Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
Converging lines of evidence implicate the beta-amyloid peptide (Ab) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Ab production by functionally inhibiting g-secretase, the activity responsible for the carboxy-terminal cleavage required for Ab production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Ab production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-di¯uoro-phenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP V717F reduces brain levels of Ab in a dose-dependent manner within 3 h. These studies represent the ®rst demonstration of a reduction of brain Ab in vivo. Development of such novel functional g-secretase inhibitors will enable a clinical examination of the Ab hypothesis that Ab peptide drives the neuropathology observed in Alzheimer's disease.
During toxicologic evaluation of a dimeric PEG-linked protein, tumor necrosis factor binding protein (TNF-bp), vacuolation of renal cortical tubular epithelium was seen in male and female Sprague-Dawley rats (200-300 g) given i.v. doses of 40, 20, or 10 mg/kg every other day for 3 months. Tubular lesions in rats treated with 20 or 40 mg/kg for 3 months were only partially reversible after a 2-month recovery period. Despite the presence of marked vacuolation, there were no changes in BUN, creatinine, urinalysis parameters, urinary NAG, urinary B2-microglobulin, or fractional sodium excretion. Single i.v. doses > or = 20 mg/kg TNF-bp caused similar but milder changes. However, equivalent doses of PEG alone or the non-PEG-linked TNF-bp did not cause light microscopic evidence of vacuolation. Treatment of rats with another PEG-linked protein of similar molecular weight resulted in similar changes. Immunostaining for TNF-bp revealed positivity in the apical cytoplasm of renal tubular epithelium within 1 h of i.v. dosing. Immunostaining of kidneys from chronically dosed rats indicated that protein was present in some vacuoles as long as dosing continued; however, kidneys from animals on a reversibility study had vacuoles but no immunostaining for TNF-bp. These results, along with a study that showed more severe lesions with PEG-linked proteins of lower molecular weight and minimal if any lesions with PEG-linked proteins > 70 kDa, suggest that TNF-bp is filtered through the glomerulus and that the protein with attached PEG is reabsorbed by the proximal tubules. Vacuolation may be a result of fluid distension of lysosomes due to the hygroscopic nature of PEG. These studies demonstrated that PEG-linked proteins have the capacity to induce renal tubular vacuolation at high doses. However, the change was not associated with alteration of clinical pathology or functional markers.
During toxicologic evaluation of a dimeric PEG-linked protein, tumor necrosis factor binding protein (TNF-bp), vacuolation of renal cortical tubular epithelium was seen in male and female Sprague-Dawley rats (200-300 g) given i.v. doses of 40, 20, or 10 mg/kg every other day for 3 months. Tubular lesions in rats treated with 20 or 40 mg/kg for 3 months were only partially reversible after a 2-month recovery period. Despite the presence of marked vacuolation, there were no changes in BUN, creatinine, urinalysis parameters, urinary NAG, urinary B2-microglobulin, or fractional sodium excretion. Single i.v. doses > or = 20 mg/kg TNF-bp caused similar but milder changes. However, equivalent doses of PEG alone or the non-PEG-linked TNF-bp did not cause light microscopic evidence of vacuolation. Treatment of rats with another PEG-linked protein of similar molecular weight resulted in similar changes. Immunostaining for TNF-bp revealed positivity in the apical cytoplasm of renal tubular epithelium within 1 h of i.v. dosing. Immunostaining of kidneys from chronically dosed rats indicated that protein was present in some vacuoles as long as dosing continued; however, kidneys from animals on a reversibility study had vacuoles but no immunostaining for TNF-bp. These results, along with a study that showed more severe lesions with PEG-linked proteins of lower molecular weight and minimal if any lesions with PEG-linked proteins > 70 kDa, suggest that TNF-bp is filtered through the glomerulus and that the protein with attached PEG is reabsorbed by the proximal tubules. Vacuolation may be a result of fluid distension of lysosomes due to the hygroscopic nature of PEG. These studies demonstrated that PEG-linked proteins have the capacity to induce renal tubular vacuolation at high doses. However, the change was not associated with alteration of clinical pathology or functional markers.
Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG1 antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety studies included an immunohistochemical tissue cross-reactivity study, in vitro hemolytic potential and blood compatibility studies, and multiple dose toxicity studies. Toxicity studies were conducted in cynomolgus monkey because rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice weekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus monkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibition of vascular invasion of the growth plate. In addition, decreased ovarian and uterine weights and an absence of corpora lutea were observed in females receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal and ovarian changes were reversible with cessation of treatment. No other treatment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for longitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.
Natalizumab had no adverse effects on the general health, survival, development, or immunological structure and function of infants born to dams treated with natalizumab during pregnancy.
Ziconotide, a potent, selective, reversible blocker of neuronal N-type voltage-sensitive calcium channels, is approved in the United States for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. In the European Union, ziconotide is indicated for the treatment of severe chronic pain in patients who require intrathecal analgesia. Nonclinical investigations of ziconotide included a comprehensive characterization of its toxicology, incorporating acute and subchronic toxicity studies in rats, dogs, and monkeys; reproductive toxicity assessments in rats and rabbits; and mutagenic, carcinogenic evaluations performed in vivo and in vitro. Additional investigations assessed the potential for cardiotoxicity (rats) and immunogenicity (mice, rats, and guinea pigs), and the presence or absence of intraspinal granuloma formation and local cell proliferation and apoptosis (dogs). The resulting nonclinical toxicology profile was predictive of human adverse events reported in clinical trials and consistent with ziconotide's pharmacological activity. Frequently observed nonclinical behavioral effects included tremoring, shaking, ataxia, and hyperreactivity. Occurrences were generally transient and reversible upon cessation of treatment, and intolerable effects occurred at doses more than 45 times the maximum recommended clinical dose. Ziconotide was not associated with target organ toxicity, teratogenicity, or treatment-related gross or histopathological changes; it displayed no mutagenic or carcinogenic potential and no propensity to induce local cell proliferation or apoptosis. Although guinea pigs developed systemic anaphylaxis, antibodies to ziconotide were not detected in mice, rats, or guinea pigs, indicating low immunogenic potential. No evidence of granuloma formation was observed with intrathecal ziconotide treatment. In summary, the results from these nonclinical safety assessments revealed no significant toxicological risk to humans treated with ziconotide as recommended.
Natalizumab had no abortifacient or teratogenic effects, but was associated with changes in fetal hematopoiesis and leukocyte trafficking.
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