Tolerance acute

Safety of the product itself for the target organism, the user (who applies it) or the environment is addressed by a range of preclinical and clinical assessments which depend on the product and its use pattern. The range of safety features to be assessed includes local and systemic tolerance, acute and chronic toxicity, mutagenicity and tumorigenicity, reproductive toxicity, immunotoxicity and, for veterinary medicinal products, also the ecotoxicity. The safety tests will be described in more detail in a separate chapter below on preclinical pharmacological and safety test procedures. 

The US EPA ECOTOX database reports that Cer-iodaphnia and Daphnia species are the most sensitive freshwater organisms following acute (48 h) exposure to benzene, with respective EC50 values of 130 and 400 ppb. Most organisms, however, can tolerate acute concentrations higher than this (in the 1-10mgl ... 

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). 

Inhalation is the chief route of worker exposure. Comparative data from acute or subchronic inhalation exposures with rats (98) indicate that nitromethane and nitroethane are the least toxic of the nitroparaffins by this route and do not induce methemoglobin formation. The nitropropanes are less well tolerated 2-nitropropane is more toxic than 1-nitropropane and is more likely to cause methemoglobinemia. 

Toxicity. Sugar alcohols are classified as relatively harmless. Acute oral toxicity values in mice for mannitol and sorbitol (5) are given in Table 4. The acute oral LD q value for xyUtol in mice is 25.7 g/kg (205). Ingestion of 10 g/d of either mannitol or sorbitol by a normal human subject for one month resulted in no untoward effects (206). XyUtol given to healthy humans for 21 d in increasing doses up to 75 g/d produced no adverse effects (207). The limiting dose of xyUtol for production of diarrhea in humans is 20—30 g (4), but tolerance usually develops on continued adrninistration (207). 

Isocyanates. Isocyanates in general are toxic chemicals and require great care in handling. Oral ingestion of substantial quantities of isocyanates can be tolerated by the human body, but acute symptoms may develop from the inhalation of much smaller amounts. The inhalation of isocyanates presents a ha2ard for the people who work with them as weU as the people who Hve in the proximity of an isocyanate plant. Adequate control of exposure is necessary to achieve a safe working environment. The suppHers Material Safety Data Sheets (MSDS) have to be consulted for the most current information on the safe handling of isocyanates. 

A number of chimerized, humanized, and one human mAb have now been approved for therapeutic use in humans in the treatment of autoimmunity, malignancy, infection and cardiovascular disease (Table 1). Some of the currently licensed mAb will be discussed here. A much larger number of mAb are currently being evaluated in Phase I, II and III trials. In general, chimeric, humanized and human mAb are very well tolerated with few side effects. Chimeric or humanized mAb still have the potential to evoke host immune response to the variable domains or CDRs of the antibody so-called HACA (human anti-chimeric antibody) or HAHA (human anti-human antibody) responses, although these responses are uncommon. Short-lived and occasionally severe infusion-related acute hypersensitivity reactions such as fever, skin itching, shivering, respiratory compromise and low blood pressure sometimes occur-. Such effects may... 

Promoting an Optimal Response to Therapy The patient with a musculoskeletal disorder may be in acute pain or have longstanding mild to moderate pain, which can be just as difficult to tolerate as severe pain. Along with pain, there may be skeletal deformities, such as the joint deformities seen with advanced rheumatoid arthritis. For many musculoskeletal conditions, drug therapy is a major treatment modality. Therapy with these drugs may keep the disorder under control (eg, therapy for gout), improve the patient s ability to carry out the activities of daily living, or make the pain and discomfort tolerable. 

Not cross-tolerant to benzodiazepines and should not be used for acute withdrawal high doses may be used to treat anxiety disorders to help maintain long-term discontinuation after abstinence has been achieved. 

Avramov MN, Shingu K, Mori K Progressive changes in electroencephalographic responses to nitrous oxide in humans a possible acute drug tolerance. Anesth Analg... 

---