Effects of a dimeric vs a monomeric nonionic contrast medium on renal function in patients with mild to moderate renal insufficiency: a double-blind, randomized clinical trial.

The efficacy and safety of nonionic dimeric contrast media in subjects with impaired renal function is largely unknown. The present study was aimed at determining the risk of tubular nephrotoxicity in patients with mild to moderate renal insufficiency who underwent intravenous urography (IVU) with the nonionic dimeric contrast agent iodixanol (Visipaque, Nycomed Imaging, Oslo, Norway). In a double-blind protocol 64 patients (55 males; mean age 68.3 years) with serum creatinine between 135 and 265 micromol/l who were to undergo IVU were randomized to receive iodixanol (a nonionic dimer) or iopromide (a nonionic monomer), 600 mg I/kg b. w. Renal function was evaluated before and 1 h, 6 h, 24 h, 48 h and 7 days after IVU with analysis of serum creatinine, urinary enzymes alanylaminopeptidase and N-acetyl-beta-glucosaminidase, and urinary microproteins alpha-1-microglobulin and albumin. Renal function remained stable in both contrast medium groups during the follow-up period. No statistically significant differences were observed between the monomer and the dimer in terms of urinary enzyme and microprotein excretion or serum creatinine. Transient radiocontrast-induced nephropathy developed in 1 patient who had received iodixanol. The administration of the nonionic dimeric contrast medium iodixanol, or of the nonionic monomer iopromide, entailed a low nephrotoxic potential in patients with mild to moderate renal insufficiency undergoing excretory urography.

Comparison between the efficacy of dimeric and monomeric non-ionic contrast media (iodixanol vs iopromide) in urography in patients with mild to moderate renal insufficiency.

Non-ionic dimers induce less diuresis than non-ionic monomers, resulting in increased opacification of the urinary tract in intravenous (i.v.) urography. This double blind, comparative, randomized, parallel trial compared the efficacy of iodixanol (non-ionic dimer) and iopromide (non-ionic monomer) in 100 patients with mild to moderate renal insufficiency (serum creatinine of 135 to 265 mumol l-1) who underwent i.v. urography. A total dose of 600 mgI kg-1 bw of iodixanol (320 mgI ml-1) or iopromide (300 mgI ml-1) was injected. Radiographs were blindly evaluated by three radiologists who analysed different parameters (renal border visualization, nephrogram density, calyceal filling and density, papillary blush detection, delineation of collecting ducts, renal pelvis opacification, visualization of ureters, bladder density, bladder distention). Densitometric evaluation on the renal pelvis and bladder was also performed. Iodixanol showed better filling and density of the calyces (p = 0.004), more frequent detection of papillary blush (p = 0.003) and better opacification of the renal pelvis (p = 0.006). No significant differences between the two contrast media were found in regard to other parameters. In conclusion, the results confirmed theoretical expectations. The non-ionic dimer iodixanol is to be preferred to a non-ionic monomer such as iopromide in i.v. urography on patients with impaired renal function.

Injection-associated pain in femoral arteriography: a European multicenter study comparing safety, tolerability, and efficacy of iodixanol and iopromide.

PURPOSE: To evaluate injection-associated pain, safety, and efficacy with the isotonic contrast medium iodixanol (Visipaque 270 mg I/ml) compared with iopromide (Ultravist 300 mg I/ml) in femoral arteriography. METHODS: A multicenter, double-blind, randomized, parallel-group clinical investigation was carried out in 54 hospitals in Europe. Of the patients evaluated, 1225 received iodixanol and 1227 iopromide in conventional and/or digital subtraction angiography. RESULTS: The iodixanol group reported statistically significantly less injection-associated pain (0.9%) than the iopromide group (9.5%) (p << 0.001). Further, 4.1% in the iodixanol group experienced pain and/or severe heat sensation vs 19. 8% in the iopromide group (p << 0.001). In the iodixanol group, 1.8% of the patients experienced contrast-related adverse events vs 2.4% in the iopromide group (p = NS). Overall diagnostic information was optimal for 94.1% in the iodixanol group and 95.3% in the iopromide group (p = NS). CONCLUSIONS: Iodixanol 270 mg I/ml causes significantly less injection-associated pain during femoral arteriography and is as safe and efficacious as iopromide 300 mg I/ml.

Iopentol (Imagopaque) in vascular procedures. A multi-centre monitoring trial assessing adverse events and diagnostic information--results from 3,587 patients in Germany.

The aims of the present open, non-comparative survey were to study the safety and efficacy of iopentol (Imagopaque, Nycomed Imaging AS, Oslo, Norway) in a large patient group. In a series of German centres, 3,587 patients underwent various contrast-enhanced examinations with iopentol. The most frequent examinations were computed tomography (CT) (1,740), phlebography (462), and digital subtraction angiography (DSA) (493). Only 82 patients (2.3%) experienced one or more adverse events. Sixty-one (1.7%) of these events were possibly or probably caused by the contrast medium. A total of 111 adverse events were registered, 54 of mild, 42 of moderate and 12 of strong intensity, and 51 events required treatment. The most frequent adverse events were nausea (34), erythema (14) urticaria (9), taste sensation (6), circulatory reactions (5) and angina pectoris (5). The frequencies of adverse events were 2.9% in CT, 2.0% in DSA, 2.0% in phlebography, 1.6% in cardioangiography, and 0.4% in urography. Patients with arteriosclerosis, an earlier contrast medium reaction, multimorbidity or age over 70 years had a statistically significantly higher risk of experiencing an adverse event. Patient tolerance was very good; the mean score was 83% on a visual analogue scale (VAS) ranging from extremely bad (0%) to extremely good (100%). Efficacy, as measured on VAS, was determined. Technical quality was scored as 80%, contrast enhancement within the vessels as 80% and delineation of lesions as 79%. The results from this large patient population confirms the experience from clinical practice that iopentol is a safe, well tolerated and efficient contrast medium.

Safety, tolerance, and pharmacokinetics of iodixanol injection, a nonionic, isosmolar, hexa-iodinated contrast agent.

RATIONALE AND OBJECTIVES: A review of clinical-chemical parameters and tolerability of iodixanol is presented. Iodixanol is a newly developed dimeric, ratio 6 radiographic contrast medium formulated to be isotonic to plasma in all concentrations by the balanced addition of electrolytes. We summarize completed trials of iodixanol. RESULTS: The increase in femoral blood flow following administration of iodixanol was significantly smaller than that seen with most other nonionic contrast media. Iodixanol appears to have less impact than other nonionic media on renal tubular function. Unlike iohexol and ioxaglate, the rate of adverse events after iodixanol administration was essentially the same for normal patients as for patients at increased risk for negative reactions (patients with previous adverse reactions to contrast administration). The risk following administration of iodixanol also appears to be similar in normal patients and in patients with other risk factors, including those with a history of congestive heart failure, renal insufficiency or disease, asthma, diabetes, hypertension, or vascular disease. A significant reduction in the sensation of injection-associated heat and pain was noted for iodixanol versus ioxaglate. Cardiac electrophysiologic measurements and contractility revealed minimal interference from iodixanol. CONCLUSION: Iodixanol is a safe and effective nonionic, isotonic contrast medium that may offer clinical advantages.

Image quality and safety after iodixanol in intravenous urography; a comparison with iohexol.

A double-blind, randomized phase III study compared intravenous urography in 100 adult patients receiving iodixanol 320 mgI ml-1 (Visipaque) with 99 patients receiving iohexol 350 mgI ml-1 (Omnipaque). The aim of the study was to investigate differences in image quality between a non-ionic dimeric contrast medium (CM) and a non-ionic monomer at 40 ml per patient and 60-100 ml per patient volume levels. There were no statistically significant differences between iodixanol and iohexol with respect to overall diagnostic information, which was found to be optimal in 86% and 79%, respectively. Immediately after the injection, the renal border was better delineated with iohexol than with iodixanol (p = 0.0001). Marked papillary blush occurred more often in the iodixanol group (16%) than in the iohexol group (0%), as did visualization of the collecting ducts (24% vs 5%) (p = 0.001). The incidence of adverse events was similar and low for both contrast media. In patients who received the higher doses of CM (60-100 ml), the frequency of discomfort was significantly lower after iodixanol than after iohexol (p = 0.006). We conclude that, in intravenous urography, iodixanol provides at least as good image quality as does iohexol. Iodixanol may cause less discomfort than iohexol, in particular when larger volumes of CM are injected.

Main results of the first comparative clinical studies on Visipaque.

The results are reviewed from 18 European clinical vascular studies in 1950 patients where iodixanol (Visipaque) - a new isotonic, dimeric, nonionic contrast medium (CM) - is compared to other CM. Visipaque gave better patient comfort, i.e., less pain and heat sensation after vascular injections than the comparative CM. Adverse events reported after Visipaque were otherwise similar to nonionic CM but lower than after ioxaglate (Hexabrix) and other ionic CM. Human renal safety of Visipaque has been extensively studied. Only small changes in glomerular filtration rate and serum creatinine were measured with the monomeric nonionic CM as well as with Visipaque. The excretion of marker enzymes for renal tubular cell function was generally lowest for Visipaque. Thus Visipaque was highly tolerable in the kidneys. To study cardiac safety, electrophysiological and hemodynamic changes were recorded. Visipaque had generally no electrophysiological or hemodynamic effects, or less pronounced effects compared to the other CM. Radiograms revealed that Visipaque 320 mg I/ml yielded the same attenuation as 350 to 370 mg I/ml of the other CM and, similarly, 270 mg I/ml of Visipaque gave as good visualization as 300 mg I/ml of comparative CM.

A double-blind study comparing safety, tolerability and efficacy of iodixanol 320 mgI/ml and ioxaglate 320 mgI/ml in cerebral arteriography.

Iodixanol is a new nonionic dimer, isotonic with blood at all concentrations. Iodixanol 320 mgI/ml was compared in a double-blind, randomized study to the ionic dimer ioxaglate 320 mgI/ml for evaluation of safety and efficacy parameters during cerebral arteriography. Eighty adult patients were enrolled and all completed the trial. Radiographic efficacy was assessed from the diagnostic information and the radiographic density. Safety was evaluated by recording discomfort and other adverse events, changes in ECG, heart rate and blood pressure, changes in intra-arterial blood pressure and circulation time. No difference between the two contrast media were noted radiographically. No clinically important changes from baseline or between the two contrast media were found in ECG, heart rate, blood pressure or intra-arterial blood pressure. Although not statistically significant, a somewhat longer mean circulation time was found with iodixanol, probably due to its slightly higher viscosity. Injection-associated warmth sensation and pain were more intense with ioxaglate than with iodixanol, and pain was statistically more frequent after injection of ioxaglate. A high incidence of adverse events other than discomfort is reported in this study, mainly related to the selective arteriographic procedure itself. The adverse events related to the contrast medium were more frequent with ioxaglate (27% of the total number of adverse events) than with iodixanol (10%). The new isotonic nonionic dimer iodixanol offers significantly better comfort to the patient than does ioxaglate. This is an important feature, especially in relatively risky procedures that are unpleasant for the patients, such as conventional cerebral angiography.

Evidence for distinct phencyclidine and SKF10047 receptors following detergent treatment of rat brain membranes.

In order to compare characteristics of benzomorphan and phencyclidine receptors, binding of the ligands [3H]SKF10047 and [3H]phencyclidine (PCP) was measured in intact rat synaptosomal membranes and in membranes treated with a detergent (CHAPS, a twitterionic derivative of cholic acid). Ligand binding was quantified in the particle containing fractions and in particle-free supernatants. About 20% of the SKF binding sites could be solubilized from the membranes by CHAPS under the conditions used here, while all PCP binding sites remained associated to particles. This observation and the inhibition patterns found for the two ligands indicate that the PCP receptors and the SKF receptors as delineated in this paper are indeed separate.

Effect of opioid agonists selective for three subclasses of opioid receptors and one sigma receptor agonist on dopamine stimulated adenylate cyclase in rat caudate nucleus.

The adenylate cyclase in rat caudate nucleus homogenate could be stimulated by dopamine and less potently by the dopamine D1 receptor specific agonist SKF38393. Agonists selective for mu[D-Ala2, MePhe4Gly(ol)5]enkephalin (DAGO) and delta opioid receptors [D-Pen2, D-Pen5]enkephalin (dPen-dPen), inhibited the dopamine but not the dopamine D1 stimulated adenylate cyclase. The kappa opioid agonist, U69593, had no effect, probably due to low kappa receptor contents in rat caudate nucleus. 10(-4) M of the sigma receptor specific agonist, 1,3-di-o-tolylguanidine (DTG), potentiated the dopamine as well as the dopamine D1 stimulated adenylate cyclase while lower concentrations of DTG had no effect.

Pharmacokinetics and effects on renal function following cilazapril and hydrochlorothiazide alone and in combination in healthy subjects and hypertensive patients.

1. Possible interactions between cilazapril and hydrochlorothiazide with respect to pharmacokinetics and renal effects were investigated in healthy subjects (single dose) and in hypertensive patients (multiple dosing). 2. No significant pharmacokinetic interaction was found between cilazapril and hydrochlorothiazide. 3. Cilazapril showed weak saluretic properties as compared with hydrochlorothiazide, but increased the saluretic effects of hydrochlorothiazide. 4. Cilazapril attenuated the hypokalaemia observed with hydrochlorothiazide in hypertensive patients. 5. The effect on blood pressure reduction obtained from the combination of cilazapril and hydrochlorothiazide lasted longer than that of cilazapril alone.

Benzodiazepine-receptor antagonist, a clinical double blind study.

In a double blind study including 18 patients in whom a benzodiazepine intoxication was suspected, the first specific benzodiazepine antagonist was compared to placebo. There was a highly significant effect on consciousness, all patients given antagonist awaked, usually within minutes. No adverse effects were observed. In 2 patients the clinical condition deteriorated 1 to 2 hrs after the antagonist was given. This might endanger intoxicated patients withdrawing from medical attention.

Total intravenous anaesthesia with midazolam and flumazenil in outpatient clinics. A comparison with isoflurane or thiopentone.

Total intravenous anaesthesia with midazolam and alfentanil, reversed with the benzodiazepine antagonist flumazenil, was studied in patients admitted for outpatient gynaecological dilatation and curettage. One hundred patients were randomly allocated to four groups with different anaesthetic techniques: I: alfentanil and thiopentone induction, 66% N2O maintenance; II: alfentanil and midazolam sedation prior to isoflurane and N2O induction and maintenance; III: midazolam and alfentanil induction; oxygen/air, placebo reversal; IV: midazolam and alfentanil induction, oxygen/air, flumazenil reversal. All methods of anaesthesia proved satisfactory with no serious side-effects or complications. Induction was faster in Group I (26 s) compared with Group III and IV (37-38 s) and Group I (62 s). Respiration was less depressed in Group II compared with the other groups. Recovery function was better in Group IV during the first 30 postoperative min and worse in Group III during the first 120 postoperative min compared with the other groups. Reduced performances in P-deletion and 4-choice reaction-time tests in the midazolam patients were not reversed by 0.5 mg flumazenil, suggesting that flumazenil did not antagonize all benzodiazepine effects in our patients. Postoperative amnesia was most pronounced in Group III. There was no significant difference in patient function 7 h postoperatively, at home in the evening or during the next days. We conclude that total intravenous anaesthesia with alfentanil and midazolam with flumazenil reversal is a promising technique for short outpatient anaesthetic procedures.

The effect of two different buffers on the high affinity 3H-ethylketocyclazocine and 3H-SKF10047 binding to guinea pig brain membranes.

In vitro mu and delta opioid receptor binding is known to be influenced by ions. High affinity 3H-SKF10047 and 3H-ethylketocyclazocine binding sites are found in brain membranes and postulated to be similar to mu opioid receptor binding. To investigate this postulate, we have studied how the high affinity binding of 3H-SKF10047, 3H-ethylketocyclazocine, a tritiated mu agonist, mu antagonist and delta agonist is altered when the radioreceptor binding assay incubation buffer is changed. The binding of 3H-ethylketocyclazocine and the mu antagonist (3H-naloxone) is highest in isotonic HEPES buffer, while the binding of the mu (3H-dihydromorphine) and delta (3H-D-ala-D-leu-enkephalin) agonist is highest in hypotonic Tris-HCl buffer. 3H-SKF10047 binding is similar in the two buffers. The inhibition of 3H-ethylketocyclazocine, 3H-SKF10047 and tritiated mu and delta opioid ligands by seven unlabeled ligands is then compared in the two buffers. Morphine chloride is a more potent inhibitor of 3H-ethylketocyclazocine binding and tritiated mu ligand in hypotonic Tris-HCl buffer than in isotonic HEPES buffer. The potency of naloxone, nalorphine, SKF10047, D-ala-D-leu-enkephalin, cyclazocine and phencyclidine in inhibiting 3H-ethylketocyclazocine binding is independent of the buffer system. None of the seven unlabelled substances change potency with buffer change when inhibiting the 1.2 nM 3H-SKF10047 binding. In sum our results show that 1 nM 3H-ethylketocyclazocine binding is influenced by buffer change in a manner very similar to mu ligand binding, while the 1.2 nM 3H-SKF10047 binding is only slightly influenced by buffer change and therefore different from mu ligand binding.

Detergent extraction from rat synaptosomal plasma membranes reveals difference in mu and delta opioid receptor binding.

Rat synaptosomal plasma membranes were extracted with a detergent (CHAPS, a zwitterionic derivative of cholic acid). mu and delta opioid receptor binding and adenylate cyclase activities were tested in the intact membranes and in the supernatants from detergent treated membranes. The 6000 X g/8 min. supernatant contained mu receptor binding equal to 33% of the mu receptor binding measured in the untreated membranes. When the detergent treated membranes were sedimented at (50,000 X g/10 min.), 23% of the mu receptor binding was recovered in the supernatant. After a 100,000 X g/30 min. centrifugation the supernatant contained 10% of the mu receptor binding when compared to untreated membranes. Of the delta receptor binding found in intact membranes, 10% or less was recovered in the 3 supernatants described above. Furthermore, the mu and delta receptor binding were distributed differently among particles in the supernatants. This indicates differences in the chemical properties of the mu and delta opioid receptors. Adenylate cyclase assays showed that the G/F site of this enzyme complex was inactivated in the supernatants from detergent treated membranes parallel to the delta receptor binding decrease. However, the catalytic part of adenylate cyclase was present in the supernatants and seemed resistant to the detergent.

Adenylate cyclase in rat synaptosomal plasma membranes and caudate nucleus homogenate: effects of dopamine, E prostaglandins, guanyl-5'-yl-imidodiphosphate and morphine.

The adenylate cyclase in two particulate preparations from rat brain, a homogenate from caudate nucleus (CN-homogenate) and a synaptosomal plasma membrane fraction (SPM-fraction) from whole rat brain was investigated. Stimulation of the enzyme by dopamine and prostaglandins E1 and E2 was found in the CN-homogenate while only a weak prostaglandin E1 and E2 stimulation and no dopamine stimulation could be found in the SPM-fraction. Guanyl-5'-yl-imidophosphate (GppNHp) and NaF could stimulate the adenylate cyclase in both preparations. Morphine up to 10(-5) M altered neither the basal enzyme activity nor any of the stimulated enzyme activities.