Possible Hormone Predictors of Physical Performance in Adolescent Team Sport Athletes.

Martin, AC, Heazlewood, IT, Kitic, CM, Lys, I, and Johnson, L. Possible hormone predictors of physical performance in adolescent team sport athletes. J Strength Cond Res 33(2): 417-425, 2019-The research aim of this study was to determine possible hormone predictors of physical performance in adolescent team sport athletes. Saliva samples were collected immediately before performance testing sessions from 114 state squad athletes (77 males, 37 females) participating in either Australian football, basketball, hockey, or netball. Participants completed tests of aerobic and anaerobic capacity, agility, power, and speed. Samples were collected over 22 months at quarterly, six-monthly, and/or yearly intervals depending on the testing schedule of the athlete. Saliva was analyzed for testosterone (T), cortisol (C), estradiol (E), and progesterone (P) levels. A strong negative correlation existed between multistage fitness test performance and T:E ratio (r = -0.76, p = 0.01) in females not taking oral contraceptives, and a strong positive correlation existed between repeat agility total time and estradiol levels (r = -0.71, p = 0.001) in females taking oral contraceptives. In males, strong negative correlations were evident for individual changes in planned agility time and estradiol levels (r = 0.87, p = 0.02), and countermovement jump (CMJ) height and T:C (r = -0.88, p = 0.01). In females taking oral contraceptives, a strong positive correlation was noted between individual change in yo-yo intermittent recovery test performance and T:E (r = 0.74, p = 0.01) and a strong negative correlation was noted between 20-m speed and T:P (r = 0.73, p = 0.01). In females not taking oral contraceptives, a strong negative correlation was found between individual change in CMJ height and T:P (r = -0.72, p = 0.02). The findings show that in adolescent team sport athletes, the P:E, T:E, and the T:P ratios are important predictors of performance in tests of physical capacity. The findings also indicate that estradiol and progesterone have a predictive function in the physical performance of adolescent male team sport athletes.

Public health relevance of drug-nutrition interactions.

The public health relevance of drug-nutrition interactions is currently highly undervalued and overlooked. This is particularly the case for elderly persons where multi-morbidity and consequently polypharmacy is very common. Vitamins and other micronutrients have central functions in metabolism, and their interactions with drugs may result in clinically relevant physiological impairments but possibly also in positive effects. On 12 April 2016, the University Medical Center Groningen (The Netherlands), as part of its Healthy Ageing program, organized a workshop on the public health relevance of drug-nutrient interactions. In this meeting, experts in the field presented results from recent studies on interactions between pharmaceuticals and nutrients, and discussed the role of nutrition for elderly, focusing on those persons receiving pharmaceutical treatment. This paper summarizes the proceedings of the symposium and provides an outlook for future research needs and public health measures. Since food, pharma and health are closely interconnected domains, awareness is needed in the medical community about the potential relevance of drug-nutrition interactions. Experts and stakeholders should advocate for the integration of drug-nutrition evaluations in the drug development process. Strategies for the individual patients should be developed, by installing drug review protocols, screening for malnutrition and integrating this topic into the general medical advice.

Oral contraceptive therapy reduces serum relaxin-2 in elite female athletes.

AIM: Recent investigations have demonstrated that athletes with high relaxin-2 levels have a high risk of anterior cruciate ligament injuries, while athletes taking oral contraceptives (OC) have low relaxin-2 levels. It has not yet been clarified whether taking OC reduces relaxin-2 levels. The purpose of this study was to investigate changes in relaxin-2 levels in athletes taking OC. METHODS: Levels of relaxin-2, estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone were measured in serum samples (n = 183) from 106 elite female athletes. Five athletes with serum relaxin-2 concentrations > 6 pg/mL during the luteal phase were recruited to assess the effect of OC therapy. RESULTS: Serum relaxin-2 concentrations were significantly higher during the luteal phase (n = 57) than in the follicular phase (n = 72), or in athletes on OC therapy (n = 10) (P < 0.001, P < 0.001 and P < 0.05, respectively). In the luteal phase, 36.8% (21/57) of the athletes had relaxin levels > 6 pg/mL. In 23 athletes, serum relaxin-2 concentrations were measured during both the follicular and luteal phases, revealing that relaxin-2 levels were significantly higher in the luteal phase compared with the follicular phase. In 5 out of 23 athletes, serum relaxin-2 concentrations were > 6 pg/mL in the luteal phase and during the second cycle of OC therapy, relaxin-2 concentrations decreased dramatically to below the detection limit (0.26 pg/mL). CONCLUSIONS: High serum relaxin-2 concentrations were only detected during the luteal phase. In athletes with high relaxin-2 concentrations during the luteal phase, OC therapy decreased serum relaxin-2 levels.

The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects.

PURPOSE: Lersivirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile that exhibits potent antiretroviral activity against wild-type human immunodeficiency virus and clinically relevant NNRTI-resistant strains. Results from in vitro and in vivo investigations suggest that lersivirine is a cytochrome P450 (CYP3A4) inducer that is metabolized by CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 2B7. In order to formally assess the effects of lersivirine on CYP3A4 metabolism and/or glucuronidation, we performed studies aimed at investigating the effects of lersivirine co-administration on the pharmacokinetics (PK) of midazolam, ethinylestradiol and levonorgestrel. METHODS: Two drug-drug interaction studies were performed. Healthy subjects were co-administered (1) single dose midazolam, a prototypical CYP3A4 substrate, followed by 14 days of lersivirine twice daily with single dose midazolam on the final day of lersivirine dosing or (2) 10 days of once-daily (QD) lersivirine and QD oral contraceptives (OCs; ethinylestradiol and levonorgestrel), substrates for CYP3A4, UGT2B7, and/or P-glycoprotein. The effects of co-administration on the PK parameters of midazolam and OCs were assessed. RESULTS: At clinically relevant lersivirine doses (500-1,000 mg total daily dose), the mean plasma exposure of midazolam was reduced in a dose-dependent manner by 20-36 %. Co-administration of lersivirine 1,000 mg QD with OCs had minor PK effects, increasing ethinylestradiol exposure by 10 % and reducing levonorgestrel exposure by 13 %. CONCLUSIONS: These data further support previous observations that lersivirine is a weak CYP3A4 inducer, a weak inhibitor of glucuronidation, and a P-glycoprotein inhibitor. In both studies, lersivirine appeared to have a good safety and tolerability profile.

Development and validation of a HPLC method for determination of levonorgestrel and quinestrol in rat plasma.

Levonorgestrel and quinestrol, commonly known as EP-1, has long been used in the control of wild rodents. Up to the present time, however, no method for simultaneous quantification of levonorgestrel and quinestrol in rat plasma has been reported. In the present study, a sensitive reverse-phase high-performance liquid chromatography with ultraviolet detection (RP-HPLC-UV) method for quantification of levonorgestrel and quinestrol in rat plasma has been developed. It uses a Kromasil ODS C(18) column and acetonitrile-0.1% formic acid (85 : 15, v/v) mobile phase at ambient temperature. The plasma sample was prepared by hexane-isoamyl alcohol extraction (90 : 10, v/v). The flow rate and detection wavelength were 1.0 mL/min and 230 nm. The correlation coefficients were greater than 0.9995 within 0.08-50 microg/mL for levonorgestrel and 0.12-50 microg/mL for quinestrol, and the limits of detection were 0.02 and 0.05 microg/mL for levonorgestrel and quinestrol, respectively. Average recovery ranged from 92.5 to 96.3% and inter-day RSDs were less than 7.56%. This method can be applied to the further pharmacokinetic study of levonorgestrel and quinestrol in rat plasma.

Pharmacokinetics of an oral contraceptive containing oestradiol valerate and dienogest.

OBJECTIVE: To evaluate the pharmacokinetics of a combined oral contraceptive (OC) containing oestradiol valerate/dienogest (E2V/DNG) administered according to a four-phasic dosing regimen with an oestrogen step-down and a progestin step-up over 26 days of active treatment. METHODS: This Phase I, open-label study included healthy women aged 18-50 years. Treatment consisted of the administration of E2V 3 mg for 2 days, E2V 2 mg/DNG 2 mg for 5 days, E2V 2 mg/DNG 3 mg for 17 days, E2V 1 mg for 2 days, and placebo for 2 days. RESULTS: Pharmacokinetic data were analysed in 15 women. Stable E2 concentrations were maintained throughout the study. Minimum mean serum E2 levels were 33.6-64.7 pg/ml during E2V administration. The ratio of oestrone:E2 in serum was approximately 5:1. Minimum mean serum DNG levels were 6.8-15.1 ng/ml during DNG administration. Minimum concentrations of DNG increased only slightly during each phase of the regimen during which DNG was being administered. On day 24 the geometric mean C(max), C(ave) and t((1/2)) of DNG were 82.9 ng/ml, 33.7 ng/ml and 12.2 hours, respectively; the median t(max) was 1.5 hours. Serum sex hormone-binding globulin concentrations increased by 40% (within the normal range). Cortisol binding-globulin levels remained almost unchanged. Treatment was well tolerated. CONCLUSIONS: Treatment with an OC containing E2V and DNG was well tolerated and was associated with stable E2 concentrations over 28 days. The pharmacokinetics of DNG were consistent with previous findings. Minimum serum concentrations of DNG increased only slightly during phases of the regimen during which DNG was administered.

A once-a-month oral contraceptive.

Poor patient adherence to oral contraceptives is the predominant cause of failure of these therapies, leading to unplanned pregnancies that can negatively affect female health worldwide. To improve patient adherence, we developed an oral contraceptive that is administered once a month. Here, we describe the design and report in vivo characterization of a levonorgestrel-releasing gastric resident dosage form in pigs.

Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.

AIMS: To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive. METHODS: Three randomized, double-blind, placebo-controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two-period crossover studies were conducted to assess (i) the effect of steady-state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady-state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two-way crossover study was conducted to evaluate the effect of steady-state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 microg ethinyloestradiol/150 microg levonorgestrel (Microgynon). RESULTS: The geometric mean ratios for C(max) and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in T(max), t(1/2) or CL(R) (where measured) for any of the compounds. CONCLUSIONS: Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel.

Simultaneous quantitation of multiple contraceptive hormones in human serum by LC-MS/MS.

OBJECTIVE: The objective was to develop a method to simultaneously quantify five commonly used hormonal contraceptives (HCs) and two endogenous sex steroids by liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) and apply this method to human serum samples. STUDY DESIGN: We developed a method to simultaneously analyze ethinyl estradiol (EE2), etonogestrel (ENG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA) and norethisterone (NET), along with estradiol (E2) and progesterone (P4), in human serum for a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. We analyzed serum collected from women self-reporting use of oral contraceptives, contraceptive implants or injectable contraceptives (n=14) and normally cycling women using no HC (n=15) as well as pooled samples from women administered various HCs (ENG, n=6; LNG, n=14; MPA, n=7; NET, n=5). RESULTS: Limits of quantitation were 0.010ng/mL for E2, EE2 and P4; 0.020ng/mL for ENG, LNG and MPA; and 0.040ng/mL for NET. Precisions for all assays, as indicated by coefficient of variation, were less than or equal to 12.1%. Accuracies for all assays were in the range of 95%-108%. Endogenous hormone values obtained from analysis of human serum samples are in agreement with levels previously reported in the literature for normally cycling women as well as for women taking the appropriate HC. CONCLUSIONS: We have developed a robust, accurate and sensitive method for simultaneously analyzing commonly used contraceptive steroids and endogenous sex steroids in human serum. IMPLICATIONS: This analytical method can be used for quantitating contraceptive steroid levels in women for monitoring systemic exposure to determine drug interactions, nonadherence, misreporting and proper dosing.

Impact of progestogens on hemostasis.

Combined hormonal contraception containing estrogen and progestogen and postmenopausal hormone therapy with estrogen ± progestogen are reported risk factors for venous thrombosis. The thrombotic risk varies by estrogen dose and type of progestogen. Estrogen combined with "newer generation" progestogens in combined oral contraceptives may have higher thrombotic risk than estrogen combined with older generation progestogens. Among postmenopausal women thrombotic risk also varies by type of hormone and mode of delivery. Although the risk of thrombosis with the different hormonal compounds is uncertain, it has definitely been attributed to the pharmacological effect of the hormones on hemostasis. Animal and cell culture studies have demonstrated the pharmacodynamics of progestogens with respect to hemostasis. Extrapolation from these studies to clinical conditions and further to clinical end points such as cardiovascular disease is, however, controversial. Few clinical studies have focused on the effect of progestogen only therapy on the hemostatic system in vivo. Most of the current knowledge regarding the in vivo effect of progestogens on hemostasis is obtained from studies with combined contraceptives. These results obviously reflect the combined influence of both estrogen and progestogen on hemostasis, and extrapolation to progestogen-only conditions is challenging. This paper discusses the pharmacodynamics of progestogens in relation to the hemostatic system, addressing results obtained in animal and cell culture studies and in clinical studies employing progestogen-only and combined oral contraceptives. The compiled results suggest that the major effect of progestogens on hemostasis is related to alterations in platelet function and the tissue factor pathway of coagulation. More studies focusing on these topics are warranted.

Valproate and neuroendocrine changes in relation to women treated for epilepsy and bipolar disorder: a review.

Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

Three-step method for menstrual and oral contraceptive cycle verification.

OBJECTIVES: Fluctuating endogenous and exogenous ovarian hormones may influence exercise parameters; yet control and verification of ovarian hormone status is rarely reported and limits current exercise science and sports medicine research. The purpose of this study was to determine the effectiveness of an individualised three-step method in identifying the mid-luteal or high hormone phase in endogenous and exogenous hormone cycles in recreationally-active women and determine hormone and demographic characteristics associated with unsuccessful classification. DESIGN: Cross-sectional study design. METHODS: Fifty-four recreationally-active women who were either long-term oral contraceptive users (n=28) or experiencing regular natural menstrual cycles (n=26) completed step-wise menstrual mapping, urinary ovulation prediction testing and venous blood sampling for serum/plasma hormone analysis on two days, 6-12days after positive ovulation prediction to verify ovarian hormone concentrations. RESULTS: Mid-luteal phase was successfully verified in 100% of oral contraceptive users, and 70% of naturally-menstruating women. Thirty percent of participants were classified as luteal phase deficient; when excluded, the success of the method was 89%. Lower age, body fat and longer menstrual cycles were significantly associated with luteal phase deficiency. CONCLUSIONS: A step-wise method including menstrual cycle mapping, urinary ovulation prediction and serum/plasma hormone measurement was effective at verifying ovarian hormone status. Additional consideration of age, body fat and cycle length enhanced identification of luteal phase deficiency in physically-active women. These findings enable the development of stricter exclusion criteria for female participants in research studies and minimise the influence of ovarian hormone variations within sports and exercise science and medicine research.

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. METHODS: In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. RESULTS: Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed. CONCLUSIONS: Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen® are recommended when coadministered with dulaglutide. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Delay of ovulation by meloxicam in healthy cycling volunteers: A placebo-controlled, double-blind, crossover study.

This study aimed to assess the effect of meloxicam on female ovulation. Twenty consented fertile females were monitored for 4 menstrual cycles: a baseline cycle, 2 treatment cycles, and a washout cycle between treatment cycles. In the first cycle visit, transvaginal ultrasound was performed, a blood sample for progesterone and meloxicam analysis was withdrawn, and volunteers were given a luteinizing hormone (LH) urine test kit and meloxicam or placebo. Volunteers started the treatment on the following day and asked to return the day the LH kit was positive to detect the dominant follicle. At subsequent visits, transvaginal ultrasound and progesterone and meloxicam levels were investigated. Compared to placebo, a 5-day delay in follicle rupture, a 55.7% increase in the mean maximum follicle diameter, and 33.5% decrease of plasma progesterone level were observed in the meloxicam-treated group. Such demonstrated meloxicam effects were reversed in participants who were randomized to meloxicam first and then placebo. Only minor side effects were reported by volunteers during the course of treatment. It is concluded that meloxicam resulted in a reversible delay of ovulation, an increase in follicular diameter, and a decrease in plasma progesterone level.

Pharmacokinetics and safety of tanaproget, a nonsteroidal progesterone receptor agonist, in healthy women.

OBJECTIVE: This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of the nonsteroidal progesterone receptor agonist, tanaproget. METHODS: A randomized, double-blind, placebo-controlled, sequential-group study of ascending single doses of tanaproget was conducted in healthy, 25- to 45-year-old women on cycle days 8 to 12. Eight subjects (six active, two placebo) per cohort received a dose of 0.1, 0.3, 1, 3, 7 (+/-high-fat meal) or 15 mg. RESULTS: The maximum concentration (C(max)) of tanaproget occurred approximately 2 to 3 h after administration. The elimination half-life (t(1/2)) ranged from 12 to 30 h, and the oral clearance was approximately 70 L/h. The pharmacokinetics of tanaproget was not noticeably altered with a high-fat meal. All doses of tanaproget decreased cervical mucus scores (using a modified Insler method), indicating poor production and poor quality of cervical mucus. The most frequent treatment-emergent adverse events were vaginal bleeding/spotting, abdominal cramping and vomiting; their incidence was not dose related and most events were mild. CONCLUSIONS: Tanaproget was safe and well tolerated, decreased cervical mucus scores and had a pharmacokinetic profile acceptable for use as a once-daily oral contraceptive.

Pharmacokinetic interaction of solifenacin with an oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women: a double-blind, placebo-controlled study.

BACKGROUND: Solifenacin succinate (YM905; Vesicare, Astellas Pharma Inc., Tokyo, Japan) is a new once-daily, orally administered muscarinic receptor antagonist under investigation for the treatment of overactive bladder. OBJECTIVE: The aim of this study was to evaluate the effect of solifenacin on the pharmacokinetic (PK) parameters of an oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: In a double-blind, placebo-controlled, 2-period, crossover study, 24 healthy, young, white women received a combined OC (EE 30 microg + LNG 150 microg) daily for two 21-day cycles, separated by a 7-day washout. On day 12 of each cycle, subjects began a 10-day regimen of solifenacin 10 mg QD, which is 2 times the suggested starting dose, or placebo. Subjects crossed over to the other treatment arm for the second cycle. Primary PK end points were C(max) and AUC from time 0 to 24 hours (AUC(0-24 h)) for EE and LNG. Women ranged in age from 20 to 37 years and had a mean body weight of 64 kg, mean height of 167.4 cm, and mean body mass index of 23 kg/m2. Seven women had never smoked, while 5 were former smokers and 12 were regular smokers. Safety assessments included the nature, frequency, and severity of spontaneously reported or observed adverse events, vital signs, electrocardiogram, laboratory values, and physical examination. RESULTS: Statistical analysis of AUC(0-24 h)/product of baseline concentration and total blood sampling time, and C(max)/baseline concentration ratios of solifenacin versus placebo for EE and LNG found the 90% CI to be within the predefined range of 0.8 to 1.25 (EE: 0.854-1.164 and 0.822-1.167; LNG: 0.920-1.125 and 0.910-1.139). The number of samples with non-quantifiable luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels were comparable after administration of the OC with either solifenacin or placebo. The adverse event most frequently reported was dry mouth (solifenacin, n = 25 [9 mild, 13 moderate, and 3 severe] vs placebo, n = 1 [moderate]). There were no clinically relevant effects on vital signs, electrocardiogram, or laboratory parameters. CONCLUSIONS: A PK interaction between solifenacin and the OC containing EE and LNG was not found in this study. Solifenacin was not found to have altered suppression of LH or FSH. The drug was well tolerated in these healthy, young, white, adult female volunteers.

Rapid quantitative analysis of ormeloxifene and its active metabolite, 7-desmethyl ormeloxifene, in rat plasma using liquid chromatography-tandem mass spectrometry.

Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator used as a once a week oral contraceptive and is intended for long-term clinical use by females. Therefore, a simple, sensitive and rapid LC-MS/MS method was developed and validated for simultaneous quantification of ORM and its active metabolite (7-desmethyl ormeloxifene, 7-DMO) in rat plasma. Also, the method was partially validated in human plasma. Chromatographic separation was achieved on Discovery HS C-18 column (5µm, 50×4.6mm) with mobile phase [acetonitrile: aqueous ammonium acetate (0.01M) buffer (85: 15, %v/v)] at a flow rate of 0.8mL/min. The calibration curve was linear (r≥0.99) for a concentration range of 0.78-100ng/mL for both the analytes. The precision (%RSD; ORM, 1.3 to 13.4; 7-DMO, 3.1 to 15.0) and accuracy (%bias; ORM, -13.8 to 12.5; 7-DMO, -10.6 to 6.8) in both rat and human plasma were within the acceptable limits. The recovery for ORM and 7-DMO was always >79.1% and >72.9%, respectively. Both the analytes were found stable in rat plasma even after 30 days of storage at -80°C and on being subjected to three freeze-thaw cycles. The method has not only short run time (3.5min) but requires a low plasma sample volume (20µL) and is the first reported LC-MS/MS method for simultaneous quantification of the marketed drug known as centchroman (INN: ormeloxifene) and the metabolite 7-DMO in plasma. The method was applied to evaluate drug-drug interaction of ORM with the commonly prescribed antidepressant drug sertraline using serial sampling in rats.

Genetic regulation of plasma levels of vitamin K-dependent proteins involved in hematostatis: results from the GAIT Project. Genetic Analysis of Idiopathic Thrombophilia.

Vitamin K-dependent proteins play a critical role in hemostasis. We have analysed the genetic and environmental correlations between measures of several vitamin K-dependent proteins in 21 Spanish extended families, including 397 individuals. Plasma functional levels of factors II, VII, IX, X, protein C and functional protein S were assayed in an automated coagulometer. Antigenic levels of total and free protein S were measured using an ELISA method. A maximum likelihood-based covariance decomposition analysis was used to assess the heritability of each trait and the genetic and environmental correlations between all possible pairs. All of the plasma levels had a significant genetic component (heritability) ranging from 22% to 52% of the phenotypic variance. Among the 28 possible pairs of genetic correlations, 18 were significant at a level of p < 0.05 and six exhibited a p-value between 0.05 and 0.10. Positive environmental correlation was observed for 25 of the pairs (p < 0.05). We conclude that genetic effects account for a large proportion of the observed phenotypic variation in vitamin K-dependent proteins. Some of the genes appear to pleiotropically influence all of these traits, since most pairs of phenotypes exhibit significant genetic correlation. However, since these phenotypes show a high degree of environmental correlation, it is also likely that the same environmental factors influence them co-jointly.

Effect of troglitazone on the pharmacokinetics of an oral contraceptive agent.

Fifteen healthy women participated in a study to determine the effect of multiple doses of troglitazone on the pharmacokinetics of Ortho-Novum 1/35 (35 micrograms ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho-Novum. During the third cycle, participants also received troglitazone 600 mg qd for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE Cmax and AUC(0-24) by 32% and 29%, respectively. Likewise, troglitazone decreased NE Cmax and AUC(0-24) by 31% and 30%, respectively. Plasma SHBG concentrations increased from 113 nmol/L during cycle 2 to 220 nmol/L during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/mL on all occasions. Thus, coadministration of troglitazone and Ortho-Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients treated with troglitazone.