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A simple but efficient computational approach to calculate p

Lipophilicity is suggested to modulate the diffusion and the cytotoxic effects of mercury compounds. To investigate this, the positive inotropic effect of four Hg compounds (HgCl2, CH3HgCl, chlormerodrin, bromomercurihydroxypropane) was studied in catecholamine-depleted isolated heart muscle preparations. The rate of development of the positive effect was inversely correlated to the concentration in the case of HgCl2 and chlormerodrin, i.e. the product of concentration (c) and time to half-maximal effect (t50) remained constant. This was in accordance with the assumption of a permeation-controlled rate of action, as was shown earlier for p-chloromercuriphenyl-sulfonic acid. In addition, the c X t50 values of the individual mercurials decreased hyperbolically with the increase in lipophilicity as measured by the octanol/water partition. The results support the view that the toxicity of mercurials increases with their lipid solubility. In conjunction with the previously reported negative inotropic effect of Hg compounds, a model is proposed allocating thiol groups responsible for the negative inotropic action to lipid compartments within the cell membrane, while SH groups conveying the increase in contraction force are thought to be situated at the internal surface of the sarcolemma.

In this paper a variety of mercurials, including a pCMB-nitroxide analogue, were used to study urea transport in human red cell ghosts. It was determined that the rate of inhibition for pCMBS, pCMB, pCMB-nitroxide, and chlormerodrin extended over four orders of magnitude consistent with their measured oil/water partition coefficients. From these results, we concluded that a significant hydrophobic barrier limits access to the urea inhibition site, suggesting that the urea site is buried in the bilayer or in a hydrophobic region of the transporter. In contrast, the rate of water inhibition by the mercurials ranged by only a factor of four and did not correlate with their hydrophobicities. Thus, the water inhibition site may be more directly accessible via the aqueous phase. Under conditions that leave water transport unaffected, we determined thator = 32,000 labeled sites per cell corresponded to complete inhibition of urea transport. This rules out major transmembrane proteins such as band 3, the glucose carrier, and CHIP28 as candidates for the urea transporter. In contrast, this result is consistent with the Kidd (Jk) antigen being the urea transporter with an estimated 14,000 copies per cell. From the experimental number of urea sites, a turnover number between 2-6 x 10(6) sec-1 at 22 degrees C is calculated suggesting a channel mechanism.

Data are given on the study of functional correlations of the pairs of organs (kidneys-liver and kidneys-lungs) that participate in provision of the functional system of secretion. The correlation of these pairs of organs contribution to the total secretion of metabolites as renal insufficiency grows is characterized by the S-shaped dependence, i.e. by a compensatory increase of the conjoined functions at the early stages and its depression at the graver stages of renal insufficiency. This approach makes it possible to determine the character, terms and significance of the participation of various organs in provision of metabolic homeostasis maintenance long before its failure and to reveal the main links in the pathogenesis of functional disorders of secretion.

197Hg-クロルメロドリンによる腎シンチグラフィについて, 基礎的, 臨床的検討を行なった。ファントム実験を行ない, 197HgのX線エネルギーが低いことがシンチグラムに及ぼす影響について203Hgと比較した。吸収層が5cmまでは両者にほとんど変わりがなく, 10cmではわずかに散乱の影響が認められた。吸収による計数率の減少の程度は5cmまではほとんど変わらず, 10cmでは203Hgの55±5%にくらべ, 197Hgは30±5%に減少した。臨床例21例について197Hg-クロルメロドリンによる腎シンチグラフィを行なった。臨床的には, 従来から用いてきた203Hg-クロルメロドリンとほとんど変わらない像を得ることができた。腎の被曝線量を軽減させるためにも, 広く用いられるべきであることを強調した。

The effects of mannitol, methylprednisolone, furosemide, inosine, indomethacin and captopril on the recovery from hydronephrosis were examined in rat kidneys. After 1 week of ureteral obstruction, left ureterocystostomy was performed in order to release the obstruction. Following ureteral release, mannitol, methylprednisolone, inosine, furosemide, captopril and indomethacin were given intravenously or orally. A saline group and non-treated control rats were also examined for comparison. 4 weeks after ureterocystostomy, 0.5 microCi of 203Hg-labelled chlormerodrin was given intravenously and the animals were sacrificed 48 h later. The left kidneys were significantly heavier in the mannitol-, methylprednisolone-, and inosine-treated groups than those of the control groups. The chlormerodrin uptake ratios of the left kidneys were significantly higher in the mannitol-, methylprednisolone-, captopril- and indomethacin-treated groups than in the control groups. These results suggest that the release of obstruction solely is not complete treatment for hydronephrosis, but that appropriate medical treatment may enhance the recovery from hydronephrosis.

The effect of diuretics on oxgen consumption rate (Q o 2 ) and swelling of mitochondria isolated from rat kidney cortex (C), outer medulla (OM) and liver was measured. In addition, the effect of isolated cell membrane fraction (ER) on the diuretic-induced changes in mitochondrial oxygen utilization was determined. Q o 2 was measured in a Gilson oxygraph utilizing either glutamate-malate or succinate as substrate. Q o 2 , expressed in natoms O 2 /mg of protein/min, was always higher in C than OM: 159.8 ± 8.3 vs 119.8 ± 11.4 (P o 2 of liver mitochondria was lower: 102.6 ± 7.1 with glutamate-malate, and 125.5 ± 9.6 with succinate. A dose-response curve was constructed for each of the following: sodium ethacrynate (EA), furosemide (F), chlorothiazide (CTZ), acetazolamide (ACTZ) and chlormerodrin (CH). All diuretics exerted an equal inhibitory effect on C, OM and liver mitochondrial Q o 2 . CH was the most potent inhibitor, followed by EA, F, CTZ and ACTZ. The concentration of diuretic which inhabited Q o 2 by 50 per cent was utilized to examine mitochondrial swelling. At these doses, F and ACTZ had only a slight effect on liver mitochondria. EA had the greatest effect, followed by CH and CTZ. By contrast, CH had the greatest effect on C and OM, followed by EA and F, while CTZ and ACTZ had only a slight effect. Cysteine and dithiothreitol prevented the effect of CH on Q o 2 and swelling. The effect of EA on swelling, but not on Q o 2 , was blocked by cysteine. The cell membrane had its greatest protective effect with CH, had only a modest effect with EA, and exerted no protective effect on F, CTZ and ACTZ.

The authors have examined the tumor affinity of various 99mTc-labelled radiopharmaceuticals to Ehrlich's tumor for the purpose of delineating positively human malignant neoplasm. This paper includes biologic distributions of 99mTc-Sn-diphosphonate (99mTc-EHDP), 99mTc-Sn-dimercaptosuccinic acid (99mTc-DMSA) and 99mTc-Sn-diethyl stilbestrol diphosphate (99mTc-DSDP, 99mTc-Honvan) as the second report on the tumor affinity to the Ehrlich-bearing mice. (a) Tumor concentration of 99mTc-EHDP was lowest and the positive delineation of implanted tumor with 99mTc-EHDP was poorest in sequential images, though the active accumulation to some soft tissue maglinant neoplasms, the breast cancer and the thyroid cancer, has been reported. (b) Tumor concentration and tumor to blood ratio of 99mTc-DMSA were not so high on the contrary of our expectation that 197Hg-DMSA may show the high tumor concentration and the high tumor to blood ratio like 197Hg chlormerodrin as same renal scanning radiopharmaceuticals. (c) Tumor concentration of 99mTc-DSDP was highest. Tumor to blood concentration ratio, however, was lower than that of the above mentioned radiopharmaceuticals but tumor to liver ratio and/or tumor to lung ratio was over 1.0 at the earlier time. Biologic distribution of 99mTc-DSDP was similar to that of 32P labeled DSDP and then it is presumed that 99mTc is labeled at phosphate ester of DSDP which is dephospholytated immediately by phospholylase in vivo following the intravenous injection. Therefore, it may be assumed that the accumulation mechanism of 99mTc-DSDP to Ehrlich's tumor is related to the phospholylase activity in neoplasms but is not known precisely.

An electrophoretic method to control the radiochemical purity of chlormerodrin-203 is described. Optimum conditions for the separation of inorganic and organically bound mercury-203 were determined by investigating its mobility in the concentration range of 1·10−5–1·10−2 M NaCl. Maximum separation, of203Hg and hydroxychlormerodrin was achieved at 0.05M NaCl, at the potential gradient of 8V/cm for 2 hrs.

Stable chelates of indium 111, indium 113m, chromium 51, ytterbium 169, and technetium 99m have proven to be useful radiopharmaceuticals for the evaluation of renal structure and function. In their pure forms, all of these materials are handled by glomerular filtration and may be used to determine GFR. Correlation with inulin clearance studies has been quite good. 99m Tc-labeled DTPA is ideally suited for renal imaging studies with the Anger scintillation camera. Images obtained within the first minute after intravenous injection of a bolus visualize the aorta and relative vascular supply to each kidney. A study at 2 min defines the morphology, and subsequent serial 5-min scintiphotos outline the excretory pathways. The radioactive chelates have a high degree of success in visualizing the kidneys in patients with severe renal insufficiency. 197 Hg chlormerodrin is primarily extracted by the liver in such patients, thereby failing to visualize the kidneys. In direct comparisons with the chelates, radioiodinated Hippuran appears to be more sensitive in detecting function in many azotemic patients. Other applications of renal imaging studies with radio-chelates include the detection of unilateral renal disease and obstructive uropathy, the differentiation of cysts and tumors, and the evaluation of function after renal transplantation.

By application of 99mTc-Penicillamine in renal scintigraphy excellent scintigraphies of the kidneys, especially by using the gamma-camera, can be obtained, even in case of damaged renal function, up to an increase of creatinine in serum of about 7 mg %.

Specific radioindicators are sequestered by acute myocardial infarctions, and their uptake is detectable by external detection systems, such as the Anger scintillation camera. The resultant scintigraphic image may be used to estimate infarct size, although inferior and subendocardial infarcts may pose difficulties. Infarct localization as to anatomic area of the heart is also reasonably accurate. The majority of the clinical experience has been with technetium chelates, particularly 99m Tc-tetracycline and 99m Tc-pyrophosphate. Optimal imaging with 99m Tc-tetracycline is within the first 3 days after infarction, with gradual return to normal of the scintigraphic appearance after this time. While larger infarcts remain positive for longer periods of time, significant uptake or reappearance of uptake after the initial period may be helpful in the identification of reinfarction or extension after an initial infarct. Tetracycline appears to be sequestered only by acutely infarcted myocardium, and therefore is a sensitive agent for distinguishing normal, previously infarcted, and ischemic myocardium from acutely infarcted myocardium. The major clinical experience has been with 99m Tc-pyrophosphate, a bone-seeking radionuclide. The major advantage of 99m Tc-pyrophosphate over 99m Tc-tetracycline is the earlier imaging interval. Optimal scans are obtained at 1–2 days after infarction and only 90 min after the administration of 99m Tc-pyrophosphate (as opposed to 24 hr with 99m Tc-tetracycline). While 99m Tc-pyrophosphate is a quite sensitive indicator of infarction, there is suggestive evidence that ischemic as well as infarcted myocardium sequesters the agent. In addition, various other conditions, including cardioversion, rib fractures, left ventricular aneurysms, and breast tumors may cause uptake of 99m Tc-pyrophosphate and lead to false positive myocardial infarct scintigrams. Thus, while only a few patients with negative scans who have been imaged at the appropriate time will turn out to have clinically detectable infarcts, a somewhat larger number without infarction will have positive scans, particularly those patients with unstable angina pectoris but without clinical infarction. While the final role of acute myocardial scintigraphy remains to be determined, its contribution to the further understanding of the pathogenesis of ischemia and infarction, as well as its clinical utility, has been significant.

1. Influx of leucine, β-alanine and 3-O-methyl glucose, substrates transported by separate systems, has been studied in chicken small intestine. 2. Influx of leucine (JmcLeu) was much more rapidly inactivated during a 15 min exposure to p-chloromercuriphenyl sulfonate (PCMBS) or 3-chloromercuri-2-methoxy-propylurea (chlormerodrin) than β-alanine or 3-O-methyl glucose influx. Diazenedicarboxylic acid bis (N,N-dimethylamide) (diamide) in short-term (min) exposures inhibited β-alanine influx to a greater degree than the other substrates. 3. Neither the organic mercurials nor diamide in 30 min exposures changed intracellular GSH levels, implying their effects were confined to the cell membrane. 4. Dithiothreitol (DTT) completely and rapidly reversed inhibition of JmcLeu caused by the mercurials, suggesting these reagents acted on memebrane sulfhydryls. DTT only slowly reversed diamide-induced inhibition, whereas added GSH was without effect, indicating an intra-membrane site of action. 5. The temporal effects of the reagents on the different substrates suggest that separate and distinct classes of spacially-organized sulfhydryl groups were present among the different systems.

197 Hg chlormerodrin delayed scans and conventional split renal clearances were performed on 6 dogs. Left renal artery stenosis was then created in 2 animals and left partial ureteral obstruction in the other 4. The studies were then repeated two and six weeks after surgery. There was a close correlation among the studies after the arterial stenosis, but the ureteral occlusion results were too variable to make the study meaningful or reliable.

Noninvasive radionuclide procedures in the evaluation of renal disease have been accepted increasingly as effective and valuable alternatives to older clinical methods. The development of suitable radiopharmaceuticals labeled with high photon intensity radionuclides and with 99m Tc in particular has stimulated this modality during the last few years. Currently several nearly ideal agents are available for anatomical and functional studies of kidney imparting very low absorbed radiation doses. These include 99m Tc-GHA and 99m Tc-DMSA for renal morphology and differential function evaluation, 99m Tc-DTPA for GFR and 123 I orthoiodohippurate for ERPF measurements. A suitable agent as a replacement for the latter labeled with 99m Tc is actively being sought. Computer-assisted processing of dynamic renal function studies enables the observer to obtain a wealth of information related to the renal extraction, uptake, parenchymal transit and pelvic transit parameters of the agent administered into the bloodstream. Each of these parameters either globally or differentially contributes to a detailed evaluation of renal disease states. Several of these procedures have been validated against classical techniques clinically but more detailed information is being sought with the recently introduced radiopharmaceuticals. With the detailed validation and increasing recognition of the clinical utility of several of the radionuclidic procedures at many centers, it is hoped that that radionuclide assessment of renal disorders ultimately will be made available routinely at all medical facilities.

Serial macroautoradiograms were obtained to determine the distribution of 203Hg-chlormerodrin, 203Hg-nigrate and 99mTc-DMSA in kidney. In the study, normal rats were used and these three radiopharmaceuticals were injected intravenously. Initial images of 203Hg-chlormerodrin showed the accumulation in the outer cortex, but no significant radioactivity in the medullary. On the other hand, delayed images revealed radioactivity shifting in concentration from the outer cortex to the inner cortex. Distribution pattern of 203Hg-nitrate was similar to that of 203Hg-chlormerodrin. In contrast to 203Hg-chlormerodrin and 203Hg-nitrate, 99mTc-DMSA was retained in the outer cortex without temporal changes in the distribution.

A review of the wide spectrum of radiopharmaceuticals developed over the last 15 yr for application in the evaluation of diseases of the kidney and urinary tract is presented below. The radiolabeled contrast agents including Hippuran have been extensively applied for renal function assessment. The kinetics of clearance of many of these agents are not yet satisfactorily established, and there is no ideal agent for routine clinical application, particularly by external counting methods. Many agents for intrarenal blood flow measurement have been reported that have yet to be adapted for obtaining clinical information. Renal morphology has been studied using several radiopharmaceuticals that are either fixed in the renal tubules for a sufficiently long time (chlormerodrin, 99m Tc-Fe ascorbic acid) or cleared from the kidneys fairly rapidly (Hippuran). These agents suffer from several disadvantages because of suboptimum energy of the radiolabel for use with imaging equipment, or relatively high radiation dose, or slow rate of excretion with inadequate organ specificity. It is hoped that the development of new radiopharmaceuticals tagged with radionuclides that have ideal imaging characteristics ( 99m Tc or 111 In) and satisfactory renal clearances will provide a major breakthrough in the continuing search for satisfactory renal agents for imaging and function tests in the near future.

The effects of four organic mercury compounds (methylmercuric chloride; bromomercurihydroypropane, BMHP; chlormerodrin; p-chloromercuribenzoic acid, PCMB) on mechanical and electrical functions of guinea-pig papillary muscles were investigated. An initial decline in contraction force was followed by a transient positive inotropic response. The first was accompanied by a shortening of the action-potential duration and by a reduction of the depolarization velocity and the duration of the Ca2+-dependent slow response. The latter was characterized by an indirect component (release of noradrenaline) and by a direct component, which was dependent on the stimulation rate and on the extracellular concentration of Na+ and K+. The direct positive effect, therefore, was likely to have resulted from inhibition of the sarcolemmal Na+ + K+-ATPase. This notion was confirmed by experiments with isolated membrane particles. The prevalence of the negative or positive inotropic action of these compounds could be ascribed to their lipophilic or hydrophilic properties, respectively.

SummaryDynamic kidney scintigraphy was performed in 8 patients after administration of 197Hg-chlormerodrin or of a new complex: 99mTc-Unithiol. Kinetics of image formation and goodness of kidney imaging were studied both quantitatively and qualitatively. The results demonstrated that 1½–3 hrs after i.v. administration of either compound equally good kidney scintigrams may be obtained. Clinical experience on more than 300 patients supports this conclusion.

The increasing frequency of renal transplantation has stimulated the development of diagnostic methods of evaluating the functional integrity of the graft. Radionuclide techniques have achieved great popularity in this regard. Although clearance studies, fibrinogen uptake, and conventional probe renography have been used with success, the imaging studies of the kidney recently have been of particular interest. Sequential scintiphotography with 131 I Hippuran has been shown to facilitate the diagnosis of problems such as vascular thrombosis, acute tubular necrosis, acute and chronic rejection, urinary extravasation, and ureteral obstruction. Although the appearance of the kidney in any one study may be diagnostic, it is of much greater value to observe improvement or deterioration of function studies with bolus injections of 99m Tc pertechnetate to establish the patency of the newly anastomosed vascular pathways.

Externally monitored radioisotopic renal function studies have proven to be diagnostically useful in a variety of urinary tract disorders. Controversy, however, concerning everything from equipment and patient preparation to information content and interpretation has surrounded the procedure since its inception. The theses presented here are that the choice of equipment is determined by the intended use, that a few major physiologic events determine the shape of the curves produced in the studies, that the information content exceeds what has been extracted to date, and that subtle renal abnormalities are better detected by intercomparison of a patient's two kidneys than by comparison to values derived from a selected normal population. Choice of patient preparation and interpretation of the results depend on understanding the physiology involved in the procedure.

The AA. discuss the usefulness of brain scans in the diagnosis of head injuries. Brain scans have been carried out on 91 patients, 51 scans with Neohydrin-Hg203 and 40 with Technetium 99m. The method is very useful for head injuries with subacute or chronic brain damage, but the minimal time for the examination (1 hour after the injection of Technetium 99m) is often too long for the diagnosis of acute lesions. 13 subdural haematomas out of 14, one intracerebral haematoma and 12 brain contusions out of 13 were correctly localized. Subdural haematomas are so clearly recognisable, that in a large percentage of cases it is possible to operate on without further neuroradiological investigations.

Renal functional and isotopic studies were performed on baboon kidneys during isolated perfusion with exposure to 100 per cent helium and in kidneys preserved with different mixtures of oxygen and helium under hyperbaric, hypothermic conditions.Renal functional results were better in kidneys exposed to high concentrations of helium. Oxygen had a vasoconstrictive effect on the cortical vessels with an increased resistance and decreased renal cortical flow, as measured by the extractions of PAH, creatinine, and electromagnetic arterial flow measurement.The Xe133 clearance method demonstrated decreased cortical flow during oxygen exposed perfusion and was found to be a very sensitive procedure in assessing variations in the renal circulation. The distribution of labelled carbon microspheres did not detect the difference in cortical flow during oxygen and helium exposure. Particles of the size employed did not remain fixed in the vascular tree. In some instances free or unbound isotope was detected. Hg203 chl...

A method for routine production of 3-chloromercuri-2-methoxy-propylurea-197 Hg or 203 Hg with a high specific activity and high radiochemical purity, has been elaborated. Important for the method are: good and standardized HgCl2, the maintenance of molar ratioe HgCl2 to sodium acetate and allylurea 1:1 and 1:5 respectively, and the time of heating of the reaction mixture in the autoclave with overpressure 0.2 - 0.3 At, not less than 6 hrs. The use of anhydrous ethyl ether for washing the precipitate removes both organic and inorganic radiochemical impurities. The method enables one to work with quantities of HgCl2 lower than 1 mg.

Brain scanning with radioactive isotopes has become sufficiently reliable to be employed in many medical centers in the detection and localization of intracranial mass lesions. Most reports indicate that certain intracranial neoplasms, i.e., meningiomas, malignant gliomas, and metastatic tumors, can usually be detected by the scan. The mechanisms of the selective localization of tracer substance in or around intracranial neoplasms are not yet fully known, nor is there evidence that a single etiological condition is operative in all instances. Among the factors that appear to be related to the increased uptake of various unstable nuclides in the brain are : (a) selective breakdown of the blood-brain and/or blood-tumor barrier, (b) increased vascularity of neoplastic tissue, (c) increased mitotic activity of neoplastic tissue, and (d) selective acquisition of a specific colloid or crystalloid by a particular tumor. If the selective accumulation of an isotope in the region of a brain tumor is not related exc...