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Biomedical subjects

M Keating

Publications and source records attributed to M Keating.

At least 181 records · Page 10Linked to original sources
PubMed1987

Comparison between the plasma and intracellular pharmacology of 1-beta-D-arabinofuranosylcytosine and 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in patients with relapsed leukemia.

The pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) and their respective 5'-triphosphates, ara-CTP and F-ara-ATP, were compared in human plasma and circulating leukemic blasts (CLB) since initial phosphorylation of ara-C and F-ara-A is catalyzed by the same enzyme, deoxycytidine kinase. These investigations were conducted in 4 patients after the first infusion of high-dose ara-C therapy (3 g/m2 i.v. infused over 2 hr) and, following the failure of each to respond, after the initial bolus of F-ara-A monophosphate (50-100 mg/m2 i.v. over 30 min) in a subsequent treatment regimen. The median terminal rate of elimination (t1/2) of F-ara-A was 8.4 hr compared to 2.2 hr for ara-C. The median t1/2 for F-ara-ATP in CLB was 12.2 hr relative to 1.9 hr for ara-CTP. To evaluate the possibility that diminished deoxycytidine kinase was a mechanism of drug resistance, the relative area under the concentration X time curve (AUC) of the active triphosphate of each prodrug in the CLB of individuals was compared. The intracellular nucleotide AUC was normalized by dividing it by the AUC of the respective nucleoside in plasma. A value of 1.0 for the resulting ratio would be expected if the accumulation and retention of F-ara-ATP and ara-CTP were identical. In these patients, however, this ratio ranged between 0.2 and 68.2. When a similar analysis was performed in vitro using four established human leukemia cell lines, a 150-fold variation was found in the normalized nucleotide AUC ratio. Thus, the metabolic characteristics of ara-CTP in CLB of patients who fail to respond to high-dose ara-C may not predict the cellular metabolism of F-ara-ATP in the same patient at a later disease stage.

Adult↗
PubMed1987

Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia.

The cytotoxic effect of cytosine arabinoside (ara-C) is presumably mediated by cytosine arabinoside 5'-triphosphate (ara-CTP). We tested for a correlation between intracellular ara-CTP pharmacokinetics and clinical response among 51 patients who received high dose ara-C (3 g/m2 at 12-hr intervals) as therapy for refractory acute leukemia. After accounting for pretreatment clinical variables that correlated with response, measurement of ara-CTP pharmacokinetics added significant prognostic information. This provides a rationale for manipulation of schedules of high dose ara-C administration in those patients whose pharmacokinetic characteristics are inconsistent with response to an every 12-hr schedule.

Acute Disease↗
PubMed1986

9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma.

The pharmacokinetics of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) in plasma and its biologically active 5'-triphosphate (F-ara-ATP) in leukemic cells obtained from the peripheral blood and bone marrow was evaluated in patients with hematologic malignancies subsequent to the first dose of 20-125 mg/m2 per day for 5 days of F-ara-A 5'-monophosphate (F-ara-AMP) administered as an IV bolus over 30 min. The terminal half-lives of elimination of both F-ara-A (8 h) in plasma and intracellular F-ara-ATP (15 h) were not dependent upon the dose of F-ara-AMP. The area under the concentration X time curves for F-ara-A and F-ara-ATP, on the other hand, were increased in proportion to the prodrug dose. There was a high correlation between F-ara-ATP levels in circulating leukemic cells and those in bone marrow cells aspirated at the same time. DNA-synthetic capacity of leukemic cells was inversely related to the associated F-ara-ATP concentration. A linear trend was noted when F-ara-ATP levels in pretreatment peripheral blood leukemic cells incubated with F-ara-A in vitro were compared with the amount of F-ara-A that was incorporated into nucleic acids. Finally, F-ara-ATP concentrations were three times higher in bone marrow cells from patients with lymphomatous bone marrow involvement than from those without evidence of marrow disease.

Antimetabolites, Antineoplastic↗
PubMed1986

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse.

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.

Acute Disease↗
PubMed1986

Chronic myelogenous leukaemia: haematological remissions with alpha interferon.

Twenty-seven consecutive patients with previously untreated, or minimally treated benign phase Philadelphia-chromosome-positive, chronic myelogenous leukaemia (CML) were treated with partially purified human leucocyte (alpha) interferon; 24 of the 27 patients responded to therapy achieving either haematological remission (20 patients) or partial haematological remission (four patients). In the responding patients the peripheral white blood cells declined from a median of 89.6 X 10 X 10(9)/l to 4.5 X 10 X 10(9)/l. The serum lactate dehydrogenase declined from a mean of 8.36 Katal/l (492 mu/ml) to 2.8 Katal/l (165 mu/ml), and the vitamin B12 levels declined from 1492 pg/ml to 838 pg/ml. Fifteen patients had splenomegaly. The spleen size normalized in four and decreased by a median of 30% in 10 additional patients. The bone marrow cellularity fell from a median of 100% to a median of 62%. In seven of the 24 responding patients, followed for greater than or equal to 6 months, the percentage of Ph1-positive cells in the bone marrow declined to a median of 70% (range 5-75%). Alpha interferon was found to be an effective therapeutic agent for controlling the myeloid proliferation in CML, and in partially restoring the nonclonal haematopoietic cells in some of the patients.

Adult↗
PubMed1986

Treatment of hairy cell leukemia with recombinant alpha-interferon.

Thirty patients with hairy cell leukemia were treated with recombinant interferon alpha-A (rIFN alpha A; Roferon-A); seven were previously untreated. Nine complete and 17 partial remissions were documented by bone marrow core biopsies. All patients' peripheral blood hematologic indexes either improved or normalized. Twelve of 13 patients with retroperitoneal or mediastinal adenopathy obtained remissions of tumor masses. All seven patients with splenomegaly showed prompt reduction in the size of the spleen to normal size. The incidence of complete remissions was significantly higher (P = .02) in previously untreated patients (5 of 7) than in those in whom splenectomy had been performed (4 of 23), a result presumed to be related to the pretreatment tumor burden. rIFN alpha A was well tolerated; mild fatigue was the most frequent complaint. In most patients, tumor remissions resulted in an improved quality of life: they eliminated the need for transfusing blood products and reduced the incidence of infections, and immune deficits were apparently restored in some of the patients. We conclude that rIFN alpha A is an effective therapy for all stages of hairy cell leukemia including previously untreated or newly diagnosed patients.

Adult↗
PubMed1986

Clinical pharmacology of homoharringtonine.

Clinical pharmacokinetics of homoharringtonine (HHT) were studied in eight patients who received uniformly labeled HHT at 3-4 mg/m2 (150 mu Ci) by continuous 6-hour infusion. The drug and metabolites were quantified by radiochemical and high-performance liquid chromatographic techniques. Computerized nonlinear least-square regression and curve stripping were used to characterize HHT and total [3H]HHT equivalent pharmacokinetics. Unchanged HHT in the plasma declined biphasically, with an alpha-half-life of 0.5 +/- 0.1 hours and a beta-half-life of 9.3 +/- 1.4 hours. The total clearance of HHT was 177.4 +/- 27.7 ml X hour-1 X kg-1, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4 +/- 0.4 L X kg-1. Correspondingly, the total [3H]HHT equivalent disappeared from the plasma in a triphasic manner. Compared with the pharmacokinetic parameters of unchanged HHT, the terminal half-life of total 3H was 67.5 +/- 7.5 hours, 7.4 times longer; the total clearance was 30.9 +/- 3.1 ml X hour-1 X kg-1, 5.5 times slower; but the volume of distribution by area was 2.7 +/- 0.1 L X kg-1, nearly the same. The 72-hour cumulative urinary excretion of total tritium was 28.2% of the administered dose and only 38.3% of this resided in unchanged HHT. Thus, urinary excretion was not a major route of elimination of HHT. Moreover, HHT underwent extensive metabolism; one major and two minor unidentified products were detected in both plasma and urine.

Adolescent↗
PubMed1985

Ticarcillin plus clavulanic acid in the treatment of patients with cancer.

Since the combination of ticarcillin with clavulanic acid is active against many otherwise resistant organisms that commonly affect patients with cancer, a therapeutic trial with ticarcillin disodium plus clavulanate potassium for treating infections in cancer patients was conducted. A total of 127 evaluable patients were treated with this antibiotic. Of these, 63 percent were women with breast carcinoma, 28 percent were patients with leukemia, and the remainder were patients with sarcomas and lung cancer. The median duration of therapy was 7.7 days. There were 63 documented infections, with bacteriologic documentation in 39 episodes. Because of the high incidence of gram-positive infections and after the failure of ticarcillin plus clavulanate potassium in two of these episodes, vancomycin was added to the regimen. The overall response rate was 75 percent. In microbiologically proved infections, the response rate was 79 percent. Thirteen of 17 gram-negative infections responded (76 percent), including four of four episodes caused by Pseudomonas aeruginosa. The only failures in this group were two episodes with Klebsiella species, one episode with Escherichia coli, and one episode with Enterobacter species. Of the gram-positive infections treated without vancomycin, five of eight (63 percent) responded and only two episodes due to Staphylococcus aureus and one due to JK diphtheroid bacteria failed. All episodes treated with the combination of ticarcillin plus clavulanate potassium and vancomycin responded. Seven of eight (88 percent) polymicrobial infections and 73 percent of those infections without identified organisms responded as well. The overall response rates for septicemia, pneumonia, soft tissue infections, and urinary tract infections were 71, 50, 71, and 83 percent, respectively. Of five microbiologically proved superinfections, three were fungal, and one each was due to Klebsiella species and S. aureus. No toxicity was observed. For 12 organisms, the minimal inhibitory concentration was lower for ticarcillin plus clavulanate potassium than for ticarcillin alone; in six it was identical. Five organisms were resistant to both, and three that were resistant to ticarcillin were sensitive to ticarcillin plus clavulanate potassium. Ticarcillin plus clavulanate potassium is a safe drug with an expanded spectrum of activity. More therapeutic trials need to be conducted to better define its role in the therapy of serious infections in cancer patients.

Adolescent↗
PubMed1985

Allogeneic bone marrow transplantation for acute leukemia refractory to induction chemotherapy.

This article compares the outcome of 14 patients with primary refractory acute leukemia who underwent bone marrow transplantation from human leukocyte antigen (HLA)-identical donors with that of 18 age-matched control patients who received chemotherapy. Complete clearing of leukemia was seen in all 14 transplanted patients. Five of the transplanted patients are alive 98 to 1790 days posttransplant, and four are free of leukemia. Nine patients have died, eight with severe graft-versus-host disease associated with interstitial pneumonia or systemic infections and one with relapse from chemotherapy-associated infections. Engraftment was seen in all patients. Severe graft-versus-host disease (grades III and IV) was seen in ten patients and resolved in three patients following high-dose corticosteroid treatment. Three of the 18 control patients are alive, none of them in complete remission. It appears that the combination of piperazinedione and total-body irradiation followed by allogeneic transplant is effective induction treatment for primary refractory acute leukemia and will be considered in the future as first salvage treatment for patients failing induction treatment.

Acute Disease↗
PubMed1985

Evaluation of a new screening system for enteric pathogens.

The two-hour Rapid SST strip (DMS Laboratories, Inc.) was compared with our standard screening system (triple sugar iron agar, lysine iron agar, and urea) for enteric pathogens. We tested 50 stock cultures of enteric pathogens and 213 stool cultures received in the Barnes Hospital Clinical Microbiology Laboratory over a two-month period. All enteric pathogens from the stock cultures and clinical specimens were identified correctly with the Rapid SST system. More false-positive reactions were observed with the Rapid SST system (34%) than with the conventional system (23%). However, the costs associated with using both systems were equivalent and the test results were available one day faster with the Rapid SST system. Thus, the Rapid SST is a rapid, accurate, and cost-effective method for screening stool specimens for enteric pathogens.

Bacteriological Techniques↗
PubMed1985

Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study.

Twelve patients with hematologic malignancies complicated by fungal infections were treated with liposomal amphotericin B (L-AmpB). Nine patients were granulocytopenic; the three additional patients with normal granulocyte counts were immunosuppressed. All patients had biopsy findings or cultural evidence of the progression of their fungal infection while being treated with conventional amphotericin B. Doses of 0.8-1.0 mg/kg of L-AmpB were administered intravenously every 24-72 hr. Three patients had a complete remission, five had a partial remission, and four showed no improvements. A total of 161 doses of L-AmpB were administered. Fever and chills occurred on seven occasions. No hematologic or blood chemistry abnormalities related to L-AmpB treatment were observed.

Adolescent↗
PubMed1985

DNA-RNA measurements in patients with acute leukemia undergoing remission induction therapy.

Prior to therapy, 111 newly diagnosed adult patients with acute leukemia had DNA content measured (cell-cycle distributions) and 91 had RNA content measured using flow cytometry of acridine orange-stained bone marrow biopsies. The RNA index (RI) (ratio of mean RNA in G0/G1 of the sample to the median RNA in G0/G1 of normal lymphocytes) distinguished acute myelogenous leukemia (AML) from acute lymphocytic leukemia (ALL). The mean RI in AML was 2.2 and in ALL 1.5. RI did not predict for achievement of complete remission (CR). In AML the mean S-phase percent was 11.2 in patients who achieved CR and 13.1 in those who failed to respond to therapy, whereas in ALL it was 14.5 in those responding and 8.0 in those not responding (P = .02). In the 77 patients with either AML or ALL who achieved CR, a low pretreatment S-phase percent and a high RI correlated with a long duration of CR. S-phase percent and RI were also measured during remission induction and during maintenance therapy. Between days 8 and 18, the RI of responders decreased. In both AML and ALL an increase in S-phase percent between days 18 and 22, prior to morphological CR, was observed in responders but not in nonresponders. The mean S-phase percent at the time of morphological remission was 17.3. A high S-phase percent at this time correlated with a longer duration of CR. Although neither pretreatment S-phase percent nor RI was found to predict for achievement of CR in AML, both predicted for length of CR. Increases in S-phase percent during therapy indicated recovery of normal hematopoiesis.

Acridine Orange↗
PubMed1984

The hematologic malignancies. Leukemia, lymphoma, and myeloma.

Many of the conceptual advances in the treatment of advanced cancer have resulted from studies of the hematologic malignancies: The signal importance of complete remission, the complete disappearance of evident disease, as the major contributor to significant palliation; the first studies of adjuvant therapy, that is chemotherapy given to patients free of disease, which demonstrated prolongation of disease-free periods; the first studies of intensification, including early, intermittent, and late; combination chemotherapy; and finally, the important observation that advanced metastatic malignancies can be cured were made in studies of these important diseases. Because of treatment advances that have occurred over the last 10 to 20 years, the majority of patients with adult hematologic malignancies that were once considered universally fatal can be either cured or have substantial palliation. Treatment for adult acute leukemia has advanced such that 15% to 20% of patients have prolonged disease and treatment-free survivorship; in Hodgkin's disease, over 70% of patients can be cured; and for the lymphomas, the majority or 50% to 60% of patients can be cured with available treatments. Major treatment advances in supportive treatment such as allogeneic transfusion and allogeneic and autologous bone marrow transplantation improve the perspective for control of the hematologic malignancies. In addition, the potential for biologic response modifiers or the biologic products of normal cells that are normally involved in the regulation of both proliferation and differentiation show enormous potential for the treatment of advanced disease. Studies of interferon have shown promising early results in chronic granulocytic leukemia and in hairy cell leukemia. A new class of drugs, the acridine analogs, of which AMSA (4'-[9-acridinylamino]methanesulfon-M-anisidide) is a member, has been introduced and has established activity against acute leukemia. VP-16 (etoposide) has just become commercially available and is an important drug both in leukemia and lymphoma. Finally, the discovery of new knowledge about the biochemical pharmacology of drugs such as arabinosyl cytosine has offered a major advance in salvage treatment and the potential for substantial further improvement in the frontline management of these diseases. The rapid advances in both palliative and curative treatment for the hematologic malignancies have generally found broad application to the management of advanced cancer arising from other organ systems.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Evolution of oligoleukemia.

Chronic lithium administration to 22 patients with oligoleukemia did not alleviate cytopenia or stimulate bone marrow proliferative activity. The authors identified, however, pretreatment characteristics discriminating two evolutionary endpoints of oligoleukemia (marrow failure, 10 patients; overt acute leukemia, 12 patients): higher marrow leukemic infiltrate, normal myeloid precursor proportion, platelet count, and female sex all favored eventual transition to overt leukemia which, in comparison with marrow failure, was associated with a significantly longer survival duration from symptoms. For patients developing overt leukemia, survival from diagnosis was inversely correlated with the degree of marrow leukemic infiltrate. The lack of lithium responsiveness in oligoleukemia is consistent with the concept of differentiated leukemia with abnormalities either at the level of a lithium-responsive adherent cell elaborating colony stimulating activity (CSA) or at the level of CSA-responsive CFUs.

Acute Disease↗
PubMed1984

Infection prophylaxis in acute leukemia. Comparative effectiveness of sulfamethoxazole and trimethoprim, ketoconazole, and a combination of the two.

In a comparative study of infection prophylaxis, patients with acute leukemia receiving remission induction therapy were assigned either no prophylaxis, sulfamethoxazole and trimethoprim, ketoconazole, or the combination of sulfamethoxazole and trimethoprim and ketoconazole. Both sulfamethoxazole and trimethoprim and the combination of sulfamethoxazole and trimethoprim and ketoconazole substantially reduced the overall incidence of infection consequent to a marked decrease in bacterial infection. However, sulfamethoxazole and trimethoprim were associated with an increased rate of fungal infection, while ketoconazole decreased this complication. No form of prophylaxis reduced infectious mortality or increased the complete remission rate. However, because of its effect in reducing infectious morbidity, we conclude that patients with acute leukemia receiving remission induction treatment should be given antibacterial and antifungal prophylaxis.

Acute Disease↗
PubMed1984

Effects of intensive induction chemotherapy for extensive-disease small cell bronchogenic carcinoma in protected environment-prophylactic antibiotic units.

Fifty-five patients with extensive-disease small cell bronchogenic carcinoma received three courses of intensive, inpatient, remission induction chemotherapy in (25 patients) or out (30 patients) of protected environment-prophylactic antibiotic (PEPA) units. Chemotherapy consisted of ECHO induction (E = epipodophyllotoxin VP-16-213; C = cyclophosphamide; H = hydroxydaunorubicin; O = Oncovin) and PRIME maintenance (PR = procarbazine; I = ifosfamide; ME = methotrexate). All evaluable patients (22 in the protected environment group and 26 in the control group) had a complete (50 percent in the protected environment group and 54 percent in the control group) or partial (50 percent in the protected environment group and 46 percent in the control group) remission. Median response and survival durations for both treatment groups were similar. The median survival duration of patients with a complete remission favored the protected environment group (16.5 versus 12.67 months; p = 0.20). Two patients (one from each group) are alive and disease-free for more than four years. Myelosuppression was intense and more pronounced in the protected environment group (p less than or equal to 0.01). Infectious complications were less common in patients receiving intravenous prophylactic antibiotics and in those treated with intravenous antibiotics in PEPA units (p less than or equal to 0.04). There were no treatment-related deaths, although treatment might have contributed to the death of three patients in the protected environment group and four in the control group. The administration of intensive ECHO induction chemotherapy to patients with extensive small cell bronchogenic carcinoma produced a high complete remission rate, although there was no significant long-term survival advantage over a program of less intensity. The administration of intravenous prophylactic antibiotics and the use of PEPA units significantly reduced the infectious morbidity of chemotherapy.

Adult↗