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      Gastrointestinal bleeding and massive liver damage in neuroleptic malignant syndrome

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          Abstract

          Background

          Neuroleptic malignant syndrome (NMS) is a rare side effect of antipsychotic therapy characterized by fever, muscular rigidity, altered mental status, increased level of serum creatinine phosphokinase, and increased number of white blood cells. The mortality rate of patients with NMS remains elevated.

          Methods

          We examined the clinical records of patients diagnosed with severe NMS admitted to the Clinical Toxicology Unit, Florence University Hospital, between 1990 and 2004.

          Results

          Eight patients presented with this neurological disorder. All were treated with supportive therapy, which included dantrolene, levodopa/benserazide, benzodiazepines, metamizole and/or paracetamol, and antibiotics. Five survived and three died. Of the three deceased, two had large hemorrhages in the gastrointestinal tract, and one had massive liver damage and diffuse hemorrhages throughout the body.

          Conclusion

          Our results suggest that gastrointestinal bleeding is a frequent cause of death in NMS patients. Bleeding may occur as a consequence of commonly accepted medical treatments (especially the use of cyclooxygenase inhibitors as antipyretic agents) and NMS-induced changes in blood coagulation status. To increase the survival rate of these patients, it is necessary to avoid using drugs that may facilitate gastrointestinal lesions and to utilize procedures known to decrease the risk of bleeding.

          Most cited references31

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          Cyclooxygenases 1 and 2.

          Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
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            Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.

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              Clinical pharmacology of platelet cyclooxygenase inhibition.

              Nonsteroidal anti-inflammatory drugs and sulfinpyrazone compete dose-dependently with arachidonate for binding to platelet cyclooxygenase. Such a process closely follows systemic plasma drug concentrations and is reversible as a function of drug elimination. Peak inhibition and extent of its reversibility at 24 hr varies consistently with individual pharmacokinetic profile. Inhibition of platelet cyclooxygenase activity by these agents is associated with variable effects on prostaglandin (PG) synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits thromboxane (TX) A2 production in a dose-dependent fashion when single doses of 0.1 to 2.0 mg/kg are given. Acetylation of the enzyme by low-dose aspirin is cumulative on repeated dosing. The fractional dose of aspirin necessary to achieve a given level of acetylation by virtue of cumulative effects approximately equals the fractional daily platelet turnover. Serum TXB2 measurements obtained during long-term dosing with 0.11, 0.22, and 0.44 mg/kg aspirin in four healthy subjects could be fitted by a theoretical model assuming identical acetylation of platelet (irreversible) and megakaryocyte (reversible) cyclooxygenase. For a given dose within this range, both the rate at which cumulative acetylation occurs and its maximal extent largely depend upon the rate of platelet turnover. Continuous administration of low-dose aspirin (20 to 40 mg/day) has no statistically significant effect on urinary excretion of either 6-keto-PGF1 alpha or 2,3-dinor-6-keto-PGF1 alpha, i.e., indexes of renal and extrarenal PGI2 biosynthesis in vivo. Whether a selective sparing of extraplatelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy, fewer toxic reactions, or both remains to be established in prospective clinical trials.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                September 2005
                September 2005
                : 1
                : 3
                : 225-230
                Affiliations
                Department of Preclinical and Clinical Pharmacology University of Florence Florence, Italy
                Author notes
                Correspondence: Guido Mannaioni Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy Tel +39 55 4271 261 Fax +39 55 4271 280 Email guido.mannaioni@ 123456unifi.it
                Article
                1661629
                18360563
                875bff03-263f-4dfc-90a9-90979b5c2a97
                © 2005 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Original Research

                Medicine
                fever,gastrointestinal bleeding,neuroleptic malignant syndrome
                Medicine
                fever, gastrointestinal bleeding, neuroleptic malignant syndrome

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