Animal studies

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

The toxicity of common acryhc monomers has been characterized in animal studies using a variety of exposure routes. Toxicity varies with level, frequency, duration, and route of exposure. The simple higher esters of acryhc acid are usually less absorbed and less toxic than lower esters. In general, acrylates are more toxic than methacrylates. Data appear in Table 5. 

Toxicity studies (108—110) estabUshed tolerance levels and degrees of irritations, indicating that the eye is the area most sensitive to fluorine. Comprehensive animal studies (111—113) deterrnined a rat LC q value of 3500 ppm-min for a single 5-min exposure and of 5850 ppm-min for a 15-min exposure. A no-effect concentration corresponded to a concentration-time value of ca 15% of the LC q levels. 

Over the years animal studies have repeatedly shown that perfluorinated inert fluids are nonirritating to the eyes and skin and practically nontoxic by ingestion, inhalation, or intraperitoneal injection (17,22). Thermal degradation can produce toxic decomposition products including perfluoroisobutene which has a reported LC q of 0.5 ppm (6 hr exposure in rats) (31). This decomposition generally requires temperatures above 200°C. 

This compound has antihistaminic activity and is usehil in the therapy of motion sickness. It may also be effective in the control of post-operative nausea and vomiting. It is classified as FDA Category B for Pregnancy, ie, no demonstrated risks shown in animal studies however, no controlled trials in pregnant women. Large doses may cause drowsiness and dry mouth owing to decreased secretion of saUva. 

Hydraziae is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydraziae irritates the skin, eyes, and respiratory tract. Liquid splashed iato the eyes may cause permanent damage to the cornea. At high doses it can cause convulsions, but even low doses may result ia ceatral aervous system depressioa. Death from acute exposure results from coavulsioas, respiratory arrest, and cardiovascular coUapse. Repeated exposure may affect the lungs, Hver, and kidneys. Of the hydraziae derivatives studied, 1,1-dimethylhydrazine (UDMH) appears to be the least hepatotoxic monomethyl-hydrazine (MMH) seems to be more toxic to the kidneys. Evidence is limited as to the effect of hydraziae oa reproductioa and/or development however, animal studies demonstrate that only doses that produce toxicity ia pregaant rats result ia embryotoxicity (164). 

Human and animal studies indicate that inorganic manganese compounds have a very low acute toxicity by any route of exposure. The toxicity values for a given Mn compound are shown in Table 20 to depend on the species of test animal as well as the route of exposure. Manganese concentrations as high as 2000 ppm were found to be tolerated by test animals over a six-month period without any ill effects (208). 

Phase II. Initial clinical studies for therapeutic safety and efficacy are performed in volunteer patients who are suffering from the disease for which the dmg has therapeutic promise. Recognition of toxic symptoms and side effects are vital at this point because these may occur here, even when not observed in animal studies or in Phase I. 

Poly(ethylene oxide) resins are safely used in numerous pharmaceutical and personal-care appHcations. Poly(ethylene oxide) resins show a low order toxicity in animal studies by all routes of exposure. Because of their high molecular weight, they are poorly adsorbed from the gastrointestinal tract and completely... 

Sevoflurane. Sevoflurane, l,l,l,3,3,3-hexafluoro-2-propyl fluromethyl ether [28523-86-6] is nonpungent, suggesting use in induction of anesthesia. The blood/gas partition coefficient is less than other marketed products (Table 1) yet similar to nitrous oxide, suggesting fast onset and recovery. In animal studies, recovery was faster for sevoflurane than for isoflurane, enflurane, or halothane (76). Sevoflurane is stable to light, oxygen, and metals (28). However, the agent does degrade in soda lime (77). 

Phosphorothioates generally protect normal tissues more than tumors. Tumor protection reported in some animal studies can pardy be explained by physiological effects of the particular dmgs, which are specific to rodents (4). WR-2721 does not appear to protect human and most animal tumors, apparentiy because of the low availabiUty of the dmg to tumor cells (4). Many tumors appear to have a reduced capillary density (44), which may mean that these tumors have altered levels of alkaline phosphatase, the enzyme that converts WR-2721 to WR-1065. A reduced abiUty of thiols to protect the hypoxic cells characteristic of many tumors may also contribute to their selectivity for normal tissues. The observation that WR-1065 protects cultured normal human fibroblasts, but not fibrosarcoma tumor cells, suggests that additional factors may contribute to the selectivity of radioprotection by WR-2721 m vivo (18). 

Animal studies have shown that teas are effective in blocking or slowing carcinogenesis (121,131,133). Administration of teas or tea polyphenols to mice or rats have also been shown to decrease oxidative biomarkers, suggesting that tea polyphenols act as antioxidants (125,134). 

Dose—response evaluation is used in describing the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data may be derived from animal studies or from studies in exposed human populations. Dose—response toxicity relationship for a substance varies under different exposure conditions. The risk of a substance can not be ascertained with any degree of confidence unless... 

In 1971 the OSHA standard for benzene (20 CFR, Part 1910.0000) adopted a permissible exposure limit (PEL) of 10 ppm benzene measured as an 8-h TWA. In October of 1976 NIOSH updated its earlier criteria document on benzene and recommended that OSHA lower the benzene exposure standard from 10 to 1 ppm. This proposed implementation was blocked by the United States Supreme Court iu 1980 on the basis of iusufficient evidence linking benzene to cancer deaths. By the mid-1980s convincing evidence of the carciuogenicity of benzene appeared through animal studies which justified reconsideration of the 1 ppm PEL (130). 

Other toxicological effects that may be associated with exposure to benzyl chloride based on animal studies are skin sensitization and developmental embryo and/or fetal toxicity. A 1980 OSHA regulation has estabhshed a national occupational exposure limit for benzyl chloride of 5 mg/m (1 ppm). Concentrations of 160 mg/m (32 ppm) in air cause severe irritation of the eyes and respiratory tract (68). 

SPACEEIL has been used to study polymer dynamics caused by Brownian motion (60). In another computer animation study, a modified ORTREPII program was used to model normal molecular vibrations (70). An energy optimization technique was coupled with graphic molecular representations to produce animations demonstrating the behavior of a system as it approaches configurational equiHbrium (71). In a similar animation study, the dynamic behavior of nonadiabatic transitions in the lithium—hydrogen system was modeled (72). 

In normal human subjects, ANP infusion for one hour causes increased absolute and fractional sodium excretion, urine flow, GFR, and water clearance (53—55). As shown in many in vitro and in vivo animal studies, ANP achieves this by direct effect on the sodium reabsorption in the inner medullary collecting duct, ie, by reducing vasopressin-dependent free-water and sodium reabsorption leading to diuresis and by indirect effect through increased hemodynamic force upon the kidney. ANP inhibits the release of renin and aldosterone resulting in the decreased plasma renin activity and aldosterone concentration (56,57). 

In an animal study of rats exposed by inhalation to ethylene oxide at 10, 33, or 100 ppm for approximately two years (245), and in a separate chronic rat study in which rats were exposed to 50 or 100 ppm of ethylene oxide (240), increased incidences of mononuclear cell leukemia, peritoneal mesothelioma, and various brain tumors have been reported. In an NTP (246) two-year inhalation study of mice at 50 and 100 ppm, alveolar/bronchiolar carcinomas and adenomas, papillary cystadenomas of the harderian gland, and malignant lymphomas, uterine adenocarcinomas, and mammary gland tumors were increased in one or both exposure groups. 

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