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Biomedical subjects

U Schuler

Publications and source records attributed to U Schuler.

50 records · Page 3Linked to original sources
PubMed1992

Prevention of viral infections after bone marrow transplantation.

After bone marrow transplantation, a number of viral infections contribute to the morbidity and mortality of the procedure. Established preventive measures to avoid primary infection and reactivation of herpes-and cytomegaloviruses are outlined. Possible future strategies against these viruses (e. g., monoclonal antibodies, transfer of T-lymphocytes) and the possible role of improved diagnostic tools are briefly discussed.

Bone Marrow Transplantation↗
PubMed1992

Intracellular cytosine arabinoside accumulation and cytosine arabinoside triphosphate formation in leukemic blast cells is inhibited by etoposide and teniposide.

Cytosine arabinoside (ara-C) is one of the most active compounds in the treatment of acute leukemias. In the majority of current protocols ara-C is combined with other cytotoxic agents in an attempt to increase antileukemic activity. The present study investigated the impact of etoposide, teniposide, amsacrine, mitoxantrone, anthracyclines, and asparaginase on the cellular accumulation of ara-C and its intracellular metabolism in order to provide a better rationale for combination therapy. Intracellular accumulation and phosphorylation of ara-C were determined in peripheral blast cells from twenty patients with acute leukemias after exposure to 1 and 10 mumol/l ara-C alone and after preincubation with 1 and 10 micrograms/ml etoposide, 10 and 100 micrograms/ml teniposide, 10 mumol/l amsacrine, 500 ng/ml mitoxantrone (or daunorubicin or doxorubicin) or 10 mumol/l asparaginase. Ara-C accumulation at 10 mumol/l was decreased by 1 microgram/ml etoposide (67 +/- 18% of control), 10 micrograms/ml etoposide (30 +/- 22%), 10 micrograms/ml teniposide (12 +/- 23%), 100 micrograms/ml teniposide (10 +/- 18%), and amsacrine (51 +/- 21%). Intracellular ara-CTP formation was determined at an extracellular concentration of 10 mumol/l and preincubation with these drugs. The intracellular formation of ara-CTP was decreased by 1 microgram/ml etoposide (77 +/- 15% of control), 10 micrograms/ml etoposide (32 +/- 22%), 10 micrograms/ml teniposide (10 +/- 9%), 100 micrograms/ml teniposide (0 +/- 0%), but not by amsacrine. These data indicate that prior exposure to etoposide and teniposide influence ara-C metabolism and possibly cytotoxicity, and thus should not immediately precede ara-C administration in clinical trials.

Acute Disease↗
PubMed1991

Pharmacokinetics and metabolism of cyclophosphamide administered after total body irradiation of bone marrow transplant recipients.

High-dose cyclophosphamide is used immediately after total body irradiation (TBI) in conditioning for bone marrow transplantation (BMT). Possible interactions of the two treatment modalities were sought by measuring the blood pharmacokinetics of CP and 4-hydroxy-cyclophosphamide (4-HOCP) in patients undergoing BMT. There was a non-significant trend to a shorter half-life of CP compared to reported values. Exposure to 4-HOCP, the major metabolite of CP, did not appear to be altered by prior TBI of the patient.

Adolescent↗
PubMed1990

Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients.

The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination.

Adult↗
PubMed1990

Pharmacokinetics and metabolism of mitoxantrone. A review.

Mitoxantrone, a cytotoxic anthracenedione derivative, has given clinical evidence of beneficial activity in breast cancer, lymphoma and leukaemia. Several different mechanisms of action have been suggested to account for this. In addition to intercalation, biological effects such as electrostatic interactions with DNA, DNA-protein cross-links, immunosuppressive activities, inhibition of topoisomerase II, prostaglandin biosynthesis and calcium release have been described. Various methods of drug monitoring in biological fluids and tissues are available: the highest sensitivity has been achieved with high performance liquid chromatography with electrochemical detection, radioimmunoassay and enzyme linked immunosorbent assay. Early pharmacokinetic studies of mitoxantrone in experimental animals using radioactive material showed an extensive tissue distribution and a long terminal plasma half-life. The best fit for the plasma concentration-time curve in humans is achieved in a 3-compartment model. All studies reported a short absorption half-life of between 4.1 and 10.7 minutes, with the distribution phase being between 0.3 and 3.1 hours. In contrast, the values of the terminal half-life are quite variable, ranging from 8.9 hours to 9 days. Differences might be attributed to assay sensitivity, number and weighting of data points beyond 24 hours and coadministration drugs. Many studies showed a very large volume of distribution with sequestration of mitoxantrone in a deep tissue compartment. In autopsy studies, relatively high tissue concentrations have been measured in liver, bone marrow, heart, lung, spleen and kidney. Bile is the major route for the elimination of mitoxantrone, with lesser amounts excreted in the urine. Several metabolites have been separated, 2 of which were identified as the monocarboxylic and dicarboxylic acid derivatives. Mitoxantrone is usually administered by rapid intravenous infusion at 3-weekly intervals; other regimens include continuous infusion, daily repeated doses or weekly administration. In peritoneal carcinosis, the pharmacological advantage of intraperitoneal administration is clear. The optimal regimen for different disease categories with respect to efficacy and side-effects remains to be determined in future clinical trials.

Animals↗
PubMed1989

Absence of significant interaction of fluconazole with cyclosporin.

The effect of a new azole antifungal drug, fluconazole, on cyclosporin concentration and pharmacokinetics was studied in ten bone marrow transplant recipients. There were no significant statistical or clinical differences in mean cyclosporin trough concentrations, peak concentrations and AUCs after fluconazole given either as a single 100 mg oral dose or as 100 mg daily for 14 days. Fluconazole was well tolerated without drug related side effects. Slight to moderate increases of liver laboratory parameters were observed in four patients during the multiple dose sequence, but these changes might be attributable, in part, to the underlying diseases or concomitant therapies. The data suggest a lack of clinically relevant pharmacokinetic interaction of fluconazole with cyclosporin. It is concluded that fluconazole may be administered to cyclosporin treated patients without enhanced risk of toxicity.

Adult↗
PubMed1987

Stability and pharmacokinetics of m-[131I]iodobenzylguanidine in patients.

A pharmacokinetic study was done to elucidate the body distribution, elimination, and metabolism of m-[131I]iodobenzylguanidine (m-[131I]IBG). For this purpose, an analytical method using solid phase extraction columns was developed. m-[131I]IBG was administered as an i.v. infusion according to different schedules with doses of 7,055 to 13,580 MBq/m2. At the start of the infusion m-[131I]IBG accounted for 93.0 +/- 2.3% (SD; n = 10) of the total radioactivity. At the end of the infusion m-[131I]IBG accounted for 88.0 +/- 7.4%. The non-m-IBG-bound radioactivity was predominantly 131I. The pharmacokinetic parameters (n = 7) are adequately described by a three compartment model. The parameters for m-[131I]IBG were determined with a mean terminal half-life of 37.0 h, a volume of distribution of 307 liters/m2, and an area under the curve value of 1091 kBq x h/ml. The total body clearance was 189 ml/min/m2. The values for 131I showed a terminal half-life of 71.6 h, a volume of distribution of 190 liters/m2, and an area under the curve value of 1537 kBq x h/ml. The total body clearance was 70 ml/min/m2. The selectivity of the m-[131I]IBG treatment might be improved by a reduction of 131I in the infusion fluid and further investigations are warranted.

3-Iodobenzylguanidine↗
PubMed1987

[Anterior wall infarct in an 18-year-old patient with Hodgkin's disease. Possible relation between mediastinal irradiation, accelerated arteriosclerosis and vincristine chemotherapy].

An 18-year-old male patient with Hodgkin's disease, having undergone radiotherapy to the mediastinum two-and-a-half years previously, developed symptoms of an acute myocardial infarction within three hours of a vincristine injection (the first course of vincristine chemotherapy had been finished eight days previously). Invasive investigation after three weeks revealed single-vessel occlusion of the anterior interventricular branch with an anterior-wall aneurysm. The most likely cause of the coronary heart disease in this patient is changes in the anterior interventricular branch resulting from the mediastinal radiotherapy. The infarct itself occurred in close temporal relationship to the vincristine injection, which in several case reports has been implicated in the triggering of coronary spasms.

Adolescent↗
PubMed1987

Repeated high-dose cyclophosphamide administration in bone marrow transplantation: exposure to activated metabolites.

Blood levels of cyclophosphamide (CP) and activated metabolites were measured in 11 patients undergoing a 2- to 4-day conditioning chemotherapy for bone marrow transplantation. Urinary excretion of CP was determined in five patients. CP half-life decreased after pretreatment from an average of 7.1 h on the 1st day to 5.5 h on the 2nd day (P less than 0.005) and to 4.3 h on the 4th day (P less than 0.005). No characteristic changes in urinary excretion could be observed. At the same time the exposure to non-protein-bound activated metabolites increased from 10.5 to 19.5 and 26.0 nmol x h/ml respectively (P less than 0.005 and P less than 0.04). Thus, in contrast to in vitro and animal studies, no evidence for an inhibition of activating enzymes could be found. On the contrary, pretreatment seems to enhance the production of the cytotoxic metabolites. The possible explanation of these changes by enzyme induction and by the role of saturated protein binding sites is discussed. Exposure to active metabolites might be altered by dose splitting or even by a change in the duration of the infusion.

Adolescent↗
PubMed1987

[Pharmacokinetic aspects in the use of new cytostatic drugs].

A knowledge of pharmacokinetic data is essential for a rational treatment with cytotoxic drugs. The use of pharmacokinetics and insight into the metabolism make it possible to elucidate, predict or prevent toxicities after single and combined drug treatment. In addition, a careful monitoring in early clinical trials might help to find the optimal dose and schedule and to avoid less effective routes of application. This might improve the therapeutic range and efficacy of drug therapy in oncology.

Antineoplastic Agents↗