Additive effect of theophylline on the cardiac response to isoproterenol

To ascertain the effect of theophylline on the cardiac chronotropic response to beta-adrenergic stimulation, isoproterenol dose-response curves in healthy young subjects were compared during saline and theophylline maintenance infusions. Each study was repeated 1 to 3 weeks later to evaluate reproducibility. Neither the dose of isoproterenol required to raise the heart rate by 25 bpm (2.32 +/- 0.81 vs. 1.55 +/- 0.46 micrograms on day 1 and 1.28 +/- 0.22 vs. 1.27 +/- 0.25 micrograms on day 2) nor the slopes of the dose-response curves were affected by theophylline. Higher heart rates were observed after isoproterenol bolus dosing during theophylline than during saline infusion because of additive chronotropic effects of theophylline and isoproterenol. Since theophylline does not interact in a synergistic fashion with isoproterenol, phosphodiesterase inhibition appears to be an unlikely mechanism of the chronotropic effect of methylxanthines at therapeutic concentrations.     

Peripheral mononuclear leucocyte beta adrenoceptors and non-specific bronchial responsiveness to methacholine in young and elderly normal subjects and asthmatic patients.

BACKGROUND--As beta adrenoceptor dysfunction occurs in both the normal elderly subject and in young asthmatic patients, the hypothesis was examined that age related beta adrenoceptor changes are important in the pathogenesis of late onset asthma in old age. METHODS--Subjects were non-smokers who comprised 17 young normal subjects of mean (SE) age 29.4 (1.3) years, 17 elderly normal subjects of 67.2 (1.3) years, seven young asthmatic patients of 31.0 (2.8) years, and 17 elderly asthmatic patients of 68.5 (1.4) years. All asthmatic patients withheld inhalers for 12 hours and oral treatment for 24 hours before each study day. Subjects underwent an inhaled methacholine challenge (Newcastle dosimeter method) on two nonconsecutive days. The slope of the flow at 50% of the vital capacity (FEF50) dose-response curve was derived from the percentage fall in FEE50 divided by methacholine dose (sFEF50). Beta-adrenoceptor density (Bmax) and affinity (%KH) were determined with (125I)iodocyanopindolol as the radioligand in membranes prepared from mononuclear leucocytes. RESULTS--Log sFEF50 was shown to be reproducible (repeatability coefficient 0.41) on the two study days and was inversely related to %KH but not to Bmax. Multiple regression analysis (all 58 subjects, overall R2 = 0.57) revealed an inverse relation between log sFEF50 and %KH, and between log sFEF50 and Bmax. The inverse relation between log sFEF50 and %KH was preserved whereas that between log sFEF50 and Bmax was lost when young asthmatic subjects or when all asthmatic subjects were excluded from multiple regression analysis. CONCLUSIONS--The beta adrenoceptor dysfunction observed in late onset asthma may be similar to that seen during ageing. Thus late onset asthma may represent the extreme of a spectrum of age associated beta adrenoceptor dysfunction.     

Pharmacokinetics of Amonafide in dogs

Summary Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. [2] has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m²) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t_1/2, of Amonofide was 2.4±0.4 min, the intermediate t_1/2, 26.8±3.7 min, and the terminal t_1/2, 21.7±4.0 h. the peak plasma concentration achieved was 6.3±1.7 g/ml. The average apparent volume of distribution was 12.84±0.541/kg, and the total clearance was 0.56±0.161/kg/h. In 24 h, 9.5%±0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4%±1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20–25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The and plasma t_1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.     

Image-directed percutaneous biopsies with a biopsy gun

Core tissue for histologic study is believed by many pathologists to be more diagnostic than material from needle aspiration. Recently, a biopsy "gun" has been introduced, which simplifies core biopsies. With this device, 182 biopsies of multiple anatomic sites were performed with ultrasonic, computed tomographic, and fluoroscopic guidance and 18-gauge needles. High-quality histopathologic specimens were obtained in 177 of the biopsies, and diagnostic target tissue was obtained in 167. Only three significant complications occurred: one bleeding complication that required transfusion and two cases of pneumothorax that necessitated placement of chest tubes. The biopsy gun eliminated the disjointed movements of conventional "skinny" needle biopsies, and none of the samples demonstrated significant "crush" artifact or obscuring blood, problems that are commonly associated with manual biopsy techniques. Patient discomfort was decreased with this system compared with that of manual biopsies, and the total procedure time was reduced. Because of these distinct advantages, the authors now use the biopsy gun exclusively for all percutaneous biopsies and recommend that other institutions consider the use of this biopsy method.     

Osteosarcomatosis

A review of the 690 cases of osteosarcoma in the radiographic file of the Armed Forces Institute of Pathology revealed 29 cases of "osteosarcomatosis" (multiple skeletal sites of osteosarcoma). Fifteen of these patients were 18 years old and under and manifested rapidly appearing, usually symmetric, sclerotic metaphyseal lesions. The remaining 14 patients were more than 18 years old and had fewer, asymmetric sclerotic lesions. In most patients (28 of 29), a radiographically dominant skeletal tumor was seen. Pulmonary metastases occurred in the majority of patients and were detected at the same time as the bone lesions. These 29 patients were studied with regard to demographic data and skeletal distribution and radiographic appearance of their lesions. As a result of the findings, a metastatic origin from a primary dominant osteosarcoma is favored over a multifocal origin as the basis for osteosarcomatosis. Osteosarcomatosis is more commonly encountered in the mature skeleton than has been previously recognized.     

ROLE OF EPIDURAL MEDICATION IN LUMBOSCIATIC SYNDROME

Role of epidural medication through caudal route was studied in 109 patients having lumbago with or without sciatica to highlight the value of this mode of treatment which relieved symptoms in more than 70% of cases without hospitalisation and without being off work for long periods as in usual methods of conservative treatment.KEY WORDS: Epidural medication, Backache, Lumbago, Sciatica