Central nervous system toxicity and

NSAIDs are associated with gastrointestinal, renal, hepatic, and central nervous system toxicity and may increase blood pressure. NSAIDs that are selective for the cyclooxygenase-2 (COX-2) isozyme are less likely to cause gastrointestinal complications but may increase the risk of cardiovascular events. They are no more effective than nonselective NSAIDs. Selective agents should be reserved for patients at high risk of gastrointestinal complications and low risk for cardiovascular events. 

An outbreak of acute human endrin poisoning associated with central nervous system toxicity and 19 deaths in 194 known cases occurred in Pakistan in 1984 (Rowley et al. 1987). The vector for exposure was not identified, but contamination of a food item was the likely cause of poisoning. 

Toxicology. Chlorinated dibenzo-p-dioxins (CDDs) cause chloracne, may cause hepato-toxicity, immunotoxicity, reproductive toxicity, developmental toxicity, and central nervous system toxicity, and are considered to be a human carcinogen. 

In rats and mice, benzyl chloride, benzotrichloride and benzal chloride produce signs of central nervous system toxicity and hyperaemia of the extremities (lARC, 1982). 

Menadione and its water-soluble derivatives are potentially toxic in excess and have been reported to cause hemolytic anemia, hyperbilirubinemia, central nervous system toxicity, and methemoglobinemia in the newborn. 

James CW, McNelis KC, Matalia MD, Cohen DM, Szabo S. Central nervous system toxicity and amprenavir oral solution. Ann Pharmacother 2002 36(1) 174. 

In humans, thiram is an eye, nose, and throat irritant, a central nervous system toxicant, and a skin sensitizer. Volunteers given daily thiram doses of 0.5 g day for several weeks showed no adverse... 

MacDonald AJ, Rostami Hodjegan A, Tucker GT, Linkens DA. Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model. Regul Toxicol Pharmacol 2002 35(2 Pt 1) 165 76. 

The isoforms of CYP450S and their regulation in the brain are of interest in defining the possible involvement of CYP450s in central nervous system toxicity and carcinogenicity. The CYP450s in the kidney and adrenal tissues include isotorms primarily involved in the hydroxylation of steroids, arachidonic acid, and 25-hydroxycholcalciferol. 

Less frequent is anaphylactic shock. To prevent this serious complication it has been recommended that one should exclude the presence of anti-asparaginase antibodies using a test with sensibilized latex before treatment starts (15 ). Side effects mentioned in only one of the two above surveys are fever in 19% and weight loss in 37% of 57 L-asparaginase courses in 35 patients (15 ), as well as elevated blood urea nitrogen in 6 and elevated serum amylase in 1 of 22 patients (22 ). One patient died after 3 doses of 500 units per kg body weight. He had an elevated blood urea nitrogen and serum creatinine level, as well as serious central nervous system toxicity and a fatty liver (22 ). 

AH four butanols are thought to have a generaHy low order of human toxicity (32). However, large dosages of the butanols generaHy serve as central nervous system depressants and mucous membrane irritants. Animal toxicity and irritancy data (32) are given in Table 4. 

Oral poisoning after accidental phenol ingestion has caused fulminant central nervous system depression, hepatorenal and cardiopulmonary failure [20]. No hepatorenal or central nervous system toxicities with properly performed chemical peels have been reported in the literature [21]. 

K. Arulanantham and M. Genel, Central nervous system toxicity associated with ingestion of propylene glycol, J. Pediatr, 93, 515 (1978). 

Poisoning episodes in humans show that the central nervous system is the primary target system of orally administered endrin. Acute human poisonings by endrin-contaminated food caused symptoms of central nervous system toxicity such as jerking of arms and legs, tonic-clonic contractions, convulsions, and sudden collapse and death (Carbajal-Rodriquez et al. 1990 Coble et al. 1967 Davies and Lewis 1956 Rowley etal. 1987 Waller et al. 1992 Weeks 1967). 

Death. Clinical reports in humans and studies in animals demonstrate that death due to central nervous system toxicity is the primary acute lethal effect associated with endrin exposure. A lethal dose of endrin in humans has not been identified, but 0.2-0.25 mg endrin/kg body weight is sufficient to cause convulsions (Davies and Lewis 1956). Liver, kidney, heart, and brain damage were reported following oral and inhalation exposures. Since endrin is no longer used commercially, the general public is not... 

Respiratory Effects. Breathing irregularities including Cheyne-Stokes respiration developed in two persons who fell into cisterns containing copper cyanide or potassium cyanide (Dodds and McKnight 1985 Trapp 1970) or whose hands were exposed to hydrogen cyanide (Potter 1950). The effects reflect the central nervous system toxicity of cyanide. 

In addition to binding to cytochrome c oxidase, cyanide inhibits catalase, peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, and succinic dehydrogenase activities. These reactions may make contributions to the signs of cyanide toxicity (Ardelt et al. 1989 Rieders 1971). Signs of cyanide intoxication include an initial hyperpnea followed by dyspnea and then convulsions (Rieders 1971 Way 1984). These effects are due to initial stimulation of carotid and aortic bodies and effects on the central nervous system. Death is caused by respiratory collapse resulting from central nervous system toxicity. 

Evidence of central nervous system toxicity in animals includes disturbed equilibrium in cats exposed to 7,200 ppm chloroform for 5 minutes, deep narcosis in cats exposed to 21,500 ppm for 13 minutes, deep narcosis in mice exposed to 4,000 ppm for 30 minutes, slight narcosis in mice exposed to 3,100 ppm for 1 hour, and no obvious effects in mice exposed to 2,500 ppm for 2 hours (Lehmann and Flury 1943). Memory retrieval was affected in mice exposed to chloroform via anesthesia (concentration not specified) (Valzelli et al. 1988). The amnesic effect was not long-lasting. 

The target organs of chloroform toxicity in humans and animals are the central nervous system, liver, and kidneys. There is a great deal of similarity between chloroform-induced effects following inhalation and oral exposure. No studies were located regarding reproductive effects in humans after exposure to chloroform alone however, Bove et al. (1995) studied the effects of drinking-water consumption on birth outcomes and found that exposure to TTHM at levels >0.1 ppm resulted in reduced birth weight and size as well as an increased risk of oral cleft, central nervous system, and neural tube defects. Since the authors... 

Neurological Effects. Neurological effects in hrnnans after acute inhalation exposure to chloroform are well documented because chloroform has been used as an anesthetic for surgery. Inhaled chloroform acts as a depressant on the central nervous system. Chronic inhalation exposure to chloroform resulted in exhaustion, lack of concentration, depression, and irritability in occupationally exposed people (Challen et al. 1958). In a case study, chloroform inhalation for 12 years resulted in psychotic episodes, hallucinations, and convulsions (Heilbmnn et al. 1945). Central nervous system toxicity was observed in humans after oral exposure to chloroform, which suggests that the effects of inhalation and oral exposure are similar. In case reports of patients who intentionally or accidentally ingested several ounces of chloroform, deep coma with abolished reflexes occurred within a few minutes (Piersol et al. 1933 Schroeder 1965 Storms 1973). 

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

Target organs of chloroform toxicity are the central nervous system, liver, and kidneys (see Section 2.2). Respiratory, cardiovascular, and gastrointestinal toxic effects have also been reported. Studies in animals also indicated that chloroform exposure may induce reproductive and developmental effects and cause cancer. Several studies investigated the possible mechanism for chloroform-induced toxicity (see Section 2.5). Proposed mechanisms of chloroform toxicity and potential mitigations based on these mechanisms are discussed below. The potential mitigation techniques mentioned are all experimental. 

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