Concentration of ethinyl estradiol in the serum of 31 young women following a treatment period of 3 months with two low-dose oral contraceptives in an intraindividual cross-over design.

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2) but different progestins (gestodene and desogestrel, respectively), were compared with respect to the relative bioavailability of EE2. The study was conducted with 31 women as an open intraindividual comparison with the ingestion of both preparations for 3 months, respectively. On days 1, 10 and 21 of the 1st, 3rd and 6th cycle, blood was sampled at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h following administration. The concentrations of EE2 were determined in the serum samples of each individual and the area under the serum concentration versus time curves, AUC (0-4 h) and AUC (0-24 h), were calculated. Corresponding parameters obtained on days 1, 10 and 21 of the 3rd and 6th month of treatment were compared on a statistical basis, and no differences were found. This result was in concordance with a previously performed study, where both formulations were administered to 18 women in a single-dose cross-over design. However, the results of the previous and the present study are at variance with the result of one other study, reporting higher EE2 levels in the serum of women taking the gestodene-containing formulation as compared to those taking the desogestrel-containing formulation.     

Endothelial function across an oral contraceptive cycle in women using levonorgestrel and ethinyl estradiol

Oral contraceptive pills (OCPs) are a popular contraception method. Currently, lower-dose ethinyl estradiol formulations are most commonly prescribed, although they have been linked to increased arterial vascular risk. The aim of this study was to investigate endothelial function in healthy young women using lower-dose ethinyl estradiol OCPs. We examined flow-mediated, endothelium-dependent and nitroglycerin-mediated, endothelium-independent vasodilation of the brachial artery, comparing two doses of ethinyl estradiol/levonorgestrel OCPs in 15 healthy young women on two study days: once during the active phase and once during the placebo phase of an OCP cycle. Group low dose (LD) (n=7) active pills contained 150 microg levonorgestrel/30 microg ethinyl estradiol versus Group very low dose (VLD) (n=8) with 100 microg levonorgestrel/20 microg ethinyl estradiol. Endothelium-dependent vasodilation was lower during the active phase in Group VLD (5.33 +/- 1.77% vs. 7.23 +/- 2.60%; P=0.024). This phase difference was not observed in Group LD (8.00 +/- 0.970% vs. 7.61 +/- 1.07%; P=0.647). Endothelium-independent vasodilation did not differ between phases in either group. Finally, we measured endothelium-dependent vasodilation in two additional women who received 10 microg of unopposed ethinyl estradiol. Endothelium-dependent vasodilation was increased by unopposed ethinyl estradiol compared with the placebo phase (10.88 +/- 2.34% vs. 6.97 +/- 1.83%). These results suggest that levonorgestrel may antagonize the activity of ethinyl estradiol. Thus both the progestin type and estradiol dose need to be considered when assessing arterial vascular risk of OCP use in women.     

Bioequivalence of two fexofenadine formulations in healthy human volunteers after single oral administration

AIM: A randomized, two-way, crossover, bioequivalence study was conducted in 25 fasting, healthy, male volunteers to compare two brands of fexofenadine 180 mg tablets, FEXOFENADINE 180 mg Film Tablet (Drogsan A.S., Ankara, Turkey) as test and Telfast 180 mg Tablet (Aventis Pharma, Frankfurt am Main, Germany) as a reference product. METHOD: One tablet of either formulation was administered after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 48 hours. Plasma samples were analysed for fexofenadine by a validated HPLC method. The pharmacokinetic parameters AUC(0-48), AUC(0-alpha), C(max), T(max), K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically. RESULTS AND CONCLUSIONS: The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Drogsan's Fexofenadine is equivalent to Telfast of Aventis Pharma, Frankfurt am Main, Germany.     

Comparison of serum ethinyl estradiol, sex-hormone-binding globulin, corticoid-binding globulin and cortisol levels in women using two low-dose combined oral contraceptives

The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (alpha = 0.05, beta = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample 24 h, after drug intake on 1 day between the 10th and the 21st day of the cycle. The concentrations of sex-hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and cortisol were measured in a 0- to 4-hour serum pool by radioimmunoassay. Ethinyl estradiol (EE2) levels were analyzed in single and pooled samples using anti-EE2-6 beta-carboxymethyloxime-bovine serum albumin antiserum. The area under the curves (AUC) up to 4 and 24 h and Cmax and tmax were evaluated. Statistical analysis (analysis of covariance) did not reveal a dependence of values on duration of treatment or day of cycle. Both treatments resulted in almost identical values for all parameters evaluated. The mean levels of SHBG, CBG and cortisol were in the range of 186-226 nmol/l, 89-93 mg/l and 280-281 micrograms/l, respectively. Mean maximum EE2 levels of 106-129 pg/ml were found 1.6-1.8 h after pill intake and AUC0-4 h accounted for 329-374 pg.h.ml-1. The recently reported differences in serum EE2 and CBG levels between two groups of 11 women each treated with desogestrel- and gestodene-containing pills, respectively, could not be confirmed.     

Pharmacokinetics of levonorgestrel in 18 women after 1 month of treatment with a triphasic oral contraceptive.

A triphasic levonorgestrel (LNG)- and ethinylestradiol-containing oral contraceptive was administered to 18 women. Plasma samples were obtained throughout a treatment cycle just before drug administration and on the last treatment day (day 21), several plasma samples were collected from each individual up to 48 h postadministration. LNG was determined by radioimmunoassay in all plasma samples. In addition, the concentration of sex-hormone-binding globulin (SHBG) was determined in plasma samples collected from the same subjects during treatment, as well as during a pre- and a posttreatment cycle. During the treatment cycle, plasma levels of LNG determined just before drug administration increased and reached steady state at about day 16. This increase was due to an increased dose of LNG according to the triphasic dose regimen, a concomitantly ethinylestradiol-induced increase in SHBG and due to pharmacokinetic accumulation, since LNG had a terminal half-life of approximately 28.5 h and the dosing interval was 24 h. Steady-state levels and pharmacokinetic parameters of LNG determined on the last day of treatment were in good accordance with previously published results.     

Bioequivalence of two brands of citalopram 40 mg tablets after single oral administration to healthy volunteers

A randomized, two-way, crossover, bioequivalence study was conducted in 26 fasting, healthy, male volunteers to compare two brands of citalopram 40 mg tablets, Citol (Abdi Ibrahim Ila? San. ve Tic A.S., Istanbul, Turkey) as a test and Cipramil (H. Lundbeck A/S, Copenhagen, Denmark) as a reference product. One tablet of either formulation was administered with low-carbonate water after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 24 hours. Plasma samples were analysed for citalopram by a validated HPLC method. The pharmacokinetic parameters AUC0-24, AUC(0-alpha), Cmax, Tmax, K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically to evaluate bioequivalence between the two brands of citalopram, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Abdi Ibrahim's Citol is equivalent to Cipramil of H. Lundbeck, Copenhagen, Denmark.     

Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

Very few studies have explored the cardiovascular effects of progesterone in premenopausal women. This study aimed to examine the short-term effects of oral progesterone alone, transdermal estrogen alone, and progesterone and estrogen combined on flow-mediated dilation (FMD) in healthy reproductive-aged women. We suppressed endogenous estrogens and progesterone in 17 premenopausal women for 10-12 days using a gonadotropin-releasing hormone antagonist. On day 4 (hormone suppression condition), subjects were tested (n = 17) and were then supplemented with either 200 mg micronized progesterone (n = 8) orally or 0.1 mg estradiol (n = 9) transdermally per day. On day 7 (progesterone-first or estradiol-first condition), subjects were tested and began supplementation with both hormones (n = 17) and were tested again on day 10 (combined hormone condition). FMD of the brachial artery was assessed using B-mode arterial ultrasound, combined with synchronized Doppler analysis. As a result, significant differences in FMD were observed between hormone suppression (7.85 ± 1.06%) and estrogen-first conditions (10.14 ± 1.40%; P < 0.05). The estradiol-induced increase was abolished when oral progesterone was also supplemented (6.27 ± 0.96%). In contrast, we observed a trend toward a decrease in FMD with unopposed progesterone administration, but no statistically significant differences were found between the progesterone-first (6.66 ± 1.23%), hormone suppression (7.80 ± 1.23%), and combined hormone conditions (7.40 ± 1.29%). In conclusion, these data suggest that short-term oral micronized progesterone administration antagonizes the beneficial effect of transdermal estradiol on FMD.     

The characterization of sulphated metabolites of norethindrone in human milk after oral administration of contraceptive steroids

The excretion of ethynyl steroids in milk from a lactating woman taking a daily dose of an oral contraceptive (Conlumin) containing 1 mg of norethindrone and 50 micrograms of mestranol has been studied. Milk was diluted with aq. triethylamine sulphate and steroids were extracted on a Sep-Pak C18 cartridge at 60-64 degrees C. Groups of unconjugated steroids, glucuronides, mono- and disulphates were separated on triethylaminohydroxypropyl Sephadex LH-20. Following hydrolysis and further purification, steroids possessing an ethynyl-substituent were isolated by chromatography on sulphohydroxypropyl Sephadex LH-20 in silver form. Gas chromatographic-mass spectrometric analysis of the O-methyloxime-trimethylsilyl ether derivatives of these steroids, showed the presence of norethindrone and mestranol in the free fraction and of tetrahydro metabolites of norethindrone with 3 alpha,5 alpha, 3 alpha,5 beta and 3 beta,5 alpha configurations in the mono- and disulphate fractions. The disulphate of the 3 alpha,5 alpha isomer was the most abundant ethynyl steroid in milk after 13 days of administration. The site of conjugation of the monosulphates was established by acetylation prior to solvolysis and analysis by gas chromatography-mass spectrometry. This showed that the 3 alpha,5 alpha isomer was conjugated mainly in the 17 beta-position while the 3 alpha,5 beta isomer was conjugated at C-3.     

Regional differences in bioavailability of an opioid tetrapeptide in vivo in rats after administration to the respiratory tract

TArPP (Tyr-D-Arg-Phe-Phe-NH(2)), 1-10 micromol/kg, was administered to anesthetized rats by nasal microinfusion, intratracheal microinfusion, intratracheal nebulization, aerosol inhalation, and i.v. bolus and infusion. Plasma concentrations of TArPP and its deamidated metabolite were determined by LC-MS-MS.Regional differences in bioavailability (F), first-pass metabolism, and absorption rate were found for TArPP after delivery to the respiratory tract. Absorption was rapid after both pulmonary and nasal administration (t(max) approximately 10-20 min). After nasal microinfusion, F was 52 +/- 9%. For all the pulmonary groups, F was higher (72-114%). First-pass metabolism of TArPP was lower in the lung than in the nasal cavity. It is evident that the pulmonary route is attractive for successful systemic delivery of small, hydrophilic and enzymatic susceptible peptides.     

The rate and extent of calcium bioavailability from two oral dosage forms in rats

The purpose of the present work was to compare oral bioavailability of calcium from two calcium preparations, Calcium Sandoz forte 500 mg and Calcium Spofa effervescens. The pharmacokinetic study was carried out on rats, and plasma levels of 45Ca after administration of labelled calcium solutions were determined. Appropriate equations describing the two-compartment open model and the one-compartment model with first order absorption were fitted to the observed i.v. and oral data, respectively, using weighted nonlinear least-squares regression analysis. The extent and the time profile of the rate of 45Ca systemic bioavailability were assessed. Both parameters suggested identical bioavailability of calcium from the two dosage forms compared.     

Stereoselective pharmacokinetics of clausenamide enantiomers and their major metabolites after single intravenous and oral administration to rats

The pharmacokinetics of clausenamide (CLA) enantiomers and their metabolites were investigated in Wistar rat. After intravenous and oral administration at a dose of 80 and 160 mg/kg each enantiomer, plasma concentrations of (-)- or (+)-CLA and its major metabolites were simultaneously determined by reverse-phase HPLC with UV detection. Notably, stereoselective differences in pharmacokinetics were found. The mean plasma levels of (+)-CLA were higher at almost all time points than those of (-)-CLA. (+)-CLA also exhibited greater t(max), C(max), t(1/2beta), AUC(0-12h), and AUC(0--> infinity) and smaller CL (or CL/F) and V(d) (or V(d)/F), than its antipode. The (+)/(-) isomer ratios for t(1/2beta), t(max), AUC(0-12 h), and AUC(0--> infinity), which ranged from 1.26 to 2.08. The ratio for CL (or CL/F) was about 0.5, and there were significant differences in these values between CLA enantiomers (P < 0.05), implying that the absorption, distribution, and elimination of (-)-CLA were more rapid than those of (+)-CLA. Similar findings for (-)-7-OH-CLA, the major metabolite of (-)-CLA, and (+)-4-OH-CLA, the major metabolite of (+)-CLA, can be also seen in rat plasma. The contributing factors for the differences in stereoselective pharmacokinetics of CLA enantiomers appeared to be involved in their different plasma protein binding, first-pass metabolism and interaction with CYP enzymes, especially with their metabolizing enzyme CYP 3A isoforms.     

The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration

Crocetin, a unique carotenoid with a short carbon chain length, is an active compound of saffron and Gardenia jasminoides Ellis used as traditional herbal medicine. The present study was undertaken to investigate the pharmacokinetic profiles of crocetin in healthy adult subjects. The study was conducted as an open-label, single dose escalation with 10 Filipino volunteers (5 men and 5 women). The subjects received a single dose of crocetin at three doses (7.5, 15 and 22.5 mg) in one week interval. Blood samples were collected from the brachial vein before and at 1, 2, 4, 6, 8, 10 and 24 h after administration. Plasma concentrations of crocetin were determined by high-performance liquid chromatography (HPLC). Crocetin was rapidly absorbed and detected within an hour of administration with a mean time to reach maximum concentration (T_max) of crocetin ranging from 4.0 to 4.8 h. The mean values of C_max and AUC_0-24 h ranged from 100.9 to 279.7 ng/ml and 556.5 to 1720.8 ng^.h/ml respectively. C_max and AUC values increased with dose proportional manner. Crocetin was eliminated from human plasma with a mean elimination half life (T_1/2) of 6.1 to 7.5 h.In summary, there were no serious adverse events up to 22.5 mg dose of crocetin while crocetin was found to be absorbed more quickly than the other carotenoids such as β-carotene, lutein and lycopene.     

Ingestion of chilli pepper (Capsicum annuum) reduces salicylate bioavailability after oral asprin administration in the rat.

The bioavailabilities of aspirin (acetylsalicylic acid) and of salicylic acid were studied in male Wistar rats after acute and chronic administration of a Capsicum annuum extract, containing 100 mg of capsaicin per gram. With a single administration of 100 mg/kg of the extract, aspirin blood levels remained unchanged, but salicylic acid bioavailability was reduced in 44% compared with control animals. With a single administration of 300 mg/kg of the extract, aspirin blood levels were undetectable while salicylic acid bioavailability was reduced in 59%. Chronic administration once daily for 4 weeks of 100 and 300 mg/kg of the extract resulted in undetectable aspirin blood levels, while salicylic acid bioavailability was reduced in 63 and 76%, respectively, compared with controls. Results show that Capsicum ingestion reduces oral drug bioavailability, likely as a result of the gastrointestinal effects of capsaicin.     

Tissue distribution of antihypertensive dipeptide, Val-Tyr, after its single oral administration to spontaneously hypertensive rats.

The distribution of an antihypertensive dipeptide, Val-Tyr (VY), in the tissues of spontaneously hypertensive rats (SHR) was investigated in this study. A single oral administration of VY (10 mg/kg) to 18-week-old SHR resulted in a prolonged reduction of systolic blood pressure (SBP) up to 9 h (SBP0h 198.0+/-3.6 mmHg; SBP9h 154.6+/-3.5 mmHg). As a result of VY determination, a roughly 10-fold higher increment of plasma VY level was observed at 1 h than that at 0 h, whereas thereafter the level declined rapidly. In tissues, VY was widely accumulated in the kidney, lung, heart, mesenteric artery and abdominal aorta with the area under the curve over 9 h of more than 40 pmol h/g tissue; of these a higher VY level was observed in the kidney and lung. In addition, a mean resident time (MRT) for each tissue (>5 h except for liver) revealed that VY preferably accumulated in the tissues rather than in the plasma (MRT 3.8 h). Significant reductions of tissue angiotensin I-converting enzyme activity and angiotensin II level were found in the abdominal aorta as well as in the kidney, suggesting that these organs could be a target site associated with the antihypertensive action of VY.     

Ultrastructure of the uterus in an ovariectomized gecko (Hemidactylus turcicus) after administration of exogenous estradiol

The uterus of an oviparous gecko, Hemidactylus turcicus, was analysed after ovariectomized females underwent a period of treatment (up to 14 days) with exogenous estradiol. Analysis focused on the uterine mucosa, which is made up of an epithelial layer and an underlying lamina propria containing the shell glands. These tissues are thought to be responsible for secretion of the eggshell components and were thus chosen for analysis using transmission electron microscopy. In ovariectomized females, the epithelial layer was low and cuboidal with minimal/no differentiation or secretory activity. Treatment with exogenous estradiol resulted in a significant increase in cell height associated with gradual differentiation of the epithelium. Development of non-ciliated cells included production of secretory granules (low electron density) at the apical cell surface. The shell glands showed less obvious changes over the course of treatment. Shell glands contained two cell types: dark cells with darkly staining nuclei and organelles, and light cells with very indistinct nuclei and organelles, except for prominent rough endoplasmic reticulum and free ribosomes. This study provides results consistent with published light microscopy studies for other reptiles and additionally provides ultrastructural details of reptilian uterine development not previously available.     

Hypoglycemic effect of insulin incorporated into liposomes after oral administration to animals with different types of experimental diabetes

Different doses of insulin incorporated into liposomes were administered to normal animals and to those with certain forms of experimental diabetes. Lecithin-cholesterol liposomes in the molar ratio 9:1 were used. They were formed by the supersound treatment of the lipid suspension with the crystalline insulin in the buffer containing 140 mM NaCl and 10 mM tris-HCl (pH 7.4). Incorporation of insulin into liposomes was 16.2% in determination by [125I] insulin and 9.7% in determination of immunoreactive insulin after destruction of liposomes. Dynamics of glycemia and insulinemia was studied in these animals. It is established that insulin from liposomes being per os administered to animals evokes an expressed hypoglycemic effect and hyperinsulinemia. Effective sugar-lowering doses of liposomal insulin for animals with the experimental diabetes were from 6 ME/kg and for normal animals--from 30 ME/kg.