Animal results

Polyalphaolefin Hydraulic Fluids. No studies were located regarding ocular effects in humans after inhalation exposure to polyalphaolefin hydraulic fluids. Ocular effects in animals resulting from direct contact with aerosols of polyalphaolefin hydraulic fluids are discussed in Section 2.3, Dermal Effects. 

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

Direct application of neurotrophins to the brain of animals results in the rapid initiation of dramatic seizure activity, reflecting the coordinated discharge of large populations of neurons. This effect is the result of neurotrophin-stimulated release of neurotransmitters and enhanced synaptic efficiency. BDNF and NT3 cause... 

In vivo dialysis studies indicate that acute blockade of the NMDA receptor in experimental animals results in a dis-inhibition of forebrain dopamine-release, suggesting that dopamine-mediated psychosis could be secondary to a more primary defect in cortical glutamatergic signaling. 

For traditional PK studies in laboratory animals, one would dose three animals via an intravenous (IV) route and three animals via oral (PO) dosing, with a minimum of 8 time points per animal, resulting in a total of 48 samples for a PK study of one compound. For a comparison of six NCEs, using this standard PK procedure would result in the need to assay 288 samples. A large pharmaceutical company may have to assay 40 to 60 or more NCEs weekly via in vivo PK screening. This led to methods for reducing the number of samples that need to be assayed. 

The in vitro study may not use adequate controls (e.g., pH, vehicle used, volume of test agent given, samples taken from sham-operated animals), resulting in artifacts of methods rather than results. 

Limited data are available regarding inhalation exposure of humans and animals. Results of these studies are discussed below and presented in Table 2-1 and Figure 2-1. 

The introduction of an antigen into the tissues of a susceptible animal results initially in increased proliferation of lymphocytes in the tissues of the reticulo-endothelial system particularly the lymph nodes and the spleen (Figure 7.1). An animal will show different responses if the antigen is completely new to it (a primary response) or if the antigen has been encountered... 

Summary The summary presents the case for the drug s approval. It includes discussion about the drug s mechanism of action, its effect on animals, results of clinical trials, manufacturing and tests methods, its stability, and proposed dosage and treatment protocol. The summary may run into hundreds of pages. It is one of the few documents being read by all the different reviewers as such, a good summary will assist with the review process. 

Countless generations of grazing by wild and domesticated animals resulted in the survival and reproduction of the specialized qualities of grasses, especially turfgrasses. The evolutionary advantages of grasses, most clearly developed in... 

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

Interest in the therapeutic potential of drugs acting on the NMDA receptor has risen with the discovery that epilepsy and related convulsive states may occur as a consequence of a sudden release of glutamate. Sustained seizures of the limbic system in animals result in brain damage that resembles the changes seen in glutamate toxicity. Similar changes are... 

Cytogenetic effects were not found in bone marrow cells from mice treated with 1,4-dichlorobenzene by gavage at levels up to 1,800 mg/kg/day in a 13-week study (NTP 1987). No increase in micronucleated cells occurred even at levels that were extremely toxic to the test animals, resulting in liver toxicity and decreased survival rates. As noted by the authors of that study, the observed carcinogenic activity of... 

Skin application to animals resulted in erythema and necrosis, and application to the eye resulted in corneal necrosis. ... 

The carcinogenic risk to humans has not been determined, but 1,1-dimethylhydrazine is classified as a suspected human carcinogen based on animal results. The National Institute for Occupational Safety and Health (NIOSH) has also noted that the role of nitrosodimethylamine, a contaminant of 1,1-dimethylhydrazine, must be considered in evaluating the tumorigenicity of 1,1-... 

Acute exposure of experimental animals resulted in adverse effects similar to those described for humans. Rats did not survive when exposed to the vapor for longer than 6 minutes at 3 000 ppm minimum lethal concentration for an 8-hour exposure was 200ppm these exposures caused hepatic necrosis, pulmonary edema, and cloudy swelling of renal tubules. Depression of the central nervous system (CNS) was observed in rats exposed at higher concentrations, and deaths occurred within 24 hours from respiratory or cardiac... 

Hematological Effects. A transient increase in blood reticulocytes was observed in workers exposed to niekel in water from a contaminated water fountain (Sunderman et al. 1988). The water was also eontaminated with boric acid, and the contribution of boric acid to this effect is not known. Inconsistent effeets on hematoerit values were found in rats following inhalation exposure (Weiseher et al. 1980). A reversible deerease in hemoglobin and increases in leukocyte counts were observed in rats after oral exposure to niekel (American Biogenics Corporation 1988 Whanger 1973). Intrarenal injection of nickel subsulfide in animals resulted in erythrocytosis (Hopfer and Sunderman 1978 Hopfer et al. 

Application of isophorone to the skin of animals results in skin irritation, and application to the eye results in severe eye damage. There is some information that dermal exposure of rabbits causes signs of neurotoxicity at high doses. This could indicate that isophorone is absorbed dermally, but other systemic effects have not been described. 

Apart from the site and route of administration, formulation, dosage, and duration of treatment, biotransformation is often also affected by several other factors including age, species differences, sex differences, diet, diseases, hormones, and environment. The activity of the liver microsomal enzymes is low in newborns and aging animals resulting in a slower rate of biotransformation. Species differences in dosage and response are often due to biotransformation differences. Inadequate protein intake approaching starvation may also decrease the rate of biotransformation (12). Diseases of the liver sometimes also interfere with the normal biotransformation capacity. In addition, increase in biotransformation may occur at high body temperatures because of an increase in the metabolic rate. 

The route of administration also determines the level of the residues in the tissues in general, oral dosing of animals results in lower residue concentrations than injections (96, 97). For that reason, detectable residues of parent tylosin cannot be found in swine liver unless the medicated feed contains at least 1000 ppm of the drug (98) residues of the parent compound are also undetectable in poultry tissues following oral administration of tylosin. 

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