Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new ortho-novum research articles will be listed here shortly after becoming available to us.
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Medical research on ortho-novum
Br J Clin Pharmacol. 2008 Apr; 65(4): 531-9
Andrews E, Damle BD, Fang A, Foster G, Crownover P, LaBadie R, Glue P
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes. * Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes. * Because co-administration of voriconazole and Ortho-Novum 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs. WHAT THIS STUDY ADDS: * Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated. * It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications. AIM: To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 microg. METHODS: In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2-4) (period 1), oral contraceptive (q24 h, days 12-32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58-60) and oral contraceptive (q24 h, days 40-60) (period 3). RESULTS: Voriconazole geometric mean AUC(tau) and C(max) increased 46% (12 682-18 495 ng h ml(-1); 90% confidence interval [CI] 32, 61) and 14% (2485-2840 ng ml(-1); 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC(tau) and C(max) increased 61% (1031-1657 ng h ml(-1); 90% CI 50, 72) and 36% (119-161 ng ml(-1); 90% CI 28, 45), respectively, and norethindrone geometric mean AUC(tau) and C(max) increased 53% (116-177 ng h ml(-1); 90% CI 44, 64) and 15% (18-20 ng ml(-1); 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE. CONCLUSIONS: Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.
Lack of effect of rifalazil on ethinyl estradiol pharmacokinetics in healthy postmenopausal women.
Int J Clin Pharmacol Ther. 2007 Jul; 45(7): 418-22
Chen YX, Cabana B, Kivel N, Pieniaszek H, Gilman S, Michaelis A
Rifalazil, a second-generation rifamycin, is being evaluated for the treatment of sexually transmitted disease and gastrointestinal infections. We determined whether rifalazil influences CYP3A4 metabolism by studying the effect of a single oral, 25 mg dose of rifalazil administered to healthy postmenopausal women, on the steady-state pharmacokinetics (PK) of ethinyl estradiol (EE) during administration of Ortho-Novum 1/35 (EE/NET). Noncompartmental PK and sequential statistical analyses were performed to establish if and when subjects achieved steady-state EE plasma concentrations and to determine whether this steady state was altered by rifalazil administration. The geometric mean ratios for the difference between EE alone and following rifalazil for EE Cmax, AUC(0-24) and Cmin were 105.9, 104.4 and 105.0, respectively. The 90% confidence intervals for each ratio fell within 80 - 125% of the reference treatment indicating no significant difference in the PK of EE before or after rifalazil administration. The posterior probabilities for the true treatment differences of Cmax or AUC(0-24) being less than 20% were > 99.99% in both cases. Based on the results of this study, there is no CYP3A4-metabolic interaction between a single oral, 25 mg dose of rifalazil and EE for either induction or inhibition. Consequently, there is minimal threat of contraceptive failure when single doses of rifalazil are administered with EE/NET. A single dose of rifalazil 25 mg was well tolerated when administered concomitantly with a combination oral contraceptive (EE/NET) by healthy postmenopausal females.
AIDS. 2006 Sep 11; 20(14): 1833-41
Aweeka FT, Rosenkranz SL, Segal Y, Coombs RW, Bardeguez A, Thevanayagam L, Lizak P, Aberg J, Watts DH,
OBJECTIVES: Zidovudine remains part of combination antiretroviral therapy. Pharmacological studies rely on quantitation of active triphosphates in peripheral blood mononuclear cells. This study evaluated the impact of female sex and contraceptive therapy on zidovudine plasma and intracellular pharmacokinetics and the impact of contraceptive therapy on HIV viral load. METHODS: Serial plasma and intracellular zidovudine pharmacokinetics following oral and intravenous dosing were determined in 18 men and 20 women treated with zidovudine. Women could repeat pharmacokinetics assessment following 2 months oral or injectable contraceptive therapy. Zidovudine plasma and intracellular mono-, di- and triphosphate concentrations were determined by liquid chromatography tandem mass spectrometry. Plasma and cervical viral loads were determined preceding and following 2 months of contraceptive therapy in women. RESULTS: Men exhibited higher area under the concentration versus time curve for intracellular zidovudine and zidovudine-monophosphate following oral and intravenous dosing and higher zidovudine triphosphate following oral dosing. There was no difference between men and women in plasma zidovudine parameters. Furthermore, contraceptive therapy had no effect on zidovudine plasma or intracellular pharmacokinetics or on plasma or cervical HIV-1 RNA levels. CONCLUSIONS: Using an optimized pharmacokinetic design, this study indicated men exhibit significantly higher zidovudine-monophosphate and zidovudine-triphosphate exposure following zidovudine oral administration, having implications for drug toxicity and overall tolerance of zidovudine therapy. The lack of an effect of contraceptive therapy on zidovudine pharmacokinetics is surprising in light of previous pharmacokinetic studies for drugs eliminated primarily through glucuronidation. Contraceptive therapy had no effect on plasma or cervical viral load, results consistent with previous findings.
Tumor-grade hyperprolactinemia induced by multiple medications in the setting of renal failure.
Endocr Pract. 1999 May-Jun; 5(3): 139-42
Ziambaras K, Dagogo-Jack S
OBJECTIVE: To describe a patient with galactorrhea and severe hyperprolactinemia in whom workup revealed a nontumoral mechanism. METHODS: We present the medical history of a woman with long-standing diabetes in whom bilateral galactorrhea and hyperprolactinemia developed. In addition, the details of her clinical course and management are reviewed. RESULTS: A 33-year-old woman with diabetes, end-stage renal disease, and gastroparesis was admitted to the hospital because of intractable nausea and vomiting. Several months before admission, she had been noted to have galactorrhea and irregular menses. Routine medications included captopril, verapamil, furosemide, prochlorperazine, metoclopramide, cisapride, and Ortho-Novum. Laboratory evaluation showed normal thyroid function, increased serum prolactin levels (up to 1,197 ng/mL), and normal findings on magnetic resonance imaging of the pituitary. Electrophoresis of the patient's serum on a protein A Sepharose column showed no evidence of macro-prolactinemia. Orally administered medications were discontinued, and the patient was given total parenteral nutrition. These measures resulted in a decrease of 300 ng/mL in serum prolactin levels in 4 days. The prolactin levels eventually normalized after withdrawal of verapamil, prochlorperazine, and metoclopramide. CONCLUSION: A modest increase in serum prolactin level often can be produced by a variety of medications, but gross hyperprolactinemia of 200 ng/mL or higher usually raises suspicion of an underlying prolactin-secreting tumor. This case report demonstrates that conventional limits for nontumoral hyperprolactinemia can be exceeded by concurrent exposure to multiple lactotropic medications in the setting of renal failure.
Clin Pharmacokinet. 2004; 43(10): 673-84
Yu Z, Yu D, Walker PS, Tang-Liu DD
OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic interaction between oral tazarotene and an oral contraceptive containing norethindrone 1mg and ethinylestradiol 0.035 mg (Ortho-Novum 1/35).DESIGN: Two separate open-label, parallel-group, single-centre, pharmacokinetic and pharmacodynamic interaction studies.PARTICIPANTS AND METHODS: Twenty-seven healthy women (age 20-55 years) completed Study I, with a duration of 64 days during three consecutive menstrual cycles. Ortho-Novum 1/35 was taken once daily from study day 0 (first cycle day 1) to day 61 (third cycle day 6), and oral tazarotene 1.1 mg was coadministered daily from study day 34 (second cycle day 7) to day 61. Twenty-nine healthy women (age 20-44 years) completed Study II, with a duration of 75 days during three consecutive menstrual cycles. Ortho-Novum 1/35 was taken once daily from study day 0 (first cycle day 1) to day 74 (third cycle day 19), and oral tazarotene 6 mg was coadministered daily from study day 48 (second cycle day 21) to day 74. In both studies, the pharmacokinetics of tazarotenic acid on study day 61 (third cycle day 6) were evaluated from plasma tazarotenic acid concentrations. Pharmacokinetic parameters of plasma norethindrone and ethinylestradiol were compared before and after tazarotene administration (cycle day 6 of the second and third cycles, respectively). Serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were compared before and after tazarotene administration (cycle days 2, 4 and 6 of the second and third cycles, respectively). In Study II, serum progesterone concentrations were also determined on cycle days 18 and 20 of the second and third cycles. Tazarotenic acid was determined by liquid chromatography-tandem mass spectrometry. Ethinylestradiol and norethindrone were determined by gas chromatography-mass spectrometry. LH and FSH were assayed by microparticle enzyme immunoassay in Study I and by double-antibody radioimmunoassay in Study II. Progesterone was determined by solid-phase radioimmunoassay.RESULTS: In Study I (tazarotene 1.1 mg), the area under the plasma concentration-time curve from zero to 24 hours (AUC24) and the peak concentration in plasma (Cmax) for tazarotenic acid were 121 +/- 27 microg. h/L and 28.9 +/- 9.4 microg/L (mean +/- SD), respectively. In Study II (tazarotene 6 mg), AUC24 and Cmax for tazarotenic acid were 379 +/- 78 microg. h/L and 111 +/- 37 microg/L (mean +/- SD), respectively. In both studies, for both norethindrone and ethinylestradiol, the 90% CIs of AUC24 and Cmax on cycle day 6 before and after tazarotene administration were within the 80-125% boundary. In Study I, the 90% CIs of serum FSH and LH concentrations on cycle day 4 were within the 80-125% boundary. FSH and LH concentrations on cycle day 6 were marginally/partially outside the 80-125% boundary as a result of high variability. However, the mean FSH and LH serum concentrations on cycle day 6 of the third cycle were lower than those of the second cycle. In Study II, the 90% CIs of serum FSH, LH and progesterone concentrations were all within the 80-125% boundary, except for LH on cycle day 2. LH concentrations on cycle day 2 were marginally/partially outside the 80-125% boundary as a result of high variability. However, the mean serum LH concentration on cycle day 2 of the third cycle was lower than that of the second cycle.CONCLUSIONS: Oral tazarotene up to 6 mg once daily does not affect the pharmacokinetics and efficacy of Ortho-Novum 1/35.
Clin Pharmacol Ther. 2004 May; 75(5): 464-75
Hendrix CW, Jackson KA, Whitmore E, Guidos A, Kretzer R, Liss CM, Shah LP, Khoo KC, McLane J, Trapnell CB
BACKGROUND: Isotretinoin is a known teratogen, and when it is prescribed to women of childbearing potential, 2 forms of contraception must be used, commonly including hormonal contraception. Although isotretinoin and estradiol are metabolized largely by cytochrome P450 (CYP) 3A4 and glucuronidation, the potential for clinical drug interaction, with subsequent pharmacodynamic impact, has not been evaluated. METHODS: We enrolled 26 healthy women who were to receive isotretinoin for the treatment of severe, recalcitrant nodular acne and who were taking or planning to take oral contraceptives. The pharmacokinetics of ethinyl estradiol and norethindrone (INN, norethisterone) (the components of Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ) and pharmacodynamic assessments of oral contraceptive effectiveness (concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone) were determined on days 6 and 20 of 2 separate oral contraceptive cycles, before and during isotretinoin treatment. RESULTS: The addition of isotretinoin to the oral contraceptive regimen resulted in small and inconsistent, although statistically significant (P .05), there was a correlation between progesterone level and oral contraceptive levels (P
The interaction between St John's wort and an oral contraceptive.
Clin Pharmacol Ther. 2003 Dec; 74(6): 525-35
Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, Hilligoss JK, Miller M, Gorski JC
OBJECTIVES: The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St John's wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Twelve healthy premenopausal women who were using oral contraception (>3 months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St John's wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles. RESULTS: Concomitant use of St John's wort was associated with a significant (P .05). Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St John's wort phase. The oral clearance of midazolam after St John's wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h) than in those who did not (97.5 +/- 37.2 L/h) (P =.005). CONCLUSION: St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort.
Contraception. 2003 Sep; 68(3): 159-76
A randomized controlled multicenter study was undertaken to monitor the effects on hemostasis of two once-a-month injectable contraceptive preparations, Mesigyna (50 mg norethisterone enanthate and 5 mg estradiol valerate) and Cyclofem (25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate) in comparison with a well-known oral contraceptive (OC) Ortho-Novum 1/35 (norethisterone 1 mg and ethinyl estradiol 35 microg). A total of 378 volunteers from four centers (Bangkok, Hangzhou, Santiago and Singapore) were monitored. Blood sampling took place in one pretreatment cycle, the third and ninth injection intervals and one posttreatment cycle. In each of the three treatment groups, a rise in hemoglobin, and increases in platelet count and in prothrombin time were observed. With treatment there was a significant increase in activated partial thromboplastin time among Mesigyna users, no change among Cyclofem users and a significant decrease among OC users. OC use led to increases in plasma levels of fibrinogen, factor VII, factor X, plasminogen, protein C and decreases in plasma levels of t-PAI and antithrombin. Use of combined injectables induced no change (Cyclofem) or decreases (Mesigyna) in plasma levels of fibrinogen, factor VII, factor X and antithrombin. Use of both combined injectables led to decreases in protein C, slight decreases in plasminogen and increases in plasminogen and fibrinogen. Overall, the injectable preparations may be more beneficial than the oral preparation in not enhancing a hypercoagulable state because of the reduced synthesis of fibrinogen, factors VII and X; however, decreases in antithrombin and protein C, which are potent coagulation inhibitors, may raise some concern. Whether these changes can lead to modifications in the risk of arterial or venous disease can only be ascertained by conducting epidemiological studies.
Epilepsia. 2003 Apr; 44(4): 540-9
Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M
PURPOSE: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure. METHODS: This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2. RESULTS: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated. CONCLUSIONS: TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.
Rhesus macaque model for ovarian cancer chemoprevention.
Comp Med. 2001 Oct; 51(5): 424-9
Brewer M, Baze W, Hill L, Utzinger U, Wharton JT, Follen M, Khan-Dawood F, Satterfield W
PURPOSE: The objective of the study reported here was to explore whether a nonhuman primate model could be developed for chemoprevention of ovarian cancer. METHODS: An initial feasibility trial was done with three monkeys to determine tolerance for these drugs and for acquisition of surgical ovarian biopsy specimens. In the study, 19 female adult Macacca mulatta (rhesus macaques) were given fenretinide (4HPR) oral contraceptive (OCP), the combination of 4HPR+OCP, or no medication for three months. Laparotomy was performed before and after drug administration, and ovarian biopsy specimens were obtained to evaluate the potential for this animal as a model for ovarian cancer chemoprevention, as well as evaluating fluorescence spectroscopy and other potential biomarkers for ovarian cancer prevention studies. RESULTS: The monkeys tolerated the drugs, surgeries, and acquisition of multiple ovarian biopsy specimens with resultant minimal morbidity. On initial data analysis, fluorescence spectroscopy was the marker that appeared the most promising. CONCLUSIONS: On the basis of results of this study, this model merits further investigation. The rhesus monkey is an excellent candidate for a nonhuman primate model for ovarian cancer chemoprevention.