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.

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.

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.

Assay of adenylate cyclase in rat brain homogenates and lysed turkey erythrocytes: two different methods give different results with brain but not with erythrocytes.

Experiments showed that the cyclic AMP (cAMP) fraction isolated by alumina or Dowex 50/alumina chromatography from brain adenylate cyclase reaction mixtures contained 32P radioactivity 10-12 times in excess of that which could be accounted for by determination of cAMP using binding assays. No such discrepancy was found when lysed turkey erythrocytes were assayed. This indicated that special precautions must be taken for the purification of 32PcAMP from brain adenylate cyclase assays due to the formation of 32P-labelled contaminants.

The action of six lipid perturbing substances on hormone receptor adenylate cyclase complex in turkey erythrocytes and intestinal mucosa cells.

Adenylate cyclase and beta-receptor binding in turkey erythrocytes is studied under the influence of dioctyl sodium sulphosuccinate (DSS), sodium dodecyl sulphate (SDS), sodium deoxycholate (DOC), filipin, oxyphenisatine and ethanol. Intact and lysed erythrocytes and erythrocyte membranes were investigated. In general the fluoride stimulated enzyme was most resistant to the action of the substances followed by the ligand binding, the hormone stimulated enzyme being most sensitive to the action of the substances. However, in certain ranges of concentrations, DSS, SDS, filipin and oxyphenisatine could further stimulate the fluoride stimulated enzyme. The adenylate cyclase in intestinal mucosa cells was studied in the presence of DSS, SDS, DOC and oxyphenisatine. The fluoride stimulated enzyme was here less stable than the basal enzyme activity, and two of the substances (SDS and oxyphenisatine) stimulating the erythrocyte enzyme could not stimulate the fluoride stimulated intestinal mucosa cell enzyme.