The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical ...trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects.
61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology.
A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005).
Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.
A 22-year-old male who was affected by epidermolysis bullosa (EB) and xeroderma pigmentosa (with structural and pathological changes that preclude orotracheal intubation) underwent right upper ...extremity amputation and ipsilateral axillary lymphadenectomy. The patient was operated without intubation, thereby assuring an optimal state of acute postoperative pain control by regional anesthesia. Intravenous administration of ketamine and remifentanil plus low-dose sevoflurane resulted in anesthesia with spontaneous breathing by the patient. Moreover, the intraoperative brachial plexus nerve block before amputation followed by positioning of an epidural catheter to deliver continuous infusion of local anesthetics close to the cut nerves during surgery obtained a very good level of acute postoperative pain control.
Adult cat fleas, Ctenocephalides felis (Bouche), were fed suboptimal in vitro concentrations of lufenuron in blood to allow hatching off flea larvae for cytological study. At concentrations of 0.125, ...0.25, and 0.5 ppm, larval hatch was 64, 15, and 4% respectively. Larvae hatching from eggs laid by adults fed lufenuron at concentrations of 0.025, 0.08, or 0.125 ppm did not differ significantly from the control. However, many larvae from the 0.08-ppm group and higher concentrations died during the 1st instar. Examination of these larvae revealed that they were dying from desiccation caused by bleeding from microscopic lesions in the cuticle or the inability to complete the molt to the next instar. Electron micrographs showed that lufenuron often disrupted formation of the endocuticle resulting in the deposition of an amorphous mass of randomly oriented chitin microfibrils. Other larvae formed normal endocuticle but were unable to digest the old endocuticle or produce new procuticle after apolysis. Failure of larvae to digest old cuticle or form new cuticle was caused by degeneration of the epidermal cells needed for the synthesis of molting fluid and chitin
When cat fleas, Ctenocephalides felis (Bouche), were fed concentrations of lufenuron in cattle blood ranging from 0.5 to 4 ppm, adult mortality increased in a dose-dependent manner to a maximum of ...approximately equal to 24% over a period of 10 d. Fleas treated with 0.5 ppm produced abnormal endocuticle consisting of protein globules embedded in an amorphous chitin matrix. At concentrations of 1.0 ppm or greater, endocuticle formation was inhibited. Ultrastructural studies demonstrated that inhibition of chitin synthesis was associated with degeneration of the epidermal cells. The amount of epidermal cytoplasm decreased and cytoplasmic organelles including mitochondria, ribosomes, and golgi showed lytic changes. At least some mortality of treated fleas was likely the result of a weakened endocuticle and the corresponding decrease in resiliency of the cuticle to expansion during blood-feeding and egg production. An unexpected result of lufenuron treatment was the inhibition of midgut epithelial cell differentiation. At concentrations of 0.5 and 1.0 ppm, partially differentiated epithelial cells were seen in the midgut of bloodfed fleas along with fully differentiated cells.
Adult cat fleas were exposed to residues of pyriproxyfen and methoprene in glass vials, then fed on a cat 24 h later to investigate the mode of action of juvenoid growth regulators on embryonic ...development in flea eggs. Eggs laid by pyriproxyfen-treated fleas within 70 h after exposure to this juvenoid were often devoid of yolk and frequently collapsed after oviposition. Minimal amounts of yolk were deposited in eggs laid after 70 h, and no blastoderm was formed. These results are significant because both modes of action were different than those observed earlier by investigators studying ovicidal effects in adult insects treated with juvenile hormone. In contrast to the pyriproxyfen results, eggs laid by methoprene-treated fleas showed no gross morphological effects, and these eggs remained turgid during embryogenesis. However, the eggs either did not hatch or the larvae died within hours after hatching. Histological examination of the eggs revealed that most of the eggs contained segmented embryos which had apparently died during blastokinesis. Although eggs of some insects exposed to juvenile hormone during oogenesis fail to undergo germ band formation, there was no evidence of this effect in methoprene-treated cat fleas
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