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Biomedical subjects

D A Noe

Publications and source records attributed to D A Noe.

At least 37 records · Page 2Linked to original sources
PubMed1991

Sequences of taxol and cisplatin: a phase I and pharmacologic study.

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.

Adult↗
PubMed1990

Phase I and pharmacokinetic study of brequinar sodium (NSC 368390).

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.

Antineoplastic Agents↗
PubMed1990

Phase I study and pharmacodynamics of piroxantrone (NSC 349174), a new anthrapyrazole.

Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.

Adult↗
PubMed1989

Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a nonclassical folate antagonist, has been evaluated clinically on several schedules. We have studied TMTX administered as an iv bolus for 5 consecutive days every 3 weeks in 35 patients with advanced solid tumors. Drug was given at doses ranging from 7.6 to 18.8 mg/m2. The maximal tolerated dose was 13.1 mg/m2 per day x 5 for patients without prior myelotoxic treatment and 7.6 mg/m2 per day x 5 for previously treated patients. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for patients not experiencing toxic effects. The dose-limiting toxicity was neutropenia. Rash and mucositis were also significant. TMTX concentrations were measured 1 and 24 hours after each dose, and the data were fit by use of a one-compartment pharmacokinetic model. With this simplified sampling and modeling scheme, the mean total body clearance (+/- SD) of trimetrexate was 31 +/- 20 mL/min per m2 and the volume of distribution was 13 +/- 7 L/m2. Mean plasma concentrations 1 hour after a dose were 1.12, 2.43, 3.33, and 3.25 mumol/L at 7.6, 9.1, 10.9, and 13.1 mg/m2, respectively. The mean TMTX concentration (+/- SD) 24 hours after a dose was 114 +/- 87 nmol/L. The mean area under the concentration-versus-time curve at 13.1 mg/m2 was 2,266 mumol.min/L. The drug concentration 1 hour after the first dose and the area under the concentration-versus-time curve were highly correlated with leukopenia and thrombocytopenia (r = .6 and .65 and P = .0007 and .0001, respectively). The maximal tolerated dose on the daily x 5 schedule was 30% of the dose tolerated on an iv bolus schedule. The choice of drug schedule for clinical trials when murine and human pharmacokinetics differ is discussed. Phase II trials are under way with both the iv bolus and the daily x 5 schedules.

Adult↗
PubMed1989

A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5-30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m2. The maximal tolerated dose (MTD) on this schedule is 220 mg/m2, which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two- or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5 +/- 21 ml/min per m2 and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (Vss) and in the terminal disposition half-life (t1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r = 0.58; P = 0.0006) and with the area under the concentration vs time curve (AUC) (r = 0.41; P = 0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r = -0.36; P = 0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily X 5 schedules are under way.

Adult↗
PubMed1989

Acute-phase behavior of factor VIII procoagulant and other acute-phase reactants in rabbits.

We measured the plasma concentrations of factor VIII procoagulant (FVIII:C) in rabbits in two laboratory models of inflammation and after injections of purified homologous interleukin 1 (IL-1). The mean FVIII:C activities 2-4 days following the intramuscular injection of turpentine were significantly elevated, as were the concentrations of fibrinogen and C-reactive protein (CRP). By contrast, rabbits given 50 ng of bacterial lipopolysaccharide intravenously developed increased levels of FVIII:C but not of fibrinogen or CRP. We then studied plasma levels of FVIII:C, fibrinogen, and CRP after injections of either form of purified rabbit IL-1. If the rabbits' temperatures were monitored, FVIII:C levels increased in a log dose-related manner. This effect was not seen unless the rabbits were restrained and was seen in restrained rabbits even if the temperatures were not monitored. Fibrinogen and CRP levels did not change after IL-1 injections. These findings demonstrate that FVIII:C is an acute-phase reactant as judged by its response to turpentine inflammation or endotoxin injections, and to injections of IL-1 in restrained rabbits. FVIII:C appears to be a more sensitive acute-phase reactant than either fibrinogen or CRP. Neither of the latter proteins responded to low-dose endotoxin injections nor to either form of purified homologous IL-1. The doses of IL-1 given did cause fever, neutrophil leukocytosis, and hypoferremia.

Acute-Phase Proteins↗
PubMed1989

Quantitative analysis of membrane and secretory protein processing and intracellular transport.

Quantitative experimental data from studies of intracellular processing and transport of secretory and membrane proteins are only rarely evaluated using kinetic modelling. Instead, the analysis of such data is usually limited to calculating either the apparent half-life or the transit time. Neither of these parameters accurately measures rates of cellular processing or transport. This paper describes a formal approach for the calculation of rate constants, half-lives and lag times for single and sequential processing and transport steps. Generalized kinetic models are presented that can be used to analyse data from both pulse-chase and continuous incubation experiments with labelled amino acids or sugars. The results from a number of published studies are reanalysed using the models to demonstrate the usefulness of kinetic modelling in the routine analysis of experimental data.

Animals↗
PubMed1988

Clinical and pharmacologic reappraisal of dichloromethotrexate.

Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.

Adult↗
PubMed1988

Clinical pharmacology of oral and i.v. N-methylformamide: a pharmacologic basis for lack of clinical antineoplastic activity.

N-Methylformamide (NMF) has been an agent of considerable interest to oncologists because of its broad spectrum of preclinical antitumor activity, tumor-differentiating abilities, and radiosensitizing and chemosensitizing properties. In this report, the pharmacokinetics of NMF are described, based on data from two phase I studies exploring both iv and oral routes of administration. Mean peak NMF plasma concentrations at recommended phase II doses were 0.46 mmol/L for NMF administered orally, 600 mg/m2 three times/week X 4 weeks every 6 weeks, and 2.78 mmol/L for NMF administered as a weekly iv bolus at 2,000 mg/m2 X 3 weeks every 4 weeks. These NMF concentrations were significantly lower than the concentrations that have been demonstrated to induce antineoplastic and relevant biologic effects in preclinical studies. Plasma disappearance curves were biphasic in the majority of patients; however, 25% of the curves were best fit by a monoexponential kinetic model. Mean alpha half-life and beta half-life values (+/- SE) were 10 +/- 2 and 732 +/- 93 min, respectively. Volumes of distribution for the theoretical central compartment (Vc) and at steady-state (Vss) were 13.8 +/- 1.1 L/m2 and 18.7 +/- 1.1 L/m2, respectively. The mean plasma clearance of NMF was 19.1 +/- 2.1 mL/min per square meter, and the relative contributions to parent compound disposition by respiratory and renal routes were insignificant. No metabolites were identified. Gastrointestinal absorption of oral NMF was rapid and nearly complete; oral bioavailability was calculated to be 0.87. Pharmacodynamic associations were observed between the magnitude of the area under the plasma disappearance curves and hepatotoxicity, the dose-limiting toxic effect of iv NMF, and the symptom complex of nausea, vomiting, and malaise, which precluded dose escalation of oral NMF.

Administration, Oral↗
PubMed1987

Prolonged infusion of hexamethylene bisacetamide: a phase I and pharmacological study.

Hexamethylene bisacetamide (HMBA, NSC 95580), a potent polar-planar differentiating agent in vitro, was studied in a phase I trial as a 10-day continuous infusion administered every 4 weeks. Since preclinical evidence had demonstrated that the duration of HMBA exposure was an important variable in the induction of differentiation, and HMBA steady-state concentrations (Css) achieved during 5-day infusions were minimally effective at inducing in vitro differentiation, this study was conducted to evaluate the feasibility of maintaining HMBA Css for 10 days similar to levels achieved and maintained for 5 days. Twelve patients received 17 evaluable courses at three dose levels, 12, 15.8, and 20 g/m2/day. Platelet toxicity limited further dose escalation. Mean nadir and percentage of decrement in platelet counts were 175,000/microliter and 66%, and 43,500/microliter and 83%, at 15.8 and 20 g/m2/day, respectively. In this 10-day study, the percentage of decrement of platelet counts was linearly related to mean HMBA Css and to the area under the plasma concentration versus time curve (AUC). However, when combined platelet and pharmacological data from both 5- and 10-day studies were analyzed, it was apparent that the duration of HMBA exposure was an additional significant variable in predicting the magnitude of thrombocytopenia. Renal and metabolic toxicities that precluded dose escalation in previous 5-day trials of HMBA were mild and insignificant in this study. Mean HMBA Css were 0.65 +/- 0.09 mmol/liter at 15.8 g/m2/day, and 0.99 +/- 0.22 mmol/liter at 20 g/m2/day. Depletion of intracellular polyamines in peripheral blood mononuclear leukocytes was noted during several courses that were associated with profound myelosuppression, but no clear relationships were apparent between the magnitude of polyamine changes and toxicity or between fluctuations in polyamines and the magnitude of mean HMBA Css values. Based on this study, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule were 20 and 15.8 g/m2/d, respectively. The administration of HMBA by a ten-day infusion at the maximum tolerated dose resulted in the delivery of lower daily doses and lower HMBA Css than on the 5-day schedule. The major toxicities differed on these schedules with thrombocytopenia being most prominent on the 10-day schedule and metabolic and CNS toxicities on the 5-day schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetamides↗
PubMed1987

A kinetic analysis of fibrinogenolysis during plasminogen activator therapy.

A mathematic model of the systemic fibrinogenolysis that accompanies coronary thrombolysis with recombinant tissue plasminogen activator (rt-PA) has been devised. The kinetic parameters of the model were estimated by nonlinear regression analysis with data from a clinical trial of rt-PA. The plasma elimination rate constant for rt-PA was estimated to be 10.0 hr-1, the second-order catalytic rate constant for the in vivo rt-PA-mediated conversion of plasminogen to plasmin 0.0078 (microgram rt-PA/kg body weight)-1 hr-1, the plasma elimination rate constant for plasmin 2.33 hr-1, and the second-order catalytic rate constant for the in vivo plasmin-catalyzed degradation of fibrinogen 0.466 (mg plasmin/dl)-1 hr-1. Computer simulation studies based on these parameter estimates show that the magnitude of fibrinogenolysis induced by rt-PA is related to the dose in a curvilinear fashion, showing diminishing increments in the effect at increasing doses. The degree of fibrinogenolysis induced by rt-PA administration is nearly independent of the dosing schedule.

Clinical Trials as Topic↗
PubMed1986

Intra-articular pressures during arthroscopic knee surgery.

Arthroscopic surgery of the knee requires effective joint distention. No reports exist in the literature relating to optimal fluid pressure and dynamics of joint distention during arthroscopic knee surgery. Static and dynamic laboratory studies were performed on a knee model to establish an accurate method of measuring pressures from the arthroscopic cannula. A prospective study of 107 subjects who underwent arthroscopic surgery by one surgeon (J.W.E.) was then performed using saline distention from a saline bag wrapped with a pneumatic cuff. Intra-articular pressures ranged from 0 to 750 mm Hg, but usually fell into the zone from 70 to 120 mm Hg. A minimum pressure of 30 mm Hg was required for visualization. Variations in pressure magnitudes as well as flow rates during the procedures were studied. Technical suggestions based upon these data include maintenance of pressure between 70 and 100 mm Hg; avoidance of abrupt changes in position of the distended knee; and maintenance of lower pressure levels (35-50 mm Hg) if the synovium has been violated as in the performance of a lateral release procedure.

Adolescent↗
PubMed1986

Plasma clearance rates of coagulation factors VIII and IX in factor-deficient individuals.

The plasma clearance rates of factors IX and VIII were determined in patients with hemophilia A and B who had received factor replacement by prolonged, continuous infusion of factor concentrates. The clearance rates were calculated by dividing the factor infusion rates by the steady-state plasma factor activities corrected for base-line factor activities. The mean factor IX clearance rate in eight factor IX-deficient patients was 233 mL/h (range 159 to 340 mL/h). The mean normalized clearance rate was 3.4 mL/h/kg. The mean factor VIII clearance rate in eight factor VIII-deficient patients was 294 mL/h (range 229 to 361 mL/h) and the mean normalized rate was 5.0 mL/h/kg. Both factors show linear relationships between the factor infusion rates and the steady-state plasma factor activities achieved.

Factor IX↗
PubMed1986

Reduction in the plasma clearance rate of warfarin induced by cimetidine.

The interaction between the histamine H-2 receptor antagonist, cimetidine, and warfarin sodium was prospectively studied in 14 patients who were previously anticoagulated for five years. The patients received warfarin and cimetidine concomitantly for a minimum of ten days. Seven of the patients experienced increases in plasma warfarin concentrations. This correspondingly resulted in abnormal prolongation of their prothrombin times. In these patients the elevation in the steady-state warfarin concentration demonstrates that coadministration of cimetidine significantly reduces the plasma clearance rate of warfarin. The serum and urine metabolite levels of warfarin were not qualitatively different in the absence in contrast to the presence of cimetidine. It is apparent that cimetidine can act as an inhibitory influence on the catabolic degradation of warfarin.

Aged↗
PubMed1985

Novel factor X deficiency. Normal partial thromboplastin time and associated spindle cell thymoma.

This report presents a heretofore undescribed laboratory variant of congenital factor X deficiency, seen in conjunction with a relatively rare tumor. The patient had a history of bleeding, a prolonged prothrombin time, and a factor X value of 4.2 percent of normal activity, but the partial thromboplastin time and Russell's viper venom clotting time were normal. Management of this case required unusual measures to treat the patient's coagulopathy.

Blood Coagulation Tests↗
PubMed1985

A model of the heterogeneity of red cell hemoglobin concentration.

A model of red cell hemoglobin concentration has been developed and computer stimulations performed to investigate quantitatively the relationship among the intraindividual heterogeneities of cell hemoglobin content, volume, and hemoglobin concentration. In the model, the cell volume and hemoglobin content frequency distributions and their joint distributions are described by Gaussian probability distributions. The frequency distributions of cell hemoglobin concentration are determined from the joint probability distributions by summing the joint probabilities of the variate pairs the ratios of which equal the specified concentration. For the parameter values considered, the mean cell hemoglobin concentration closely approximates the average (i.e., statistical mean) concentration. The heterogeneity of cell hemoglobin concentration increases with increasing coefficients of variation of cell hemoglobin content and cell volume and with decreasing correlation coefficients. When the correlation coefficient is greater than 0.7, cell hemoglobin concentration shows less relative dispersion than the component indices.

Erythrocyte Indices↗
PubMed1984

Thyroxine and thyroxine-binding globulin: discriminant formulae for the separation of the diagnostic classes of thyroid function.

The biochemical classification of thyroid functional status is often accomplished by the use of the thyroxine to thyroxine-binding globulin (T4:TBG) ratio. It has recently been shown, however, that the reference range of the T4:TBG ratio varies with the concentration of TBG. This makes the T4:TBG ratio an unwieldy diagnostic index. A more accurate and economical way to define thyroid function using T4 and TBG measurements is by linear discriminant formulae. This is so because T4 varies linearly with TBG at the T4 reference limits over a wide range of TBG concentrations. Using the T4 reference ranges established by Attwood and Atkin (Ann Clin Biochem 1982; 19: 101-3), the following formulae are obtained: T4 (nmol/l)--4.05 TBG (mg/l) greater than 94.5 indicates hyperthyroidism; T4 (nmol/l)--2.72 TBG (mg/l) less than 23.8 identifies hypothyroidism.

Humans↗