ABSTRACT
This article reviews the regulatory guidelines that provide for the inclusion of recovery groups in toxicology studies, presents the challenges in the design and interpretation of nonclinical recovery studies, and summarizes the best practices for the role of an anatomic pathologist regarding toxicology studies with recovery groups. Evaluating the potential recovery of histopathologic findings induced by a biopharmaceutical requires the active participation of one or more anatomic pathologists. Their expertise is critical in risk assessment regarding the potential for recovery as well as providing scientific guidance in the design and evaluation of studies with recovery groups.
Subject(s)
Toxicity Tests/methods , Toxicity Tests/standards , Animals , Biopharmaceutics/standards , Guidelines as Topic , Pathology/methods , Pathology/standards , Research Design , Toxicology/methods , Toxicology/standardsABSTRACT
We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.
Subject(s)
Acetates/chemistry , Amyloid Precursor Protein Secretases/metabolism , Fluorine/chemistry , Piperidines/chemistry , Acetates/chemical synthesis , Acetates/pharmacokinetics , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Diazonium Compounds/chemistry , Disease Models, Animal , Mice , Mice, Transgenic , Peptide Fragments/genetics , Peptide Fragments/metabolism , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Receptors, Notch/metabolismABSTRACT
Recombinant rat growth hormone (rrGH) and recombinant mouse growth hormone (rmGH) were developed to evaluate the potential carcinogenicity of each biologically active growth hormone (GH) as assessed in the respective species. Biological activities of rrGH and rmGH were demonstrated by showing an increase in body weight gain and serum levels of insulin-like growth factor-1 (IGF-1) in hypophysectomized rats receiving daily sc injections for 6 days. With the exception of pharmacologically mediated weight gain, rrGH and rmGH had no adverse effects in 5-week oral toxicity studies and no production of anti-recombinant GH antibodies. The high doses selected for the carcinogenicity studies provided systemic exposures of GH up to approximately 10-fold over basal levels. In the 105-week mouse carcinogenicity study, daily sc injections of rmGH at 0.1, 0.2, or 0.5 mg/kg/day were well tolerated and had no effects on survival or incidence of tumors. In the 106-week rat carcinogenicity study, daily sc injections of rrGH at 0.2, 0.4, or 0.8 mg/kg/day had a favorable effect on longevity in female rats administered 0.4 or 0.8 mg/kg/day, an increased weight gain in females and males, and no increase in the incidence of tumors. The absence of carcinogenic effects of recombinant GH administered daily for 2 years to rodents was consistent with publications of clinical experience, indicating a lack of convincing evidence for an increased risk of cancer in children receiving human recombinant GH replacement therapy.
