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The association of Ethinylestradiol 0.03 mg and Levonorgestrel 0.15 mg is a hormonal contraceptive that combines estrogen and progestogen. According to a bibliographic survey, these combined drugs present at least 18 known degradation products, which are required to control the potential impurities harmful to human health. The high number of impurities and the low concentrations of the active pharmaceutical ingredients (APIs) and their respective degradation products increase the complexity of the stability-indicating method development for this medicine. Thus, this work aimed to develop and optimize the stability-indicating method using the quality by design (QbD) approach and in-silico tools for application in samples of oral contraceptives sold in Brazil. The analysis samples were initially subjected to a forced degradation study through 7 days of exposure under acid and alkali hydrolysis, oxidative condition, and oxidation by metal ions. In addition to the chemical exposure, the sample was subjected to physical stress through 10 days of exposure under dry heat, moisture, and photolytic degradation. These exposure samples were analyzed in the development and optimization of chromatographic conditions. As a result, the developed method was able to separate 20 known substances, including the two APIs and their respective 18 degradation products, as well as unknown degradation products obtained by the forced degradation study. Finally, this stability-indicating method was successfully applied for comparative analysis of contraceptive drugs marketed in Brazil, newly purchased and subjected to accelerated stability condition at 40 °C and 75% RH over the 6-month period. • The development and optimization of the stability-indicating method using QbD approach and in silico tools. • Monte Carlo method was used for establishing the in silico chromatogram simulator worksheet. • The developed method was able to separate 20 known substances as well as unknown degradation products. • Comparative analysis among contraceptive drugs marketed newly purchased and subjected to accelerated stability condition. [ABSTRACT FROM AUTHOR]

Abstract: In Experiments 1, 2, and 3, we evaluated the effects of temporary weaning (TW), equine chorionic gonadotropin (eCG), and follicle-stimulating hormone (FSH) treatments on results of a fixed-time artificial insemination (TAI) protocol in postpartum Bos indicus cows. In Experiment 1, treatment with 400 IU eCG or with TW for 48h consistently improved pregnancy rates (PRs) at TAI, but, in Experiment 2, FSH treatment was less effective than eCG or TW. In Experiment 3, the inclusion of eCG treatment in cows subjected to TW did not improve PRs. We concluded that TW or 400 IU eCG should be included in the TAI protocol in postpartum Bos indicus cows to enhance fertility. In Experiment 4, we used records from heifers and cows treated with the proposed protocol during the 2006–2007 (n =27,195) and 2007–2008 (n =36,838) breeding seasons from multiple locations in Brazil to evaluate factors potentially affecting PRs. Overall PR at TAI was 49.6% (31,786 of 64,033). Pregnancy rate differed (P <0.01) among farm within location (results ranging between 26.8% and 68.0%; P <0.01), cow group within farm, by breed (Bos indicus, 48.3% [26,123 of 54,145]; Bos taurus, 61.7% [3652 of 5922]; and crossbred Bos indicus × Bos taurus, 50.7% [2011 of 3966]), category (nulliparous, 39.6% [2095 of 5290]; suckled primiparous, 45.2% [3924 of 8677]; suckled multiparous, 51.8% [24,245 of 46,767]; and nonsuckled multiparous, 46.1% [1522 of 3299]), body condition score at TAI (≤2.5, 43.0% [3409 of 7923]; 3.0, 49.6% [18,958 of 38,229]; and ≥3.5, 52.7% [9419 of 17,881]). Days postpartum at beginning of protocol did not affect PR (30 to 60 d, 47.6% [4228 of 8881]; 61 to 90 d, 51.7% [16,325 to 31,572]; and 91 to 150 d, 50.8% [7616 to 14,991]; P >0.1). Pregnancy rate was also consistently affected (P <0.01) by sire (results ranging from 7.2% to 77.3%) and artificial insemination technician (results ranging from 15.1% to 81.8%). [Copyright &y& Elsevier]

This prospective, multicenter study was conducted to evaluate the contraceptive reliability, cycle control and tolerability of a 21-day oral contraceptive regimen containing 20 μg ethinylestradiol and 75 μg gestodene in four Latin American countries (Mexico, Argentina, Brazil and Colombia). Participants took trial medication daily for 21 days. Contraceptive efficacy, cycle control and tolerability were evaluated over a period of 13 cycles. Efficacy data gathered from 5,109 treatment cycles were obtained from 393 participants. The trial medication proved to be an effective contraceptive and provided good cycle control. One pregnancy because of poor compliance was recorded. This resulted in a study Pearl index of 0.25. Forty-six percent of Latin American women reported one intracyclic spotting bleeding episode and 37.6% reported one intracyclic breakthrough bleeding (medium/excessive bleeding) episode during cycles 2–4 (primary target). Overall, intracyclic bleeding was reported in 41%. Overall, there was a trend towards a lower incidence of spotting in all the countries and this difference had statistical significance between Argentina and the others three countries (p < 0.05) during cycles 2–4. This trend was also apparent with respect to breakthrough bleeding, but again the difference did not achieve statistical significance. The discontinuation rate because of adverse events was low (3%); no serious adverse events were reported. More than 78% of the women in the four countries maintained constant body weight or lost weight (2 kg) during the study. The treatment effect on blood pressure was negligible. There were no appreciable changes in mean laboratory values over the course of the study. [Copyright &y& Elsevier]

Tambaqui (Colossoma macropomum Cuvier, 1818) is the main native fish species farmed in Brazil, and 17β-estradiol (E 2) is a natural steroid hormone commonly used for the production of female fish monosex population, which, in tambaqui, shows a higher growth rate than the male. Thus, to assess whether the fish meat of treated tambaqui contains hormonal residue levels, a high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC-MS/MS) method for the determination of E 2 residues in fish muscle was developed and validated. A QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) dispersive solid phase extraction method was used for the sample preparation. The chromatographic separation was performed in a Poroshel EC-18 reverse phase column. The mobile phase was a mixture of acetonitrile with 0.01% ammonium hydroxide (A) and water with 0.01% ammonium hydroxide (B). The ratio of A:B phases was 60:40 (v/v) used in an isocratic mode. The method validation was performed according to Commission Decision 2002/657/EC and Veterinary International Conference Harmonization (VICH GL49). Since matrix effects were observed, matrix-matched analytical curves are recommended for quantitation. The linearity, selectivity, intraday and interday precision, accuracy, decision limit, detection capability, and detection and quantitation limits of the method are reported. The limits of detection and quantitation were 0.3 ng/g and 1.0 ng/g, respectively. At these limits and slaughtering fish 7 months after the end of the treatment, the muscle of tambaqui did not show detectable hormone residue level. Thus, consumption of tambaqui edible tissue from fish treated with E 2 for the purpose of sexual reversion is unlikely to represent a risk associated with the exposure of human subjects as residue levels of this hormone are not detected in the fish muscle. Unlabelled Image • UHPLC-MS/MS method for quantitation of 17β-estradiol residues in tambaqui muscle • Reliable bioanalytical method to quantitate 17β-estradiol residues in fish muscle • QuEChERS sample preparation for quantitation of 17β-estradiol in fish muscle • Throughput method for surveillance 17β-estradiol residues in fish muscle • 17β-estradiol not detected in muscle of fish treated for sexual reversion purposes [ABSTRACT FROM AUTHOR]