dextromethorphan and Pneumonia

Dextromethorphan (DM) has been shown to protect against endotoxic shock in mice. Heatstroke resembles sepsis in many respects. The objective of this study was to examine the heat-induced acute lung inflammation and injury in rats with or without DM, and for comparison with those of the rats with MK-801 (an N-methyl-D-aspartate receptor antagonist), SA4503 (a sigma-1 receptor agonist), or fluoxetine (a serotonin reuptake inhibitor). Heatstroke was induced by exposing the anesthetized rats to heat stress (43°C for 68 min). At 68 minutes after start of heat stress, animals treated with vehicle medium, DM (10-30 mg/kg of body weight, intramuscular), MK-801 (1 mg/kg of body weight, intraperitoneal), SA4503 (1 mg/kg of body weight, intraperitoneal), or fluoxetine (5 mg/kg of body weight, intraperitoneal) were allowed to recover at room temperature (26°C). As compared with vehicle-treated heatstroke rats (25-31 min; n = 8), DM (30 mg/kg)-treated heatstroke rats and MK-801 (1 mg/kg)-treated heatstroke rats had significantly greater survival time (193-209 min [n = 7] and 121-133 min [n = 8], respectively). However, the survival times for the SA4503-treated heatstroke rats (28-34 min; n = 8) or the fluoxetine-treated heatstroke rats (20-26 min; n = 8) were not significantly different from the vehicle-treated heatstroke rats. DM treatment significantly: (1) reduced acute lung injury, including edema, neutrophils infiltration, and hemorrhage scores; (2) decreased acute pleurisy; and (3) decreased bronchoalveolar fluid levels of the proinflammatory cytokines, and ischemia and oxidative damage markers during heatstroke. Our results indicate that DM therapy may improve outcomes of heatstroke in rats by antagonizing the N-methyl-D-aspartate receptors.

Topics: Acute Lung Injury; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Dextromethorphan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluoxetine; Heat Stroke; Hemodynamics; Inflammation Mediators; Lung; Male; Piperazines; Pneumonia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Time Factors

Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.

Topics: Analgesics, Opioid; Antitussive Agents; Codeine; Cough; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dextromethorphan; Genotype; Humans; Lung Diseases, Fungal; Male; Methylation; Middle Aged; Phenotype; Pneumonia

To describe the death of a toddler after a therapeutic dose of dextromethorphan and its investigation.. Case report, cytochrome P450 phenotype and genotype determination in the victim and post-mortem drug redistribution study performed in rats.. A 20-month Asian male who received 3 mg of dextromethorphan once at 09:00 h and again at 22:00 h was found dead at 04:35 h. Post-mortem examination showed signs of early bronchopneumonia (bacterial cultures were negative); dextromethorphan and dextrorphan blood concentrations taken from the heart cavity were 500 ng/ml (1. 84 micromol/l) and 200 ng/ml (0.78 micromol/l), respectively. Despite the dextromethorphan level being almost 100-fold higher than expected after therapeutic doses, intentional or unintentional overdose was extremely unlikely; other potential causes were investigated. Post-mortem drug redistribution study performed in rats showed that dextromethorphan does not undergo extensive redistribution after death (6+/-5-fold increase) and could not explain the observed dextromethorphan level. The dextromethorphan/dextrorphan concentration ratio of 2.5 found in this toddler was compatible with a slow CYP2D6 metabolizer phenotype. However, the toddler exhibited a fast metabolizer genotype. Potential reasons for this discrepancy are discussed.. CYP450 phenotypes derived from post-mortem blood levels should be interpreted with caution and preferably confirmed by a genotype analysis.

Topics: Animals; Antitussive Agents; Cause of Death; Cytochrome P-450 CYP2D6; Dextromethorphan; Dextrorphan; Excitatory Amino Acid Antagonists; Genotype; Humans; Infant; Male; Phenotype; Pneumonia; Rats; Rats, Wistar; Tissue Distribution