Synthesis, structure and in vitro cytotoxicity testing of some 1,3,4-oxadiazoline derivatives from 2-hydroxy-5-iodobenzoic acid.

The syntheses of nine new 5-iodosalicylic acid-based 1,3,4-oxadiazoline derivatives starting from methyl salicylate are described. These compounds are 2-[4-acetyl-5-methyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6a), 2-[4-acetyl-5-methyl-5-(4-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6b), 2-(4-acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate, C19H17IN2O4 (6c), 2-[4-acetyl-5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16FIN2O4 (6d), 2-[4-acetyl-5-(4-chlorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16ClIN2O4 (6e), 2-[4-acetyl-5-(3-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6f), 2-[4-acetyl-5-(4-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6g), 2-[4-acetyl-5-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6h) and 2-[5-(4-acetamidophenyl)-4-acetyl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6i). The compounds were characterized by mass, 1H NMR and 13C NMR spectroscopies. Single-crystal X-ray diffraction studies were also carried out for 6c, 6d and 6e. Compounds 6c and 6d are isomorphous, with the 1,3,4-oxadiazoline ring having an envelope conformation, where the disubstituted C atom is the flap. The packing is determined by C-H...O, C-H...π and I...π interactions. For 6e, the 1,3,4-oxadiazoline ring is almost planar. In the packing, Cl...π interactions are observed, while the I atom is not involved in short interactions. Compounds 6d, 6e, 6f and 6h show good inhibiting abilities on the human cancer cell lines KB and Hep-G2, with IC50 values of 0.9-4.5 µM.

Systemic, pulmonary and renal haemodynamic effects of large intravenous doses of high and low osmolar contrast media. An investigation in the pig of ratio 1.5 and ratio 3 media.

The central, peripheral and renal haemodynamic effects of intravenous infusion (1 ml/s) of large doses (4 ml/kg body weight) of non-ionic (iohexol) and ionic (metrizoate and ioxaglate) contrast media were studied in 24 anaesthetized pigs. All contrast media showed marked haemodynamic effects with an increase of mean right atrial pressure, mean pulmonary arterial pressure, mean pulmonary occlusion pressure, cardiac output and stroke volume. The response of the pulmonary circulation to contrast media was a fall rather than a rise in pulmonary vascular resistance. No significant changes were detected in the renal circulation after infusion of contrast media.

Metabolic myopathy produced by acute inhibition of glyceraldehyde-3-phosphate dehydrogenase with ortho-iodosobenzoic acid.

A previously developed model of exercise-induced muscle contracture using iodoacetate to inhibit glyceraldehyde-3-phosphate dehydrogenase in rat hindlimb muscles produced selective type II myofiber damage. Utilizing a modification of the same model system, rats were given intra-aortic ortho-iodosobenzoic acid (700 nmol/kg body weight), which cleaves tryptophanyl peptides from glyceraldehyde-3-phosphate dehydrogenase. Within 2-4 h, spontaneous electrically-silent contracture developed in the injected musculature resulting in a plantar-flexed position of the hindlimb. After 24 h, the extensor digitorum longus and tibialis anterior muscles appeared grossly swollen (edematous) and discolored. Microscopically, the extensor digitorum longus (composed predominantly of type II myofibers) contained many randomly scattered, damaged myofibers, reduced glycogen content, absent glyceraldehyde-3-phosphate dehydrogenase activity, interstitial edema and focal collections of mononuclear phagocytes. Damaged fibers showed degenerative changes and contained stainable intracellular calcium. On modified trichrome-stained sections, an outer red staining rim of material was identifiable in many fibers. The fibers of the soleus muscle (composed predominantly of type I myofibers) were not damaged, indicating a preferential ortho-iodosobenzoic acid effect on type II myofibers.

Reproductive, developmental, and genetic toxicology of ioversol.

The authors examined the reproductive, developmental, and genetic toxicity of ioversol in several in vivo and in vitro systems. In Segments I, II, and III reproductive toxicity studies, ioversol did not produce teratogenic effects in either rats or rabbits at daily intravenous dose levels of up to 3.2 g I/kg/day. Daily intravenous injections in male and female rats did not adversely affect fertility or reproductive function. Offspring derived from dams treated with ioversol also developed and reproduced in a normal fashion. Four genetic toxicity studies employing bacterial and mammalian assay systems, and using both in vitro and in vivo methods, indicated that ioversol did not possess mutagenic or clastogenic activity.

Acute and subacute toxicity studies of ioversol in experimental animals.

The authors examined the acute and subacute toxicity of the low-osmolality nonionic radiographic contrast agent, ioversol. The median lethal dose (LD50) of ioversol administered intravenously to mice, rats, rabbits, and dogs was more than 12 g I/kg, which exceeds the maximal anticipated clinical dose by at least tenfold. When the acute intravenous toxicity of 35% I, wt/vol, ioversol was compared with 35% I, wt/vol, iohexol and 37% I, wt/vol, iopamidol in mice, no significant differences in LD50 values or general toxicity were found. Ioversol also was administered via intrathecal routes to rats, dogs, and monkeys. In a comparative study, acute intracisternal injections of 35% I, wt/vol, ioversol in rats demonstrated far less toxicity than 35% I, wt/vol, iohexol and 37% I, wt/vol, iopamidol, a result that may be due to the increased hydrophilic tendency of ioversol relative to iohexol and iopamidol. Acute intracisternal injections of 43% I, wt/vol, ioversol, 35% I, wt/vol, iohexol, and 37% I, wt/vol, iopamidol into dogs at 160 or 240 mg I/kg, demonstrated comparable, but only minimal, toxicity. Monkeys given lumbar intrathecal injections of ioversol tolerated 60 mg I/kg well with no resulting arachnoiditis. Subacute toxicity studies involving 4-week daily intravenous injections (0.2, 0.8, and 3.2 g I/kg/day) in rats and dogs showed ioversol to be well tolerated. The signs of toxicity included a reversible renal cytoplasmic tubular vacuolation in the rat at high doses and a reversible hepatocyte vacuolation in the dog at the same high dose. However, clinical chemistry tests showed no signs of renal or hepatic dysfunction, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of the risk of ventricular fibrillation in the isolated rabbit heart by small additions of electrolytes to non-ionic monomeric contrast media.

Perfusion of the isolated rabbit heart with solutions (350 mg I/ml) of the non-ionic contrast media iohexol and iopentol, both containing NaCl (20 mmol/l), caused a significantly lower frequency of ventricular fibrillation (VF) than solutions without NaCl. Iohexol or iopentol with NaCl (10 mmol/l) caused an intermediate frequency of VF. Iohexol with 10 or 20 mmol NaCl/l caused about the same frequency of VF as iohexol solutions with about the same total electrolyte concentration but with electrolyte composition as that of Krebs' solution. At 320 mg I/ml, solutions of iohexol (20 mmol NaCl/l), iodixanol (20 mmol NaCl/l) and ioxaglate (155 mmol Na/l) all produced a significantly lower frequency of VF than iohexol without NaCl. Ioxaglate caused the largest and iodixanol the smallest decrease in contractile force of the media. The investigation suggests that the small risk of VF from non-ionic monomeric media can be further reduced by adding a small amount of sodium chloride or of the electrolytes of Krebs' solution.

Ortho-iodosobenzoic acid: its acute toxicity and neurobehavioral effects in mice.

o-Iodosobenzoic acid (IBA), in a surfactant micellar medium, is a rapid and efficient catalyst for the hydrolysis of organophosphate (OP) esters. Since little is known about the toxicity of IBA, a primary screen of neurobehavioral toxicity was evaluated in male ICR mice. IBA was administered intraperitoneally in a pH 7.4 phosphate buffer solution containing 8% dimethylformamide. The predominant overt signs of toxicity included an immediate and transient writhing reflex and/or persistent spasmodic myotwitching of the abdomen, and conspicuous suppression of orienting/exploratory behavior and emotional defecation. The dose ranges for ED50 of writhing response, suppression of rearing and spontaneous motor activity overlapped at levels of about one-tenth the acute LD50, 742 (633-856) mumol/kg, being 94.9 (74.5-122.5), 69.8 (47.9-105.4) and 71.1 (49.9-101.3) mumol/kg, respectively; the dose ranges for ED50 of abdominal myotwitching and depression of emotional defecation in a novel environment also overlapped but at levels of about one-fifth the acute LD50, being 138.4 (115.3-167.2) and 146.2 (110.7-196.3) mumol/kg, respectively. Morphine (1.25-10 mg/kg s.c.) antagonized the IBA-induced writhing response and abdominal myotwitching in a dose-dependent manner, with a PD50 of 4.2 and 4.9 mg/kg, respectively. The present report demonstrates that acute intraperitoneal administration of IBA produces an intriguing, non-specific behavioral syndrome, probably resulting from nociceptive stimulation. This implies that IBA might be irritating to the skin and mucosa.

Tolerance to iotrolan after subarachnoid injection in animals.

Neural tolerance after intracisternal administration of iotrolan was compared with that after iohexol, iopamidol, and metrizamide in mice, rats, and guinea pigs. Around the level of the ED50 (approximately two to four times the human dose) tolerance to iotrolan appeared to be much better than tolerance to the other agents. A study in rabbits comparing iotrolan with iohexol produced approximately the same result. High doses of iotrolan, iohexol, and iopamidol were almost equally well tolerated by rats, as were iotrolan and iohexol by rabbits. Tolerance to metrizamide by rats and to iopamidol by guinea pigs was vastly inferior. In support of this very good general tolerance histologic examinations of the spinal tract and of the brain did not reveal any substance-related changes in beagles after lumbar administration of a high dose. An investigation in rats using mannitol and sorbitol formulations with differing osmotic pressures indicates that contrast tolerance is influenced primarily by the chemotoxicity and not by increased osmotic pressure. As shown by the results of the preclinical investigations, iotrolan should be ideal for use in myelography and also appears highly suitable for the examination of other body cavities.

Organ-specific and general tolerance of iotrolan 280 after intravenous administration: phase I study in healthy volunteers.

Iotrolan 280, the first water-soluble, nonionic, blood-isotonic, dimeric contrast medium, was administered intravenously to 12 healthy male volunteers. In a Phase I study with an intraindividual design in comparison with placebo, four doses between 0.15 and a maximum of 0.9 g I/kg body weight were administered in accordance with the principle of dose titration. The highest volume administered was 270.6 ml. The injection rate was 10 ml/min. The observation period was 5 days, with the exception of thyroid parameters (14 days). Iotrolan displayed good general and local tolerance. The typical side effects known from x-ray contrast media either did not occur or were minor after administration of iotrolan. No allergy-like reactions and no effects on hemodynamic parameters were observed. Although one observation is under discussion no effects of iotrolan on impulse generation and propagation in the myocardium could be confirmed. The blood and laboratory and chemical parameters analyzed showed no differences in comparison with placebo. In the treatment group with the highest dose (= 0.9 g I/kg body weight) there was one subject who showed a transient increase of the urinary glucose concentration and one case of a slight transient increase of the serum chloride concentration. No such side effects were seen in the subjects of the treatment groups with lower doses. All renal functions tests were normal. In this study iotrolan showed excellent tolerance after intravenous injection up to 0.9 g I/kg body weight.

Effect of contrast media on beta-endorphin secretion. An in vitro study.

The central nervous system may be highly susceptible to the toxic effects of contrast media (CM). Previous experiments demonstrated that vasopressin is released after the intravenous administration of CM. The present study examined the response of the opiocortin system to CM. Neurons of the rat basal hypothalamus, dispersed and attached to Cytodex-3 beads, were perfused with sodium diatrizoate, metrizamide or iohexol (3 mg iodine/ml). The effluent was collected, and the beta-endorphin (B-E) content was measured by a radioimmunoassay technique. Results, normalized to the internal positive control, were compared with release from normal saline (negative control) by analysis of variance. Diatrizoate and metrizamide caused significant release of B-E (p less than 0.03). Iohexol did not stimulate release of B-E. These results suggest that diatrizoate and metrizamide, but not iohexol, can stimulate the release of hormones from hypothalamic neurons. The phenomenon may play a role in some reactions to intravascular CM administration since these neurons are not protected by a blood-brain barrier.

The effect of sodium on the fibrillatory potential of ioversol.

The spontaneous ventricular fibrillation (VF) potential of the nonionic contrast media, ioversol (IOV), with and without the addition of sodium was examined during right coronary artery (RCA) injections into anesthetized closed-chest dogs. Protocols included fixed volume (6 mL) and fixed rate (0.4 and 0.6 mL/sec) injections to compare two or more of the following: IOV, IOV + (0.075-0.9% wt/vol) NaCl, and sodium/meglumine diatrizoate (DIA). In these studies, the incidence of VF for IOV alone was either greater that with IOV + NaCl formulations or, if equivalent, the incidence of other arrhythmias was greater with IOV alone than with the sodium formulations. When DIA was included in the comparisons, the incidence of VF was always greater than IOV with or without sodium. There was a sodium-related concentration prolongation in QT interval that, at 0.9% NaCl, approximated that with DIA, even though the incidence of VF for the sodium formulation was 0/15 vs. 6/12 for DIA. Thus, the addition of sodium to IOV appears to reduce the propensity for sponteneous VF in the canine model.

Clinical trial program for iopentol. A new nonionic ratio 3.0 contrast medium with emphasis on clinical phases I and II.

Iopentol is a new nonionic, water-soluble ratio 3.0 roentgen contrast medium (CM) for vascular use. The aim is to present the vascular clinical trial program for iopentol and to report the findings from the clinical phases I and II. The clinical program started with an intravenous (IV) safety and pharmacokinetic phase I trial (24 volunteers) and continued with six open, noncomparative phase II trials (61 patients) for studying cardiovascular and arterial tolerance (two trials in cardioangiography), venous tolerance (two trials in IV computed tomography [CT] enhancement), and cerebral and arterial tolerance (2 trials in cerebral arteriography). One volunteer in the phase I trial was excluded because of a vasovagal reaction following saline injection, and four patients were protocol deviators in cardioangiography. Mainly renal glomerular filtration of unmetabolized iopentol, close to 100% recovered after 24 hours in the urine, was found in the phase I study. No unexpected or severe contrast-induced reactions were encountered in phases I and II. Good diagnostic efficiency was obtained in phase II. As also expected, iopentol seemed to be well-tolerated. However, its relative efficiency and tolerance profile can only be documented from the ongoing comparative phase III trials.

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.

Hemodynamic effects of contrast media during coronary angiography: a comparison of three nonionic agents to Hypaque-76.

Coronary angiography with standard ionic contrast media is associated with marked alterations in cardiac hemodynamics because of the depressant effects of the contrast media on cardiac contractility. Nonionic contrast media have been reported to produce less hemodynamic alteration than standard ionic contrast media. However, there is no information on how one nonionic media compares to another. Thus we compared the hemodynamic effects of three nonionic contrast media, Iopamidol (IOP), Iohexol (IOH), and Ioversol (IOV) to each other as well as to the standard ionic contrast media Hypaque-76 (H76). In 20 closed-chest anesthetized dogs, we recorded the maximal change in left ventricular systolic pressure (LVSP), mean aortic pressure, left ventricular diastolic pressure (LVDP), and left ventricular dp/dt during 10-cc left main coronary artery injections of H76, IOP, IOH, and IOV. The mean aortic pressure and LVSP decreased 36 +/- 17 mm Hg and 46 +/- 21 mm Hg with H76 but only 5 +/- 5 mm Hg and 6 +/- 5 mm Hg with IOP, 5 +/- 4 mm Hg and 6 +/- 6 mm Hg with IOH, and 5 +/- 4 mm Hg and 7 +/- 6 mm Hg with IOV (P less than 0.001). The LVDP increased 6 +/- 5.0 mm Hg with H76 but only 0.2 +/- 0.5 mm Hg with IOP, 0.2 +/- 0.3 mm Hg with IOH, and 0.5 +/- 1.0 mm Hg with IOV (P less than 0.001). The LV dp/dt decreased 545 +/- 261 mm Hg/sec with H76 but increased 886 +/- 477 mm Hg/sec with IOP, 910 +/- 96 mm Hg/sec with IOH, and 473 +/- 335 mm Hg/sec with IOV (P less than 0.001). Whereas each nonionic agent produced significantly less hemodynamic abnormalities than H76, there was no significant difference between any of the nonionic agents on any hemodynamic parameter. Thus, as compared to H76, these nonionic contrast media produced only trivial alterations in hemodynamics and LV dp/dt. These agents may be preferable in patients with LV dysfunction.

[Acute cardiac side effects of iodecol, a new nonionic dimer roentgen contrast medium, in intracoronary injection]. / Akute kardiale Nebenwirkungen von Iodecol, einem neuen nichtionisch-dimeren Röntgenkontrastmittel, bei intrakoronarer Injektion.

The effects of intracoronary injections of Iodecol, a nonionic-dimeric contrast medium (iodine content 350 mg/ml, osmolality 0.34 osmol/kg, viscosity 13.8 mPa X s) on haemodynamics, coronary blood flow, ECG, and cationic content as well as osmolality of coronary sinus blood have been evaluated and compared to those of Iopamidol and Amidotrizoate. Experiments were carried out in 9 closed-chest dogs using heart catheterisation techniques. After Iodecol and Iopamidol only positive inotropism was seen while Amidotrizoate initially had cardiodepressive effects. Iodecol caused less increase of peak velocity of pressure rise and systolic blood pressure than Iopamidol. All contrast media led to an increase in coronary blood flow of the same extent. ECG changes were most marked following Amidotrizoate and only slight after Iodecol. Decrease of cationic content and increase of osmolality in coronary sinus blood were seen after each compound. Changes were only small after Iodecol and always greater after Amidotrizoate. Moreover, an overproportional decrease of coronary sinus calcium content was seen after Amidotrizoate due to calcium binding. Thus, based on these animal experiments, a further slight reduction of acute cardiac side effects during coronary arteriography could be expected from the use of nonionic dimeric compounds, compared to ionic and currently used nonionic contrast media.

Effects of intravenous administration of a new nonionic dimeric contrast medium on the coronary circulation. Comparison with monomeric ionic and nonionic media.

Contrast media injected into the circulation produce a variety of cardiovascular effects. Agents with low osmolality and low concentrations of cations cause considerably less hemodynamic effects. This study compared the effects of a nonionic dimer, iotrol, which has an osmolality (340 mosm/kg) close to that of serum (290 mosm/kg), with a standard ionic monomer, meglumine diatrizoate, and a nonionic monomer, iosimide. The effects of intravenous bolus injection of these three contrast agents on coronary and systemic hemodynamics were studied in eight anesthetized dogs. The influence of the contrast media on subendocardial and subepicardial perfusion was assessed by injecting radioactive microspheres into the left atrium 30 seconds after injection of the media. Alterations in coronary hemodynamics occurred with both iosimide and meglumine diatrizoate. Iotrol produced minimal changes in coronary hemodynamics. Thus, iotrol is the least perturbing contrast indicator and seems the best for use in quantitative digital subtraction and dynamic computed tomography studies designed to measure myocardial perfusion.

Nephrotoxicity of ionic and non-ionic contrast media in aorto-femoral angiography.

Nineteen patients examined with aorto-femoral angiography were randomized into two contrast medium groups (meglumine metrizoate and iohexol). Urine activity of beta-hexosaminidase, a specific renal enzyme, was determined before and on three occasions after angiography. No change of beta-hexosaminidase activity was found after angiography with iohexol, while there was a significant increase after examination with meglumine metrizoate. This indicates that meglumine metrizoate even following injection into the abdominal aorta damages renal cells which could not be shown with iohexol as contrast medium. We therefore recommend that at least patients with impaired renal function should be examined with the non-ionic contrast medium iohexol to minimize the danger of further damage to the kidneys and a possible renal failure.

Renal function following nephroangiography with metrizamide and iohexol. Effects on renal blood flow, glomerular permeability and filtration rate and diuresis in dogs.

The non-ionic ratio 3.0 contrast media metrizamide and iohexol used in high-dose unilateral nephroangiography in dogs produce homogeneous nephrograms and no marked effects on renal blood flow, glomerular filtration rate, and osmotic diuresis, in contrast to previously reported results using the same technique with iodine-equivalent doses of the ionic ratio 1.5 contrast medium diatrizoate (25). Iohexol affected glomerular permeability significantly less than metrizamide and diatrizoate.

Temporomandibular joint arthrography: comparison of morbidity with ionic and low osmolality contrast media.

We compared patient morbidity associated with temporomandibular joint (TMJ) arthrography using both meglumine/sodium diatrizoate (60%) and the new monoacidic dimer, Hexabrix, in a double-blind randomized clinical trial in 31 patients. Patients experienced maximal discomfort from TMJ arthrography with the initial joint filling and joint distension; this rapidly resolved over 10 minutes. Delayed exacerbation of pain is less than described for shoulder arthrography. The newer contrast media promise to decrease patient morbidity with arthrography.