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PubMed1992

Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

PURPOSE: 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS: The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS: Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS: Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Blood Platelets↗

PubMed1994

[High-performance biosignal amplifier for electrophysiologic studies for special safety requirements].

For the recording of minute bioelectric signal voltages in the fields of medical research and diagnostic applications, a high-performance amplifier is needed to provide the signal levels necessary for a significant analysis. Irrespective of the concrete application, the major parameters required for a comparative evaluation of such systems are sensitivity, bandwidth and noise. Some applications also make special demands on electrical safety measures. With the aim of using an amplifier with a particularly powerful magnetic stimulator, and in view of the special requirements for brain voltage recording in a fully conscious patient, a universally applicable amplifier system has been developed that incorporates safety measures that ensure virtually risk-free application. The stimulation artefact can be suppressed completely by means of automatic offset regulation of the preamplifier. The circuit elements in electrical contact with the organism are separated from the rest of the measuring system by a high-voltage insulation barrier. The main innovation and central subject of this article is an active protective system with an extremely short response time, which reliably cuts off the relevant amplifier circuits as soon as the ceiling signal level is exceeded. In accordance with relevant regulations, the user is warned of any first failure by a program-controlled self-test run by the protective unit and done automatically when the amplifier is activated. Exhaustive tests with a prototype have confirmed, among other things, that the integration of the new protective device does not reduce the amplifier output to any measurable extent.

Amplifiers, Electronic↗

PubMed1996

Analysis of plasma metabolites during human PET-studies with three receptor ligands, [11C]YM-09151-2, [11C]doxepin and [11C]pyrilamine.

Carbon-11 labeled metabolites in human plasma were analyzed by high-performance liquid chromatography during positron emission tomography (PET) studies using the dopamine D2 ligand [11C]YM-09151-2 as well as the histamine H1 ligands [11C]doxepin and [11C]pyrilamine. For all the three tracers, blood clearance of the radioactivity was extremely rapid after an i.v. injection. The plasma protein-binding of [11C]YM-09151-2 and [11C]doxepin had protective effects upon the metabolic alteration of the ligands, whereas [11C]pyrilamine was free from the protein-binding and immediately degraded. The degradation of [11C]doxepin was more rapid in epileptic patients on medication than in normal subjects. These results indicate that analysis of metabolites in the plasma is necessary to determine the accurate arterial input function for quantitative PET measurement.

Adult↗

PubMed1992

Metabolic design of combination therapy: use of enhanced fluorodeoxyglucose uptake caused by chemotherapy.

In order to quantify effects of an experimental chemotherapy, MCF7 cells were studied with 14C-fluorodeoxyglucose (FDG) and high-performance liquid chromatography (HPLC). Uptake measurements were performed 1 and 4 hr after the end of a therapy with hexadecylphosphocholine (HPC). A dose- and time-dependent increase of the FDG uptake after therapy was observed, with a maximum at 1 hr after therapy. These data were used to develop a new metabolic design of combination treatment. Several time-dose combinations of HPC and deoxyglucose (DOG) were analyzed for their effects on growth inhibition. The combinations using DOG in the period of pronounced enhancement of FDG uptake (1 hr after HPC treatment) were found to be the most effective with an improvement of up to 520% in growth inhibition. This metabolic design of combination treatment may also be applied in vivo, and PET can be used to optimize the time and dose schedule of the modified treatment protocol.

Antineoplastic Agents↗

PubMed1992

[Combined use of real-time digital subtraction radioscopy and computerized tomography: potential advantages in diagnostic and interventional radiology].

The idea of combining fluoroscopy and CT arose from the daily practice in diagnostic and interventional radiology. A Diasonics OEC high-performance image intensifier complete with a digital subtraction system was connected to a Siemens Somatom-DRH CT scanner to work in tandem. CT is used for a localization in-depth and fluoroscopy for the subsequent maneuvers within an organ or body compartment. With this combination, complex procedures such as transarterial portography, percutaneous embolizations, pain treatment and manipulation for catheterization of the bile ducts and urinary tract could be performed in one place and in one session. CTF is especially useful when patients should not be moved about from room to room or undergo an examination in several sessions, as it happens with children or critically ill or contagious patients.

Adult↗

PubMed1992

Expert system design in hematology diagnosis.

A two-part study was designed to test the hypothesis that sufficient information is available from a modern hematology analyzer (the Coulter STKS) to reach a reliable intermediate conclusion which can be used as input to the next decision-making level in the design of a high-performance expert system for hematology diagnosis. In phase one, we analyzed the performance of three probabilistic systems (using Bayes' rule) which interpret STKS data: a control system which took the traditional approach of classifying cases into specific diagnoses, and two test systems which were designed to reach only an intermediate conclusion but not a final diagnosis. One of the test systems classified cases into "textbook categories" of disease and the other utilized defined diagnostic patterns. The systems were tested with 150 cases. The pattern approach ranked the correct choice first in 141 of 150 cases (94%). In phase two, we abandoned Bayes' rule, reformulated the pattern approach into a heuristic classification system, and tested its reliability on 820 cases. The algorithm of the reformulated system was able to classify all 820 cases into the same predominant pattern as a panel of three experienced laboratory hematologists.

Algorithms↗

PubMed1991

[The effect of a thigh tourniquet on the pharmacokinetics of midazolam].

Although the general pharmacokinetics of midazolam (M) are well documented, little is known about the possible effects of a thigh tourniquet on the distribution and elimination of this drug. METHOD. Institutional approval for the study and individual informed consent were obtained. We studied 30 patients (ASA-I) without premedication who electively underwent a surgical procedure of the lower limb. Patients were divided into three groups of 10. The procedure was done in groups I and II with and in group III without tourniquet use. Anesthesia was induced in groups I and II with 0.1 mg/kg M, fentanyl 5 micrograms/kg, alcuronium-dichloride 0.15 mg/kg and etomidate 0.1-0.2 mg/kg i.v. and maintained with enflurane 0.3-1.0 vol.-%. About 20 min after midazolam injection and after exsanguination the tourniquet was applied on the proximal thigh in group I. In group II anesthesia was induced with etomidate 0.2 mg/kg and alcuronium-dichloride 0.15 mg/kg i.v., and maintained about 20 min with enflurane 1.0-1.5 vol.-% until exsanguination and tourniquet application. After this, these patients also received 0.1 mg/kg M and 5 micrograms/kg fentanyl i.v. Through an indwelling arterial line, blood samples were obtained prior to and 2, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165 and 180 min after M injection. Plasma M levels were measured by high-performance liquid chromatography with UV detection. These concentrations were fitted to a two-compartment open model. Comparison between groups was performed using the Kruskal-Wallis test and p less than 0.05 was considered to indicate significance. RESULTS. The groups were all comparable in age and weight, and groups I and II also in duration of thigh ischemia. Midazolam elimination half-time (t beta 1/2) was significantly shorter in group II than in groups III and I (52 min vs 126 min and 139 min; p less than 0.05). Of the calculated distribution volumes (volume of the central compartment, volume in the steady state and volume in the elimination phase), only the volume in the steady state was significantly smaller in group II than in groups III and I (p less than 0.05). Groups III and I did not differ significantly in the computed parameters. The measured initial midazolam mean concentrations in group II were twice those in groups III and I (655 ng/ml vs 323 ng/ml and 332 ng/ml). Since clearance was not significantly different between any two groups, the shorter t beta 1/2 in group II was probably due to the reduced distribution volume. CONCLUSION. These data demonstrate that in the presence of a thigh tourniquet the timing of the injection - before or after application of the tourniquet is of decisive importance. Injection after the application of a tourniquet leads to an higher plasma level and shortens the elimination half-life.

Adult↗

PubMed1989

Phototherapy for neonatal hyperbilirubinemia.

New light has recently been shed on the way phototherapy reduces bilirubin concentration in icteric infants. The introduction of a high-performance liquid chromatography technique led to the discovery of new photoisomers of bilirubin, the configurational and structural isomers with high and low quantum yields, respectively, and to a renewed interest in the photochemical properties of bilirubin in vitro and in vivo. Circular dichroism and absorption spectroscopies have then shown that bilirubin behaves like a bichromophoric system, with the 2 halves of the molecule strongly interacting in the excited state. This coupling mechanism makes the quantum yields of bilirubin photochemistry wavelength-dependent, with marked effects in the long wavelength edge of the bilirubin absorption spectrum. The photochemistry of bilirubin is substantially similar in icteric rats and babies, and is consistent with what is observed in vitro. However, the metabolism of bilirubin photoproducts in rats sometimes differs quite significantly from that in babies. In particular, only the low quantum yield structural isomer, lumirubin, is efficiently excreted by babies. Although the relative role of the bilirubin photoprocesses in the therapy of hyperbilirubinemia is not yet known with certainty, the structural photoisomerization is generally assumed to represent the main route of bilirubin elimination. As a consequence, the determination of the spectral band that optimizes the process of formation of lumirubin in neonate may represent an important step in the improvement of the clinical protocol of phototherapy. Therefore, in addition to reviewing the most recent data on bilirubin photochemistry and the metabolism of bilirubin products, this article presents a computation of the optimal light for lumirubin formation. The combined effects of long-wavelength photochemistry of bilirubin and skin attenuation show that the optimal spectral range should be between 480 and 510 nm.

Chromatography, High Pressure Liquid↗

PubMed1988

Task difficulty and EEG alpha asymmetry: an amplitude and frequency analysis.

The effects of mathematical, spatial and verbal task difficulty on EEG alpha amplitude and mean frequency asymmetry were investigated. Twenty right-handed subjects with no familial left-handedness (10 female, 10 male) were presented 3 levels of difficulty for each type of task. Difficulty was varied through increasing the rate of auditorily presented numerical stimuli. Also examined were EEG alpha correlates with measures of performance anxiety, subjective difficulty, loss of vigilance, confusion, the tendency to rely on a guessing strategy and performance. While increasing task difficulty led to right-parietal and posttemporal alpha acceleration for all tasks, task-dependent bilateral changes in alpha frequency were also observed. Increased mathematical task difficulty widened parietal amplitude asymmetry differences between high- and low-performance subjects, and produced performance-dependent changes in left-parietal and right-temporal alpha frequency. A curvilinear relationship between spatial-task difficulty and relative right-hemisphere alpha attenuation was found for the high-performance group only. Finally, numerous correlations were found between alpha measures and subjective and performance variables. Most of these correlations were found to be both task- and difficulty-level-specific. Task anxiety appeared to play a significant role in the determination of parietal- and temporal-lobe asymmetry.

Adult↗

PubMed1985

Cyclosporine disposition in the dog. Comparison of radioimmunoassay with high-performance liquid chromatographic assay and pharmacokinetics following intravenous administration.

Radioimmunoassay (RIA) and high performance liquid chromatography (HPLC) with ultraviolet absorbance detection have been compared as potential tools for cyclosporine pharmacokinetic studies in dogs. RIA clearly affords greater assay sensitivity, although crossreactivity with cyclosporine metabolites causes an over-estimation of parent drug concentrations with a subsequent reduction in the apparent values of clearance and volume of distribution. HPLC appears to be specific for parent cyclosporine. Thus, with the sacrifice of some sensitivity, HPLC-measured time-course data afford more reliable estimates of cyclosporine pharmacokinetic parameters. After the selection of a dosage regimen from preliminary studies, the pharmacokinetics of i.v.-administered cyclosporine were studied in six adult male mongrel dogs. Following administration of 20 mg/kg by constant-rate 30-min i.v. infusion the time courses of cyclosporine were studied in plasma and urine. Concentrations were measured by reversed-phase HPLC with ultraviolet absorbance detection. Data were fitted to triexponential equations using a digital computer with the CSTRIP and NONLIN programs, and pharmacokinetic parameters were calculated. Present findings suggest that cyclosporine is slowly yet extensively distributed into peripheral body regions that might serve as slowly releasing storage areas. Large volumes of distribution along with moderately slow clearances resulted in long half-lives for the disposition of cyclosporine. Less than 1% of the administered dose was recovered as parent cyclosporine in the urine, suggesting that renal clearance of cyclosporine was negligible. The potential relevance of present findings to cyclosporine therapy of transplant patients is discussed.

Absorption↗

PubMed1979

New developments in analysis of isoenzymes separated by "high-performance" liquid chromatography.

We have developed two enzyme analyzers for use in "high-performance" liquid chromatography. In both systems two detectors are used, placed after the column effluent has been combined with assay reagent. In one system, an absorbance detector is placed before and after a post-column reaction coil. Peaks observed at one detector are subtracted from those at the other, to produce a two-point measurement of enzyme activity. The linear dynamic range was 17--1700 U/L for lactate dehydrogenase (EC 1.1.1.27). In the other system, two reaction coils were used and a single fluorescence detector was placed at the end of each coil. These coils were kept at different temperatures, and an automated switching valve diverted equal amounts of column effluent and reagent into both coils. The fluorescence readings were then subtracted to produce a differential measurement of enzyme activity. The linear dynamic range was 20--1000 U/L. We used both systems to chromatographically analyze lactate dehydrogenase isoenzymes, and could separately determine both the distribution and activity of sample isoenzymes.

Autoanalysis↗

PubMed1984

Prediction of arterial wall failure under acceleration stress in high-performance aircraft.

Experimental results indicate that the passive mechanics (no smooth muscle action) of the larger arteries, such as the aorta and pulmonary, in humans are closely related to the elastin content at low strain and to the collagen content at high strain. In an aerial combat maneuver, the acceleration stress typically rises to a maximum, remains there for several seconds, and then falls off. The arterial wall viscoelastic property relevant here is hysteresis. The strain remaining when the stress is removed is called "permanent set." This so-called permanent set will decay away exponentially with a comparatively long time constant on the order of several hundred seconds. A first approximation to the permanent set, after a hysteresis loop has been executed, has been derived. Collagen can only stretch by 20% before failing. Choosing combat scenarios in which the maneuver is repeated at 1-min intervals so that the decay in permanent sets can be ignored, the number of maneuvers required to damage or rupture the collagen is computed for ranges of acceleration (g) values equivalent to increases in the arterial intraluminal pressures. The calculations are done for the external carotid, abdominal aorta and pulmonary arteries. For example, applying the continual recruitment of collagen fibers theory to the pulmonary artery produces the following result. The permanent set at net acceleration value of 5 g is 0.085 and the number of sequential maneuvers required to damage 2.5% of the collagen is 2.4. Based on discontinuous recruitment of 100% collagen at a strain of 1.7 in the pulmonary artery, the number of maneuvers required to rupture the collagen would be 58 at an acceleration of 5 g. At 10 g, this number falls to about 10 maneuvers. The results emphasize the importance of present protective measures, such as the use of G suits and valsalva maneuvers. But these measures can only reduce the effects predicted here, not eliminate them. The results also highlight the necessity for servo-controlled seat orientation, and for the introduction of integrating accelerometers for all aircrew to record acceleration exposure history.

Acceleration↗

PubMed1983

C-11-labeled glucose and its utilization in positron-emission tomography.

Carbon-11-labeled glucose was prepared photosynthetically using the green alga Scenedesmus obtusiusculus Chod. The carbohydrates were extracted from the cells with dilute HCI and the glucose was isolated and purified using high-performance liquid chromatography. The manipulations in the hot cell are described. Analysis of the material (gas liquid chromatography and HPLC) showed that the glucose obtained was radiochemically pure. The total incorporation of the 11CO2 added to the algae was 60-80%. The radiochemical yield of pure carrier-added glucose was approximately 25%, at 40 min after E.O.B. including the HPLC purification and sterile filtration. The C-11 glucose uptake in rat brain was compared with that of commercial D[U-14C]glucose, and preliminary PET studies with D-[11C]glucose in a patient with a brain infarct are presented.

Animals↗

PubMed1980

Multiparameter appraoch to the "fingerprinting" of fluorescent Pseudomonads.

A recent study has shown that an emission-excitation matrix could be used to provide a unique fingerprint for the selective identification and characterization of certain species of Pseudomonas. This paper describes the results of a systematic study of the variables that contribute to the uniqueness of the fingerprint. Additional insight concerning the nature of the fluorescent pigments of these species is gained by analysis with a high-performance liquid chromatograph/video fluorometer combination. While providing information about the analytical variables contributing to the analysis, this combination also added the variable of chromatographic retention time for unambiguous fingerprinting.

Autoanalysis↗

PubMed1982

Production of L-[1-11C]valine by HPLC resolution.

Based on a recently developed analytical technique, preparative high-performance liquid chromatographic (HPLC) resolution of DL-[1-11C]valine has been achieved. A conventional reverse-phase HPLC column and a chiral mobile phase (aqueous solution of L-proline, cupric acetate, and sodium acetate) were used. The copper can be removed from the L-valine fraction by precipitation as the sulfide, and final purification by cation-exchange chromatography yields L-[1-11C]valine in a form that is acceptable for clinical positron tomographic studies. This purification method does not remove the L-proline introduced in the resolution process, but added L-proline did not affect the tissue distribution of L-[1-14C]valine in rats. We have produced up to 60 mCi of L-[1-11C]valine in an overall synthesis and resolution time of 50 min. This procedure should be adaptable to the rapid resolution of other C-11-labeled amino acid racemates.

Carbon Radioisotopes↗

PubMed1982

High-performance liquid chromatography of platinum complexes on solvent generated anion exchangers. III. Application to the analysis of cisplatin in urine using automated column switching.

Platinum complexes are retained on solvent generated anion exchangers, prepared by coating reversed-phase (C-18) supports with a monolayer of hexadecyltrimethylammonium bromide. The retention mechanism is described in terms of ion--dipole interactions in the stationary phase, reinforced by a hydrophobic effect. The high degree of ligand selectivity exhibited by these systems arises from the use of purely aqueous mobile phases which maximize the differences in solute dipole and hydrophobic surface area. By using stationary phases of different surface characteristics and the application of automated column switching, the technique is applicable to the clinical analysis of cisplatin in urine. After chromatography, the purified cisplatin fractions area determined by atomic absorption spectrophotometry. The recovery of cisplatin from urine is 101.1% with a relative standard deviation of 3.6% and the limit of detection is 2 micrograms/ml.

Automation↗

PubMed1995

Super-early iodine-123-iodoamphetamine SPECT imaging of human primary motor cortex.

UNLABELLED: This study was designed to visualize the motor function area related to finger movements in normal human brain using super-early (first 640 sec of acquisition) [123l]iodoamphetamine ([123I]IMP) SPECT. METHODS: Seven healthy male volunteers performed paired, isolated baseline and task sessions. The task was a right thumb-to-fingers opposition task, which was loaded for the initial 11 min of the session. A high-performance, four-head SPECT camera was used. At each session, administration of 222 MBq [123I]IMP was followed by 16 serial 160-sec dynamic SPECT acquisitions. To obtain matched brain anatomical images, MRI was also performed using the same slice formation as in the SPECT study. After image reconstruction, ROIs were set on bilateral sensorimotor hand areas (SMHA), the supplementary motor area (SMA), the frontal, temporal and occipital lobes and the cerebellar hemispheres. The percent increase of ROI activity (%INC) in the task session compared with that in the baseline session was calculated in each ROI after normalization to the global brain radioactivity. RESULTS: There was significant activation of the left SMHA by the task, the amplitude of which was maximal in the initial phase of dynamic images (the super-early phase). This area was located in the left peri-central area identified on the analogous slice in the MR image. The left SMHA showed gradual and statistically significant decrease of %INC during the three phases. CONCLUSION: Super-early [123I]IMP may be used to identify the primary motor cortex and to evaluate its function in some pathological conditions.

Adult↗

PubMed1996

Monitoring gene therapy with cytosine deaminase: in vitro studies using tritiated-5-fluorocytosine.

UNLABELLED: Genetically modified mammalian cells that express the cytosine deaminase (CD) gene are able to convert the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil (5-FU). PET with 18F-5-FC may be used for in vivo measurement of CD activity in genetically modified tumors. METHODS: A human glioblastoma cell line was stably transfected with the Escherichia coli CD gene. After incubation of lysates of CD-expressing cells and control cells with 3H-5-FC high-performance liquid chromatography (HPLC) was performed. The uptake of 5-FC was measured after various incubation times using therapeutic amounts of 5-FC. In addition, saturation and competition experiments with 5-FC and 5-FU were performed. Finally, the efflux was measured. RESULTS: We found that 3H-5-FU was produced in CD-expressing cells, whereas in the control cells only 3H-5-FC was detected. Moreover, significant amounts of 5-FU were found in the medium of cultured cells, which may account for the bystander effect observed in previous experiments. However, uptake studies revealed a moderate and nonsaturable accumulation of radioactivity in the tumor cells, suggesting that 5-FC enters the cells only through diffusion. Although a significant difference in 5-FC uptake was seen between CD-positive and control cells after 48 hr of incubation, no difference was observed after 2 hr of incubation. Furthermore, a rapid efflux could be demonstrated. CONCLUSION: 5-Fluorocytosine transport may be a limiting factor for this therapeutic procedure. Quantitation with PET has to rely more on dynamic studies and modeling, including HPLC analysis of the plasma, than on nonmodeling approaches.

Chromatography, High Pressure Liquid↗