Validation of the international normalized ratio (INR) in a new point-of-care system designed for home monitoring of oral anticoagulation therapy.

The new CoaguChek XS system is designed for use in patient self testing with a measuring range from 0.8 INR up to 8.0 INR, which has been calibrated against the mean INR of rTF/95 and ERM-AD149. This study was performed to confirm the correct INR results received from two routinely manufactured lots of test strips when compared with the international reference preparations (IRP) rTF/95 and ERM-AD149. At one study site capillary and noncitrated venous whole blood samples from 20 normal donors and 62 anticoagulated patients were applied to two test strip lots of the new system in duplicate. Additionally blood was collected in citrate tubes, processed to plasma, and PT results were obtained using rTF/95 and ERM-AD149 by the manual tilt tube method. Method comparisons of the INR results of the CoaguChek XS system vs. the mean INR of the IRP demonstrated a mean relative bias of -0.02% to -0.4%, mean absolute relative deviations of 6.4-9.6%, and accuracy observing >95% of CoaguChek XS INR within limits of +/-14% to +/-21.5% to the mean INR of the IRP. The results of the study confirm the successful calibration of two lots of the new CoaguChek XS system, demonstrate the validity of the calibration concept and prove the accuracy of the new system in comparison with the IRP. Clinical decisions in oral anticoagulation therapy may be reliably made upon the INR results of the new system.

Results of the performance verification of the CoaguChek XS system.

BACKGROUND: This is the first paper reporting a performance verification study of a point-of-care (POC) monitor for prothrombin time (PT) testing according to the requirements given in chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard "Clinical laboratory testing and in vitro medical devices - Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy". The monitor under investigation was the new CoaguChek XS system which is designed for use in patient self testing. Its detection principle is based on the amperometric measurement of the thrombin activity generated by starting the coagulation cascade using a recombinant human thromboplastin. METHODS: The system performance verification study was performed at four study centers using venous and capillary blood samples on two test strip lots. Laboratory testing was performed from corresponding frozen plasma samples with six commercial thromboplastins. Samples from 73 normal donors and 297 patients on oral anticoagulation therapy were collected. Results were assessed using a refined data set of 260 subjects according to the ISO 17593:2007 standard. RESULTS: Each of the two test strip lots met the acceptance criteria of ISO 17593:2007 versus all thromboplastins (bias -0.19 to 0.18 INR; >97% of data within accuracy limits). The coefficient of variation for imprecision of the PT determinations in INR ranged from 2.0% to 3.2% in venous, and from 2.9% to 4.0% in capillary blood testing. Capillary versus venous INR data showed agreement of results with regression lines equal to the line of identity. CONCLUSION: The new system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek XS system complies with the requirements in chapter 8 of the ISO standard 17593:2007.

Formaldehyde as a possible mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to yield non-alkylating species in vitro.

N-Nitramines are biologically active compounds of environmental significance. In this study the suggested bioactivation of N- nitrodimethylamine via oxidation at the methyl-group was confirmed, as was indicated by formaldehyde liberation. N- Nitrodimethylamine and formaldehyde as well as the suggested metabolites, N- nitrohydroxymethylmethylamine and N- nitromethylamine were tested for mutagenicity in histidine auxotrophic Salmonella typhimurium strains in a variety of conditions. N- Nitrodimethylamine was mutagenic only in S. typhimurium TA 100 after pre-incubation with bacteria and a complete metabolizing mixture containing 9000 g liver supernatant and NADPH-regenerating cofactors. N- Nitrohydroxymethylmethylamine and formaldehyde were approximately equally mutagenic without the metabolizing mixture in TA 100 and TA 98, but not in TA 1535. The addition of the 9000 g supernatant of homogenized liver increased the yield of his+ revertants induced by the two compounds. N- Nitromethylamine was not mutagenic with or without the metabolic activation system. The results suggest that formaldehyde is possibly the mutagenically active intermediate formed during in vitro metabolism of N- nitrodimethylamine . Furthermore the participation of formaldehyde as the mutagenic intermediate of other non-alkylating N-nitro and N-nitroso compounds is demonstrated.

Biochemical and biological properties of prospective N-nitrodialkylamine metabolites and their derivatives.

The metabolic conversion of N-nitrodimethylamine and of N-nitrosodimethylamine was compared in vitro. The biochemical properties of the two compounds were nearly identical; however, the biological activities (carcinogenicity, mutagenicity and toxicity) of the nitramine are many times less potent. N-Nitrodimethylamine was found to be mutagenic to Salmonella typhimurium TA100 when applied at above 200 mumol/plate with metabolic activation. Its suggested metabolite, N-nitromethylamine, was not mutagenic, N-Nitromethylhydroxymethylamine, N-nitromethylacetoxymethylamine and formaldehyde were mutagenic only to S. typhimurium TA100 at low concentrations and toxic above 2 mumol/ plate. The evidence suggests that formaldehyde is the intermediate responsible for the mutagenicity of the nitramine derivatives and of the parent compound, N-nitrodimethylamine.