Development of dapsone toxicity in patients with inflammatory dermatoses: activity of acetylation and hydroxylation of dapsone as risk factors.

BACKGROUND: Alternative independent routes of dapsone metabolism include N-hydroxylation to the hydroxylamine, a potentially toxic metabolite, by cytochrome P450 enzymes and acetylation to a nontoxic metabolite by N-acetyltransferase. Potentially, therefore, the relative extents of these two routes in an individual could determine the occurrence of adverse reaction with dapsone therapy. METHODS: Phenotypic activity of these two routes of metabolism was assessed in 18 patients receiving longterm dapsone therapy for inflammatory dermatoses and was related to the development of dapsone toxicity. N-Hydroxylation was assessed by the dapsone recovery ratio, a ratio of dapsone hydroxylamine to the sum of hydroxylamine and dapsone in 8-hour urine, whereas N-acetylation was assessed by the acetylation ratio, a ratio of monoacetyldapsone to dapsone in 8-hour plasma sample after an oral dose of dapsone. RESULTS: There was wide intersubject variation in both the acetylation ratio and the dapsone recovery ratio, but both phenotypic measures remained stable within individuals. The dapsone recovery ratio showed a tendency toward being lower in fast than in slow acetylators, but this was not statistically significant. There was an inverse relationship between acetylation and hydroxylation (r = -0.69; P < .005) at steady state that was not apparent after the first dose. Neurotoxicity developed in two subjects and hemolytic anemia developed in two subjects. Plasma levels of dapsone in these four subjects were similar to those in subjects who showed no toxicity. All four were slow acetylators and three were rapid hydroxylators, consistent with the toxic nature of dapsone hydroxylamine. CONCLUSIONS: These observations are consistent with what is known about the toxicity profile of dapsone metabolites and suggest that assessing N-acetylation and N-hydroxylation capacities can help to identify subjects at increased risk of a toxic response. This approach of assessing the phenotypic measures of drug-metabolizing activity to predict adverse reaction may also apply to other drugs with metabolic-based adverse effects.

Endothelins 1 and 3: potent cholestatic agents secreted and excreted by the liver that interact with cyclosporine.

Autoradiographic studies have shown that the liver accumulates endothelin. High-affinity binding sites for endothelin have been identified on rat liver plasma membranes. We investigated the role of endothelin isopeptides as mediators of cholestasis with isolated rat liver perfused by a recirculating solution of buffer and blood. These studies demonstrated that endothelin-1, as measured by means of radioimmunoassay, was cleared from the perfusate by the liver and that the liver concentrated both endothelin-1 and endothelin-3 in bile. Addition of endothelin-1 to the liver perfusate solution increased the concentration of endothelin-3 measured in the perfusate, suggesting that endothelin-1 caused release or secretion of endothelin-3. Both endothelin-1 and endothelin-3 at 5 nmol/L caused almost complete cessation of bile flow, but this effect was more prolonged after endothelin-1 than after endothelin-3 administration. Because it has been reported that cyclosporine increases endothelin levels, we studied the interaction of these two compounds. Cyclosporine (100 mumol/L) also produced cholestasis. Endothelin-3 secretion in bile, however, was decreased in livers perfused with cyclosporine compared with secretion in controls. Simultaneous addition of endothelin-1 and cyclosporine that on their own were not significantly cholestatic produced cholestasis. In conclusion, endothelin is a potent cholestatic agent secreted and excreted by the liver. It may potentiate the cholestatic action of cyclosporine.

Actions and reactions. Effects of employee theft on worker health.

The health and safety problems that arise from employee theft are considerable and should be recognized. Effective prevention of employee theft should focus on employee selection, education, and the factors associated with theft such as drug and alcohol abuse. When physical barriers are used at work sites to prevent theft, work site egress should be safe. Interaction between management and occupational health professionals can focus attention on the relationship between work site theft and employee health.

Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part II: Hyperchloraemia and genitourinary symptoms.

Exposure to elemental mercury vapour is known to influence renal function; however, severe renal disease has not been consistently identified. Eleven men were evaluated for renal disease after acute, massive mercury poisoning. Significant hyperchloraemia was identified in this group of patient and a reversible renal tubular defect was suggested by low normal serum bicarbonate, a normal serum anion gap and a positive urinary anion gap. The only other evidence of renal dysfunction was transient, mild proteinuria in one of the 11 patients. During this same time period, neuropsychological impairment was identified on a test of cognitive and visual-motor function, 'Trailmaking B', in seven of the 11 patients. Additionally, dysuria and ejaculatory pain occurred without evidence of urological disease. These complaints were more frequent in those patients with impairment on 'Trailmaking B' suggesting a neurological basis for these symptoms. The findings of this study support earlier observations that the brain rather than the kidney is the critical target organ after elemental mercury vapour exposure.

Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part I: History, neuropsychological findings and chelator effects.

Mercury poisoning occurred after the acute, prolonged exposure of 53 construction workers to elemental mercury. Of those exposed, 26 were evaluated by clinical examination and tests of neuropsychological function. Patients received treatment with chelation therapy in the first weeks after exposure. Eleven of the patients with the highest mercury levels were followed in detail over an extended period. Observations included the evaluation of subjective symptoms of distress, using the 'Symptom Check List 90-Revised' (SCL-90R) and tests of visual-motor function such as 'Trailmaking Parts A and B', 'Finger Tapping', 'Stroop Colour Word Test' and 'Grooved Pegboard.' On day 85 +/- 11 (mean +/- s.d.) after exposure, these 11 men again received either 2,3-dimercaptosuccinic acid (DMSA) or N-acetyl-D, L-penicillamine (NAP) in a short-term study designed to compare the potential to mobilize mercury and the incidence of drug-induced toxicity of these two chelating agents. Rapidly resolving metal fume fever was the earliest manifestation of symptoms. CNS symptoms and abnormal performance on neuropsychological tests persisted over the prolonged period of follow-up. There were significant correlations between neuropsychological tests and indices of mercury exposure. Serial mercury in the blood and urine verified the long half-life and large volume of distribution of mercury. Chelation therapy with both drugs resulted in the mobilization of a small fraction of the total estimated body mercury. However, DMSA was able to increase the excretion of mercury to a greater extent than NAP. These observations demonstrate that acute exposure to elemental mercury and its vapour induces acute, inorganic mercury toxicity and causes long-term, probably irreversible, neurological sequelae.

Cholestasis in transplant patients--what is the role of cyclosporin?

The use of the drug cyclosporin is limited by toxicity. It would be advantageous to develop therapeutic monitoring of cyclosporin which would predict the development of clinical toxicity. In the present study, alternative methods of measuring cyclosporin levels were evaluated in a heterogenous population of transplant patients, comparing a fluorescent polarization immunoassay using a non-specific polyclonal antibody, which measures both cyclosporin and its main metabolites, and a specific high-performance liquid chromatography assay for unchanged cyclosporin in blood. Neither measured variable alone correlated with laboratory evidence of renal toxicity (serum creatinine) or liver toxicity (serum glutamate transaminase, lactic dehydrogenase, alkaline phosphatase, or serum bilirubin). The relationship between metabolites and parent cyclosporin was quantitated using the ratio of cyclosporin levels determined by fluorescent polarization immunoassay over levels determined by high-performance liquid chromatography. A cohort of patients with markedly elevated ratios of cyclosporin were identified. When patients' data were reviewed collectively and individually there was a correlation between an elevated ratio and the serum bilirubin (r = 0.41, P less than 0.001). This association could be either due to cyclosporin as a cause of cholestasis or to cholestasis from any cause resulting in metabolite accumulation. Further studies are needed to clarify the role of cyclosporin in hepatic dysfunction and develop early, specific markers for this cyclosporin-associated toxicity.

Increased blood and urine copper after residential exposure to copper naphthenate.

Despite widespread industrial use of copper naphthenate, there are no reports of the relationship of copper naphthenate and copper absorption in humans or animals. We report a family of three individuals who lived in a home where copper naphthenate was sprayed on the inner foundation. Subsequently, these individuals developed non-specific complaints. In two of these individuals, serum copper levels were elevated when first measured months after copper naphthenate was sprayed in the home. A gradual decline over several years in urine and serum copper levels was observed in the individual who maintained follow-up. It is not known if symptoms reflected exposure to naphthenate, the solvent vehicle, volatilized copper, or the stress of exposure to a malodorous compound perceived as toxic. Exposure to copper naphthenate may be another cause of an elevated serum and urine copper level but the interpretation of these levels as "normal" or "toxic" requires additional study for clarification. This report suggests the need for further study of the absorption and relative toxicity of copper naphthenate.

The effect of pentoxifylline on the energy metabolism of ischemic gerbil brain.

Pentoxifylline decreases the cerebral edema resulting from cortical freezing lesions in cats, produces mitochondrial hypertrophy with preservation of structure in gerbils, and increases survival rate in gerbils rendered ischemic by temporary bilateral carotid occlusion. Since all these findings may be related to energy metabolism, the effect of the drug on postischemic cerebral phosphocreatine and ATP concentrations and on cytochrome oxidase activity has been studied. Brain slices prepared from animals subjected to bilateral carotid occlusion for 30 min and treated with pentoxifylline at release of occlusion, then allowed 3 h for recovery, exhibited higher concentrations of ATP and higher levels of cytochrome oxidase activity than did those of the untreated animals.

Analgesic potentiation and the distribution of morphine in the presence of triplennamine in mice.

Interest in the interaction of opioids and histamine antagonists arose from the observation that abusers of pentazocine and triplennamine experience a heroin-like euphoria that neither drug alone produces. The present study was conducted to evaluate the analgesic properties of the combination of the histamine antagonist, triplennamine (TRP), and morphine (MS). Analgesia was assessed using the hot plate at 55 degrees C and all drugs were administered intravenously. TRP had no analgesic effect. When a suboptimal dose of MS (3.5 mg/kg) was combined with TRP in a dosage range of 2.5-5 mg/kg, the latency in response to pain 10 minutes after drug administration was significantly increased and this potentiation was still evident 30 minutes after drug administration. Naloxone completely reversed the analgesia of MS and the MS-TRP combination. The distribution of 3H morphine in representative brain areas and plasma was not different in the presence or absence of triplennamine.