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J Schüller

Publications and source records attributed to J Schüller.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pharmacokinetic drug interaction between epirubicin and interferon-alpha-2b in serum and red blood cells.

The influence of interferon-alpha-2b (CAS 99210-65-8, IFN) on the pharmacokinetics of epirubicin (CAS 56420-45-2, EPR) was investigated in 10 patients (4 male, 6 female). EPR was injected as an i.v. bolus over 2 min in a dose of 60 mg/m2 IFN was pre-administered 3 times a week in a dose of 5 x 10(6) IU as a s.c. injection. The comparison of the pharmacokinetics after injection of EPR and EPR+IFN did not show remarkable differences. A statistical significant influence in regard to the terminal elimination half-life (gamma-HL) and the total clearance (CLtot) was found, indicating a reduction of gamma-HL from 18.18 +/- 16.7 for EPR to 8.47 +/- 8.67 h for EPR+IFN and a reduction of the total clearance from 72.33 +/- 55.4 ml/min for EPR to 48.41 +/- 12.7 ml/min for EPR+IFN. The area under the concentration-time curve (AUC, according to the 3-compartment model) increases under the influence of IFN from 2004 +/- 1105 ng/ml.h for EPR up to 2582 +/- 1024 ng/ml.h for EPR+IFN. However, this increase is statistically irrelevant due to the high deviation ranges. Besides, the influence of IFN on the interactions of EPR with red blood cells (RBCs) was investigated in 6 patients under the above conditions. The percental concentration of EPR in RBCs is reduced from 35.4% to 34.7% after administration of IFN. Two metabolites, 13-dihydroepirubicin (M I) and 7-deoxydoxorubicinone (M II), were detected both in serum and RBCs, whereas IFN showed no significant interference with the metabolism or with the binding of the metabolites to RBCs.

Adult↗
PubMed1993

Clinical pharmacokinetics of 5-fluorouracil. Influence of the biomodulating agents interferon, dipyridamole and folinic acid alone and in combination.

The pharmacokinetics of the antimetabolite 5-fluorouracil (5FU, CAS 51-21-8) were investigated under the influence of the biomodulating agents folinic acid (FA), FA combined with dipyridamole (DPM), DPM, interferon-alpha-2b (IFN), and IFN combined with DPM. IFN as well as IFN/DPM cause an enormous increase of the 5FU plasma concentrations resulting in a statistically significant change of the pharmacokinetics. The mean initial plasma concentrations of 5FU are increased at about 143% under the influence of IFN and at 162% under the influence of IFN/DPM. Accordingly, the mean area under the concentration-time curve is elevated at 114% for IFN and at 184% for IFN/DPM. The volume of distribution (IFN - 39%, IFN/DPM - 38%) as well as the total body clearance (IFN - 30%, IFN/IFN - 44%) are lowered distinctly. In contrary, the coadministration of either FA or DPM or FA/DPM to 5FU does not lead to a significant change in the pharmacokinetic profile of 5FU, but also causes higher plasma concentrations. The present results indicate that the coadministration of biomodulators can lead to distinct changes of the 5FU kinetics, but must not be useful in each case.

Aged↗
PubMed1992

[The binding of 5-fluorouracil to serum protein fractions, erythrocytes and ghosts under in vitro conditions].

The binding of 5-fluorouracil (1) to erythrocytes and to serum proteins under in vitro conditions was investigated. The binding rate of 1 to erythrocytes is dose-independent and amounts from 16.8 to 31.7% (concentration range 1 to 20 micrograms/ml). The mean coefficient of partition for erythrocytes is 0.25 (+/- 0.03), no binding to ghosts was observed. 1 is bound at about 4% to proteins, whereby 0.7% are bound to alpha-globulin, 0.8% to beta-globulin, 1.6% to gamma-globulin, and 0.8% to albumine. The mean partition coefficient for proteins is 0.04 (+/- 0.006).

Blood Proteins↗
PubMed1992

[Pharmacokinetics of 5-fluorouracil in erythrocytes following i.v. administration].

The in vivo binding of the antineoplastic agent 5-fluorouracil (1) to erythrocytes in the whole blood of patients was investigated. The vascular availability of 1 is influenced by erythrocytes at 38.6 +/- 7.2% (calculated as AUC0-60-values), the coefficient of partition is 0.65 +/- 0.18. In comparison with serum, the volume of distribution and the total clearance are elevated by the erythrocytes, the half-lives of the compartment distribution and of the terminal elimination are not influenced.

Erythrocytes↗
PubMed1992

Influence of interferon alfa-2b with or without folinic acid on pharmacokinetics of fluorouracil.

Interferon alfa has been demonstrated to enhance the effect of fluorouracil (5-FU) on human colon cancer cell lines as well as in clinical studies. By several authors interest in focussed on the question whether the interaction between these two agents is reflected by changes of 5-FU kinetics. In the present study the pharmacokinetic behavior of 5-FU was investigated in combination with interferon alfa (IFN-alpha-2b) and further after adding the second well-established biomodulating agent folinic acid (FA). Ten patients with advanced gastrointestinal cancer received 5-FU as a weekly bolus injection of 750 mg/m2, IFN-alpha-2b 5 million units three times per week subcutaneously and FA as a short time infusion at 200 mg/m2. 5-FU plasma levels were determined by high performance liquid chromatography as a baseline measurement on day 1 before starting IFN-alpha-2b. Analysis was repeated at the second or third cycle of 5-FU administration 1 hour after the last IFN-alpha-2b injection, and finally after also adding FA immediately infused before 5-FU injection. Biomodulation of 5-FU by IFN-alpha-2b alone resulted in a significant alteration of 5-FU kinetic parameters as demonstrated by an increase of area under the curve by 80%, and of blood concentration (co) by 65%, and a decrease of total clearance at 50%. These data may partly explain the observed enhancement of antiproliferative and toxic effects of this combination. On the other hand, when FA was added to this schedule, no significant changes of 5-FU kinetics could be documented. Therefore the theoretical benefit of such a double modulation cannot be supported by our findings. Further preclinical and clinical investigations are required to define the role of a triple combination of 5-FU with IFN-alpha-2b and FA.

Aged↗
PubMed1992

Pharmacokinetic aspects of interferon alfa-2b after intrahepatic or intraperitoneal administration.

The pharmacokinetics of interferon alfa-2b (IFN-alpha-2b) were determined following intraperitoneal (IP) infusion of escalating doses, ie, 5, 10, and 15 million units (MU) and intrahepatal-intraarterial (IA) (IA, bolus v 24 hours continuous infusion of 3 and 5 MU) administration in patients with metastatic cancer. Pharmacokinetic parameters show that bioavailability of IFN-alpha-2b after IP administration is 30 times higher for the peritoneal fluid (PF) than for peripheral blood (PB) explaining also the low incidence of side effects. The high affinity of IFN-alpha-2b to the peritoneal cavity is furthermore substantiated by the total compartment clearance, which is only about 1 1/minute for the PF in comparison to about 30 1/minute as determined for PB. IFN-alpha-2b is eliminated from the PF with a half life (t1/2) of elimination 10 to 32 hours and from the blood with t1/2 of 5 to 13 hours. After IA bolus, IFN is distributed from the blood with a t1/2 below, 2 hours, with dose-dependent serum peak concentrations (c = 47 IU for 3 MU and 145 IU for 5 MU). Twenty-four-hour infusion leads to a steady state within 4 to 6 hours and maximum concentration of 8.5 or 12.5 IU/mL, respectively. During infusion IFN alpha-2b is slowly eliminated with a t1/2 of 16 hours. The lower area under the curve levels after bolus injection may suggest a better tissue uptake of IFN-alpha-2b by the liver. Further studies on pharmacokinetics are warranted to establish exact dose recommendations for an optimal schedule using this route and mode of IFN-alpha-2b administration in mono- and combination therapies.

Female↗
PubMed1991

Treatment of patients with advanced colorectal cancer with cisplatin, 5-fluorouracil, and leucovorin.

Based on in vitro studies that have demonstrated synergy between 5-fluorouracil (5-FU), leucovorin (LV), and cisplatin (CDDP) against human colon cancer cell lines, a clinical trial was initiated to determine the effects of this combination in patients with advanced unresectable colorectal carcinoma. Fifty-nine patients were enrolled in the study and 12 of them had received prior conventional 5-FU chemotherapy. Treatment consisted of 4 weekly courses of high-dose LV (200 mg/m2) administered by intravenous (IV) bolus, followed by 5-FU (550 mg/m2) and CDDP (20 mg/m2) each administered as a 2-hour infusion on 4 consecutive days. After a median of 5.5 treatment cycles, objective tumor response was seen in 20 of 59 patients (34%) (this included 3 complete remissions). The response rate in the 47 previously untreated patients was 38% (95% confidence limits, 26% to 53%). Stable disease occurred in 16 (27%) patients, whereas the tumor progressed in 23 (39%) patients. The median survival time was 11.5 months, with 15% of the patients alive at 2 years. The regimen was well tolerated and the primary side effects were mild and reversible gastrointestinal symptoms and myelosuppression. There was no episode of life-threatening toxicity. Eastern Cooperative Oncology Group (ECOG) Grade III adverse reactions that required 25% dose reductions occurred in only 14% of the patients. The results of this trial suggest that 5-FU, LV, and CDDP is an active, safe, and well-tolerated combination regimen in patients with advanced colorectal cancer.

Adenocarcinoma↗
PubMed1991

[The effect of the vasoconstrictor glycylpressin on the bioavailability of mitomycin C].

During an intra-arterial chemotherapy of patients with liver metastases the plasma concentration-time curves of Mitomycin C (1) after occlusion of the common hepatic artery by the vasoconstricting agent Glycylpressin (2) were investigated. Vasoconstriction by 2 leads to significantly (p less than 0.01) lower blood levels of 1 in contrast to bolus injection of 1 without 2 under identical dosage regimens. This reduction of systemic availability of about 50% leads to a corresponding higher availability for the tumor region.

Aged↗
PubMed1991

[Pharmacokinetics of carboplatin after intraperitoneal administration].

The concentration-profile of the antineoplastic agent carboplatinum in serum and intraperitoneal-fluid (IPF) of six female patients was studied. Pharmacokinetical analysis showed a rapid distribution-phase between both compartments within the first 4h after administration (t1/2 serum = 4.4 h, t1/2 IPF = 3.3 h). Elimination half-life of carboplatinum of 20.3 h from the blood-vessel-system was significantly higher than from the intraperitoneal-compartment (t1/2 = 10.6 h). The relative bioavailability (calculated as AUC-values) was at least 6 times higher for the IPF than for serum within the first 48 h. 98% of measured amount were eliminated from both compartments within this time. The desired high IPF-levels support this route of administration.

Carboplatin↗
PubMed1991

Interferon alfa-2b with VMCP compared to VMCP alone for induction and interferon alfa-2b compared to controls for remission maintenance in multiple myeloma: interim results.

The present trial was designed to evaluate whether interferon (IFN) combined with standard induction chemotherapy and/or interferon remission maintenance treatment improve treatment results in patients with multiple myeloma. Up to now 89 patients have received IFN plus vincristine/melphalan/cyclophosphamide/prednisolone (VMCP) as induction therapy, and 86 conventional VMCP. The proportion of patients with progressive disease was significantly lower (P less than 0.005) under IFN + VMCP as compared to the VMCP treatment group. Survival times were significantly longer (P less than 0.02) after IFN + VMCP induction therapy than after VMCP alone. In the second phase of this investigation, 33 progression-free myeloma patients were assigned to receive IFN as maintenance therapy, and 41 patients served as untreated controls. Patients maintained with IFN showed a tendency towards increased progression-free survival. Haematological side effects were observed significantly more often in patients receiving IFN, with more severe haematological toxicity in patients on the combined IFN + VMCP regimen and an increased number of patients with mild haematological toxicity in the group maintained with IFN. Other side effects, such as fever and fatigue, remained within tolerable limits. In conclusion, the preliminary results of this current clinical trial indicate significant advantages of combined IFN + VMCP induction treatment in terms of reduced disease progression and prolonged survival and possible benefits of IFN maintenance therapy in patients with multiple myeloma.

Adult↗
PubMed1991

[Non-selective digital subtraction angiography of aortocoronary bypasses].

Intra-arterial DSA was performed on 225 patients with a total of 552 coronary bypasses (515 aorto-coronary venous bypasses and 37 internal mammary artery bypasses). Four hundred and ninety-five bypasses were examined in the four weeks following surgery; of these, 428 (85.9%) were patent. Demonstration of the distal anastomosis was obtained in 40.4% of bypasses of the right anterior interventricular artery and in 36.1% of the right coronary artery, at least in their proximal parts. Bypasses of smaller branches showed filling in 12.8 to 19.2%. Because of the unsatisfactory demonstration of distal vessels by non-selective intra-arterial DSA, this method is suitable only for showing the patency of a bypass in the postoperative phase, but should not be used for investigating cardiac signs and symptoms following a bypass examination.

Adult↗
PubMed1991

[Pharmacokinetic aspects of the combination of interferon-alpha-2b and folic acid with fluorouracil].

The plasma levels of fluorouracil (5-fluorouracil, 5FU; CAS 51-21-8) after intravenous administration have been monitored without, under influence of interferon-alpha-2b (IFN) and under influence of IFN combined with folic acid (FA). IFN causes a highly significant change of the pharmacokinetic parameters of 5FU (p less than 0.001) compared to 5FU administration without IFN. The bioavailability of 5FU (compared as the AUC0-60 values) is elevated to 80%. In contrary, the combination of IFN with FA leads to a non-significant change of the 5FU pharmacokinetics, although the bioavailability is increased to 18%. The higher plasma levels of 5FU under the influence of IFN might be causes by a changed renal clearance, which is indicated by the reduction of the total plasma clearance at about 53%. The combination IFN/FA did not show a similar effect. Yet, in both cases an improvement of the tumor response and of the clinical picture could be observed.

Aged↗
PubMed1991

[Comparative bioavailability of fluorouracil and its prodrug, ftorafur, following intra-arterial, intravenous and preoral administration].

The blood-plasma levels in 28 patients, suffering from colorectal cancer with liver metastases, which were treated by a cyclic chemotherapy with fluorouracil (1) after p.o. and intraarterial (i.a.) administration of 1 or its prodrug ftorafur (2), respectively, were compared with those obtained after i.v. administration and the pharmacokinetics were calculated. In the case of 1 as well as of 2 the i.a. administration has been found to be optimal for distribution into the tumor tissue of liver metastases due to lowered blood-plasma concentrations. The absolute bioavailability, was 78% for p.o. and 57% for the i.a. administration of 1 respectively, and 98% for p.o. and 61% for the i.a. administration of 1 (given as 2), Accordingly, p.o. administration of both substances leads to therapeutical sufficiently high plasma levels with a steady state of css = 2.9 micrograms/ml/tss = 14 min for 1 and css = 3.5 micrograms/ml/tss = 20 min for 2.

Administration, Oral↗
PubMed1991

[Pharmacokinetics and local availability of mitomycin. The influence of vasoconstriction and chemoembolization].

The influence of the vasopressin-pro-drug glycylpressine (GP) and of a chemoembolisation with Spherex starch-particles (SP) on the availability of mitomycin (CAS 50-07-7, mitomycin C, MMC) was investigated in 30 patients with liver metastases, MMC administration was performed after blocking of the common hepatic artery by different concentrations of SP and after different time-intervals of GP. The comparison of plasma-levels after bolus injection without GP and after administration of MMC after 2, 5 and 15 min of vasoconstriction and after chemoembolisation with 450 mg or 900 mg SP, respectively, showed a remarkable reduction in the systemic circulation of MMC in the blood vessel system at about 40% (GP) and 45% (SP). A statistically significant influence on the pharmacokinetics of MMC with regard to CO, Vd, T 1/2zp, AUC and Cl(tot) was found, but not in t1/2el, t1/2biol and Vl. Both methods cause a distinctly accelerated diffusion of MMC into the tissue of the tumor region by change of the hemodynamics, leading to lowered side-effects. Thus the clinical picture was improved by MMC.

Biological Availability↗