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Biomedical subjects

E Frei

Publications and source records attributed to E Frei.

At least 289 records · Page 16Linked to original sources
PubMed1980

High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity.

Methotrexate (MTX) in high doses (3 to 7.5 g/m2) with leucovorin rescue (HDMTX-LCV) can be delivered on a weekly basis in a setting of proper pharmacologic monitoring. Myelosuppression occurs in 28 per cent of the patients and in 8 per cent of the courses and usually results from delayed MTX excretion secondary to mild reversible nephrotoxicity. The incidence of tumor regression was 50 per cent in head and neck cancer; 59 per cent in non-Hodgkin's lymphoma; 40 per cent in small cell lung cancer; 24 to 50 per cent in breast cancer and 50 per cent in osteogenic carcinoma, for an over-all response rate of 39 per cent (70 of 178) in patients with disseminated cancer. HDMTX-LCV is not recommended for the conventional treatment of metastatic cancer because of the potential for toxicity and the fact that the response rates cited are probably not superior to those which can be achieved by conventional doses of MTX. However, the relative lack of myelosuppression and mucositis, when compared to conventional unrescued MTS, and the achievement of therapeutic concentrations of MTX in the central nervous system with the HDMTX-LCV program have led to its incorporation into clinical trials of combination chemotherapy.

Adult↗
PubMed1980

Efficient transfer of highly resolved small DNA fragments from polyacrylamide gels to DBM paper.

A procedure is described that combines high resolution of small DNA molecules (10 to 250 bases) with high transfer efficiency from polyacrylamide gels to diazobenzyloxymethyl (DBM) paper. The DNA fragments are separated electrophoretically in denaturing or nondenaturing step gels. These consist of a short gel of relatively high polyacrylamide concentration (8%) above a long gel of relatively low polyacrylamide concentration (4%). Step gels permit a high resolution of small DNA fragments in gels of sufficiently low polyacrylamide concentration from which efficient transfer to DBM paper is feasible. The combination of the step gel with a short treatment of the gel before transfer ensures a high transfer efficiency. As much as 30% and 50% of the DNA applied to nondenaturing and denaturing gels, respectively, are bound covalently to the DBM-paper. Optimal conditions for hybridization to DBM-linked DNA molecules of 30 to 250 base length are described.

DNA↗
PubMed1980

Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.

The results of treatment of 198 patients with Hodgkin's disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkin's disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkin's disease appears to be curable by chemotherapy.

Adolescent↗
PubMed1980

Clinical indications for human serum albumin.

Three indications have been considered for the clinical use of human serum albumin: nutrition, binding and transport, and the volume effect due to the oncotic properties of the protein. The use of albumin as an intravenous nutrient is clearly inappropriate. The literature on its binding and transport properties is as yet clinically inconclusive, and it seems premature to enforce product specifications based on these characteristics. The effects on blood volume and hypoproteinemia are firmly established in patients with an intact capillary system. The therapeutic implications of a capillary "permeability lesion" are a subject of current debate. Such lesions occur following extensive injuries and in patients with septic pulmonary failure. Although the data are contradictory, it is largely agreed that the serum albumin level should be kept above 30 g/litre or the total serum protein above 50 g/litre.

Colloids↗
PubMed1980

Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil with concurrent thymidine infusions in a Phase I trial.

The serum half-life of 5-fluorouracil (5-FUra) in humans is best described as a biexponential decay function, with t1/2 alpha = 7.8 +/- 2.6 (S.E.) min and t1/2 beta = 36.8 +/- 13.5 min during initial courses of this drug alone. Pharmacokinetics of 5-FUra during courses of daily therapy (for 5 days) revealed prolongation of t1/2 in both components of the decay curve, which has not been previously reported. Despite the efficacy of thymidine (dThd) given as a continous i.v. infusion of 8 g/sq m/day in prevention of high-dose methotrexate toxicity, continuous infusion of dThd at this dose does not prevent the toxicity of 5-FUra orreverse inhibition of DNA and RNA synthesis by 5-fura. On the contrary, continuous infusion of dThd appears to increase the toxicity of 5-FUra during continuous dThd infusion revealed prolongation of the 5-FUra t1/2 which remained stable through the course of 5 days of 5-FUra with dThd. This protracted t1/2 is believed to account at least in part for the increased toxicity of 5-FUra with dThd. Dose-limiting mucositis, myelosuppression, and gastrointestinal toxicity were observed at 5-FUra doses ranging from one-half to two-thirds the customarily tolerated dose of 5-FUra alone in similar courses of daily bolus therapy (for 5 days).

Adult↗
PubMed1980

Thymidine arrest and synchrony of cellular growth in vivo.

Thymidine (TdR) has been used to study the kinetics of in vitro cell proliferation and is currently being used clinically as a single agent at high doses. We have explored the in vivo cytokinetic effects of TdR on rapidly proliferating cell populations by continuous infusions in rats. The nucleoside was lethal at high doses when serum levels approached 10(-2) M.. At levels of 10(-3) M, TdR exposure for greater than 24 hours resulted in bone marrow hypocellularity and peripheral myelosuppression. Pathologic findings were also noted in the intestinal mucosa. Serum TdR levels of 10(-4) M were sufficient to induce arrest of cell growth in S phase by inhibition of DNA synthesis. Subsequent release after TdR exposure produced partial synchronization of the bone marrow and intestinal mucosa cell populations, as shown by microfluorometry and labeling studies to monitor DNA synthesis. A similar arrest of cell cycle traverse has been demonstrated in a tumor cell population by infusing rats bearing transplantable subcutaneous myeloblastomas. The inhibition of DNA synthesis, as determined by labeling studies, was comparable for bone marrow, intestinal mucosa, and myeloblastoma at serum TdR levels of 10(-3) M. This arrest of myeloblast cell growth was dependent on tumor burden and did not effect survival when maintained during 72-hour infusions. The continuous infusion of TdR provides an approach for studying cell kinetics in vivo, and findings similar to those described here have been observed in our clinical studies.

Animals↗
PubMed1979

Phospholipase A2 from sheep erythrocyte membranes. Ca2+ dependence and localization.

The calcium dependence and the time course of phosphatidylethanolamine and phosphatidylcholine degradation by sheep erythrocyte membrane suspensions in presence of Triton X-100 were investigated. One enzyme with phospholipase A2 specificity was found to be responsible for both phosphatidyl-ethanolamine and phosphatidylcholine degradation. The localization of this enzyme in the membrane of the sheep erythrocyte was investigated by proteolytic treatment of sealed erythrocyte ghosts from the outside and of ghosts which had both sides of the membrane exposed to chymotrypsin. The inability of sealed ghosts to take up chymotrypsin was followed by flux measurements of [14C]dextran carboxyl previously trapped in the ghosts. No efflux of the marker was found during the proteolytic treatment. By comparing the residual phospholipase activities in the membranes from both ghost preparations, we concluded that the phospholipase is oriented to the exterior of the sheep erythrocyte.

Acetylcholinesterase↗
PubMed1979

Comparative metabolism and excretion of adriamycin in man, monkey, and rat.

Adriamycin and its fluorescent metabolites in bile (man, monkey, and rat) and urine (man and monkey) were determined by means of a simple, rapid, and highly reproducible high-performance liquid chromatographic procedure. Species differences in metabolism and biliary excretion were observed with respect to aldoketo reductase and conjugase activities.

Animals↗
PubMed1979

Cytokinetic comparison of thymidine and leucovorin rescue of marrow in humans after exposure to high-dose methotrexate.

The cytokinetics of marrow recovery were compared in patients receiving a standard exposure to high-dose methotrexate followed by either thymidine rescue, leucovorin rescue at the doses used in most clinical protocols (10 mg/sq m every 6 hr), or leucovorin rescue at a 5-fold higher dose rate (50 mg/sq m every 6 hr). Thymidine rescue initiated a prompt recovery of DNA synthesis, as detected by [3H]deoxycytidine incorporation, and progression of cells through the cell cycle monitored by flow cytometry, even in the presence of methotrexate levels that prevented initiation of rescue by the lower doses of leucovorin. Dose dependency for leucovorin in vivo in humans was suggested by the observation that the higher leucovorin dose rate was successful in initiating recue within the first 24 hr, whereas the lower dose was not. Recovery of DNA synthesis is more rapid and/or complete with thymidine rescue than with either dose of leucovorin. Thymidine rescue was accomplished without requirement for purines over and above those present in plasma. These results suggest that the kinetics of marrow recovery is quite different for thymidine and leucovorin rescue.

Bone Marrow↗
PubMed1979

A Phase 1 study of high doses of aminopterin with leucovorin rescue in patients with advanced metastatic tumors.

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.

Aminopterin↗
PubMed1979

Initial clinical evaluation of N-trifluoroacetyladriamycin-14-valerate (AD-32), an adriamycin analog.

N-Trifluoroacetyladriamycin-14-valerate (AD-32) is superior to Adriamycin in murine L1210 and P388 leukemias and in a number of solid tumor systems, including Ridgway osteogenic sarcoma and Lewis lung carcinoma. In preclinical toxicology studies, AD-32 was less toxic than Adriamycin in both tumor- and non-tumor-being mice and in rabbits. An initial clinical trial was carried out in 23 patients who received a total of 74 courses of AD-32 over a dose range of 100--700 mg/m2 administered at 21-day intervals. Hydrocortisone given during the period of infusion prevented all clinical manifestations of acute toxicity. The AD-32 dose-limiting toxicity, leukopenia, was comparable to that of Adriamycin at a dose of 10:1, but at these equivalently myelosuppressive doses, AD-32 induced less gastrointestinal toxicity and alopecia than Adriamycin and it did not cause local tissue damage following inadvertent paravenous extravasation. Although two responses are reported, the therapeutic activity of AD-32 cannot be assessed because of an inadequate number of patients in any given tumor type. A phase II study is being initiated at a dose of 600 mg/m2 given at 21-day intervals.

Doxorubicin↗