Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

Objective: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication.

Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising therapeutic modality for oncology indications. The concept of an ADC platform is to increase the therapeutic index (TI) of chemotherapeutics through more selective delivery of cytotoxic agents to tumor cells while limiting exposure to healthy normal cells. Despite the use of antibodies targeting antigens abundantly and/or exclusively expressed on cancer cells (i.

Fishing for teratogens: a consortium effort for a harmonized zebrafish developmental toxicology assay.

A consortium of biopharmaceutical companies previously developed an optimized Zebrafish developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 to 6 h post fertilization and assessed for morphological integrity at 5 days post fertilization. With the original 20 test compounds, this achieved an overall predictive value for teratogenicity of 88% of mammalian in vivo outcome [Gustafson, A. L.

Summary of the HESI consortium studies exploring circulating inhibin B as a potential biomarker of testis damage in the rat.

The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper.

The inhibin B response to testicular toxicants ethylene glycol monomethyl ether or dibromoacetic acid in male rats.

Background: This study was conducted as part of an ILSI-HESIconsortium effort to assess the utility of circulating inhibin B as an early biomarker of testicular toxicity in rats.

Methods: Two known testicular toxicants were selected for use in this study: ethylene glycol monomethyl ether (EGME) and dibromoacetic acid (DBAA). EGME (200 mg/kg/day), DBAA (250 mg/kg/day), or vehicle control (0.

Male and female fertility assessment in the cynomolgus monkey following administration of ABT-874, a human Anti-IL-12/23p40 monoclonal antibody.

Background: ABT-874 is an anti-IL-12/23 monoclonal antibody that binds to the p40 subunit of human IL-12 and IL-23. As part of its preclinical safety assessment, studies were conducted to asses its potential effects on the reproductive system in male and female cynomolgus monkeys.

Methods: Sexually mature male cynomolgus monkeys (n = 6/group) were administered once weekly subcutaneous doses of 0, 5, 25, or 100 mg/kg ABT-874 for 13 weeks.

Pre- and postnatal development in the cynomolgus monkey following administration of ABT-874, a human anti-IL-12/23p40 monoclonal antibody.

Background: ABT-874 is an anti-IL-12/23 monoclonal antibody that binds to the p40 subunit of human IL-12 and IL-23. As part of its preclinical safety assessment, studies were conducted to assess its potential effects on pre- and postnatal development in cynomolgus monkeys.

Methods: In the embryo-fetal development studies, ABT-874 was administered once weekly subcutaneously to adult female cynomolgus monkeys at doses of 0, 5, 25, or 100 mg/kg during gestation days (GD) 20 to 48.

Effects of SCH 486757, a nociceptin-1 receptor agonist, on fertility and reproductive hormone levels in female CRL:CD®[SD] rats.

Background: SCH 486757 is a nociceptin-1 receptor agonist that was in development as an antitussive. Studies were conducted to characterize its effects on female fertility and to examine its potential modes of action.

Methods: Female rats were administered up to 20 mg/kg SCH 486757 before/during mating through gestation day (GD) 7; female fertility and embryonic development were assessed on GD 14.

Developmental and reproductive toxicology studies in IL-12p40 knockout mice.

Background: Interleukin (IL)-12 is a cytokine that can exert regulatory effects on T and NK cells. This study was designed to identify potential developmental and reproductive hazards associated with IL-12p40 knockout in mice.

Methods: In the combined fertility and teratology study, female F0 C57/BL6 wild-type control mice and female F0 C57/BL6 IL-12p40 homozgyous knockout mice were assessed for estrous cyclicity, sperm, and mating parameters.

Effects of an antagonist of neurokinin receptors 1, 2 and 3 on reproductive hormones in male beagle dogs.

Background: SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels.

Methods: Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days.

Assessment of hydroxypropyl methylcellulose, propylene glycol, polysorbate 80, and hydroxypropyl-β-cyclodextrin for use in developmental and reproductive toxicology studies.

Background: A series of studies were conducted to assess Polysorbate 80 (PS80), Propylene Glycol (PG), and Hydroxypropyl-β-Cyclodextrin (HPβCD), when compared with Hydroxypropyl Methylcellulose (MC) in developmental and reproductive toxicology (DART) studies.

Methods: In the rat fertility study, 20 mg/kg MC, 10 mg/kg PS80, 1,000 mg/kg PG, 500 mg/kg HPβCD or 1,000 mg/kg HPβCD were administered orally before/during mating, and on gestation Day (GD) 0-7, followed by an assessment of embryonic development on GD 14. In the rat and rabbit teratology studies, the doses of MC, PS80, PG, and HPβCD were the same as those in the fertility study.

Effects of the histamine H1 antagonist chlorcyclizine on rat fetal palate development.

Background: The effects of histamine H1 antagonist chlorcyclizine on rat palate development were characterized following in utero exposure.

Methods: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg chlorcyclizine on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg chlorcyclizine at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR.

Comparative effects of interferon alpha-2b and pegylated interferon alpha-2b on menstrual cycles and ovarian hormones in cynomolgus monkeys.

Background: The covalent modification of interferon (IFN) alpha2b with monomethyoxy polyethylene glycol (PEG) reduces its clearance rate and increases its half-life. High doses of interferon (IFN) alpha2b have previously been shown to affect maintenance of pregnancy in rhesus monkeys. Given the role of ovarian hormones in reproductive function and pregnancy, this study was conducted to assess the effects of PEG-IFNalpha2b or IFNalpha2b (comparative control) on ovarian hormones and menstrual cyclicity in cynomolgus monkeys.

Diagnosing complicated grief: a closer look.

Over the past decade, a number of researchers have proposed a separate DSM category for complicated grief. Recently, there have been attempts to determine empirically the number and nature of variables comprising the complicated-grief syndrome. The present research addresses one such procedure for defining these variables.

Age-related changes of the somatotropic axis in cloned Holstein calves.

To determine if the development of the somatotropic axis in somatic clones (clones) is similar to that in heifers produced by artificial insemination (controls), serum samples were collected every 30 min for 6 h, once per month, for 7 mo from 4 clones generated from a 13-yr-old cow and from 4 age-matched controls. Average concentrations of growth hormone (GH) were not different between clones and controls, and GH concentrations declined over time in controls. Average concentrations of insulin-like growth factor I (IGF-I) were less in clones than controls, and IGF-I concentrations increased over time in both groups.