Interaction of covalently closed circular PM-2 DNA and hedamycin.
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Anti-Bacterial Agents↗
Biomedical subjects
J E Strong
Publications and source records attributed to J E Strong.
Use of covalently closed circular deoxyribonucleic acid for prescreening for antitumor compounds.
The interactions of PM-2 deoxyribonucleic acid (DNA) with 20 known antineoplastic agents were studied using agarose gel electrophoresis and fluorescence assay systems. Actinomycin D and adriamycin (and all other anthracyclines studied) induced superhelical conformational changes in PM-2 DNA. Bleomycin A2, tallysomycin, neocarzinostatin, macromomycin, and hedamycin degraded PM-2 DNA under various conditions. The potential utility of PM-2 DNA as an antitumor antibiotic prescreening tool was further studied by examining the effects of 200 broths on PM-2 DNA employing both fluorescence and agarose gel electrophorectic assays. The assays were shown to be sensitive and rapid and to provide information not provided by other prescreens with which the PM-2 DNA assays were compared.
Antineoplastic Agents↗
Use of PM-2 DNA degradation as a pharmacokinetic assay for bleomycin.
The PM-2 DNA fluorescence assay has been shown to be a rapid, sensitive, and reproducible assay for bleomycin biochemical activity. The assay can detect bleomycin in human serum in the nmol range. The method measures DNA degradative activity of bleomycin and could be used to determine activity of bleomycin analogs and metabolites. The usefulness of the assay to perform bleomycin pharmacokinetic studies in cancer patients has been demonstrated. Linear regression analyses of parallel bleomycin assays with the radioimmunoassay gave a coefficient of correlation of 0.98 to 0.78 with trichloroacetic acid-treated serum. These results indicate excellent agreement between the two assays.
Adult↗
The pharmacokinetics of bleomycin in man.
A series of studies were carried out to investigate the pharmacokinetics of the antineoplastic antibiotic bleomycin in patients with neoplastic disorders. Drug was administered by long (four to five days) and short (10 minutes) zero-order infusions, and serial plasma and urine samples were collected. Serum and urine bleomycin concentrations were determined by radioimmunoassay. The disposition of bleomycin after the 10-minute infusion was described by a two-compartment open model. However, following multiple-day infusion estimates were obtained that were inconsistent with those from the short infusion. Parameters from the long infusions agreed with those from the short infusion when terminal plasma bleomycin levels less than 10 microunits/ml were excluded. The time to reach steady state following the long infusion (ca. 12 hours) was consistent with the half-life (3 hours) predicted by the short infusion and the long infusion excluding levels less than 10 microunits/ml. Possible explanations include assay interference by an unknown metabolite or strong binding of drug to tissues with release at a rate much less than the apparent rate of elimination of drug from the body.
Adult↗
Studies on the clinical pharmacology of bleomycin.
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Adult↗
Bacterial endocarditis: an analysis of factors affecting long-term survival.
The records of 108 patients treated for bacterial endocarditis were reviewed. Six were diagnosed at autopsy and had not been treated for endocarditis. Of the 102 treated patients, 32 died during the first 30 days and 32 more were dead by 365 days. Although some reports indicate a much greater survival rate, our findings are more in keeping with those reports giving a rather poor long-term outlook for patients with endocarditis.
Adolescent↗
Radioimmunoassay and radioenzymatic assay of a new aminoglycoside antibiotic, netilmicin.
A radioimmunoassay and a radioenzymatic assay for netilmicin, a new aminoglycoside, were developed in our laboratories to assist in the study of the pharmacology of the drug and to establish values for use in its monitoring. The assays are sensitive, precise, and rapid, giving results that correlate (r = 0.90) with each other and with those of a microbiological assay in which Klebsiella pneumoniae is used as the test organism. Preliminary pharmacological studies show the drug to have a biological half-life of 135 min. which is comparable to that for other aminoglycosides.
Biological Assay↗
Clinical pharmacology of bleomycin following intravenous infusion as determined by radioimmunoassay.
The clinical pharmacology of bleomycin administered by continuous intravenous infusion over a 4 to 5 day period was examined by nine patients. Patients receiving 30 units per day attained an average steady state plasma level of 145.8 (+/- 43.1) ng/ml bleomycin. Elimination of bleomycin was initially described by first order rate kinetics (t 1/2 = 1.32 +/- 0.39 hour). However, at times greater than 12 hours following termination of infusion, a second elimination phase was observed (t 1/2 = 8.9 +/- 2.7 hour). There was also a high correlation between renal bleomycin clearance and creatinine clearance. The importance of renal clearance was indicated in a patient with renal impairment. This patient attained a steady state bleomycin concentration of 1046 ng/ml and exhibited a terminal elimination half-life of 33 hours. Overall plasma clearance of bleomycin (Qbeta) was generally greater than renal clearance, indicating that a nonrenal clearance mechanism was also important in bleomycin elimination. This nonrenal mechanism became especially apparent during renal failure.
Adult↗
The development of mexiletine in the management of ventricular dysrhythmias.
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Arrhythmias, Cardiac↗
Specificity of antisera produced against bleomycin.
The specificity of antisera produced in a goat or rabbit for use in bleomycin radioimmunoassay has been examined using competitive experiments employing several bleomycin analogs. These studies demonstrate that the antiserum distinguished alterations in both the nucleus and the terminal structure of the molecule. Removal of the terminal structure or addition of an aminosugar moiety in the bleomycin nucleus resulted in a significant decrease in immunoreactivity. Antisera produced in goat and rabbit hosts had different specificity for the terminal structure. The goat antisera demonstrated greater specificity for the terminal side chain than the rabbit antisera although this may not reflect a species-related event.
Animals↗
Effects of variations in renal function on the clinical pharmacology of bleomycin administered as an iv bolus.
The clinical pharmacology of bleomycin administered as an iv bolus has been studied in a homogeneous group of patients receiving a single regimen containing bleomycin, vinblastine, and cis-dichlorodiammineplatinum (II). These studies demonstrated that in patients with creatinine clearances greater than or equal to 35 ml/minute, the serum (or plasma) terminal elimination half-life of bleomycin was approximately 115 minutes. In patients with creatinine clearances less than 25-35 ml/minute, the terminal elimination half-life increased exponentially as the creatinine clearance decreased. The volume of distribution was approximately 20 liters, and was unaffected by changes in the creatinine clearance. The microbiologic assay and radioimmunoassay employed gave equivalent results.
Adolescent↗
Radioimmunoassay of iodinated gentamicin.
A radioimmunoassay is described for the aminoglycoside antibiotic, gentamicin. Iodinated gentamicin was prepared using an 125I-labeled acylating agent: 3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester which spontaneously reacts with gentamicin to produce an iodinated conjugate. The radioimmunoassay with iodinated gentamicin produced a straight line on a logit/log plot yielding an assay sensitivity of 80 pg. A Scatchard plot plus an equilibrium technique were used to estimate the affinity constant at 8 X 10(9) 1 mol-1 and 10.5 X 10(9) 1 mol-1, respectively. Kanamycin and neomycin, two chemically related aminoglycoside antibiotics, did not crossreact with gentamicin until concentrations were 10(5) greater than those found in blood. Assay of patients' serum samples by both a microbial assay and radioimmunoassay resulted in a statistically significant (p less than 0.001) correlation between the two methods.
Animals↗
Radioimmunoassay of iodinated tobramycin.
A radioimmunoassay for tobramycin was developed using antisera from rabbits injected with a tobramycin-bovine serum albumin conjugate. The antibody had a relatively high affinity for (125)I-labeled tobramycin (1.6 x 10(9) liters/mol), thus indicating little interference in immunoreactivity by iodination. The radioimmunoassay was highly specific, and only minor cross-reaction occurred with other aminoglycoside antibiotics. The radioimmunoassay was also more sensitive than previously published tobramycin assays (minimum sensitivity, 280 pg), and there was a significant correlation (P < 0.05) with both the radioenzymatic and microbiological assays.
Animals↗
Radioimmunoassay of sisomicin.
An antibody induced in rabbits against a gentamicin-bovine serum albumin conjugate cross-reacted with the chemically related aminoglycoside, sisomicin, facilitating the development of a sisomicin radioimmunoassay. Sisomicin was labeled with (125)I using an acylating agent [3-(4-hydroxyphenyl)propionic acid-N-hydroxy-succinimide ester]. The resulting assay produced a linear standard curve on a logit-log plot with a sensitivity of 140 pg. Comparison with a microbiological assay showed no significant difference (P < 0.001) in the measurement of sisomicin by these two methods.
Animals↗
Radioimmunoassay of bleomycin.
A radioimmunoassay for bleomycin has been produced using 125l-labeled bleomycin and antisera raised in rabbits against a carbodiimide-catalyzed bleomycin-bovine serum albumin conjugate. 125l-Labeled bleomycin was synthesized by direct iodination of the drug using the chloramine-T technique. The standard curve of the assay was linear on a logit-log plot and the lower limit of sensitivity was 250 pg bleomycin sulfate. A mean recovery of 102.6% (+/- 3.3% S.E.) was obtained using bleomycin added to normal sera. No significant decrease in bleomycin immunoreactivity was observed following 24 hr incubation of the drug in serum at 37 degrees. The radioimmunoassay was also suitable for measuring bleomycin in the presence of other drugs since the assay was not significantly affected by the other antineoplastic agents tested. The sensitivity and specificity of the radioimmunoassay for bleomycin should provide a new means for pharmacokinetic and toxicity studies of bleomycin.
Animals↗
Radioimmunoassay of antibiotics and chemotherapeutic agents.
Theapeutic monitoring of drugs has become of major importance and has stimulated development of new assay systems. Chemotherapeutic agents, many of which are toxic, have until recently been assayed by microbiological systems or other complex techniques that are impractical for a clinical laboratory. Radioimmunoassays have now been developed for some of these agents. We review the techniques for producing hapten protein conjugates and radiolabeling at specific sites on the drug molecule, and the use of these assays in clinical medicine and pharmacology.
Anti-Bacterial Agents↗
Phenylbutazone self-poisoning treated by charcoal haemoperfusion.
A case is presented of a patient who ingested a potentially fatal dose of phenylbutazone. Her clinical condition deteriorated despite adequate supportive therapy and the use of charcoal haemoperfusion proved life-saving.
Adolescent↗