Replication of an avian myxovirus in tumor cell cultures obtained from effusions of mammary carcinoma patients.

In view of the possible use of viruses for the immunotherapy of breast cancer, the replication of a strain of fowl plaque virus was studied in the tumor cells of 11 mammary carcinoma patients with malignant effusions. The tumor cells were obtained by centrifugation on iodamide solutions, then cultured in vitro, and infected by a fowl plaque virus previously adapted to grow in a mammary carcinoma cell line. Virus multiplication was observed in all cases, a prerequisite for the use of autologous viral oncolysates for immunotherapy in mammary carcinoma patients.

Sulfhydryl group quantitation of hepatoma and liver microsomal fractions.

The relationship of sulfhydryl and disulfide groups to protein synthesis in normal and rapidly growing tissues was investigated by quantitation of sulfhydryl groups in endoplasmic reticulum and polyribosomes of normal liver and hepatomas. Stripping by ethylenediaminetetraacetate and potassium chloride of normal liver smooth and rough endoplasmic reticulum reduced by 15 percent and increased 30 percent, respectively, the sulfhydryl groups available for carboxamidemethylation by iodoacetamide. This could reflect the removal of ribosomes from rough endoplasmic reticulum with the subsequent exposure of sulfhydryl groups. Exposed sulfhydryl groups of normal mature female rat liver smooth endoplasmic reticulum were decreased to a similar degree by the stripping procedure with ethylenediaminetetra-acetate and potassium chloride when quantitated by either iodoacetamide or 4,4'-dithiodipyridine. This was not the case in young male and female rats, where the stripping procedure failed to decrease the exposed sulfhydryl groups of smooth endoplasmic reticulum. An increase in the quantity of exposed sulfhydryl groups of normal young and mature rat liver rough endoplasmic reticulum after stripping by ethylenediaminetetraacetate and potassium chloride was observed with iodoacetamide. However, when 4,4'-dithiodipyridine was used, no change could be detected. The hypothesis that smooth endoplasmic reticulum arises by degranulation of the rough endoplasmic reticulum in vivo is not supported by our sulfhydryl group quantitation of smooth endoplasmic reticulum and in vitro degranulated rough endoplasmic reticulum. A negative correlation between exposed sulfhydryl groups on the polyribosomes and the rate of growth of normal liver and of Morris hepatomas 6 and 38B suggests that the conformation of the free polyribosomal proteins could be a control factor for the rate of protein synthesis. Faster growing hepatomas also have greater quantities of sulfhydryls and disulfides.

One enzyme for the 5'-deiodination of 3,3',5'-triiodothyronine and 3',5'-diiodothyronine in rat liver.

Many studies suggest that one enzyme is involved in the phenolic ring deiodination of iodothyronines in rat liver and kidney and another one in the tyrosyl ring deiodination. This study describes some characteristic of the phenolic ring (5'-) deiodination of rT3 and 3',5'-T2 by rat liver microsomes. At pH 7.2 the Km values of the 5'-deiodination of rT3 and 3',5'-T2 were 0.103 and 0.77 microM, respectively. 3',5'-T2 and rT3 inhibited the respective 5'-deiodination reactions competitively, the Ki values being 1.05 and 0.134 microM, respectively. Several radiographic contrast agents markedly inhibit the 5'-monodeiodination or rT3 and 3',5'-T2, the type of inhibition being competitive. Of these compounds iopanoic acid, ipodic acid and iophenoxic acid are the most potent inhibitors with Ki values of approximately 2 microM for both reactions. The non-iodine containing compound 8-anilino-1-naphthalene sulphonic acid (ANS) appeared to be a very strong competitive inhibitor of both 5'-deiodinations (Ki 4.3-4.7 microM), whereas salicylic acid, which as ANS inhibits the binding of iodothyronines to T4-binding globulin, inhibited these reactions to a much lesser extent (Ki 300-500 microM). On the other hand, diiodosalicylic acid was a very strong inhibitor. The beta-adrenergic blocker D,L-propranolol was a weak noncompetitive inhibitor of both 5'-deiodinations (Ki 0.4-0.7 mM). These reactions were also inhibited by various 2,6-diiodophenol derivatives, triiodophenol being the strongest and diiodotyrosine the weakest inhibitor tested. Comparing the Ki values of various inhibitors for the 5'-deiodination of rT3 and 3',5'-T2, a positive correlation between these values was found (r = 0.97). It was concluded that rT3 (to 3,3'-T2) and 3'-5'-T2 (to 3'-T1) monodeiodinating activities are very similar to each other and that there may just be one monodeiodinase catalyzing the 5'-deiodination of iodothyronines in rat liver.

Intravenous ionic contrast media cause local prostacyclin release in man.

The effect of intravenous administration of ionic contrast media on local release of prostacyclin (PGI2) was investigated in man. Iodamide and ioxaglate, high- and low-osmolality contrast media, respectively, both significantly increased PGI2 levels at the site of injection. Iodamide was the most active, whereas an identical volume of isotonic saline had no effect. This study suggests that local formation of PGI2 may adequately reflect the degree of endothelial irritation that is caused by contrast media and that depends in part on their osmolality.

Transcatheter microembolization with ferropolysaccharide. A new approach to ferromagnetic embolization of tumors: preliminary report.

A new embolic material has been devised to improve the therapeutic effect of ferromagnetic embolization upon tumors. Iron sponge microspheres (diameter 10-30 mu) were suspended in viscous, aqueous polysaccharide solution, dextran 40, and sodium carboxymethyl cellulose (Ferro-polysaccharide, FPS). Transcatheter embolization with FPS was performed under external magnetic control (2,800 gauss) in dog kidneys and VX2 carcinomas of rabbits, causing widespread, intraparenchymal vascular occlusion of target vessels. Neither recanalization nor collateral circulation was found to the infarcted areas, and the embolized tumors had extensive necrosis with resultant tumor regression. No significant untoward reaction or other undesirable embolization was noted serologically or histologically, even after intravenous administration of FPS. Clinical application to two patients, one with a hepatoma and the other with a renal cell carcinoma, resulted in excellent tumor infarction with no significant side effects.

Vicarious excretion of water-soluble contrast media into the gallbladder in patients with normal serum creatinine.

Ten patients with normal serum creatinine and no evidence of acute cholecystitis were found to have vicarious excretion of water-soluble contrast media into the gallbladder 20 minutes to 72 hours after injection. Eight of the ten had unilateral renal pathology. Two patients, however, had bilaterally normal kidneys. The patients had been injected with either diatrizoate, iothalamate, or iodamide. The mechanisms and pathophysiology of vicarious contrast excretion are discussed. The vicarious excretion of intravascular contrast in the gallbladder does not in itself indicate renal or hepatobiliary disease. Although commonly associated with unilateral renal pathology, vicarious gallbladder excretion of urographic contrast may be a normal variant in some patients.

Assays for plasma complement activation by x-ray contrast media.

Hemolytic complement activity and a C3a radioimmunoassay (RIA) were investigated for their ability to characterize contrast media (CM) with respect to complement activation. The CM tested were commercial formulations of diatrizoate, iodamide, iothalamate, ioxaglate, iohexol, and iopamidol. When plasma was exposed to CM, the hemolytic complement activity decreased and the C3a concentration increased. The C3a assay had a larger dynamic range and therefore more ability to discriminate among the CM. Using C3a data from pooled plasma or from individual donors' plasma, nonionic iopamidol (as Isovue 300) had lower complement-activating potential (P less than .005 and P greater than .05, respectively) than all of the ionic media based on diatrizoate, iothalamate, iodamide, and ioxaglate. The ranges of mean C3a values generated by saline, nonionic CM, and ionic CM were 48 to 60, 65 to 173, and 807 to 3272 ng C3a/50 microL, respectively. Complement activation was found to correlate with osmolality (r = 0.945, all media) and with molarity (r = 0.994, diatrizoates).

Effect of iodinated contrast media on the synthesis and metabolism of leukotriene B4.

To investigate whether the endogenous vasoactive substrate, leukotriene B4 (LTB4), was induced in adverse reactions observed after intravenous injection of iodinated contrast media (CM), the authors measured the in vitro production and metabolism of LTB4 by human polymorphonuclear leukocytes (PMNs) after stimulation with different doses of commercial CM preparations: iopamidol, 300 mg I/mL; iodamide, 300 mg I/mL; iohexol, 300 mg I/mL; ioxaglate, 320 mg I/mL; and the experimental preparation, iomeprolo. This study showed that the CM studied do not stimulate the production or metabolism of LTB4 by isolated human blood PMNs. All of the CM studied except iodamide do not inhibit the production or metabolism of LTB4 in PMNs stimulated by A23187. The in vitro hepatic microsomal oxidation of exogenous LTB4 to (omega-1)OH LTB4 and omega-OH LTB4 was inhibited by all the CM studied. LTB4 production by PMNs seems not to play a major role in anaphylactoid reactions observed after iodinated CM. However, a transient blockade by CM of LTB4 metabolism, leading to an increase of steady-state concentrations of LTB4, could not be excluded by these experiments.

Mechanism of renal excretion of various X-ray contrast materials in rabbits.

The excretory behavior of nine nephrotropic contrast agents with varying physicochemical properties such as charge, lipophilicity, and molecular size was investigated. Renal clearance in comparison with inulin was determined by means of the continuous infusion method. Each contrast agent was infused at three dose levels in four to six rabbits. The investigations show that tubular transportation in proportion to glomerular filtration decreases with increasing dosages of all the contrast agents. Thus, with the highest concentration in plasma all contrast agents are eliminated at more or less the glomerular filtration rate (GFR). After administration of the low dosages the following differences are found: 1) Net tubular secretion increases for the monomeric contrast agent acids with increasing lipophilicity, in the order diatrizoate congruent to iothalamate less than iodamide less than acetrizoate. 2) The clearance studies do not reveal any tubular secretion or reabsorption for a hydrophilic cationic contrast agent. 3) The nonionic contrast agents do not show net secretion. The more lipophilic they are, the more they are reabsorbed. 4) Two dimeric contrast agents also do not reveal any tubular secretion. They seem to be reabsorbed more than monomers with the same charge.

Pharmacokinetics of iodamide in normal subjects and in patients with renal impairment.

The pharmacokinetic characteristics of iodamide, a contrast agent for excretion urography, were studied in seven normal subjects and in 15 patients with various degrees of renal impairment. Two different formulations were administered, namely, a 65% solution (iodamide 300) by slow intravenous injection and a 24% solution by slow intravenous (drip) infusion. Both preparations of iodamide exhibited characteristics of an open two-compartment model. In both normal subjects and patients, the contrast agent was excreted almost exlusively in urine. In normal subjects, the pharmacokinetic parameters of both formulations were similar, with a distribution half-life (1/2alpha) of about 3 minutes and a disposition half-life (t1/2beta) of about 69 minutes. An average of 84 per cent of the dose was excreted in urine within 4 hours after administration of iodamide with net renal tubular secretion of about 38 per cent. The binding of iodamide to plasma proteins was negligible, and the extent of biotransformation of iodamide was minimal. In patients with renal impairment, the disposition half-life (t1/2beta) of iodamide ranged from 4.1 to 16.4 hours. Other changes in pharmacokinetic parameters were also seen in patients with renal impairment.

Electrocardiographic changes with intravenous pyelography in healthy individuals.

Fifty apparently healthy individuals undergoing intravenous pyelography had electrocardiographic evaluation before, during, and after the examination. No patient had a major electrocardiographic change after contrast injection. Of the 7 patients with abnormal baseline electrocardiograms, all had a striking (greater than 40 beats per minute) rise in rate. The 43 patients with normal electrocardiograms had a small but significant rise in rate. No ischemic changes or major arrhythmias occurred. Although electrocardiographic aberrations were better correlated with baseline electrocardiograms than history or physical evaluation, our experience and a review of the literature confirms the safety of this examination in healthy people.

The old and the new: a study of five contrast media for urography.

Five contrast media, Conray 280 and 420, Urografin 370, Uromiro Sodium 300 and Niopam 370, were compared in a randomised trial involving a total of 482 patients. The best urographic agent was Conray 420 and the worst Conray 280, these control agents defining the ends of the scoring system. Uromiro Sodium 300 was very nearly as good as Conray 420. A non-ionic agent, Niopam 370, scored nearly equal with Urografin 370; both were rather better than Conray 280. There was little difference in minor reactions between the media. No reason was found to prefer non-ionic to ionic agents for general use in urography; indeed for a diagnostic examination the sodium salt of an ionic agent is preferable.

Decrease of plasma prekallikrein and kallikrein inhibitors during intravenous phlebography.

Complex contact activation systems may have major involvement in side effects of i.v. contrast media. To investigate this, quantitative measurements of several factors (plasma prekallikrein, kallikrein inhibitory activity, haematocrit, alpha-2-macroglobulin, antithrombin III, alpha-1-antitrypsin and beta-thromboglobulin) were made before and after i.v. contrast phlebography in two groups of patients (each containing 21 patients) with no thrombosis, using a high- (meglumine iodamide) and a low-osmolality (ioxaglate) contrast medium. A statistically significant decrease in plasma prekallikrein was observed after the high-osmolality contrast medium, which is a sign of the activation of the kallikrein-kinin system and an indicator of the activation of the intrinsic coagulation. These events may play an important role in the adverse effects of contrast media.

High contrast enhancement of the liver in CT by repeated doses of contrast medium.

A technique consisting of repeated injections of contrast medium has been used in 530 cases of upper abdominal CT studies for evaluation of hepatic and pancreatic disease. Out of 530 cases, 105 patients had hepatic lesions, 62 metastatic, 3 adenomas, 4 haemangiomas and 6 hepatomas. The remaining 30 patients had cystic lesions involving the liver. Using a repeat dose technique and rapid scanning, the accuracy rate ranged about 90%. Th authors feel that this technique should be employed routinely for evaluation of hepatic problems and that other techniques should be abandoned.

Serious or fatal complications after inadvertent administration of ionic water-soluble contrast media in myelography.

The consequences of the inadvertent administration, by the intrathecal route, of ionic contrast media instead of iopamidol in seven subjects are reported. The ionic compounds were diatrizoate, iodamide and ioxitalamate. The outcome was fatal in three out of seven subjects, and it depended on the type and the dose of the administered contrast agent. The serious or fatal reactions observed are a tragic confirmation of the predictive power of neurotoxicity data obtained in animal studies with various iodinated water-soluble compounds. The margin of safety, represented by the ratio of LD50 i.ce. in mice to clinical dose in humans, both normalized to bodyweight, appears to reliably reflect the risk of toxic reactions after intrathecal administration of iodinated contrast agents.

Contrast media-induced side effects on excitation and conduction of electrical activity in the heart on intracardiac application. Investigations in anaesthetized dogs.

In several series of experiments with intracardiac application in anaesthetized dogs, the following contrast media were tested for their adverse effects on excitation and conduction of electrical activity in the heart. Diatrizoate, lysine-diatrizoate, lysine-sodium-diatrizoate, ioxaglate, iopamidol, iodamide, ioxitalamate, ioglicinate and metrizamide. Blood pressure and, using the His' bundle-ECG technique, the parameters P0-P1 (heart rate), A1-H1 period (conduction time in the AV-node), and H1-V1 period (conduction time in the TAWARA branches) were measured. A statistical correlation exists between osmolarity and blood pressure (higher osmolarity causes a greater decrease in blood pressure), as well as between osmolality and decrease in heart rate (higher osmolarity causes a greater decrease in heart rate). The delay in conduction time in the AV-node correlates only with viscosity and sodium content (increased viscosity with increased sodium content delays the time of conduction). A tendency towards delay in conduction in the TAWARA branches could not be correlated to any one of the physico-chemical parameters studied.

[The pharmaco-kinetics of angiographic contrast media with special reference to the extra-vascular spaces. Fundamental studies on dog for the characterisation of angiographic media. I The pharmaco-kinetics of various contrast media under conditions of constant infusion (balanced flow)]. / Pharmakokinetik angiographischer Kontrastmittel unter besonderer Berücksichtigung des extravasalen Raumes. Eine experimentelle Grundlagenstudie an Hunden zur Charakterisierung der Angiographica. I. Mitteilung:Pharmakokinetik verschiedener Kontrastmittel unter den Bedingungen der Dauerinfusion ("Fliessgleichgewicht")

The pharmaco-kinetics of angiographic contrast media in the extra-vascular space, which are largely unknown, were investigated experimentally in dogs. As part of a basic study, using radio-active contrast media, it was possible to determine the concentration and rate of elimination in practically all organs and tissues. Measurements were carried out first after prolonged infusion of the contrast under conditions of balanced flow, and secondly six hours after the end of the infusion. It was therefore possible to determine the inflow and loss of contrast medium in various organs, or organs systems. The most commonly used angiographic contrast media in Germany were investigated. Their kinetic behaviour is largely identical, their pattern of distribution and elimination depended principally on the organ or tissue. A comprehensive discussion of the results of all the experiments will be given in the third article.

Histamine release and endothelial leakage from an intravascular contrast medium.

The endothelial injury produced by meglumine iodamide was studied in the rat aorta. A mixture of blood and contrast medium was more toxic to the endothelium than the pure contrast agent. This difference disappeared after premedication with antihistamine, which did not affect the injury produced by the pure contrast agent. Meglumine iodamide appears to cause a release of histamine from blood but not from the aortic endothelium nor from surrounding tissues in amounts demonstrable by this method. Leucocytes are a source of histamine after intravascular contrast medium administration.

[The urethrocystogram and perineal sonography compared]. / Urethrozystogramm und Perinealsonographie im Vergleich.

Perineal sonography and urethrocystography were performed on 45 patients in the same sitting to evaluate the sonographical method with regard to its applicability as a routine examination method. Corresponding results were obtained 14 times (= 30%). In 31 patients (= 70%) urethrocystographic and ultrasonic measurements diverged. The urethrocystogram must therefore remain an integral part in the work-up of urinary incontinence.

An automated multidimensional screening approach for rapid method development in high performance liquid chromatography.

Despite enormous advancements in the area of high performance liquid chromatography (HPLC) in recent years, method development remains a major challenge. This is primarily due to the unknown nature of the matrix material which sometimes is difficult to characterize (e.g. biological matrices). To improve the efficiency of method development a multidimensional screening approach was presented. This approach was based on two major steps: (1) a matrix spiked with drug was eluted from a large number of columns, each under different mobile phase compositions, to provide the preliminary selectivity-separation information; (2) this information was then used to compose column switching pairs (each pair consisted of a preparatory column followed by an analytical column) and the elution profile was evaluated to determine the suitable clean up and quantitation conditions. An example was provided using ethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate (EEDA), an X-ray enhancement agent, in human plasma. Since the HPLC system was fully automated the data generation time, and consequently the method development time, can be significantly reduced.