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Renal clearance in mice as a bioassay for radiopharmaceuticals: Method and evaluation
Abstracts about the swallow-functionis derived from radiological findings obtained after a barium-swallow. Even in its thinest form the barium solution is different in It is therefore consistency compared to water. suggested that the REG is more reliable for water swallow-function.
Conclusion The REG offers a new approach for the functional and anatomic study of the esophagus which supplements the available radiologic and endoscopic methods. It is a clinical study that is particularly indicated for: The study of the swallowing function; # The evaluation of swallowing dysfunction; (3) Early detection of esophageal fistulas and leakages; and (4) The assessment of the result of treatment and the follow up of patients with dysphagia.
Windowless a-n Semiconductor Radiation Detector for the Measurement of Gaseous 14C0, in wivo and in vitro, by T. KOBAYASHI, T. SUGITA, S. TAKAYANAGI, M. IIO* and H. YAMADA * . Toshiba Research and Development Center, Kawasaki, and *Second Department of Internal Medicine, School of Medicine, University of Tokyo, Tokyo, Japan. FOR THE measurement of precise dynamic biomedical and bacteriological fermentation process with aid of radioisotopes, such as 14C and ?!j, stable windowless semiconductor detectors for low-energy beta-ray in vivo or in vitro counting were developed and the fundamental characteristics of the detecton were studied. The detectors developed have a sensitive area ranging from 4 mms to 2 cm2. The effective window (dead layer) of the detector is less than 0.3 ,um. The fundamental characteristics of counting rate vs. discriminator level and counting rate vs. temperature were studied for the detector developed, especially the O-2 ems and 2 cm2 area detectors, using either water solution, or thin solid source of 14C. The counting efficiency of the detector is proportional to the sensitive area of the detector at the constant discriminator level. The counting rate was about 200 cpm/cm2 for 3 m$X/cm2 of 14C solid source at the discriminator level of 15 keV. The experimental results show that 20 mm2 area detector is feasible for the in z&o measurement of lowenergy beta-ray, such as those emitted by 14C and 5
65
%, and that a large area detector is feasible for in vitro application, according to its high counting efficiency at room temperature. For in z&o application of windowless j-n semiconductor radiation detector, the counting system for measurement of the release of 14C02 resulting from the metabolism of 14C-glucose during bacteria growth was constructed. The counting system consists of the windowless semiconductor detector, gas container, culture vial, and associated electronic circuits to handle the data automatically. The evaluation of this instrument was carried out using blood cultures and urine samples. After the addition of the bacteria (E-coli) to 1 ml of sterile serum, 5 ,uCi of uniformly labelled 14C-glucose was added, and the culture was incubated at 37°C. Radioactive carbon dioxide (14C02) released from culture was measured automatically with chartrecorder and electronic counter. The counting rate of 14C0, was increased after 2 h of incubation time while the culture was agitated continously. However, the content of 14C02 released from the culture was less without continuous agitation. The advantage of this counting system is that continuous dynamic measurement of exhaled 14C02 or released 14COs from 14C labeled compounds can be made without complicated procedures. The culture vial which is used for automatic sequential sampling of many samples was also reported.
Renal Clearance in Mice as a Bioassay for Radiopharmaceuticals: Method and Evaluation, by T. KONIKOWSKI, H. J. GLENN, T. P. HAYNIE and L. E. FARR*. The University of Texas at Houston M. D. Anderson Hospital and Tumor Institute, Houston, Texas, and *State Department of Health, Berkeley, California. IN EVALUATING radiopharmaceuticals, there is a need for a variety of bioassays for assessing physiological distribution and turnover of radiopharmaceuticals. Those radiopharmaceuticals principally cleared by the kidney can be evaluated by classical techniques for renal clearance, including glomerular filtration rate (GFR) and renal plasma and blood flow (RPF and RBF) . Using Yale-Swiss mice we have developed and are reporting on a reproducible technique by which GFR, RPF and REF can be rapidly assessed in sequence, utilizing standard reagents such as inulin14-C-carboxyl and 1311-orthoiodohippuric acid (OIH) .
66
Abstracts
With these standards, a variety of radiopharmaccuticals can be evaluated to determine their rate and principle route of clearance by their inulin and OIH ratios. A simple i.v. injection of radiopharmaceutical is made and urine collected quantitatively. Heart blood samples are obtained simultaneously. Data are used to derive curves showing cumulative product urine excretion, and blood disappearance with time. Clearance values are calculated by the standard UV/B or lJV/P formulas. Details of this procedure have been published elsewhere.(l*s) We have evaluated this biotest system in several ways. The renal plasma clearances of several DTPAlabeled compounds have been compared with the clearances of our standards. lsOYb-DTPA is cleared 11 per cent faster than purified OIH at low plasma concentration, but 47 per cent slower at high plasma concentration. 113m-In-DTPA is cleared 34 per cent slower, and 56 per cent slower than OIH at low and high plasma concentrations respectively. OomTcDTPA is cleared the slowest of all, 87 per cent slower than OIH at high plasma concentrations. There is now doubt as to whether or not OOmT~-DTPA prepared in this manner is a true chelate. All clearance values are standardized to 1.73 m2 body surface area. We have also intercompared the OIH clearances of four lots of OIH from various commercial sources. The OIH from source A was cleared 1 per cent faster at low plasma concentrations and about 19 per cent slower at high plasma concentrations than the OIH standard. The material from source B was cleared 36 and 31 per cent slower than standard at low and high plasma concentrations. That from source C was cleared 54 and 38 per cent slower, and that from source D, 67 and 41 per cent slower than standard at low and high plasma concentrations respectively. This difference in clearance rates can be explained by differences in formulation, free iodide content, and nephrotoxicity. We have also done brain tumor uptake studies of several common radiopharmaceuticals in mice (same strain) with implanted braintumors. Maximum brain tumor uptake has been found to vary inversely with the renal blood clearance (UV/B). Renal clearance in mice has been shown to be a valuable bioassay for evaluating and comparing radiopharmaceuticals. Additional details relating to this work are published elsewhere. References 1. KONIKOWSKI T., I&YNIE T. P. and FARR L. E. Proc. Sot. exp. Biol. Med. 135, 320 (1970). 2. KONIKOWSKI T., ~~YNIE T. P., GLENN H. J. and FARR L. E. Proc. Sot. exg. Biol. Med. 137, 1343 (1971).
Rates of Pulmonary Clearance of 150 Labeled 0,, CO and CO,, by C. S. LAMONTE, W. G. MONAHAN, R. S. TILBURY, A. J. DW~ER, R. S. FREEMAN and J. S. LAUGHLIN. SloanKettering
Institute
for Cancer
Research.
IN AN attempt to determine the normal clearance rate of radio-labeled gases, studies have been performed in five healthy mongrel dogs, anesthetized with pentobarbitol, utilizing Os, CO and CO, labeled with 150 produced on a small medical cyclotron by a d-n reaction on nitrogen gas. The 150 produced has been used as 5% 150s in N,; as C150s after heating over charcoal at 500’ and CuO at 860’. A single breath of 450 ml with specific activity of 5 mCi/l. has been administered via an animal respirator, sustained in inspiration for 30 s while dynamic measurements of activity in the lungs have been recorded on the Total Organ Kinetic Imaging Monitor. The digital output of this 64 x 64 matrix is displayed on an alphabetic IBM printout in which each letter signifies count rate levels which are 2 standard deviations away from the next higher level. Within 5 weeks, 6-10 determinations of the rate of clearance of each gas have been performed on 3-5 different days in each animal. After correction for physical decay of the isotope, the mean half time has varied in the five animals between 14.8 and 27.6 s for 0,, with standard deviation 15.0-37.2 per cent of the mean; between 6.1 and 11.5 s for CO, with standard deviation 18.5-26.0 per cent of the mean; and between 5.4 and IO.5 s for CO,, with standard deviation 14.0-32.8 per cent of the mean. The weighted mean half-time clearance of the three gases are 17.6 s for oxygen; 7.4 s for carbon monoxide; and 6.5 s for carbon dioxide.
The Renogram Findings in Patients of Epidemic Hemorrhagic Fever, by C. S. KOH, M. H. LEE and J. S. LEE. Department of ht. Med. and Radioisotope Clinic, Seoul National University Hospital, Seoul, Korea. EPIDEMIC Hemorrhagic Fever is a disease characterized by high fever, impaired capillary permeability and renal failure. The etiology is yet unknown. Korea is one of a few known endemic areas of the world. It occurs sporadically around the year but has two seasonal peaks in June and October. It affects mainly adults but can be seen rarely iu
Conclusion The REG offers a new approach for the functional and anatomic study of the esophagus which supplements the available radiologic and endoscopic methods. It is a clinical study that is particularly indicated for: The study of the swallowing function; # The evaluation of swallowing dysfunction; (3) Early detection of esophageal fistulas and leakages; and (4) The assessment of the result of treatment and the follow up of patients with dysphagia.
Windowless a-n Semiconductor Radiation Detector for the Measurement of Gaseous 14C0, in wivo and in vitro, by T. KOBAYASHI, T. SUGITA, S. TAKAYANAGI, M. IIO* and H. YAMADA * . Toshiba Research and Development Center, Kawasaki, and *Second Department of Internal Medicine, School of Medicine, University of Tokyo, Tokyo, Japan. FOR THE measurement of precise dynamic biomedical and bacteriological fermentation process with aid of radioisotopes, such as 14C and ?!j, stable windowless semiconductor detectors for low-energy beta-ray in vivo or in vitro counting were developed and the fundamental characteristics of the detecton were studied. The detectors developed have a sensitive area ranging from 4 mms to 2 cm2. The effective window (dead layer) of the detector is less than 0.3 ,um. The fundamental characteristics of counting rate vs. discriminator level and counting rate vs. temperature were studied for the detector developed, especially the O-2 ems and 2 cm2 area detectors, using either water solution, or thin solid source of 14C. The counting efficiency of the detector is proportional to the sensitive area of the detector at the constant discriminator level. The counting rate was about 200 cpm/cm2 for 3 m$X/cm2 of 14C solid source at the discriminator level of 15 keV. The experimental results show that 20 mm2 area detector is feasible for the in z&o measurement of lowenergy beta-ray, such as those emitted by 14C and 5
65
%, and that a large area detector is feasible for in vitro application, according to its high counting efficiency at room temperature. For in z&o application of windowless j-n semiconductor radiation detector, the counting system for measurement of the release of 14C02 resulting from the metabolism of 14C-glucose during bacteria growth was constructed. The counting system consists of the windowless semiconductor detector, gas container, culture vial, and associated electronic circuits to handle the data automatically. The evaluation of this instrument was carried out using blood cultures and urine samples. After the addition of the bacteria (E-coli) to 1 ml of sterile serum, 5 ,uCi of uniformly labelled 14C-glucose was added, and the culture was incubated at 37°C. Radioactive carbon dioxide (14C02) released from culture was measured automatically with chartrecorder and electronic counter. The counting rate of 14C0, was increased after 2 h of incubation time while the culture was agitated continously. However, the content of 14C02 released from the culture was less without continuous agitation. The advantage of this counting system is that continuous dynamic measurement of exhaled 14C02 or released 14COs from 14C labeled compounds can be made without complicated procedures. The culture vial which is used for automatic sequential sampling of many samples was also reported.
Renal Clearance in Mice as a Bioassay for Radiopharmaceuticals: Method and Evaluation, by T. KONIKOWSKI, H. J. GLENN, T. P. HAYNIE and L. E. FARR*. The University of Texas at Houston M. D. Anderson Hospital and Tumor Institute, Houston, Texas, and *State Department of Health, Berkeley, California. IN EVALUATING radiopharmaceuticals, there is a need for a variety of bioassays for assessing physiological distribution and turnover of radiopharmaceuticals. Those radiopharmaceuticals principally cleared by the kidney can be evaluated by classical techniques for renal clearance, including glomerular filtration rate (GFR) and renal plasma and blood flow (RPF and RBF) . Using Yale-Swiss mice we have developed and are reporting on a reproducible technique by which GFR, RPF and REF can be rapidly assessed in sequence, utilizing standard reagents such as inulin14-C-carboxyl and 1311-orthoiodohippuric acid (OIH) .
66
Abstracts
With these standards, a variety of radiopharmaccuticals can be evaluated to determine their rate and principle route of clearance by their inulin and OIH ratios. A simple i.v. injection of radiopharmaceutical is made and urine collected quantitatively. Heart blood samples are obtained simultaneously. Data are used to derive curves showing cumulative product urine excretion, and blood disappearance with time. Clearance values are calculated by the standard UV/B or lJV/P formulas. Details of this procedure have been published elsewhere.(l*s) We have evaluated this biotest system in several ways. The renal plasma clearances of several DTPAlabeled compounds have been compared with the clearances of our standards. lsOYb-DTPA is cleared 11 per cent faster than purified OIH at low plasma concentration, but 47 per cent slower at high plasma concentration. 113m-In-DTPA is cleared 34 per cent slower, and 56 per cent slower than OIH at low and high plasma concentrations respectively. OomTcDTPA is cleared the slowest of all, 87 per cent slower than OIH at high plasma concentrations. There is now doubt as to whether or not OOmT~-DTPA prepared in this manner is a true chelate. All clearance values are standardized to 1.73 m2 body surface area. We have also intercompared the OIH clearances of four lots of OIH from various commercial sources. The OIH from source A was cleared 1 per cent faster at low plasma concentrations and about 19 per cent slower at high plasma concentrations than the OIH standard. The material from source B was cleared 36 and 31 per cent slower than standard at low and high plasma concentrations. That from source C was cleared 54 and 38 per cent slower, and that from source D, 67 and 41 per cent slower than standard at low and high plasma concentrations respectively. This difference in clearance rates can be explained by differences in formulation, free iodide content, and nephrotoxicity. We have also done brain tumor uptake studies of several common radiopharmaceuticals in mice (same strain) with implanted braintumors. Maximum brain tumor uptake has been found to vary inversely with the renal blood clearance (UV/B). Renal clearance in mice has been shown to be a valuable bioassay for evaluating and comparing radiopharmaceuticals. Additional details relating to this work are published elsewhere. References 1. KONIKOWSKI T., I&YNIE T. P. and FARR L. E. Proc. Sot. exp. Biol. Med. 135, 320 (1970). 2. KONIKOWSKI T., ~~YNIE T. P., GLENN H. J. and FARR L. E. Proc. Sot. exg. Biol. Med. 137, 1343 (1971).
Rates of Pulmonary Clearance of 150 Labeled 0,, CO and CO,, by C. S. LAMONTE, W. G. MONAHAN, R. S. TILBURY, A. J. DW~ER, R. S. FREEMAN and J. S. LAUGHLIN. SloanKettering
Institute
for Cancer
Research.
IN AN attempt to determine the normal clearance rate of radio-labeled gases, studies have been performed in five healthy mongrel dogs, anesthetized with pentobarbitol, utilizing Os, CO and CO, labeled with 150 produced on a small medical cyclotron by a d-n reaction on nitrogen gas. The 150 produced has been used as 5% 150s in N,; as C150s after heating over charcoal at 500’ and CuO at 860’. A single breath of 450 ml with specific activity of 5 mCi/l. has been administered via an animal respirator, sustained in inspiration for 30 s while dynamic measurements of activity in the lungs have been recorded on the Total Organ Kinetic Imaging Monitor. The digital output of this 64 x 64 matrix is displayed on an alphabetic IBM printout in which each letter signifies count rate levels which are 2 standard deviations away from the next higher level. Within 5 weeks, 6-10 determinations of the rate of clearance of each gas have been performed on 3-5 different days in each animal. After correction for physical decay of the isotope, the mean half time has varied in the five animals between 14.8 and 27.6 s for 0,, with standard deviation 15.0-37.2 per cent of the mean; between 6.1 and 11.5 s for CO, with standard deviation 18.5-26.0 per cent of the mean; and between 5.4 and IO.5 s for CO,, with standard deviation 14.0-32.8 per cent of the mean. The weighted mean half-time clearance of the three gases are 17.6 s for oxygen; 7.4 s for carbon monoxide; and 6.5 s for carbon dioxide.
The Renogram Findings in Patients of Epidemic Hemorrhagic Fever, by C. S. KOH, M. H. LEE and J. S. LEE. Department of ht. Med. and Radioisotope Clinic, Seoul National University Hospital, Seoul, Korea. EPIDEMIC Hemorrhagic Fever is a disease characterized by high fever, impaired capillary permeability and renal failure. The etiology is yet unknown. Korea is one of a few known endemic areas of the world. It occurs sporadically around the year but has two seasonal peaks in June and October. It affects mainly adults but can be seen rarely iu