Janice M. Cosgriff

Acetylator Phenotype in Human Bladder Cancer

The acetylator phenotype of 26 bladder cancer patients and 26 controls was determined by the sulfamethazine method to evaluate whether patients with the slow acetylator phenotype have a greater susceptibility for bladder cancer. This hypothesis has been suggested by experimental animal and human epidemiological observations. Of the 26 bladder cancer patients 12 (46 per cent) had the slow acetylator phenotype compared to 18 of 26 controls (69 per cent). Within the bladder cancer group there was no striking excess of the slow acetylator phenotype when subgrouped by occupational and smoking history. Our results show no significant association between the slow acetylator phenotype and human bladder cancer.

Influence of Phenytoin on Theophylline Clearance

The influence of phenytoin on theophylline elimination was studied in six healthy, nonsmoking subjects who were not taking any other drugs. Subjects were given an intravenous infusion of theophylline (aminophylline), 5 mg/kg, and several blood specimens were drawn over the following 24 hr for theophylline concentration determination. Subjects then began a 2‐wk course on oral phenytoin, 300 mg/day, and on day 15 were again challenged with theophylline. For each subject theophylline clearance (ClT) was greater when taking phenytoin (range 31 % to 65%). Mean ClT of the six subjects was 45% greater when taking phenytoin than when not taking phenytoin. In one subject, 24‐hr urine collections were obtained in the untreated and treated state for analysis of theophylline metabolites. These results showed a general increase in excretion for each of the three major theophylline metabolites in the phenytoin pretreated state compared to the control state. Results indicate that phenytoin increases theophylline elimination. Patients taking phenytoin may require larger theophylline doses than recommended to achieve therapeutic blood theophylline concentrations.

Cord Serum Bromide Concentration: Variation and Lack of Association with Pregnancy Outcome

Excessive maternal bromide exposure during pregnancy from drugs and occupation have been reported to have adverse effects on the fetus and newborn, including central nervous system depression at birth and possible teratogenicity. To define further fetal bromide exposure during pregnancy, we determined the cord serum bromide concentration in 1267 newborn babies born in Rochester, New York, during the 6-month period from January 1, 1984 to June 30, 1984. There was a normal distribution of the cord serum bromide concentration values (mean +/- SD = 8.6 +/- 2.6 mg/L; range 3.1 to 28.5 mg/L). The highest concentration was still significantly below the minimal bromide concentration associated with toxic effects (720 mg/L). There was no association between the cord serum bromide concentration and indices of fetal health including Apgar scores, presence of congenital malformations, and neonatal disposition. No mothers were taking significant amounts of bromide-containing drugs during pregnancy. The second highest cord serum bromide concentration (21.4 mg/L) was in a woman who was an amateur photographer and developed her own film, which required her to use chemicals containing bromide. Our results indicate that excessive fetal bromide exposure is rare and probably occurs only in the setting of maternal use of bromide-containing drugs or occupational exposure during pregnancy.

No Effect of Smoking on Sulfamethazine Acetylation

Seven healthy subjects who smoked at least one pack of cigarettes/d were acetylator-phenotyped with sulfamethazine (SMZ) while they were actively smoking, and again at least one month after they had completely stopped. There were no significant differences of the acetylation profiles in the smoking vs. nonsmoking state, as measured by %ASMZ in serum six hours post-SMZ dosing or by %ASMZ in urine five to six hours post-SMZ dosing. We conclude that smoking does not influence SMZ acetylation and probably does not affect drug acetylation in general.

Variation and Significance of Elevated Cord Serum Bromide Concentration (CSBC)

At least 4 cases of neonatal bromism secondary to maternal ingestion or exposure to bromide-containing compounds during pregnancy have been reported. The cardinal features in these babies were weakness and hypotonia. The maternal exposure in 3 cases was from drugs and in one case from presumed occupational exposure to bromide salts in the photographic film manufacturing industry. To determine the variation in CSBC and whether unsuspected neonatal bromism might be responsible for unexplained neonatal problems, we measured the CSBC in 196 consecutive babies born at Strong Memorial Hospital, Rochester, N.Y., during January 1984, using a sensitive HPLC method. The CSBC ranged from 3.4 - 17.0 mg/1 with a mean (± 1 SD) of 7.4 mg/l±2.1. There was no apparent increased frequency of neonatal complications in babies with higher CSBC. Most noteworthy was that the highest CSBC (17.0 mg/1) was in a baby whose mother was a professional photographer. This study suggests that there is variation in CSBC and that occupational exposure to bromides from use or processing of photographic film may cause increased CSBC.

Biochemical Profiles following Aspirin Administration in Reye's Syndrome Patients and Controls

Is aspirin an important factor in the pathogenesis of Reyes syndrome (RS)? We have challenged 11 control individuals (C), 5 first degree relatives of RS patients (FR) and two patients who have recovered from RS (RS-1 & RS-2) with standard doses of aspirin for 12 hrs. (600 mg. q 4 hrs.) while fasting. There were no differences in the preaspirin and postaspirin concentrations of ammonia, glucose, AST, or LDH in the RS patients compared to the controls. However, both RS patients showed increased lactate, decreased pyruvate, and decreased β-hydroxybutyrate concentrations following the aspirin challenge while controls showed an opposite trend as illustrated below:These biochemical differences in the RS patients compared to controls suggest an altered cytosolic redox state which is also an indirect index of mitochondrial function. One interpretation of these preliminary observations is that individuals who develop RS may be susceptible to mitochondrial injury when exposed to aspirin during fasting.