High-dose 1,2,4-triglycidylurazol given in regimens preparatory to bone marrow transplantation. A preclinical pharmacology study.

To elucidate its potential role in the framework of bone marrow transplantation, we studied the toxicologic and pharmacologic properties of high doses of the triepoxide derivate 1,2,4-triglycidylurazol (TGU) in a preclinical dog model. Dose-dependent and dose-limiting gastrointestinal toxicity occurred in a dose range between 40 and 75 mg/kg, with the lethal dose for 50% of animals (LD50) being estimated at 60 mg/kg. Severe and life-threatening hematologic toxicity developed at all dose levels examined but was generally reversible. The combination of TGU and total-body irradiation produced synergistic gastrointestinal toxicity, necessitating reductions of the TGU dose by 50% as compared with the single-agent dose. In contrast, the combination of TGU and high-dose busulfan resulted in no apparent nonhematologic synergistic toxicities. The immunosuppressive properties of TGU given in this combination enabled sustained histocompatible allogeneic marrow engraftment in three of four animals. The pharmacokinetics of TGU were not influenced by prior total-body irradiation or high-dose busulfan. We conclude that the myelotoxic, pharmacologic and immunosuppressive properties of high-dose TGU observed in this preclinical model seem to render the drug particularly suitable for use in regimens preparatory to bone marrow transplantation.

Clinical results and the Essen concept of TBI.

Total body irradiation (TBI) prior to bone marrow transplantation (BMT) is applied for treatment of 230 patients in the period 1975-1988. The clinical results of 169 patients treated by four different TBI dosage and treatment techniques are analysed. The risk of leukemic relapse is low after fractionated TBI (9%) as well as after single dose TBI (14%). The lowest frequency of interstitial pneumonitis (21%) occurred when the patient translation technique was used for fractionated homogeneous pa/ap TBI with 10 Gy (8 Gy lung dose) in 4 fractions in 4 days. Prophylaxis of GVHD and the modus of protective environment were two other factors which influence the risk of IP.

Total body irradiation in Essen--dosimetry and physical treatment planning.

Since 1975, in Essen 109 patients received total body irradiation (TBI) prior to bone marrow transplantation. About 80 patients were treated by bilateral 5.7 MeV photon beams. Three new TBI techniques were developed providing precise, homogeneous, reliable and reasonable a. p./p. a. TBI for adults and children. Systematic TBI dosimetry and the beam-zone method enable for individual treatment planning.

[Function tests of the lower small intestine with 75selenium-labeled homotaurocholic acid in Crohn disease and resections of the small intestine]. / Funktionsuntersuchungen des unteren Dünndarms mit 75Selen-Homotaurocholsäure bei Morbus Crohn und Dünndarmresektionen.

UNLABELLED: Faecal excretion of bile acids was investigated using 75Se-homotaurocholic acid (75SeHCAT) in a total of 75 patients: 9 with irritable colon, 58 with Crohn's disease and 8 with small-bowel resection due to various indications but without Crohn's disease. Bile acid malabsorption, taken as a pathological bile acid retention of less than 19%, was found present in 43 patients with diseased terminal ileum or with more than 20 cm resection of this organ, except in one case (12 cm). On the other hand a normal bile acid retention (21 to 27%) was found in 29 of 72 patients (including 9 patients with irritable colon) who showed either no radiologically detectable lesion of the ileum (n = 21) or changes involving an extension of up to 30 cm (inflammation or resection) in the terminal ileum (n = 8), with the exception of one case (50 cm). Three patients had a raised bile acid excretion contrary to clinical expectation: they had colitis Crohn without radiologically detectable involvement of the small intestine. Thus using the 75SeHCAT-retention test it seems possible to recognize functional disorders in diseased segments of the bowel before the appearance of radiologically detectable changes. CONCLUSION: 75SeHCAT is a suitable substance for investigations on the function of the lower small intestine.

[Comparative studies of various methods of measuring bile acid secretion using 75Se-labelled homotaurocholic acid (75Se-HCAT)]. / Vergleichende Untersuchung über verschiedene Messverfahren zur Beurteilung der Gallensäurenausscheidung mittels 75Se-markierter Homotaurocholsäure (75Se-HCAT).

The simple determination of whole-body retention of the bile acid analogue 75Se-HCAT provides results which are in agreement with those of the established but more difficult measurement of 24-14C-TCA excretion in the feces. Determining whole-body retention of 75Se-HCAT is not only practicable with a whole-body counter but also, with precision, with the more widely used gamma camera. Therefore, the bile acid retention test may be employed wherever there is a gamma camera available.

[Analysis of vesico ureteral reflux by functional scintigraphy (author's transl)]. / Die Analyse des vesiko-uretero-renalen Refluxes mittles Funktionsszintigraphie.

With a large view scintillation camera and gamma 11/34 DEC-System it is possible to detect a reflux out of the bladder, if the volume is 0.2 ml or larger. Description of the function of upper urinary tract is given. Time of reflux beginning a bladder volume combined with measurement of intravesical and intraabdominal pressure and more details of the reflux dynamic are demonstrated. Background activity and absorption of body soft tissue should be corrected by phantom measurement. The results of investigations of 26 patients are shown in tables and by examples of morphologic and functional analyses.

[Changes of renal function following revascularisation of renal arteries especially by Dotter's technique (author's transl)]. / Veränderung der Nierenfunktion nach Eingriffen an den Nierenarterien unter besonderer Berücksichtigung der Methode nach Dotter.

The rapid sequential scintigraphy with 131I-hippuran is a well established valuable procedure in follow-up studies of patients after non surgical revascularisation of renal artery stenosis. With this non invasive easily reproducible method both the changes of renal circulation and of renal function can be assessed simultaneously.

Scintiphotographic studies for long-term results in carotid cavernous sinus fistulae.

Scintiphotographic studies as a method for analyzing the brain perfusion in carotid cavernous sinus fistulae before and after surgical treatment with different techniques are presented. Twelve patients have been reexamined long after their operation to prove the sufficient crossover circulation through the circle of Willis while the homolateral carotid artery is impatent. Sufficient perfusion of both hemispheres could be well-documented by this radionuclide method. No neurological deficit was found in clinical examination either.

Basal and insulin-stimulated glucose metabolism of isolated human fat cells.

Glucose-U-14C-activity added to the incubation medium of isolated human fat cells was studied for its conversion to CO2 and its incorporation into fat cell triglyceride. In view of the wide scatter of the figures found under basal conditions as well as in the presence of 100 muU/ml of insulin, the correlations of fat cell glucose metabolism to ponderal index, total body fat mass weight, mean fat cell diameter, fat cell TG-content and age were analysed. The activity of glucose metabolism in obese individuals was found to be inversely related to the degree of obesity under basal conditions as well as under the effect of insulin. According to partial regression analysis, of all these parameters it was the ponderal index which showed the most significant inverse correlation to the activity of fat cell glucose metabolism. No appreciable relationship was found between the production of CO2 from glucose and age. Incorporation of 14C-activity into fat cell triglyceride showed a slight age-related increase under basal conditions as well as on insulin stimulation. It is concluded that at the cellular level it is the triglyceride saturation of fat cells which constitutes the endogenous regulatory factor responsible for the impaired biological action exerted by insulin on the enlarged fat cells in obesity.