Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Clonidine Use and Abuse Among Methadone Program Applicants and Patients

Forty-eight consecutive applicants and 30 known clonidine-abusing methadone patients at three methadone treatment programs were surveyed regarding their use of clonidine. Two distinct patterns of clonidine use emerged. Of 22 applicants who took clonidine illicitly, 15 used it primarily to decrease opioid withdrawal, as well as for its sedating effect. Applicants mostly obtained it from physicians, used an average dose of 0.37 mg at a time, and about one third believed clonidine to be addictive. In contrast, clonidine-using patients took clonidine primarily for its psychoactive effects, including the interaction with methadone, in addition to decreasing opioid withdrawal. Patients obtained clonidine frequently on the street and from family or friends, but less from physicians. The average reported dose for patients was 0.6 mg. The vast majority of these patients felt clonidine was addictive. Our findings, when coupled with the risk inherent in clonidine overdose, suggest that further research into the identification and treatment of clonidine abuse among methadone patients is warranted.     

Effects of dietary protein, fat and energy intake during an initiation phase study of 7,12-dimethylbenz[a]anthracene-induced breast cancer in rats

A factorial experiment was conducted to examine the effects of dietary protein (8, 16, 32% of energy from casein) and dietary fat (12, 24, 48% of energy from corn oil) on the initiation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in rats. Forty weanling female Sprague-Dawley rats were assigned to each of nine diets fed ad libitum. After 4 wk each rat received DMBA (20 mg/kg) via gastric intubation. For an additional 22 wk after carcinogen administration all rats consumed a diet containing 16% of dietary energy from protein and 24% from fat. Dietary fat, protein and ad libitum energy consumption exhibited statistically significant effects on final tumor prevalence, but interactive effects were not found. At necropsy, rats fed corn oil at 12, 24 and 48% of energy prior to DMBA administration showed tumor prevalences of 58, 58 and 85% with 116, 153 and 231 total tumors, respectively. The data indicate a significant nonlinear effect of dietary fat. Corresponding numbers for rats fed casein at 8, 16 and 32% of energy prior to DMBA were prevalences of 79, 65 and 59%, with total tumor counts of 194, 144 and 162. Higher dietary protein during the initiation phase was associated with a significant reduction in tumor prevalence, which was most striking between 8 and 16% of energy from protein. In addition, results of multiple logistic regression showed that tumorigenesis was increased with greater ad libitum energy intake. The odds of a tumor at necropsy were multiplied by 1.19 for each kilocalorie increase in ad libitum energy intake averaged over the post-DMBA phase of the experiment. An additional six weanling rats fed each diet for 4 wk were killed for assay of hepatic carcinogen metabolizing enzymes at the time corresponding to DMBA administration in the initiation experiment. Both protein and fat showed independent effects on the activity of several enzymes. However, enzyme activity did not suggest a unifying mechanism whereby these nutrients influence DMBA-induced mammary carcinogenesis.     

Minimally Invasive Axillary– Coronary Artery Bypass

Axillary artery-to-coronary artery bypass using reversed saphenous vein provides a simple method of applying the minimally invasive coronary bypass grafting procedure when the internal thoracic artery is not an adequate conduit. Although this may allow extended use of the minimally invasive coronary bypass procedure, the long-term patency of this technique is unknown.     

Rapadilino syndrome

We report on a boy with severe radial hypoplasia, absent thumbs and patellae, short stature, persistent diarrhea, slender nose and normal intelligence as another example of the RAPADILINO syndrome. © 1992 Wiley-Liss, Inc.     

Wheat bran and the induction of intestinal benzo(a)pyrene hydroxylase by dietary benzo(a)pyrene

The mucosa of the intestine responds to polycyclic aromatic hydrocarbons (PAH) with the rapid induction of benzo(a)pyrene hydroxylase (BPH). Studies were conducted to determine if dietary fiber would reduce exposure of the intestine to dietary benzo(a)pyrene (BP) as indicated by intestinal BPH activity. In all studies, female Sprague-Dawley rats were fed a fiber-free purified diet for 7 d, whereupon they were switched to experimental diets for 48 h. After 48 h their small intestinal mucosa was assayed for BPH activity. Diets for the initial study contained 0, 100, 400, 800, or 1200 mg BP/kg diet, each with and without 10% soft white wheat bran. Enzyme induction with 100 and 400 mg BP/kg diet was partially inhibited by bran, but with higher concentrations of BP there was no protective effect. The inhibition in BP-induced intestinal BPH activity was observed with 10% wheat bran but not with 3.3 or 6.6%. Subsequent studies showed no significant inhibition in BPH induction with cellulose or lignin, whereas all forms of wheat bran (hard red, soft white, or finely ground soft white) caused significant inhibition. In the final study, a diet containing charcoal-broiled beef, a known source of PAH, was compared with diets containing raw beef or soybean protein, each with and without 10% soft white wheat bran. BPH activity remained low with raw beef and soybean protein whether or not fiber was added. However, intestinal BPH activity was raised ninefold by charcoal-broiled beef. The addition of bran reduced BPH activity to 65% of that observed with the fiber-free, charcoal-broiled beef diet.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy.

The increasing interest in 5-fluorouracil (5-FU) modulation and the development of new antifolates has focused attention in recent studies on the expression of the target enzyme thymidylate synthase (TS) as a determinant of drug sensitivity and resistance. Resistance to TS-directed drugs has been shown to occur in vitro and in vivo with increased expression of the enzyme (determined by enzymatic assays as well as protein and gene expression assays). Several studies have evaluated the role of TS as a prognostic indicator of clinical response to chemotherapy containing TS-directed drugs. We have used a polyclonal antibody to recombinant human TS to establish a silver-enhanced immunogold staining method to localize TS in human tumours. Human tumour cell lines with acquired resistance to TS inhibitors owing to increased levels of TS were used to confirm the specificity of immunostaining. Stained sections were evaluated by image analysis. Immunostaining in tumour sections was greatly reduced (>80%) by preabsorption of the antiserum with recombinant TS. The method was used to determine the extent of TS immunostaining in 134 primary human colorectal tumours. The results were then compared with the clinical outcome and response to chemotherapy for the treatment of subsequent metastatic disease. A wide range (approximately 100-fold) of TS immunostaining was observed in these primary tumour sections. Normal mucosal tissue levels were 5-10 times lower than those observed in the adjacent tumour tissue. The values for TS immunostaining did not correlate with clinical endpoints, such as time from diagnosis to relapse, response to chemotherapy for disseminated disease, nor with Dukes'' staging. This lack of correlation may be because this group of patients was selected on the basis of their need for palliative chemotherapy and did not include patients who were cured of their disease. Also, primary tumour TS expression may not give a good indication of the TS expression in metastatic lesions. The prognostic significance of TS protein expression in primary and metastatic lesions requires further evaluation.     

Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioral model of clinical drug action

Latent inhibition (LI) of a conditioned emotional response (CER) has been proposed as a quantitative measure of selective attention. We have assessed the parallels of the pharmacology of LI in rats with the clinical pharmacology of schizophrenia. Drug and vehicle treated rats were divided into groups and preexposed 20 times to cage illumination as a CS, or not preexposed. All groups were conditioned with 2 CS-footshock pairings. The following day CER, as measured by interruption of drinking in response to CS presentation, was recorded. LI was observed as a decreased CER in preexposed relative to non-preexposed animals. LI was enhanced by haloperidol 0.3 mg/kg after 7 or 14 daily treatments, but not after a single acute dose. Haloperidol doses of 0.3 and 0.03 mg/kg enhanced LI, while doses of 0.003 and 3.0 mg/kg had no effect. Haloperidol enhancement of LI was unaffected by the coadministration of the anticholinergic agent trihexyphenidyl. Enhancement of LI is exhibited by the antipsychotic drugs fluphenazine, chlorpromazine, thiothixene, thioridazine, mesoridazine, and metoclopramide but not clozapine. The non-antipsychotic drugs pentobarbital, imipramine, chlordiazepoxide, trihexyphenidyl, and promethazine failed to enhance LI. LI exhibits striking parallels to the clinical pharmacology of schizophrenia.Preliminary data were presented in part at the Society for Neuroscience Annual Meeting, Phoenix, AZ, 1989