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Biomedical subjects

G Ehninger

Publications and source records attributed to G Ehninger.

At least 289 records · Page 16Linked to original sources
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

Drug monitoring of quinine by HPLC in cerebral malaria with acute renal failure treated by haemofiltration.

The monitoring of quinine by HPLC in 3 patients suffering from cerebral malaria with acute renal failure and treated by haemofiltration is reported. The recommended dose of quinine in this situation is reduced to 10 to 15 mg.kg-1.day-1. However, in the first patient, when given quinine 10 mg kg-1.day-1 the plasma concentration was mainly below the recommended therapeutic range of 5 to 15 mg/l. In consequence, the dose of quinine in the second patient was elevated to quinine dihydrochloride 15.1 mg.kg-1.day-1 which produced plasma concentrations in the low therapeutic range. In the third patient, an unreduced dose of quinine dihydrochloride 25.7 mg.kg-1.day-1 was employed, resulting in plasma concentrations above 15 mg/l, which is generally assumed to be toxic, although, no sign of acute quinine toxicity was seen. The antimalarial effect in all three patients was satisfactory. Quinine was estimated in the haemofiltrate in two patients and was found to be below the limit of sensitivity (0.25 mg/l). Plasma quinine did not change during or shortly after haemofiltration. It is concluded that in case of acute renal failure in cerebral malaria the dose of quinine should be reduced, but that the common recommendation of 10 to 15 mg.kg-1.day-1 may be too low, and that haemofiltration has no marked influence on the total body clearance of quinine.

Acute Kidney Injury↗
PubMed1987

Surveillance cultures and benefit of laminar airflow units in patients undergoing bone marrow transplantation.

The effectiveness of gastrointestinal and topical decontamination, as well as isolation in laminar airflow (LAF) units were investigated in 20 patients. On a weekly basis, surveillance cultures were taken. Environmental controls were taken on the medical ward outside the two LAF units and from the LAF unit itself when being used by a patient. The use of LAF units seems to be of benefit in preventing exogenous infections, but there are two weak points in the isolation techniques: the opening of the tent (with a free entry into the tent itself) and the water delivery system. By using appropriate decontamination measures, it was possible to greatly reduce the number of bacteria and species of the normal flora in all regions with the exception of the oropharynx. Individual patients with oxacillin resistant coagulase-negative staphylococci and/or Candida albicans continued to show the presence of these organisms during this time. The detection of Clostridium difficile and/or its toxin B in eight patients at the beginning of the individual observation period was significant. Four out of 15 fever episodes were attributable to endogenous bacterial infections. Each of the causative organisms had been previously isolated in the surveillance cultures, thus the clinician was able to initiate a calculated antimicrobial therapy. As evident from the low incidence of infectious complications, gastrointestinal and topical decontamination of the skin as well as reverse isolation in LAF units are efficient protective measures for bone marrow transplant patients.

Adolescent↗
PubMed1987

Phase-I study of intraperitoneal mitoxantrone--clinical and pharmacokinetic evaluation.

Mitoxantrone, a recent anthracenedione derivative is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue-binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leukopenia) was observed in 4 patients only after 35 mg/m2 and 40 mg/m2 i.p. Pharmacokinetic analysis using high-performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to serum was 1,108. The peritoneal clearance ranged from 2 ml/min to 9,617 ml/min and the disappearance half-life from 0.6-28.9 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase-I study we recommend phase-II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.

Drug Evaluation↗
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↗
PubMed1987

Coupling of mitoxantrone to poly(I).poly(C) reduces absorption after intraperitoneal administration.

Coupling of mitoxantrone (M), an intercalating cytostatic, to macromolecular polynucleotides may reduce side effects after direct intraperitoneal chemotherapy by interfering with systemic absorption of M. We have administered free M (30 mg/m2) or M mixed with poly(I).poly(C) (90 mg/m2) intraperitoneally to 5 patients with peritoneal carcinosis (cross-over study): peak plasma levels (HPLC assay) were 62 +/- 12 versus 28 +/- 4 ng/ml (p less than 0.0025), AUC0-24h were 583 +/- 126 versus 481 +/- 57 ng X h/ml (p less than 0.025). Coupling of M to poly(I).poly(C) seems to reduce M absorption after intraperitoneal administration.

Absorption↗
PubMed1987

Pregnancy after bone marrow transplantation for severe aplastic anemia.

Two women suffering from severe aplastic anemia were treated by bone marrow transplantation (BMT). They became pregnant 17 and 40 months after the procedure. During the first 20 weeks of pregnancy, one of them continued to receive cyclosporin A (CSA) to prevent graft-versus-host disease. Her CSA serum levels during these first 4 months ranged from 35 to 280 ng/ml. The course of pregnancy was uneventful and a healthy boy was delivered at term by Cesarean section. The other patient was shown to have rejected the transplanted marrow 4 months after BMT; autologous regeneration had occurred. During the last 2 months of her pregnancy, the hemoglobin and platelet numbers decreased again. Nevertheless, a healthy girl was delivered at term. Three months after delivery this patient's hematologic parameters are almost back to normal.

Anemia, Aplastic↗
PubMed1987

[Treatment of congenital varicella with acyclovir].

We describe three newborns who developed varicella six hours, five or eight days after delivery. Because of the high lethality rate of congenital varicella treatment with acyclovir appeared to be indicated. Acyclovir was administered intravenously in a dosage of 3 X 5, 3 X 7.5, and 3 X 10 mg/kg/day for three to five days. All patients showed prompt clinical improvement and the skin lesions disappeared. Side effects were not observed. Dependent on the dosage radioimmunological determination of acyclovir serum levels revealed basic values between less than 0.34 to 13.9 mumol/l; peak levels ranged from 14.0 to 70.2 mumol/l. Our preliminary results demonstrate that acyclovir can be successfully used to treat congenital varicella. A dosage of at least 3 X 7.5 mg/kg/day is recommended.

Acyclovir↗
PubMed1986

[Oral prophylaxis of herpes infections using acyclovir following bone marrow transplantation: a clinical and clinico-pharmacological study].

Viral infections are one of the major complications after bone marrow transplantation, with high mortality and morbidity. Fourty-six patients between 3 and 48 years old (median 15 years) received orally 400 mg (under age 6, 200 mg) acyclovir 4 times daily from day -12 before to day 84 after BMT. All patients were isolated in laminar-airflow units for at least 23 days with total enteral decontamination. They were concomitantly treated with anti-CMV-hyperimmunoglobulin and cotrimoxazol. During acyclovir prophylaxis seven patients had herpes simplex virus infections, all of them were seropositive before BMT. Acyclovir plasma concentrations were measured by use of a new HPLC method. No acyclovir was present (detection limit 40 ng/ml) in the plasma of five out of six patients with HSV infections. Three of them had non-compliance, and a lack of acyclovir absorption developed in two patients under conditioning regimen. No drug-related side effects were observed. Laboratory tests did not show liver or renal toxicity. Take and hematologic reconstitution were unchanged. In our study, oral acyclovir reduced the incidence of herpes simplex infections after bone marrow transplantation. Herpes infections only occurred in patients with non-compliance or lack of acyclovir absorption.

Acyclovir↗
PubMed1986

[Bone marrow transplantation in acute leukemia, chronic myeloid leukemia, severe aplastic anemia and stage IV neuroblastoma. Effect of antiviral prevention with anti-CMV-hyperimmunoglobulin and acyclovir].

Bone marrow transplantation was performed between IV/82 and X/85 in 64 patients with acute leukemia (n = 36), chronic myelogenous leukemia (CML; n = 13), severe aplastic anemia (n = 12), and neuroblastoma stage IV (n = 3). Of these patients 57 received allogeneic marrow from HLA-ABCDR identical, MLC-negative sibling donors. Six transplants were performed with syngenic marrow and one with autologous marrow. Of the 64 patients 48 survived 40-1,250 days after transplantation, resulting in a survival rate (SR) of 75% and a survival probability (SP) of 71%. Of the 36 patients suffering from acute leukemia (SR = 64%, SP = 51%), patients with acute myelogenous leukemia (AML) in first complete remission (n = 11; SR = 81%, SP = 76%), as well as patients with acute lymphatic leukemia (ALL) in 1st to 4th complete remission at the time of transplantation (n = 14; SR = 81%, SP = 76%) show a favorable prognosis. A poor survival rate was seen for patients with AML when transplanted in second or partial remission (1/5; SR = 20%), as well as for patients suffering from ALL and transplanted during relapse or partial remission (1/6; SR = 16%). Of 13 patients suffering from CML 12 survived the transplantation free of relapse (SR = 93%, SP = 92%), and one patient died from varicella zoster pneumonia. Of the transplanted patients with severe aplastic anemia, 12 of 13 are surviving with complete hematologic reconstitution; one patient, however, died on day 10 from a sepsis. In our patient group, the SR as well as the SP has been improved through changes in the irradiation protocol concomitant with prophylactic application of anti-CMV hypergammaglobulin, as well as through additional oral medication of Azyklovir. The 41 patients (BMT No. 7-47) with total body irradiation at one time show an SR of 44% and an SP of 41%. The following 46 patients (BMT No. 48-93) have reached an SR of 83% and an SP of 74% under the regimen of fractionated total body irradiation, plus prophylaxis with anti-CMV hypergammaglobulin and Azyklovir. Within this group, no fatal CMV pneumonia was encountered as opposed to six patients lost from CMV pneumonia in the first group.

Acyclovir↗
PubMed1986

[Effective treatment of peritoneal carcinosis by intraperitoneal cis-diamminedichloroplatinum (c-DDP) administration with systemic sodium thiosulfate protection. Clinical results and pharmacokinetics].

Thirteen patients with cytologically or histologically confirmed ascites from various malignancies have received 37 courses of intraperitoneal cis-platinum (cDDP). The tumor had to be confined to the peritoneal cavity or cause major symptoms by peritoneal carcinosis. cDDP (90-150 mg/m2 in 21 saline) was administered intraperitoneally with concurrent i.v. infusion of sodium thiosulfate. Courses were repeated in 4-week intervals. Total platinum was assayed by flameless atomic absorption spectrophotometry. With a dwell of 4 h 31.5 +/- 17.2% of platinum was recovered. Mean peak platinum concentration in the peritoneal cavity was 54.6 +/- 21 micrograms/ml and that in serum was 2.6 +/- 1.1 micrograms/ml. The ratio of peritoneal to serum platinum concentration dropped from 41 +/- 18.2 after 1 h to 6.9 +/- 4.7 after 5 h. The area under the curve for the peritoneum was approximately 11-fold greater than the area under the curve for serum. Within 12 h 31.7 +/- 10.7% of the administered dose was excreted in urine. Ten patients had disappearance of ascites lasting 6-135 + weeks. The treatment was generally well tolerated, no serious side effects were observed. This study demonstrates a pharmacokinetic advantage of intraperitoneal chemotherapy with cDDP and an effectiveness against peritoneal carcinosis from various malignancies with minimal systemic toxicity.

Adult↗
PubMed1986

[Bone marrow transplantation in severe aplastic anemia].

Bone marrow transplantations were performed on 15 patients (aged 5-39 years) with severe aplastic anaemia. Twelve patients are alive 76-1930 days (median 668 d) after transplantation, with complete haematopoetic recovery. Total-body radiation with 3.6 Gy in four patients, cyclosporin A administration to ten patients and buffy-coat transfusion to nine patients entirely prevented early rejection. Two patients died of pneumonia (aspergillus; varicella-zoster virus), one patient died of bleeding from a splenic-artery aneurysm. In patients under the age of 40 years with severe aplastic anaemia bone marrow transplantation as early as possible after diagnosis is the treatment of choice if HLA-identical siblings are available as donors. In patients over 40 years treatment should at first be tried with antithymocyte globulin.

Acute Disease↗
PubMed1986

[Bone marrow transplantation in chronic myeloid leukemia. Influence of gnotobiotic measures, especially antiviral prophylaxis].

Bone marrow from HLA-identical siblings was transplanted in 14 patients with chronic myeloid leukaemia (CML), including one patient in acceleration phase and one in chronic phase following 2 blast crises. Restoration of the bone-marrow occurred in all cases and Philadelphia chromosome could not be detected in any of the patients after the transplantation. Two patients died due to lung complications. Twelve patients who received antiviral prophylaxis (aciclovir per os, anti-CMV-hyperimmunoglobulin) after the transplantation are in very good condition with 140 to 790 days complete clinical and cytogenetic remission. Bone-marrow transplantation, as a curative measure for patients with CML up to the age of 45 (50), should be included in therapy schemes when an HLA-identical sibling is available.

Acyclovir↗
PubMed1986

Age adapted induction and intensified consolidation therapy in acute myelogenous leukemia.

52 patients entered a study for remission induction and intensified consolidation in AML. Group I (age less than or equal to 50 years) received a combination of DNR, ara-C and VP16-213 for induction and early consolidation and HDara-C/DNR for late consolidation. Of 34 evaluable patients (25 first diagnosis, 9 first relapse), 27 achieved CR. 13 patients received 1-2 courses of HDara-C/DNR. Toxic symptoms of HDara-C/DNR were severe myelosuppression, infections, skin reactions, diarrhea and hepatotoxicity. CNS toxicity was not observed. 2 patients died from infection. The duration of granulocytopenia (less than 500/microliter) was 7-43 days (range) and of thrombocytopenia (less than 25,000/microliter) 5-34 days (range). Patients of group II (age greater than 50 years) received a modified regimen with reduced toxicity. Their number is too small for evaluation as yet.

Aclarubicin↗
PubMed1986

Mitoxantrone and VP-16 in refractory acute myelogenous leukemia.

Phase I/II-studies suggested that mitoxantrone is effective in the treatment of acute leukemia. In this study we have investigated its efficacy in combination with VP-16 in patients with refractory acute myelogenous leukemia. The regimen consists of: mitoxantrone 10 mg/m2/day i.v. from days 1 to 5, VP-16 100 mg/m2/day as short infusion from days 1 to 3. A dosis escalation of VP-16 was attempted. As of August 1985, 27 patients have been enrolled in the study and 21 patients are now evaluable. Of these 21 patients, 6 (28.6%) have achieved complete remission including 3 with primary refractory disease, 2 with early relapse (less than 6 months after CR), and 1 with relapse under maintenance therapy. Two other patients have attained a partial remission. Toxicity was mild and, except one case of early death, no life threatening complications were observed. This combination seems to be an active regimen in refractory acute myelogenous leukemia and its incorporation in front line therapy seems warranted.

Adolescent↗