Chemistry: electrical and wave energy – Apparatus – Electrolytic
Reexamination Certificate
2000-02-08
2002-03-05
Warden, Sr., Robert J. (Department: 1744)
Chemistry: electrical and wave energy
Apparatus
Electrolytic
C435S013000, C422S073000
Reexamination Certificate
active
06352630
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns an individual system for determining whole blood coagulation time, a disposable sensor of small dimensions including a specific thrombin enzyme reagent allowing an electrochemical determination and an electronic measuring apparatus allowing an electric signal received from said sensor to be correlated when it has been introduced into the apparatus and a drop of the blood to be analysed has been deposited thereon.
The invention concerns more particularly a measuring apparatus and sensor of this type allowing the prothrombin time (PT) to be determined by amperometry when the reagent composition deposited on the sensor includes a chemical substrate of which a terminal fraction can be selectively cut off by the thrombin enzyme by releasing a charged group.
Checking the blood coagulation time, i.e. the aptitude of the blood constituents to form a clot to prevent the risk of haemorrhage, forms part of the routine examinations, or even daily examinations, performed in numerous acquired pathological, traumatic or postoperative situations. It is for example necessary during treatment with anticoagulants in the case of heart related diseases to be able to adjust the dosage of the medicine accurately, for example warfarin or heparine, in order to avoid the risk of haemorrhages in the event of an overdose or conversely, the risk of thrombosis if the quantity of anticoagulant administered is insufficient.
Different parameters have been retained for performing this determination, but the most common is measuring the prothrombin time (PT) after activation, i.e. the period of time after which the formation of a clot is observed with a blood sample taken from the patient. Such analyses were for a long time entirely dependent upon the expertise of specialised laboratory personnel equipped with complex and cumbersome apparatus. This had the drawback of obliging the patient to travel, requiring preparation of a blood sample taken at home, for example by adding citrate, to wait until a laboratory analysis could be performed.
Progress made as regards miniaturisation, in particular using electronic components, has, for slightly more than ten years or so, enabled the patient to have various types of more compact equipment allowing him to perform a coagulation time measurement at home. Most of these individual pieces of equipment rely on the same principles as laboratory apparatus, namely direct observation of the erythrocyte dynamics in a blood sample, to which the usual coagulation reagents have been added, when it changes from a fluid state to a viscous or clotted state.
According to a first principle, the period of time after which a prepared blood sample no longer flows through a capillary tube, or through the calibrated choke of a tube of larger diameter, supported by single use receiving means which can be fitted to a measuring apparatus, is measured. This flow is generally forced by means of a pneumatic pump device integrated in the measuring apparatus, and the period of time after which coagulation occurs is generally detected by optical means. Devices of this type are for example disclosed in U.S. Pat. Nos. 3,486,859, 3,890,098 and 5,302,348. An apparatus relying on this principle is for example that proposed under the trademark <<Hemochron>> or according to a more recent variant under the trademark <<Protime Microcoagulation System>> by International Technidyne Corporation (NJ-USA). The measuring apparatus obviously includes a power source for supplying power both to the mechanical part (pump) and the end of coagulation check (optical detection). It will further be observed that each receiving means for the blood sample to be analysed, which is disposable after the first use is relatively cumbersome (approximately 3×9 cm) and depends upon a precision technology (calibration of the capillary tube or the choke) which necessarily contributes towards increasing the cost of each analysis performed.
According to a second principle, one measures the period of time after which a prepared blood sample, deposited in a disposable cupel allows the immobilisation by coagulation of a magnetic object moved by a rotating magnetic field, the detection of the coagulation phenomenon being again most often performed by optical means. U.S. Pat. No. 3,967,934 already discloses this principle wherein the container intended to receive the sample contains a ferromagnetic ball. Such as device is for example used in the apparatus distributed by Nycomed Pharma (Oslo, Norway) under the trademark <<Thrombotrack>>. According to another variant, described for example in U.S. Pat. No. 5,154,082, the ball is replaced by ferromagnetic particles, which are also subjected to an electromagnetic field. This has enabled a reagent to be made in a dry form, deposited on a support, the mobility of the erythrocytes still being detected by optical means. A device of the preceding type corresponds for example to a Boehringer Mannheim (Germany) apparatus sold under the trademark Coaguchek. The products proposed corresponding to this second principle have the same drawbacks as those already mentioned for the apparatus according to the first principle with the exception perhaps of the lower cost of the blood sample receiving means for the Coaguchek apparatus.
Comparative tests performed with the methods and devices of the aforecited prior art (<<Home Prothrombin Estimation>> by Angelida Bernado et al., Thrombosis, Embolism and Bleeding, ch. 3.5—E.g. Butchart and E. Bodnar ICR Publishers 1992) have demonstrated that the medical follow-up of a patient at home was at least as satisfactory as that of a patient in a hospital environment, but that reliable and reproducible results could not be obtained unless the patient had had a reasonable period of training. The apparatus of the prior art are of course provided for domestic use, can easily be moved but yet remain relatively too voluminous for a patient to be able to keep at home about his person, for example in a pocket, while he moves around. It is doubtless also desirable, for the reliability of the measurements which depend upon devices which are both optical and electromechanical, for said apparatus to be moved as little as possible.
It will be observed finally that, according to one or other of the above principles, the electric power source necessary for supplying power to the optical and electromechanical devices must be relatively large when it is autonomous (battery) but that it is never directly involved in the coagulation time measurement.
Reference can however be made to a U.S. Pat. No. 3,674,014 of 1972 which discloses a syringe whose inner wall includes a succession of electrodes allowing the variation in impedance of the analyte to be measured, by means of an oscilloscope connected to said syringe, progressively as the coagulation phenomenon occurs. Such a device still only relies on the variation in the properties of the analyte during coagulation and is evidently not intended for individual use.
The device disclosed in European Patent No. EP 0 679 193, allowing inter alia, the prothrombin time to be measured, includes two electrodes which are only involved in said determination to detect, from a signal representing the resistance variation between the electrodes, the presence of a blood sample on the receiving means, and have no direct role in measuring a period of time. In this device, the period of time measurement is performed by a photometric determination of the fluorescence of the medium from an oligopeptidic substrate having Rhodamine as its leaving group able to be released by being cut off by the thrombin enzyme. A substrate of this type is for example disclosed in U.S. Pat. No. 4,557,862. A colorimetric method using a slightly different substrate, having p-nitroaniline as chromatophore, corresponds for example to the product marketed by Nycomed Pharma under the trademark <<NYCOTEST-CHROM>>.
These calorimetric methods have the advantage of no
Frenkel Erik Jan
Haeberli André
Moresi Anita
Asulab S.A.
Olsen Koj K.
Sughrue & Mion, PLLC
Warden, Sr. Robert J.
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