3D-HyCoSy provided advantages of better assessment of uterine cavity over XHSG. Compared with conventional XHSG, the efficacy of 3D-HyCoSy to assess tubal patency was acceptable. In addition, the procedure of 3D-HyCoSy appears to be better tolerated, requiring no sedation or anesthesia and a reduced examination time. Thus, 3D-HyCoSy with saline as a contrast medium is feasible and could comprise a routine outpatient procedure in the initial evaluation of infertile women.
Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response, and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers.
Weanling male Sprague-Dawley rats were fed one of four diets that varied in Cu, Zn or Cd content. To the control diet (I) Cu, Zn and Cd were added at 10, 100 and 0 mg/kg diet, respectively. Diets II and III also contained 10 mg/kg of dietary Cu, except that Zn was elevated to 1000 mg/kg for diet II, or Cd was added at 10 mg/kg for diet III. Diet IV was deficient in Cu (less than 1 mg/kg) with Zn at 100 mg/kg and no added Cd. At wk 6 postweaning, half of the rats fed diets I and IV were injected once with Cd acetate (5 mg Cd/kg body weight). The immediate response to Cd injection was an increase in metallothionein accumulation (three- to fourfold) and in Cu,Zn superoxide dismutase (SOD) accumulation (1.2- to 1.5-fold) in liver. SOD was estimated in an ELISA. These responses were not influenced by a change in Cu status (I vs. IV). However, in functional assays, SOD enzymatic activity was about half that of the control values. In this regard, SOD appears to be given high priority with respect to the utilization of cellular Cu, i.e., a 10-fold reduction in hepatic Cu only resulted in a twofold reduction in SOD activity and the amount of apoenzyme remained at normal levels.
Background This is an update to our 2012 publication on clinical trial considerations on male contraception and collection of pregnancy information from female partner, after critical review of recent (draft) guidances released by the International Council for Harmonisation [ICH] the Clinical Trial Facilitation Group [CTFG] and the US Food & Drug Administration [FDA]. Methods Relevant aspects of the new guidance documents are discussed in the context of male contraception and pregnancy reporting from female partner in clinical trials and the approach is updated accordingly. Results Genotoxicity The concept of a threshold is introduced using acceptable daily intake/permissible daily exposure to define genotoxicity requirements, hence highly effective contraception in order to avoid conception. The duration for highly effective contraception has been extended from 74 to 90 days from the end of relevant systemic exposure. Teratogenicity Pharmacokinetic considerations to estimate safety margins have been contextualized with regard to over- and underestimation of the risk of teratogenicity transmitted by a vaginal dose. The duration of male contraception after the last dose takes into account the end of relevant systemic exposure if measured, or a default period of five half-lives after last dose for small molecules and two half-lives for immunoglobulins (mAbs). Measures to prevent exposure of the conceptus via a vaginal dose apply to reproductively competent or vasectomized men, unless measurements fail to detect the compound in seminal fluid. Conclusion Critical review of new guidance documents provides a comparison across approaches and resulted in an update of our previous publication. Separate algorithms for small molecules and monoclonal antibodies are proposed to guide the recommendations for contraception for male trial participants and pregnancy reporting from female partners. No male contraception is required if the dose is below a defined threshold for genotoxic concern applicable to small molecules. For men treated with teratogenic mAbs, condom use to prevent exposure of a potentially pregnant partner is unlikely to be recommended because of the minimal female exposure anticipated following a vaginal dose. The proposed safety margins for teratogenicity may evolve with further knowledge.
The relationship between 6-mercaptopurine-induced alterations in mineral metabolism and the teratogenic effects of the drug were investigated. Pregnant Sprague-Dawley rats were fed diets containing 4.5, 100, or 1,000 micrograms Zn per 1 g diet. On day 11 of gestation, dams were given intraperitoneal injections of 6-mercaptopurine (27.5 mg/kg). At term, dams fed the 1,000-micrograms Zn per 1 g diet showed fewer drug-induced deleterious effects on reproduction and embryogenesis than did those fed lower levels of zinc. Mineral analysis of maternal and fetal tissues revealed pronounced effects of 6-mercaptopurine on metabolism of zinc, copper, iron, calcium, and magnesium. The results of this study indicate that 6-mercaptopurine teratogenesis may be due in part to drug-induced changes in mineral metabolism.
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