Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer

Summary The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 g/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forC _o (21.7±1.82 g/ml),K _m (2.66±0.68 g/ml) and V_max (0.86±0.06 g ml^–1 h^–1). On subsequent repeated dosing with PyG, both theK _m (4.31±0.48 g/ml) and the V_max (1.83±0.13 g ml^–1 h^–1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.Abbreviations PyG 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione - AG aminoglutethimide - CSCC cholesterol side-chain cleavage - HPLC high-performance liquid chromatography - AUC area under the concentration versus time curve This study was supported in part by grants to the Institute of Cancer Research (Royal Cancer Hospital) from the Cancer Research Campaign and Medical Research Council     

Detection of contamination with antineoplastic agents in a hospital pharmacy department

The contamination with fluorouracil, cyclophosphamide and methotrexate was studied in a hospital pharmacy department where these drugs were prepared. In the preparation room, air samples were taken before and during preparation of the drugs. Methotrexate was detected in one sample which was collected during preparation (0.3g/m³). Spot samples were taken in the vertical laminar airflow safety hood before and after preparation of the drugs and after cleaning of the hood. Contamination of the laminar airflow hood was: cyclophosphamide: 1–160 ng/cm²; fluorouracil: 10–62 ng/cm² and methotrexate: 2–633 ng/cm². Spot samples from the floor in front of and beneath the laminar airflow hood showed contamination with especially fluorouracil (48–236g/m²). The gloves used during preparation of the drugs were contaminated mainly with fluorouracil (5–980 ng/cm²). Urine samples from two workers involved in the preparation of the drugs were analysed for unmetabolized cyclophosphamide; it was not detected. Although no uptake of cyclophosphamide was established, it is shown that the methods for measurement of cyclophosphamide, fluorouracil and methotrexate in the preparation room are applicable for the control of occupational exposure to these drugs.     

Computed tomography as an adjunct to ultrasound in the diagnosis of acute acalculous cholecystitis

The sonographic and computed tomographic (CT) findings were reviewed in 17 patients with acute acalculous cholecystitis (AAC) over a 6-year period from 1984 to 1989. Of the six patients in whom both ultrasound and CT were performed, CT revealed marked gallbladder (GB) wall abnormalities, including perforation, and pericholecystic fluid collections in five patients not demonstrated by sonography. Of the total group, five patients had GB wall thicknesses of 3 mm (normal) at pathologic examination, which demonstrated a spectrum of disease ranging from acute hemorrhagic/necrotizing, to gangrenous acalculous cholecystitis with perforation. Sonography was falsely negative or significantly underestimated the severity of AAC in seven of the 13 patients examined by sonography. CT because of its superior ability to assess pericholecystic inflammation may provide additional diagnostic information even after a thorough sonographic study in cases of AAC.     

Transforming growth factor-beta plasma dynamics and post-irradiation lung injury in lung cancer patients.

PURPOSE: To investigate the relevance of transforming growth factor-beta (TGF-beta) dynamics in plasma for identification of patients at low risk for developing pneumonitis as a complication of thoracic radiotherapy (RT). PATIENTS AND METHODS: Non-small cell lung cancer patients undergoing conventional RT were included in the prospective study. Concentrations of TGF-beta were measured in the patients' plasma prior to and weekly during 6 weeks of RT. The incidence of symptoms of early post-irradiation lung injury, i.e. symptomatic radiation pneumonitis, was correlated with TGF-beta parameters. RESULTS: Forty-six patients were included in the study. Eleven patients (24%) developed symptomatic radiation pneumonitis. Absolute TGF-beta plasma levels did not differ between the groups of patients without or with pneumonitis. However, patients who developed pneumonitis tended to show increases in TGF-beta levels in the middle of the RT course relative to their pre-treatment levels while TGF-beta plasma levels of patients who did not develop pneumonitis tended to decrease over the RT treatment. The difference in the relative TGF-beta dynamics between the groups reached marginal significance in the third week of the treatment (P = 0.055) but weakened towards the end of the RT course. The utility of TGF-beta testing was evaluated at each RT week based on the test's ability to yield more accurate estimate of complication probability in an individual patient compared to empirically expected probability in similar group of patients. The ratio of TGF-beta level at week 3/week 0 being <1 showed an ability to improve the prediction of freedom from pneumonitis, yet with a large degree of uncertainty (wide confidence intervals). The accuracy of prediction deteriorated at later time points (weeks 4, 5 and 6) rendering the end-RT ratios without predictive power. CONCLUSIONS: We observed a trend of plasma TGF-beta concentration to decrease below the pre-treatment value during the RT treatment in patients who did not develop pulmonary complications after the RT treatment. However, this trend was not consistent enough to warrant safe decision-making in clinical setting.     

Stability of benefits of mime therapy in sequelae of facial nerve paresis during a 1-year period.

OBJECTIVE: To assess the stability of benefits of mime therapy, a modality of physiotherapy for patients with facial nerve paresis, during a period of 1 year. STUDY DESIGN: A prospective follow-up build on a randomized clinical trial in which a treatment group is compared with a control group. SETTING: Physiotherapy outpatient department. PATIENTS: Forty-eight patients with a history of a facial nerve paresis of 9 months or more. INTERVENTION: Mime therapy. METHOD: Sequelae of facial nerve paresis were measured using the same measurement instruments as in the randomized clinical trial--the Sunnybrook and the House-Brackmann (HB) Facial Grading Systems, the lip length and pout indices, a stiffness scale, and the Facial Disability Index. Stability of outcome level and of interpatient differences is analyzed. RESULTS: Of the 46 patients who completed the follow-ups, repeated-measures analyses of covariance revealed no significant differences in the average scores nor significant trends of the posttherapy measurements, except for the pout index and the Facial Disability Index-social. For six sequelae (except HB), 95% of patient-sequel combinations showed immediate improvement after mime therapy, for HB grades this was 74%. Where sequelae improved, the posttherapy individual courses (T2-T3-T4) showed, also for HB, in majority absence of deterioration; benefits obtained were stable. CONCLUSION: Mime therapy is effective in patients with facial nerve paresis and benefits are stable 1 year after therapy.     

Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.

PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.     

Bromobenzene-induced hepatotoxicity at the transcriptome level.

Rats were exposed to three levels of bromobenzene, sampled at 6, 24, and 48 h, and liver gene expression profiles were determined to identify dose and time-related changes. Expression of many genes changed transiently, and dependent on the dose. Few changes were identified after 6 h, but many genes were differentially expressed after 24 h, while after 48 h, only the high dose elicited large effects. Differentially expressed genes were involved in drug metabolism (upregulated GSTs, mEH, NQO1, Mrps, downregulated CYPs, sulfotransferases), oxidative stress (induced HO-1, peroxiredoxin, ferritin), GSH depletion (induced GCS-l, GSTA, GSTM) the acute phase response, and in processes like cholesterol, fatty acid and protein metabolism, and intracellular signaling. Trancriptional regulation via the electrophile and sterol response elements seemed to mediate part of the response to bromobenzene. Recovery of the liver was suggested in response to BB by the altered expression of genes involved in protein synthesis and cytoskeleton rearrangement. Furthermore, after 48 h, rats in the mid dose group showed no toxicity, and gene expression patterns resembled the normal situation. For certain genes (e.g., CYP4A, metallothioneins), intraday variation in expression levels was found, regardless of the treatment. Selected cDNA microarray measurements were confirmed using the specific and sensitive branched DNA signal amplification assay.     

Psychological Problems among Head and Neck Cancer Patients in Relation to Utilization of Healthcare and Informal Care and Costs in the First Two Years after Diagnosis

Background: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients. Method: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses. Results: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs. Discussion: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.