Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection

A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F ₁ female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant V_max of 0.424 g/min/ml, a Michaelis influx constant K_m of 1,42 g/ml, and a first-order efflux constant of 0.047 min^–1.The model simulations were not sensitive to V_max, K_m,and so long as the ratio V_max/was approximately 9g/ml. The values of V _max ,K _m ,and which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.     

Pets for the mentally ill

After studying the historical importance of the domestic animal through the ages and the role of the "pet" animal in the contemporary world, the authors present an analysis of the literature dealing with the function of the animal in child development and the use of animals as therapeutic "tools". The author's then consider, based on a series of observations, the relationship certain mentally ill patients may establish with one or several pet animals and the significance this object relation may have for the patient : animals become invested as counter depressive or delusional objects, auxiliary means for identification and projection, symbiotic relationship, as well as encouraging feeling of security and responsibility.     

Interleukin-2 and interferon-alpha2b as a daily alternating schedule in advanced renal cell cancer

Summary Interferon-alpha (IFN-) and interleukin-2 (Il-2) are effective as single agents in metastatic renal cell cancer (RCC) with response rates of 15–30%. Additionally, IFN- is assumed to act synergistically with Il-2 in the induction of lymphokine-activated killer cells. (LAK cells) in vitro. With the aims of increasing the response rate by combining both cytokines and of reducing side effects, we started a clinical trial with a daily alternating schedule of 10×10⁶ units/m² s.c. rIFN-_2b (Essex, Munich, FRG) and 3×10⁶ Cetus units/m² rIL-2 (EuroCetus, Frankfurt, FRG) in the form of 1 h infusions over a period of 14 days. Patients found to have progressive disease after two cycles of therapy were withdrawn from the study; patients with stable disease or better received two further cycles.Of the 27 patients included in the study, 22 (16 male, 6 female) are evaluable for response. In 1 patient with multiple pulmonary metastases complete remission was achieved, in 5 patients partial remission, and in 2 a minor response. The schedule was practicable; the main side effects were influenza-like symptoms, fatigue and hypotension. Some patients suffered from arthralgias and erythemas up to 3 weeks after finishing the therapy cycle. On the whole, the side effects seem to be less severe than those arising from schedules using continuous Il-2 infusions.This work was supported by Grant No. 01GA8802 of the Bundesministerium für Forschung und Technologie (BMFT)     

Preferences of elderly music listeners residing in nursing homes for art music, traditional jazz, popular music of today, and country music

The purpose of this study was to investigate seniors' comparative music preference for four generic styles including art music, country music, popular music of today, and traditional jazz. The study also attempted to identify certain variables that have an effect on preference. Sixty-three subjects with a mean age of 82.5 from four nursing homes in the South Central Michigan area participated in the study. An interview and musical preference test were administered to the subjects individually. The listening test consisted of 16 music selections, four from each style. The seniors judged how much they liked the selections on a scale from 1 to 5, with 5 indicating greatest preference. Results indicated that country music style was preferred the most, followed by traditional jazz, art music, and lastly popular music. Variables that were found to affect preference were education level, community size in which the seniors grew up, and music training outside the school setting.     

Method for Dissection of Mesenteric Metastases in Mid-gut Carcinoid Tumors

With adequate medical management the midgut carcinoid tumor generally is an indolent malignancy associated with substantial life expectancy and appreciable life quality, even in the presence of liver metastases and significant tumor burden. Abdominal complications may occur in this entity of carcinoids owing to entrapment of intestines and encasement of mesenteric vessels by mesenteric metastases and associated marked mesenteric fibrosis. This may be the cause of abdominal pain, disabling diarrhea, weight loss to the extent of malnutrition, and eventually the risk of death with acute or chronic intestinal obstruction or intestinal gangrene. Operative removal of the mesentericointestinal lesion is often indicated to prevent or treat these complications but may be technically difficult when mesenteric metastases extend in the vicinity of major vessels in the mesenteric root. At laparotomy 56 patients with advanced midgut carcinoids underwent removal of the mesenteric tumor with a method for preserving the mesenteric vessels. This was feasible by mobilizing and releasing the right colon and mesenteric root from posterior adhesions, identifying the mesenteric artery below the pancreas, and free-dissecting this artery on the tumor capsule in the mobilized mesentery. Dissection was successful even with tumors initially judged inoperable unless tumor growth completely surrounded the mesenteric vessels or extended retroperitoneally. One patient was subjected to distal intestinal artery bypass. Symptom relief was been substantial and often of long duration after mesenteric tumor removal in patients who prior to surgery often had threatening intestinal ischemia. Patients with advanced midgut carcinoids may benefit markedly from dissectional removal of mesenteric tumors, which (conceivably better than conventional wedge resection) preserves the length of the remaining intestine.     

Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).

PURPOSE: We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN-alpha-2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN-alpha-2a and IV vinblastine. RESULTS: Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P =.0248). Both arm A (median overall survival, 25 months; P =.0440) and arm B (median overall survival, 27 months; P =.0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN-alpha-2a-based therapies were moderately or well tolerated. CONCLUSION: Our results established the safety and improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF-alpha-2a-based outpatient immunochemotherapies, compared with sc-INF-alpha-2a/IV vinblastine.     

The history of endocrine therapy of benign and malignant diseases of the prostate

The discovery of endocrine therapy of diseases of the prostate can be regarded as one of the most important events in the history of medicine and in urology in particular. This article delivers an overview about scientists and clinicians involved in this work during the last 200 years. A close historical relation between the endocrine therapy of benign prostatic hyperplasia and prostate cancer can be recognized. The historical framework between the work of John Hunter in the late eighteenth century, that of Charles Brenton Huggins in the late 1930s, and that of Andrew Schally in the 1970s has been assembled herein. With respect to all the other men who contributed greatly to this medical achievement, e.g., Edward L. Keyes and Russell S. Ferguson, with their first report on radioorchiectomy for the treatment of metastatic prostate cancer in 1936, this historical vignette is intended to make them part of the historical record.     

Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression

A 15 year old boy with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome suffered recurrent episodes of severe intractable diarrhoea, steatorrhoea, and hypocalcaemia. The only treatment modality, which controlled the malabsorption syndrome, was immunosuppression with intravenous high dose methylprednisolone and oral methotrexate maintenance therapy.