ray, Amitabha Mukhopadhyay, A K GiriAbstract:Centchroman (CC)--a contraceptive and a candidate drug for breast cancer has been developed by the Central Drug Research Institute. It has been successfully marketed as a contraceptive for last several years. CC has also been reported to exhibit partial to complete remission of lesions in 40.5% breast cancer patients. Recently, we have reported the antimutagenic effects of CC in Ames Salmonella assay and in vivo and in vitro mammalian cells in multiple mutational assay. The potent antimutagenic activity of CC and its anti-breast cancer activity prompted us to evaluate the antimutagenic effects of its enantiomers, i.e., D-Centchroman (DC) and L-Centchroman (LC) in the Ames Salmonella strains TA97a, TA98, TA100 and TA102 against known bacterial mutagens. Attempts have also been made to compare the results of antimutagenicity assays of CC and its enantiomers with the known breast cancer drug tamoxifen (TM). The main objective was to identify the best suitable form of CC having antimutagenic effects with anticancer profile similar to TM, would replace the latter for toxicity reasons. When mutagenicity assays were carried out with these compounds as expected like CC, none of these enantiomers or TM showed any mutagenic effects in these Salmonella strains. In the antimutagenicity assay a significantly reduced number of bacterial histidine revertant colonies were observed when positive compounds were co-incubated with certain concentrations of LC compared with bacterial plates treated with respective positive compound. This was observed in some concentrations in all the four strains in both plate incorporation and preincubation tests. The protective effects of LC in preincubation tests were slightly more than in plate incorporation tests. Both the DC and TM showed protective effects only in certain concentrations in some strains in either plate or preincubation tests. Thus the above results indicate that LC showed more protective effects in Salmonella strains TA97a, TA98, TA100 and TA102 than either DC or TM.
A K Giri - One of the best experts on this subject based on the ideXlab platform.
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Anticlastogenic effects of Centchroman and its enantiomers in Swiss albino mice. I. Acute study and their comparison with tamoxifen.
Cancer letters, 1999Co-Authors: Amitabha Mukhopadhyay, Suprabhat Ray, Sutapa Gupta, A K GiriAbstract:Abstract Centchroman (CC), a non steroidal oral contraceptive and a candidate drug for breast cancer, has been reported to exhibit partial to complete remission of lesions in 40.5% of breast cancer patients. Recently, we have reported the antimutagenic effects of CC in multiple mutational assays. The potent antioestrogenic activity, negligible side effects, anti-breast cancer activity and antimutagenic effects of CC prompted us to evaluate the anticlastogenic effects of CC and two of its enantiomers. i.e. d -Centchroman (DC) and l -Centchroman (LC) in the acute in vivo studies in female Swiss albino mice as measured by chromosome aberrations (CA) and sister chromatid exchange (SCE) assays against two known positive mutagen compounds, i.e. dimethylbenz[ a ]anthracene (DMBA) and cyclophosphamide (CP). The results of anti-mutagenicity assays of CC and its enantiomers have been compared to the known breast cancer drug tamoxifen (TM). CC and LC reduced both DMBA and CP induced CA when compared with the group treated with only DMBA and CP. DC did not reduce the DMBA-induced CA when compared with the DMBA-treated group alone. It reduces only the CP induced CA. TM also reduces both DMBA and CP induced CA when compared with group received only DMBA or CP. SCE were carried out only for LC. A weak but significant decrease in SCE was observed in both LC plus DMBA- and LC plus CP-treated groups when compared with respective positive controls alone. Thus the overall results indicate that both CC and LC are more effective in reducing the genotoxic effects of DMBA and CP than DC.
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Comparative antimutagenic effects of D- and L-Centchroman and their comparison with tamoxifen in Salmonella assay.
Mutation research, 1999Co-Authors: Sutapa Gupta, Suprabhat Ray, Amitabha Mukhopadhyay, A K GiriAbstract:Centchroman (CC)--a contraceptive and a candidate drug for breast cancer has been developed by the Central Drug Research Institute. It has been successfully marketed as a contraceptive for last several years. CC has also been reported to exhibit partial to complete remission of lesions in 40.5% breast cancer patients. Recently, we have reported the antimutagenic effects of CC in Ames Salmonella assay and in vivo and in vitro mammalian cells in multiple mutational assay. The potent antimutagenic activity of CC and its anti-breast cancer activity prompted us to evaluate the antimutagenic effects of its enantiomers, i.e., D-Centchroman (DC) and L-Centchroman (LC) in the Ames Salmonella strains TA97a, TA98, TA100 and TA102 against known bacterial mutagens. Attempts have also been made to compare the results of antimutagenicity assays of CC and its enantiomers with the known breast cancer drug tamoxifen (TM). The main objective was to identify the best suitable form of CC having antimutagenic effects with anticancer profile similar to TM, would replace the latter for toxicity reasons. When mutagenicity assays were carried out with these compounds as expected like CC, none of these enantiomers or TM showed any mutagenic effects in these Salmonella strains. In the antimutagenicity assay a significantly reduced number of bacterial histidine revertant colonies were observed when positive compounds were co-incubated with certain concentrations of LC compared with bacterial plates treated with respective positive compound. This was observed in some concentrations in all the four strains in both plate incorporation and preincubation tests. The protective effects of LC in preincubation tests were slightly more than in plate incorporation tests. Both the DC and TM showed protective effects only in certain concentrations in some strains in either plate or preincubation tests. Thus the above results indicate that LC showed more protective effects in Salmonella strains TA97a, TA98, TA100 and TA102 than either DC or TM.
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absence of sister chromatid exchange and chromosome aberrations in mice after in vivo exposure of Centchroman a new non steroidal oral contraceptive
Cytologia, 1995Co-Authors: A K Giri, Kaleem Ahmed KhanAbstract:Centchroman (3, 4-trans-2, 2-dimethyl-3-phenyl-4p (β-pyrrolidinoethoxy phenyl)-7-methoxy chroman), a non-steroidal oral contraceptive has been developed by the Central Drug Research Institute, Lucknow India. Sister chromatid exchange (SE) and chromosome aberrations (CA) was carried out after in vivo exposure of Centchroman in bone marrow cells of female mice. No significant changes of either SCE or CA were observed when the treated groups were compared with solvent controls. Trend tests for the evidence of dose response effects were also insignificant. This indicate that Centchroman was not genotoxic in bone marrow cells of mice.
Manoj Khurana - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Interaction of Tetracycline with Centchroman in Healthy Female Volunteers
Drugs in R & D, 2003Co-Authors: Manoj Khurana, Jawahar Lal, Swaran Nityanand, Ved P. Kamboj, Ram C. GuptaAbstract:Objective: 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 (C_max) [35%] and a shorter time to reach C_max (t_max) 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 C_max (47%) and area under the concentration-time curve from time zero to infinity (34%) of Centchroman (p < 0.05) with a significant decrease in t_max. 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.
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Pharmacokinetic Interaction of Tetracycline with Centchroman in Healthy Female Volunteers
Drugs in R&D, 2003Co-Authors: Manoj Khurana, Jawahar Lal, Swaran Nityanand, Ram Chandra GuptaAbstract:Objective: 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.
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Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of Centchroman in rats
Contraception, 2002Co-Authors: Manoj Khurana, Jawahar Lal, M M Singh, Jyoti Paliwal, Ram Chandra GuptaAbstract:Centchroman (Ormeloxifene) is a nonsteroidal, selective estrogen receptor modulator, oral contraceptive and anticancer agent, and is intended for long-term use by women. In view of its vast clinical application and the interaction of steroidal oral contraceptives with certain commonly used therapeutic agents, evaluation of interaction of certain concomitantly administered therapeutic agents (ibuprofen, rifampicin, diazepam, salbutamol, nifedipine, paracetamol, haloperidol, and tetracycline), in terms of both the postcoital contraceptive efficacy and pharmacokinetic profile, with Centchroman was undertaken in female Sprague-Dawley rats. Among the representatives from each commonly used therapeutic category, interaction (pharmacokinetic) was observed with ibuprofen (60 mg/kg, twice daily), haloperidol (0.7 mg/kg, twice daily), and tetracycline (140 mg/kg, twice daily) coadministration on Days 1 through 5 postcoitum. Of these three therapeutic agents, only tetracycline interfered with the contraceptive efficacy of Centchroman. It reduced the bioavailability of Centchroman and its active metabolite by increasing their excretion through bile and feces. Increased metabolite excretion on tetracycline coadministration indicates the enterohepatic recirculation of the metabolite, not the parent drug. However, the effect of tetracycline was negated by the inclusion of lactic acid bacillus spores in the regimen.
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Binding of Centchroman with human serum as determined by charcoal adsorption method.
International journal of pharmaceutics, 1999Co-Authors: Manoj Khurana, Jyoti Paliwal, Ram Chandra GuptaAbstract:Abstract Protein binding of drugs is an important factor influencing both pharmacokinetic and pharmacodynamic parameters. Thus, knowing the extent of protein binding of drugs is crucial. Centchroman is a non-steroidal once a week oral contraceptive. It has been reported to be useful for the treatment of breast cancer and osteoporosis. Ample data has been generated on pharmacokinetics of Centchroman in animals and humans. The extent of protein binding of Centchroman has not been established so far. Non-specific adsorption of the drug limits the use of conventional methods like ultrafiltration and equilibrium dialysis. A method of charcoal adsorption as reported by Yuan et al. (method I) was used after modification (method II) to determine its binding to human serum. The extent of protein binding (%) is estimated from decline of percent drug remaining in the supernatant after adding the charcoal. Study was carried out at 1- and 10-μg/ml concentrations in drug free human serum samples and an HPLC assay was used to determine concentration-time data. The percentage of Centchroman remaining in serum versus time data was analysed using non-linear fitting programs on WinNonlin software. Method II was found to give higher estimates of protein binding than the former method by preventing the dilution effect. Using this method, the extent of protein binding of Centchroman was found to be 101.83±1.28 and 94.87±3.59% at 1 and 10 μg/ml, respectively. However, it was ∼90% in the individual serum samples showing intersubject variability in protein binding of Centchroman.