Exemestane dose steroids

Guzman-Soto and colleagues (2016) noted that recent findings have shown that GnRH administration in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE) improves clinical signs of locomotion.  These researchers examined if the administration of the synthetic analog of GnRH, leuprolide acetate (LA) -- besides its effects on clinical signs of locomotion -- also has an effect on the activation/expression levels of molecular markers of EAE, namely transcription nuclear factor (NF)-κB and the pro-inflammatory cytokines IL-1β, IL-17A, IL-23 and TNF-α.  EAE spinal cords were collected from control and LA-administered rats.  Lumbar sections were processed at 4 different time points during the course of the disease to analyze NF-κB activation by chemiluminescent Western blot, and during the EAE recovery phase to evaluate pro-inflammatory cytokine levels by quantitative real-time PCR.  It was found that LA administration to EAE rats promoted a significant reduction of NF-κB activation during the course of the disease and also decreased the mRNA expression levels of the pro-inflammatory cytokines IL-1β, IL-17A and TNF-α in the EAE recovery phase; both effects were consistent with the decrease in the severity of clinical signs of locomotion induced by the treatment.  The authors concluded that LA caused a reduction in the severity of locomotor activity, as well as in the activation of NF-κB and the number of pro-inflammatory markers in rats with EAE.  They stated that these findings suggested the use of this agonist as a potential therapeutic approach for multiple sclerosis.

Metabolism: Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity [see Clinical Pharmacology ( ) ] . Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases.

Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values that were approximately times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5'-DFUR AUC values that were approximately times the AUC values in patients administered the recommended daily dose.

A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC (0–24hr) levels in male (1418 ± 287 /mL) and female (2318 ± 1067 /mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose.

Exemestane dose steroids

exemestane dose steroids

A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC (0–24hr) levels in male (1418 ± 287 /mL) and female (2318 ± 1067 /mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose.

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