Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.

[Value of dynamic MRI in the diagnosis of hypophyseal microadenomas]. / Wertigkeit der dynamischen MRT in der Diagnostik des hypophysären Mikroadenoms.

PURPOSE: To evaluate dynamic MR imaging of the pituitary gland. MATERIAL AND METHODS: 19 patients with suspected mass lesions of the pituitary gland were examined at 1.5 Tesla with dynamic and standard MRI using a Turbo-FLASH sequence (1 image/s for 40 s). RESULTS: In 13/19 patients microadenomas were detected. One of the 13 microadenomas was detected using dynamic imaging and was not seen on standard MRI. The remaining 12 microadenomas were diagnosed with standard MRI. CONCLUSION: Dynamic imaging of the pituitary gland is a time-consuming and costly diagnostic technique. If laboratory results suggest the presence of a microadenoma and conventional MRI is unable to localise it, dynamic imaging should be performed.

Preparation for burn center verification.

Today's managed care environment has challenged health care institutions to deliver quality cost-effective health care. In the burn community the American Burn Association/American College of Surgeons Burn Center Verification has become an increasingly sought after quality credential. Essential to successful completion of the verification process is the identification of key components that must be in place before an application is submitted. These components must be well documented and present in the application and during the site visit. Adequate burn team preparation is a significant contributor to successful verification. In addition, the process necessitates self-examination and acquires the benefits of validating current practices and identifying opportunities for improved patient care and efficient operation. This article details the preparation process undertaken by one burn center before its successful verification.

Neurological rehabilitation in children and adolescents.

We report about 38 patients aged between 1 and 19 years (36.8% female, 63.2% male; mean age 7.8 years) admitted as inpatients for further neurorehabilitation mostly 4 weeks after severe acquired brain injury (ABI) of different aetiology. Of the patients, 73.7% were in a state of minimal responsiveness (vigilance score < 7 WVS) on admission. We evaluate the course of rehabilitation and the outcome 6 months after the end of the inpatient-period. The average stay of 15.5 weeks is strikingly low. The average intensity of therapy comes to about 16 units per week including strategies of rehabilitative education. The incidence of good rehabilitation was 21%, whereas almost 45% of patients displayed severe impairment. Although further improvements were found in almost 40% of patients 6 months later, these only slightly changed the overall picture of the GOS values. More than 3/4 returned to their families after rehabilitation, often despite great functional impairment. A return to the former environment outside the family (kindergarten, school) was, however, possible in 2/3 of the subjects. The proportion of minimally responsive patients fell from 73.7% to 18.4% during the stationary rehabilitation phase. After a further 6 months (follow up), 36.4% of the originally minimally responsive patients achieved a GOS value of > 5.

gamma-Glutamyltransferase and the inhibition of azo dye-produced neoplasia by concomitant administration of disulfiram.

The concentration and total amount of DNA in the livers of SD rats fed 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) gradually increased and reached a maximum in developing tumors. In SD rats fed 3'-Me-DAB plus disulfiram (DSF), the concentration of DNA was higher than in controls, but it soon became stabilzed and the total amount of DNA in the liver did not differ substantially from that in rats fed DSF alone. In rats given 3'-Me-DAB, neoplastic nodules and liver carcinomas appeared after 3 months, but in those fed both compounds these formations were absent even after 6 months. The activity of gamma-glutamyltransferase (GT-ase), a marker of chemically induced carcinogenesis in rat liver, gradually increased to extremely high levels in tumors even after 75 days when the diet of the animals was changed to a normal one. In rats fed 3'-Me-DAB plus DSF, GT-ase activity increased for the greater part of 80 days, gradually leveled off around the 100th day, and returned to almost normal levels when the rats were given a normal diet after 100 days. We concluded that DSF 1) did not interfere with 3'-Me-DAB-induced proliferation of preneoplastic cells and the increase in GT-ase associated with this reversible adaptation to the influx of 3'-Me-DAB; and 2) inhibited malignant transformation and, consequently, prevented the formation and proliferation of neoplastic cells and the increase in constitutive GT-ase related to neoplasia.

gamma-Glutamyltransferase, a common marker of human epithelial tumors?

Having previously established gamma-glutamyltransferase (GGT) as a marker of experimental carcinogenesis in rat liver, we investigated whether human tumors differ from their tissue or origin by showing a higher activity or different localization of this enzyme histochemically. We found such differences in each of the human carcinomas we examined. The presence of GGT activity in carcinomas arising in organs normally containing little (tongue) or no GGT activity (larynx, urinary bladder, and esophagus) clearly distinguished cancerous from normal epithelium. In the breast, colon and prostate, GGT activity was normally present in a defined anatomical distribution bordering luminal surfaces. Carcinomas arising from these tissues showed a loss of the normal pattern of activity and contained cells with almost homogenous GGT activity in the cytoplasm. Such differences clearly distinguished carcinomatous from normal epithelium in these organs. The increased GGT activity observed in all nine carcinomas arising from seven different organs suggests that GGT may be a common marker of human epithelial tumors and staining for GGT may become a useful tool in the detection of human epithelial neoplasms.

Inhibition of 3'-methyl-4-dimethylaminoazobenezene-induced hepatocarcinogenesis by portacaval shunt.

Adult male Sprague Dalwey rats on which end-to-side portacaval shunt (PCS) operation was performed did not hyperplastic nodules and hepatoms when they were fed 3'-methyl-4-dimethylaminoazobenzene in semisynthetic basal diet for periods of up to 169 days. In contrast, all the intact rats fed the same diet for only 75 days, developed hyperplastic nodules in the liver. Transferred to normal pellet for another 25 days, hepatomas developed in 100% of these animals. The amount of protein-bond 3'-Me-DAB was found to be much smaller in operated rats than in intact animals. The glutathione (GSH) level in PCS-operated rats was lower than in intact controsl. A single large dose of 3'-Me-DAB led to the increase of only about 30% in the concentration of GSH during the period of 24-48 h, compared to the increase of 50-100% in non-operated rats. No clear tendency to a gradual increase in the activity of gamma-glutamyl transpeptidase was noted in PCS-operated rats during the period of 5 1/2 months of 3'-Me-DAB feeding. The increase in GT-ase activity never exceeded 30% above the level of GT-ase in the livers of PCS-operated rats fed basal diet without the carcinogen. This striking inhibibiton of GT-ase increase induced by 3'Me-DAB in PCS-operated rats contrasted with an increase of GI-ase activity by 5,000% found in livers of non-operated rats with hyperplastic nodules after 75 days of 3'-Me-DAB feeding and the increase by up to 10,000% in developed hepatomas. These effects and the inhibition of 3'Me-DAB-induced hepatocarcinogenesis, manifested by lack preneoplastic morphologic changes and the absecnce of hepatomas in rats after PCS, can best be explained by functional deficiency of the liver to metabolize the procarcinogen 3'-Me-DAB into an activated carcinogen.

Gamma glutamyl transpeptidase in colon cancer induced by 1,2-dimethylhydrazine.

The study of the gamma-glutamyl transpeptidase (GTase) in colon of adult rats showed that in the sequence: duodenum, jejunum, ileum, cecum and colon, the colon has the lowest activity. There are, on the other hand, relatively small differences between GTase activities in the ascending, transverse and descending portions of the large intestine. GTase activity in the colon of neonatal rat is several times higher than in the colon of adult rats. Colon adenocarcinoma induced by 1,2-dimethylhydrazine were found to have a much higher GTase activity than the homologous normal tissue. Because these tumors resemble human colonic adenocarcinomas, it is suggested that the assay of GTase levels of human colon mucosa might be of potential value in the diagnosis of neoplastic changes.

Glutathione and gamma glutamyl transpeptidase in rat liver during chemical carcinogenesis.

Continued administration of several hepatocarcinogens led to an increase in the concentration of glutathione (GSH) in the livers of intact, but not of hypophysectomized or adrenalectomized rats. The concentration of GSH remained high untill the development of hyperplastic nodules. Subsequently, the concentration of GSH dropped to the normal level or below. A single dose of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) produced an increase of GSH which, within a certain range, depended upon the amount of the carcinogen. In well differentiated, slowly growing hepatomas, the concentration of GSH approached the level in normal adult rat liver. On the other hand, in nondifferentiated and rapidly growing hepatomas, GSH was only 30-40% of that in normal liver. The activity of gamma-glutamyl transpeptidase (GTase) increased within 24-48 hours after a single large dose of 3'-Me-DAB. Continued feeding of 3'-Me-DAB led to an exponential increase of GTase. During hepatocarcinogenesis, the level of GTase activity corresponded to the degree and size of pathologic changes produced in rat liver. Chloramphenicol partially inhibited the increase of GTase induced by 2-acetylaminofluorene. Pretreatment with 3-methylcholanthrene partially inhibited the increase of GTase that had been induced by a single dose of 3'-Me-DAB. Puromycin partially inhibited the increase of GTase induced by several doses of dimethylnitrosamine. These observations indicated a close connection between the activation of GTase and chemical carcinogenesis in rat liver. Measurements of GTase activity in 12 Morris hepatomas supported this conclusion; their GTase levels were greatly elevated compared with that in normal adult rat liver.