Lack of effect of rosiglitazone on the pharmacokinetics of oral contraceptives in healthy female volunteers

The effect of rosiglitazone (Avandia [BRL 49653C]) on the pharmacokinetics of ethinylestradiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho-Novum 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, double-blind, placebo-controlled crossover study. Thirty-four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28-day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(0-24) was 1126 and 1208 pg.h/mL (PE: 0.92; 90% CI: 0.88-0.97), and mean norethindrone AUC(0-24) was 178 and 171 ng.h/mL (PE: 1.04; 90% CI: 1.00-1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.     

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.     

Pharmacokinetics of tazarotene cream 0.1% after a single dose and after repeat topical applications at clinical or exaggerated application rates in patients with acne vulgaris or photodamaged skin

OBJECTIVE: To evaluate the safety and pharmacokinetics of tazarotene cream 0.1% under standard (face only) or exaggerated (15% body surface area, including the face) application conditions after a single dose and after repeat topical applications once daily to patients with acne vulgaris or photodamaged skin. METHODS: Two separate, randomised, single-centre, nonblinded, parallel-group pharmacokinetic studies were conducted. In one study, tazarotene cream 0.1% was applied either to the face of eight female patients with moderate acne or to 15% body surface area of ten female patients with severe acne. In the other study, tazarotene cream 0.1% was applied either to the face (six females, two males) or to 15% body surface area (8 females, 8 males) of patients with photodamaged skin. In both studies, tazarotene cream 0.1% was applied once daily (except on days 1 and 2) for 30 days. Blood was drawn for measurement of plasma concentrations of tazarotenic acid at defined time intervals after application of the cream. Plasma tazarotenic acid concentrations were determined by a validated gas chromatography-tandem mass spectrometry method with a lower limit of quantification of 0.005 microg/L. RESULTS: At exaggerated application rates in patients with acne vulgaris, the maximum average peak concentration (C(max)) and 24-hour area under the concentration-time curve (AUC) values of tazarotenic acid were (mean +/- SD) 1.20 +/- 0.41 microg/L (n = 10) and 17.0 +/- 6.1 microg. h/L (n = 10), respectively, and occurred on day 15. The single highest C(max) was 1.91 microg/L. At standard application rates in patients with acne vulgaris, the maximum average C(max) and AUC values of tazarotenic acid were 0.10 +/- 0.06 microg/L (n = 8) and 1.54 +/- 1.01 microg. h/L (n = 8), respectively, and occurred on day 15. At exaggerated application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were (mean +/- SD) 1.75 +/- 0.53 microg/L (n = 16) and 23.8 +/- 7.0 microg. h/L (n = 16), respectively, and occurred on day 22. The single highest C(max) was 3.43 microg/L on day 29. At standard application rates in patients with photodamaged skin, the maximum average C(max) and AUC values of tazarotenic acid were 0.236 +/- 0.255 microg/L (n = 8) and 2.44 +/- 1.38 microg. h/L (n = 8), respectively, and occurred on day 15. Gender had no influence on the systemic exposure of tazarotenic acid. The most common treatment-related adverse events were signs and symptoms of local irritation, of mild or moderate severity. CONCLUSIONS: The pharmacokinetics of tazarotene cream 0.1% in patients with acne vulgaris or photodamaged skin are similar. The maximum average plasma concentrations of tazarotenic acid after topical application of tazarotene cream 0.1% to the face were less than 0.25 microg/L. The maximum average plasma concentrations of tazarotenic acid following application to an exaggerated body surface area (15%) were less than 1.8 microg/L.     

Disposition and biotransformation of the acetylenic retinoid tazarotene in humans

Oral tazarotene, an acetylenic retinoid, is in clinical development for the treatment of psoriasis. The disposition and biotransformation of tazarotene were investigated in six healthy male volunteers, following a single oral administration of a 6 mg (100 microCi) dose of [14C]tazarotene, in a gelatin capsule. Blood levels of radioactivity peaked 2 h postdose and then rapidly declined. Total recovery of radioactivity was 89.2+/-8.0% of the administered dose, with 26.1+/-4.2% in urine and 63.0+/-7.0% in feces, within 7 days of dosing. Only tazarotenic acid, the principle active metabolite formed via esterase hydrolysis of tazarotene, was detected in blood. One major urinary oxidative metabolite, tazarotenic acid sulfoxide, accounted for 19.2+/-3.0% of the dose. The majority of radioactivity recovered in the feces was attributed to tazarotenic acid representing 46.9+/-9.9% of the dose and only 5.82+/-3.84% of dose was excreted as unchanged tazarotene. Thus following oral administration, tazarotene was rapidly absorbed and underwent extensive hydrolysis to tazarotenic acid, the major circulating species in the blood that was then excreted unchanged in feces. A smaller fraction of tazarotenic acid was further metabolized to an inactive sulfoxide that was excreted in the urine.     

Influence of avosentan (SPP3OI) on the pharmacokinetics of a second generation oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers

BACKGROUND: Avosentan (SPP301) is a potent and highly selective ETA receptor blocker and is clinically investigated in diabetic nephropathy. This study was designed to evaluate whether avosentan influences the pharmacokinetics of steroid oral contraceptives. METHODS: During a run-in phase, 16 healthy females received an oral contraceptive containing ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg for the first 21 days of a minimum of one menstrual cycle. In a subsequent double-blind, randomized two menstrual cycle crossover treatment phase, subjects received either avosentan 25 mg or placebo once daily concomitantly with the oral contraceptive. Serum ethinylestradiol and plasma levonorgestrel concentrations were measured on Days 14 and 15 of the two treatment periods for the evaluation of the 24-hour kinetic parameters, and an additional sample was collected on Day 21 to determine their trough concentrations. Serum progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels as well as plasma avosentan and Ro 68-5925 levels were determined on Days 13, 14, 15 and 21 of each cycle of the treatment phase. RESULTS: Avosentan had a statistically significant lowering effect of 9 - 15% on the ethinylestradiol serum concentration levels. The 90% confidence intervals of the pharmacokinetic parameters did not include 1 or exceeded the 0.8 - 1.25 acceptance range for lack of interaction. The plasma concentration-time curves and pharmacokinetic parameters of levonor-gestrel were not statistically different during concomitant treatment with either avosentan or placebo. Compared to placebo, avosentan lowered the serum concentrations of progesterone statistically significantly by about 8% and increased slightly the LH and FSH serum concentrations. Safety and tolerability patterns were comparable during avosentan and placebo administration. CONCLUSION: Because of the effect of avosentan on the concentration levels of ethinylestradiol and progesterone, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during avosentan treatment.     

炔雌醇环丙孕酮片治疗多囊卵巢综合征的诱导排卵功效探讨

目的 探讨应用炔雌醇环丙孕酮片治疗多囊卵巢综合征（PCOS）诱导排卵的临床效果。方法选取桂林市妇幼保健医院2009年5月～2011年10月收治的90例PCOS患者,服用炔雌醇环丙孕酮片治疗4个月经周期,用药前后分别测定患者体质量指数（BMI）、空腹胰岛素（FINS）、雌二醇（E2）、睾酮（T）、黄体生成素（LH）、卵泡刺激素（FSH）、周期排卯率、临床妊娠率。结果90例患者在服用炔雌醇环丙孕酮片后,其BMI、FINS、T、LH、LH／FSH均低于治疗前,差异具有统计学意义（P〈0．05）,FSH、E2在治疗前后差异无统计学意义（P〉0．05）。所有患者经治疗后其周期排卵率达到83_3％,临床妊娠率达到37．8％。结论应用炔雌醇环丙孕酮片治疗多囊卵巢综合征患者性排卵障碍者,可以降低血糖及高雄激素血症,提高排卵率和临床妊娠率,有效改善患者的临床症状,值得临床推广应用。     

Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis.

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.     

二甲双胍联合炔雌醇环丙孕酮片治疗多囊卵巢综合征疗效观察

目的：探讨二甲双胍、炔雌醇环丙孕酮片治疗多囊卵巢综合征的临床效果。方法：收集2009年1月～2010年1月多囊卵巢综合征患者55例,将其随机分为3组,A组18例单独应用二甲双胍500mg/次,每日3次;B组20例单独应用炔雌醇环丙孕酮片,每日1次,每次1片;C组17例炔雌醇环丙孕酮片和二甲双胍联合用药,每组均3个疗程共3个月,于第4个月经周期第2天复查血清促黄体生成素（LH）、促卵泡素（FSH）、睾酮（T）及雌二醇（E2）水平,比较3组治疗前后激素水平变化情况。结果：3组患者治疗前后激素水平有显著差异（P〈0.05）,C组治疗前后激素水平变化与A组及B组比较差异明显（P〈0.05）。结论：二甲双胍联合炔雌醇环丙孕酮片能有效纠正高雄激素血症,达到治疗多囊卵巢综合征的效果。     

Influence of losigamone on the pharmacokinetics of a combined oral contraceptive in healthy female volunteers

OBJECTIVES: The influence of the new antiepileptic drug losigamone (CAS 112856-44-7/123783-52-8) on the pharmacokinetics of a combined oral contraceptive containing ethinylestradiol (CAS 57-63-6) and levonorgestrel (CAS 797-63-7) was investigated in 16 healthy women. METHODS: This phase I study consisted of 3 periods with an uncontrolled first period and a double-blind, placebo-controlled, cross-over design in the second and third period. All subjects received a single dose of 200 mg losigamone (1 tablet) in period 1 (on day 14) as well as multiple doses of losigamone (3 tablets = 600 mg per day) or placebo for 15 days in periods 2 and 3. During all three periods an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel was given. Single-dose pharmacokinetics was investigated on day 14 of period 1. Multiple-dose pharmacokinetic investigations were performed on day 15 of periods 2 and 3. The samples were assayed to derive pharmacokinetic data of ethinylestradiol and levonorgestrel. In addition, the concentrations of losigamone racemate (AO-33) and its enantiomers AO-242 and AO-294 were determined in these samples. RESULTS: The mean values of the pharmacokinetic parameters AUC and Cmax of ethinylestradiol and levonorgestrel after multiple-dose treatment with losigamone or placebo were quite similar and met the criteria for bioequivalence. The 90% confidence intervals of the log-transformed ratios of the geometric means of the primary pharmacokinetic variables were included in the respective acceptance ranges of 80% to 125% (AUC) and 70% to 143% (Cmax). CONCLUSIONS: The study demonstrated that multiple doses of losigamone did not influence the multiple dose kinetics of ethinylestradiol and levonorgestrel. The single- and multiple-dose kinetics of 200 mg losigamone and its enantiomeres did not differ from each other in a significant way. The combination of losigamone and the combined oral contraceptive was well tolerated and no serious adverse events occurred. It can be stated that the antiepileptic drug losigamone and the combined contraceptive do not interact each others metabolism.     

二甲双胍联合氯米芬对多囊卵巢综合征患者的促排卵疗效观察

目的 探讨二甲双胍联合氯米芬在多囊卵巢综合征（PCOS）患者中的促排卵治疗效果. 方法 46例PCOS不孕症患者中对照组27例单用氯米芬促排卵治疗,试验组19例用二甲双胍联合氯米芬促排卵.对照组从月经周期第5天开始口服氯米芬,每次50 mg,1次/d,连服5 d,共3个周期.试验组先口服二甲双胍,每次500 mg,3次/d,连服3个月,随后从月经周期或撤退性出血的或撤退性出血的第5天开始加用氯米芬,用法同对照组.监测各组患者治疗前后生殖激素水平,阴道B型超声监测卵泡发育.分析各组排卵率和妊娠率. 结果 对照组治疗前后比较,各项生殖激素变化差异均无统计学意义（P＞0.05）;试验组治疗后睾酮、LH/FSH比值分别为[（0.54±0.28）μg/L、（1.27±0.32）],较治疗前[（1.02±0.86）μg/L、（1.93±0.72）]明显下降,差异有统计学意义（P＜0.05）;试验组妊娠12例（63.2%）,优于对照组的7例（25.9%）,差异有统计学意义（P＜0.05）. 结论 二甲双胍能改善PCOS患者高雄激素状态,提高PCOS患者对氯米芬的敏感性;二甲双胍和氯米芬联用能获得更高的排卵率和妊娠率.     

Testicular effects of the Leydig cell toxicant ethane dimethanesulphonate given to neonatal rats.

Neonatal rats were injected with either 50 mg/kg ethane dimethanesulphonate (EDS) or vehicle on days 1 to 5 inclusive or on day 1 alone. Studies were made on days 6, 28, and 63 of testicular structure; related endocrinologic parameters were measured in the day 1 to 5 treated animals only. Leydig cells and their activities were identified by cell counts using sections stained for 3 beta-hydroxysteroid dehydrogenase, hCG binding to LH receptors in testicular homogenates, and assays of intratesticular testosterone, plus pituitary and/or serum concentrations of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH). Given on days 1 to 5, EDS reduced Leydig cell populations estimated by morphometry and 125I-HCG binding, and testicular and body weights between days 6 and 63, and permanently retarded the development of the seminiferous epithelium. Decreases of serum and intratesticular testosterone occurred with homeostatic rises in FSH and LH. Injection on day 1 reduced Leydig cell numbers only on day 6 although body weight remained retarded. The data illustrate the susceptibility of the developing rat testis to the cytotoxicant EDS; whether this is related to withdrawal of androgen production or nonspecific cytotoxicity remains to be evaluated.     

Multicentre study with a new biphasic oral contraceptive containing ethinylestradiol and desogestrel. Report on efficacy, cycle control and adverse experiences with special emphasis on blood pressure and weight.

In a multicentre study 882 women were treated during a total of 12850 cycles with a new biphasic oral contraceptive: CTR 24. The study period was 18 cycles. The biphasic preparation CTR 24 contains 25 micrograms desogestrel (CAS 54024-22-5) plus 40 micrograms ethinylestradiol (CAS 57-63-6) daily for the first 7 days followed by the combination of 125 micrograms desogestrel and 30 micrograms ethinylestradiol daily for the subsequent 15 days. One pregnancy occurred. The woman had forgotten one tablet on Day 6 of Cycle 12. The Pearl Index was 0.1 (0.0-0.5) for patient failure. The combination had a good cycle control and only few side effects were reported.     

Estrogenic activities of estradiol enantate and ethinylestradiol compared at a clinical level

Healthy menopausic women accepted to receive two consecutive estrogenic treatments: 1. ethinylestradiol 0.030 mg/d p.o. during 21 days; 2. a single dose of estradiol enantate (estra-1,3,5(10)-triene-3-ol-17 beta-heptanoate, one of the components of Perlutal or Topasel) 10 mg i.m. Both treatments were separated by a 1-month wash-out period, without any medicine. FSH, LH and prolactin serum levels were measured in each one of the subjects by radioimmunoassay before the beginning of each treatment and for at least 14 times during 31 days thereafter. A temporary decrease of the FSH levels and a temporary increase of the prolactin levels were induced by both treatments. In this respect the estradiol enantate effect was more precocious but the quality and the magnitude of the responses were similar among the two substances. The LH profile evolution was different: there was a decrease under estradiol enantate, but a very sharp increasing peak was observed on the 17th day under ethinylestradiol. By comparing the obtained results no significant statistical differences between the estrogenic potencies of the therapeutic schemes applied were found.     

腹腔镜卵巢手术对卵巢储备功能的影响

目的：观察腹腔镜卵巢手术对卵巢储备功能的影响。方法：对44例良性卵巢疾病患者采用腹腔镜手术治疗,于月经周期第8～12天施行手术。术后随访半年以上,观察月经情况。于术前及术后第1、3个月经周期的第3天采用放射免疫分析法测定FSH、E2及LH水平,判断卵巢储备功能。结果：术后第1个月经周期,42例（95.5%）正常,2例（4.5%）推迟,至第2个周期恢复正常。随访半年内,术后月经正常39例（88.6%）,4例（9.1%）月经量较术前减少,减少量为20%～30%,1例（2.3%）月经稀发。所有患者术后第1个周期均出现E2下降,FSH、LH增高现象,与术前比较差异有统计学意义（P〈0.05）,至第3个周期时,E2有所增高,而FSH、LH下降,大多数都恢复至正常,与术前比较差异无统计学意义的（P〉0.05）。第3个周期时6例（13.6%）有卵巢储备功能下降,未发现卵巢功能衰竭者,其余38例（86.4%）患者卵巢储备功能正常。结论：腹腔镜卵巢手术一定程度上会影响患者的卵巢储备功能,应该采取相应的预防措施。     

他扎罗汀倍他米松乳膏对小型猪经皮给药后的系统吸收及其相互作用研究

目的：通过与已上市单方他扎罗汀凝胶（tazarotene gel）和二丙酸倍他米松乳膏（betamethasone dipropionate cream）比较，研究新的复方制剂他扎罗汀倍他米松乳膏（tazarotene and betamethasone dipropionate cream，简称"复方"）对小型猪经皮给药后的药物吸收以及药物组分间吸收的相互影响。方法：将18只小型猪随机分入复方组、他扎罗汀凝胶组和二丙酸倍他米松乳膏组，每组6只。小型猪按20%的体表面积2 mg·cm^-2给予相应组别的药物，并在给药后24 h清除药物。分别于给药前和给药后不同时间点采集血样。高效液相色谱-串联质谱（liquid chromatography-tandem mass spectrometry，LC-MS/MS）法测定血浆中他扎罗汀及其代谢物他扎罗汀酸和/或二丙酸倍他米松及其代谢物倍他米松的浓度。DAS 2.1.1软件进行药代动力学（pharmacokinetic，PK）参数计算并统计分析。结果：复方他扎罗汀倍他米松乳膏与单方他扎罗汀凝胶中的他扎罗汀均不易透过小型猪皮肤到达血液，系统吸收非常低，而复方组血浆中的他扎罗汀及其活性代谢产物他扎罗汀酸较单方组更低；复方他扎罗汀倍他米松乳膏和二丙酸倍他米松乳膏中的二丙酸倍他米松几乎不透过小型猪皮肤到达血液，系统吸收非常低，其中复方组与单方组中二丙酸倍他米松及其代谢产物倍他米松到达血液的量未见明显的差异。结论：复方制剂中他扎罗汀对二丙酸倍他米松的系统吸收未产生相互作用，而二丙酸倍他米松对他扎罗汀的系统吸收产生了有益的相互作用，有利于用药安全。     

Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel

Background: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance.Objective: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel.Study Design: Healthy women aged 18–50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2mg/dienogest 2 mg, 17 days estradiol valerate 2mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03mg/levonorgestrel 0.15mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three.Results: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/ levonorgestrel.Conclusion: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/ levonorgestrel.     

Cytochrome P450 2C8 and flavin-containing monooxygenases are involved in the metabolism of tazarotenic acid in humans.

Upon oral administration, tazarotene is rapidly converted to tazarotenic acid by esterases. The main circulating agent, tazarotenic acid is subsequently oxidized to the inactive sulfoxide metabolite. Therefore, alterations in the metabolic clearance of tazarotenic acid may have significant effects on its systemic exposure. The objective of this study was to identify the human liver microsomal enzymes responsible for the in vitro metabolism of tazarotenic acid. Tazarotenic acid was incubated with 1 mg/ml pooled human liver microsomes, in 100 mM potassium phosphate buffer (pH 7.4), at 37 degrees C, over a period of 30 min. The microsomal enzymes that may be involved in tazarotenic acid metabolism were identified through incubation with microsomes containing cDNA-expressed human microsomal isozymes. Chemical inhibition studies were then conducted to confirm the identity of the enzymes potentially involved in tazarotenic acid metabolism. Reversed-phase high performance liquid chromatography was used to quantify the sulfoxide metabolite, the major metabolite of tazarotenic acid. Upon incubation of tazarotenic acid with microsomes expressing CYP2C8, flavin-containing monooxygenase 1 (FMO1), or FMO3, marked formation of the sulfoxide metabolite was observed. The involvement of these isozymes in tazarotenic acid metabolism was further confirmed by inhibition of metabolite formation in pooled human liver microsomes by specific inhibitors of CYP2C8 or FMO. In conclusion, the in vitro metabolism of tazarotenic acid to its sulfoxide metabolite in human liver microsomes is mediated by CYP2C8 and FMO.     

Alterations in hypothalamic and pituitary hormone levels induced by neonatal treatment of female mice with diethylstilbestrol.

Neonatal female mice of the NMRI strain were treated with the synthetic estrogen diethylstilbestrol (DES), 5 micrograms daily for the first 5 days after birth, or with vehicle only. Levels of LH and FSH (pituitary and serum) and LHRH (hypothalamus) were measured by radioimmunoassay (RIA) in 6- to 56-day-old females with 6- to 7-day intervals. Compared to controls, DES-treated females had low levels of LH on days 6, 12, and 21 in the pituitary, and on days 6 and 12 in serum; increased LH levels were seen in both the pituitary and serum on day 42. The FSH levels of DES-treated females were decreased on days 6 and 12 in the pituitary and on day 6 in serum; an increased FSH content occurred on day 21 in the pituitary. In the preoptic area and basal hypothalamus of DES-treated females, levels of LHRH were increased on day 21 and decreased on day 42. On day 56, the serum levels of FSH and LH and the hypothalamic content of LHRH were similar in controls and DES females. A second study including both synthetic and natural estrogen was performed in 12-day-old females. Treatment with 10(-2) micrograms DES or lower doses or 5 micrograms estradiol-17 beta (E2) on days 1 to 5 after birth had no depressive effect on serum LH. The hypothalamic-pituitary-ovarian feedback system reacted similarly to ovariectomy and E2 challenge in 15-day-old control and DES-treated females. DES-treated 56-day-old females had a reduced LH response to ovariectomy but increased response to exogenous E2 compared to controls. These results show that neonatal treatment with DES has pronounced effects on the hypothalamic-pituitary system in the developing female mouse, which may be of importance for the altered ovarian function in these females as adults.     

Effect of prenatal melatonin exposure on gonadotropins and prolactin secretion in male and female rat pups.

We evaluated whether melatonin administration to pregnant rats during the final week of pregnancy affects prepubertal secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin in offspring. Melatonin was administered in the drinking water from day 14 to delivery. LH, FSH and prolactin concentrations were determined in plasma sampled from offspring between 5 and 30 days in the dark portion of the diurnal cycle. Administration of 2 or 20 microg/ml melatonin did not affect LH or FSH in male or female offspring. The 20-microg/ml dose caused a significant increase in prolactin in males and females at day 15. In contrast, melatonin, 2 or 20 microg/ml, decreased prolactin at days 25 and 30 in females and day 25 in males. Thus, prenatal melatonin exposure alters prolactin secretion, but not that of LH and FSH in infantile and prepubertal male and female rats.     

Naltrexone effects on pituitary and gonadal hormones in male and female rhesus monkeys

The long-acting opioid antagonist, naltrexone, stimulates LH and FSH in women during the early follicular phase of the menstrual cycle and is a new provocative test of hypothalamic-pituitary function (42,63). The acute effects of naltrexone (0.25, 0.50 and 1.0 mg/kg IV) on anterior pituitary (LH, FSH, PRL) and gonadal steroid (T or E2) hormones were studied in 7 female and 4 male rhesus monkeys (Macaca mulatta). Integrated plasma samples were collected at 20 min intervals for 60 min before and for 300 min after intravenous infusion of naltrexone over 10 min. In females studied during the early follicular phase (cycle days 1-3), naltrexone did not stimulate LH and significantly suppressed E2 (p less than 0.0003-0.0001) and FSH (p less than 0.006-0.0001). Naltrexone (0.50 and 1.0 mg/kg) also did not stimulate LH release in late follicular phase females (cycle days 10-12) when estradiol levels were in the peri-ovulatory range. FSH and E2 were significantly suppressed (p less than 0.01-0.05) after 1.0 mg/kg naltrexone, but not after 0.5 mg/kg naltrexone. However, in males all doses of naltrexone significantly stimulated LH (p less than 0.003-0.0001) and T (p less than 0.001-0.0001) but not FSH. LH increased significantly above baseline within 20 to 40 min and T increased significantly within 60 min. These gender differences in naltrexone's effects on pituitary gonadotropins and gonadal steroid hormones were unanticipated. These data are not concordant with clinical studies which report significant naltrexone stimulation of LH in men and in women during the early follicular phase.(ABSTRACT TRUNCATED AT 250 WORDS)