Erik Andrew

Elimination of the non-ionic X-ray contrast media iodixanol and iohexol in patients with severely impaired renal function

Iodixanol (Visipaque) and iohexol (Omnipaque) are dimeric and monomeric, respectively, non-ionic X-ray contrast media (CM), with well-characterized pharmacokinetics in healthy volunteers. This study was undertaken to study the pharmacokinetics of the contrast media in patients with severely impaired renal function. A total of 16 patients referred for preoperative abdominal angiography were randomized to form two groups of eight patients, receiving either iodixanol 320 mgI ml-1 or iohexol 350 mgI ml-1. Urine and faeces were sampled before the examination and collected quantitatively for five days afterwards, and blood samples were drawn frequently. The concentrations of iodine and contrast medium in urine and in serum, and the amount of iodine in faeces were determined. Mean baseline creatinine clearance was 13.6 and 9.9 ml min-1 1.73 m-2 in the iodixanol and iohexol groups, respectively. Patients in the iodixanol group received on average 0.34 gI per kg bodyweight (bw) and those in the iohexol group 0.39 gI per kg bw. The semilogarithmic plots of serum concentration of CM vs. time indicated elimination according to a two-compartment model. The mean elimination half-life was 23.0 h for iodixanol and 27.2 h for iohexol, and the mean apparent volume of distribution was similar for the two CM, ranging from 0.20 to 0.30 1 per kg bw. Mean plasma clearance of iodixanol was 10.4 ml min-1 1.73 m-2 and 6.9 ml min-1 1.73 m-2 for iohexol, whereas the mean renal clearances were 8.7 and 6.1 ml min-1 1.73 m-2, respectively. Mean faecal recovery was 8.2% for iodixanol and 6.1% for iohexol, and the respective figures for that in urine were 76.1 and 74.8%. Renal clearance of radiolabelled iothalamate, a marker of glomerular filtration rate (GFR), measured simultaneously, indicated that both CM were eliminated by the kidneys by glomerular filtration only. Thus, both media are suitable as GFR markers.

Nephrotoxic Effects of X-Ray Contrast Media

The annual sale of x‐ray contrast media (CM) now represents 60 million doses, and contrast nephropathy (CN) has been the third‐leading cause of hospital‐acquired acute renal failure. In this review article, physicochemical, pharmacokinetic, and pharmacodynamic properties of CM are surveyed. The definition of CN is presented, as well as the mechanisms involved in the pathogenesis. Low osmolar monomeric CM (LOCM) are less nephrotoxic than the older ionic high osmolar CM (HOCM), but in risk patients the incidence of CN is still high after intravascular administration of LOCM. Non‐ionic dimeric CM are iso‐osmolar to plasma (IOCM), and they have reduced the nephrotoxicity even more than LOCM. The most important risk factors for CN are diabetes mellitus and impaired renal function. Selection of patients, hydration, and type of CM are essential for prevention and prophylaxis of CN. We do not recommend routine prophylaxis with N‐acetylcysteine (NAC) during CM investigations, but its use in high‐risk patients should be considered.

Renal Effects of the Non-Ionic Contrast Medium Iopentol after Intravenous Injection in Healthy Volunteers

Renal effects of the new non-ionic contrast medium iopentol in increasing doses were assessed and compared with the effects of physiologic saline. Twenty-four healthy male volunteers, allocated to three dose groups, were given iopentol intravenously in doses of 0.3, 0.6, and 1.2 g I/kg body weight, respectively. The highest dose group was also given physiologic saline separately as a control. The diuresis increased in all groups, most in the highest dose group, and with a concomitant fall of urine osmolality and increase in osmolar clearance. A slight decrease of serum osmolality, creatinine and urea occurred at 3 hours due to hemodilution. The glomerular filtration rate was unaffected by iopentol. The urinary excretion of albumin and β2-microglobulin was unchanged. However, urinary N-acetyl-β-glucosaminidase and alkaline phosphatase increased significantly, most in the highest dose group. All changes were reversible.

Pharmacokinetics of Gadodiamide Injection in Patients with Moderately Impaired Renal Function

Objectives and Methods. The pharmacokinetic properties of gadodiamide injection were examined in 10 adult kidney-transplanted patients with stable or slowly deteriorating renal function. Total body clearance of gadodiamide and iothalamate and renal clearance of gadodiamide, iothalamate, and endogenous creatinine were compared to investigate whether gadodiamide injection has any influence on glomerular filtration and to evaluate the mechanism of excretion of gadodiamide in the kidneys. Results and Conclusions. The mean elimination half-life in these renally impaired patients was 5.8 hr, approximately five times longer than that observed in healthy adult volunteers. The volume of distribution of gadodiamide was found to be analogous to that seen in healthy volunteers, demonstrating that distribution of this agent is independent of renal function. Excretion of gadodiamide was delayed in these renally impaired patients, but the total fraction excreted in urine was analogous to that of healthy volunteers. After 5 days, the mean fraction excreted in feces was 0.4%, indicating minimal fecal elimination of gadodiamide, even in patients with impaired renal function.

Mortality and morbidity of poisonings in the Nordic countries in 2002

Aim. To map and compare mortality and morbidity of poisonings in Denmark, Finland, Iceland, Norway, and Sweden in 2002 and to establish a common understanding of methods and procedures among the National Poisons Information Centres (NPIC) in order to create a Nordic toxico-epidemiological platform. Methods. Morbidity was for this study defined as acute poisonings treated in hospitals given the ICD-10 codes T36-T65 and F10-F19. The figures were extracted from the National Patient/Hospital Registers. Acute poisonings listed as main as well as side diagnoses were included. Deaths recorded as acute poisoning (using the same ICD-10 codes) were collected from the National Death Cause Registers. Results. Annual mortality of acute poisonings per 100,000 inhabitants (rate) was 16.6 in Finland and between 8.6 and 11.1 in the other Nordic countries. Morbidity rates varied between 150 and 255 per 100,000 inhabitants. Conclusion. The death rate due to acute poisoning was 50% higher in Finland compared to the rate in the other Nordic countries. The variable data between countries obtained for morbidity of acute poisonings need further elucidations to verify if the differences are real and not only due to heterogeneous procedures and practice for data collection and recording.

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.

Poisonings in the Nordic countries in 2007: A 5-year epidemiological follow-up

Aim. To map mortality and morbidity of poisonings in Denmark, Finland, Iceland, Norway and Sweden in 2007 and undertake a comparison with a corresponding study in 2002. Methods. Morbidity was as for 2002 defined as acute poisoning (ICD-10 codes, main and subsidiary diagnoses) treated in hospitals. The figures were extracted from the National Patient/Hospital Registers. Deaths recorded as acute poisoning (using corresponding ICD-10 codes) were collected from the National Cause of Death Registers. Results. Annual mortality of acute poisonings per 100000 inhabitants (rate) for 2007 was 22.4 in Finland, an important increase from 16.7 per 100000 in 2002. The increase was mainly due to a change in coding of alcohol, but also represented a slight increase in fatal alcohol intoxications per se. The poisoning death rate in the other Nordic countries varied between 8–13 and was at the same level as for 2002. The morbidity rates for 2007 between158–285 per 100000 inhabitants represented a slight increase compared to 2002 figures. Conclusion. The increase in poisoning death rate for alcohol, and thus total rate in Finland in 2007 compared to 2002, has further increased the gap to the other Nordic countries. Poisoning morbidity rates in the Nordic countries are of the same level, but the variability shown indicates that more harmonization and collaboration is needed to increase the data quality.

Oral magnetic particles. Results from clinical phase II trials in 216 patients.

Oral magnetic particles (OMP) have been evaluated in a clinical phase II trial program comprising 216 patients in 7 European centers. Adult patients referred for MR imaging for various abdominal pathologies were examined. The patients received OMP at a concentration of 0.1 g/l (ultralow field) or 0.5 g/l (mid/high field) and OMP was diluted in water or in a more viscous liquid formulation. Depending on the area of interest, OMP was ingested in a volume of 300 to 800 ml. OMP was well tolerated with no serious adverse events and the patient acceptability was good. OMP had a good contrast effect on all applied pulse sequences. The viscous formulation of OMP was homogeneously distributed through the entire gastrointestinal tract without inducing disturbing susceptibility artifacts. The postcontrast diagnostic information was improved in 70% of the cases. Based on the encouraging results in phase II, OMP has been advanced to phase III clinical trials.

Paracetamol poisonings after the lifting of the place of sale restriction

BACKGROUND Before 2003, the sale of paracetamol in Norway was restricted to pharmacies only. In November 2003 this place of sale restriction was lifted, allowing sale of paracetamol in non-pharmacy locations. The purpose of this study was to investigate the incidence, severity and mortality of paracetamol poisoning before and after the lifting of the place of sale restriction. MATERIAL AND METHODS Incidence was assessed using discharge data from three selected hospitals and the enquiry database of the National Poisons Information Centre (PIC). Evaluation of poisoning severity was based on degree of hepatotoxicity in admitted patients, number of requests regarding evaluation for liver transplantation at the National Transplantation Unit and PIC severity grading of cases. Data regarding mortality of paracetamol poisoning was obtained from the National Cause of Death Register. Data for the two-year period before (2001-2002) the place of sale restriction was lifted was compared with two years after (2005-2006). RESULTS There was no significant change in the number of hospital admissions due to paracetamol poisoning in any of the three hospitals following the lifting of the place of sale restriction. The number of inquiries to PIC regarding paracetamol intake showed a statistical significant increase. The extent of severe paracetamol poisoning might be rising, but the mortality of paracetamol poisoning does not appear to have increased since the place of sale restriction was lifted. INTERPRETATION There is no evidence that the number of paracetamol poisonings or deaths has increased since the place of sale restriction was lifted. The proportion of patients with liver toxicity/liver damage, and the number of patients evaluated for liver transplantation may be increasing. However, the development in paracetamol poisoning should be monitored in the coming years.

Incidence of Roentgen Contrast Medium Reactions after Intravenous Injection in Pre-Registration Trials and Post-Marketing Surveillances

The relative risk of adverse drug reactions of ionic versus non-ionic contrast media injected i.v. were compared for different types of trials using odds-ratio. The absolute and relative risk found in large post-marketing trials were compared with that found in the iohexol pre-registration trials. The absolute risks were 2 to 10 times higher in the pre-registration trials compared to the post-marketing surveillances. The relative risk for all adverse drug reactions was 3 to 6 times higher for ionic vs. non-ionic media and independent of pre- or post-registration studies. The odds-ratio seems to be a feasible method of comparing the relative risk of adverse reactions in various trials.