New! View global litigation for patent families

US3653841A - Methods and compositions for determining glucose in blood - Google Patents

Methods and compositions for determining glucose in blood Download PDF

Info

Publication number
US3653841A
US3653841A US3653841DA US3653841A US 3653841 A US3653841 A US 3653841A US 3653841D A US3653841D A US 3653841DA US 3653841 A US3653841 A US 3653841A
Authority
US
Grant status
Grant
Patent type
Prior art keywords
solution
glucose
lower
aqueous
selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
Inventor
Bernard Klein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann-La Roche AG
Hoffmann-La Roche Inc
Original Assignee
F Hoffmann-La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Images

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by the preceding groups
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/11Automated chemical analysis
    • Y10T436/117497Automated chemical analysis with a continuously flowing sample or carrier stream
    • Y10T436/118339Automated chemical analysis with a continuously flowing sample or carrier stream with formation of a segmented stream
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/14Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333Saccharide [e.g., DNA, etc.]
    • Y10T436/144444Glucose

Abstract

Colorimetric methods and compositions for quantitatively determining the glucose content of blood plasma or serum by heating a deproteinized sample of blood plasma or serum with an alkaline ferricyanide solution, followed by the addition of ferric ions and a 5-(2-pyridyl)-2H-1,4-benzodiazepine or water soluble salts thereof to produce a brilliant purple colored solution which can be quantitated by standard colorimetric means.

Description

United States Patent Klein [451 Apr. 4, 1972 [54] METHODS AND COMPOSITIONS FOR DETERMINING GLUCOSEIN BLOOD OTHER PUBLICATIONS Hawk et a1., Practical Physiological Chemistry, 13th ed., Me-

[72] Inventor: Bernard Klein, New Hyde Park, NY. Hill QP514H4, 95 P- 567, 575 Assignee Hoffman La Roche I Nu N J Aloe Scientific Co., Catalog 103, p. 1011, 1041, 1065, 1073 I nc., ey,

22 Filed; 19, 19 9 Primary Examiner-Morris O. Wolk Assistant Examiner-R. M. Reese [21] APPI'NO: 8 At'torneySamuel L. Welt, Jon S. Saxe, Bernard S. Leon,

Gerald S. Rosen and R. Hain Swope [52] US. Cl. ..23/230 R, 23/230 B, 252/408,

260/239.3'D ABSTRACT [3;] int. ..C09k 3/2273?! Colorimetric methods and compositions for quantitatively 1 e o m 2SZ'I4O8 determining the glucose content of blood plasma or serum-by heating a deproteinized sample of blood plasma or serum with [56] R f cted an alkaline ferricyanide solution, followed by the addition'of e erences l ferric ions and a 5(2-pyridyl)-2H-l,4-benzodiazepine or UNITED STATES PATENTS water soluble salts thereof to produce a brilliant purple colored solution which can be quantitated by standard 3,098,717 7/1963 Ferrari, Jr ..23/230 colorimetric means 3,449,081 6/1969 Hughes ..23/253 3,506,404 4/1970 Evans et a1. ..23/230 B 11 Claims, 3 Drawing Figures SAMPLE O PLATE O0 O0 SAMPLE ml/min F WM 0,0I5 0.|o

DIALYZER DMC 19.9,;- 0 i N, SALINE 0.100 3140 MIXERS I i -l-@-f- AIR 0065 1.60 G; Fe (CN)? 0.!00 3.40

n AIR 0065 L60 A HEATING I U FeCl 0.073 200 BATH H2 I Q REAGENT 0.0m 2450 l I 3W6 wAsTE F/C 0.065 1.60 Cg PROPORTIOI'VING I 'Q TUBE SIZE INCHES RECORDER 5B0nm AUTOMATED GLUCOSE ANALYSIS FLOW DIAGRAM Patented April 4, 1972 2 Sheets-Sheet 2 SBOnm M FIG. 2

1 I I v 0 50 I00 200 300 40 mg GLUCOSE IOOml E C O (I) \0 1 I l 1 1 l 1 l 1' BACKGROUND OF THE INVENTION The need for a quantitatively accurate method for the deter- 5 B is selected from mination of glucose in blood, e.g. plasma and serum, using small amounts of specimen, yet which is simple enough to be effectively utilized in the clinical situation and sufficiently economical for mass screening has long been felt. In addition, it has been considered most desirable that such a method be readily adaptable to an automated sequential or continuous flow system in order that a great many samples may be processed rapidly and with the highest possible accuracy. There is a need forsuch an automated sequential or continuous flow of system which is capable of highly accurate results before the diagnostic testing of large numbers of persons for the incidence of diabetes among them. A simple accurate test, which is both rapid and reliable, is of great value as an aid in the detection and treatment of diabetes and as an adjunct to routine screening operations in clinics and for periodic screening of patients in hospitals, nursing homes and similar institutrons.

Many techniques have been developed for quantitatively determining the glucose content of blood, plasma or serum. One such technique utilizes the enzyme glucose oxidase which catalyzes the oxidation of glucose to gluconic acid. In the more common test, this enzyme is combined with a substance having a peroxidative activity which induces the oxidation of an indicator such as o-toluidine in the presence of hydrogen peroxide formed by the glucose oxidase. This method, though specific, has proved to be too complex, expensive and time consuming for general use.

Other further metric techniques which are adaptable to automated procedures have been found to be not sufficiently sensitive for todays standards or undesirable in that they require comparatively large volume of specimen.

The diagnostic compositions and methods of the present invention provide a reliable, convenient test for the quantitating of glucose in the blood as well as affording a method whereby the quantitative determination may be carried out in a continuous sequential or flow system. Further, the diagnostic compositions and methods of the present invention overcome many of the disadvantages of the prior art methods of determining glucose in blood by not requiring a high degree of laboratory skill and technology using a small specimen volume, yet being highly accurate in the clinical situation.

BRIEF SUMMARY OF THE INVENTION In accordance with the invention, a 5-(2-pyridyl)-2H-l,4- benzodiazepine or water soluble salt thereof preferably in combination with a buffer, is added with an aqueous solution of ferric chloride to deproteinized plasma or serum which has been treated with an aqueous alkaline ferricyanide solution, whereby a purple solution is obtained which can be quantitated as to its glucose content by standard colorimetric means.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the invention a compound selected from the group consisting of compounds of the formula wherein A is selected from the group consisting of and and CH,; R is selected from the group consisting of halogen, hydrogen, trifluoromethyl, nitro and amino; R, is selected from the group consisting of H R1---Rg 9 hydrogen, lower alkyl and 1 Re C uHzn sisting of hydrogen, hydroxy, lower alkyl, lower alkoxy and lower alkanoyloxy; R is Z-pyridyl; R is selected from the group consisting of lower alkyl and hydrogen; R is selected and R and R where taken together with their attached nitrogen atom form a radical selected from the group consisting of piperazinyl, lower alkyl substituted piperazinyl, pyrrolidinyl, lower alkyl substituted pyrrolidinyl, piperidinyl and lower alkyl substituted piperidinyl; R is lower alkyl; and R is selected from the group consisting of lower alkyl and hydrogen and water soluble salts thereof, preferably in combination with a buffer, is added with an aqueous solution of ferric chloride to deproteinized blood plasma or serum which has been treated with an aqueous alkaline ferricyanide solution, whereby a purple solution is obtained which can be quantitated by standard colorimetric means.

Examples of benzodiazepine compounds of formula I above which are particularly suitable as the color-forming reagent in the process of this invention include the following:

7-bromo-l ,3-dihydro-l-[4-(4-methyl-l-piperazinyl)butyl]- 5-(2-pyridal)-2H-l ,4-benzodiazepin-2-one;

7-aminol ,3-dihydro-5-( 2-pyridyl)-2H-l ,4-benzodiazepin- 2-one;

benzodiazepin-2-one;

2H- 1 ,4-benzodiazepinel -yl)propyl]urea whose preparation is disclosed in US. Pat. No. 3,464,978 issued Sept. 2, 1969;

benzodiazepine;

7-amino-l ,3-dihydrol -methyl-5-( 2-pyridyl)- l H- l ,4-

benzodiazepine;

7-bromol ,3-dihydro-( 3-dimethylaminopropyl)-5-( 2- pyridyl)-2H- l ,4-benzodiazepin-2-one;

7-bromol ,3-dihydro-5-(2-pyridyl)-2I-I-l ,4-benzodiazepin- 2-one-4-oxide;

7-bromol ,3-dihydro-5-( 2-pyridyl)-2H- l ,4-benzodiazepin- 2-one;

7-bromol ,3-dihydrol B-hydroxypropyl)-2-( 2-pyridyl 2H- 1 ,4-benzodiazepin-2-one; and

7-bromo-5-( 2-pyridyl)-l ,3.-dihydrol 3-( N- cyanomethylamino )propyl]2I-I- 1 ,4-benzodiazepin-2-one whose preparation is disclosed in US. Pat. No. 3,464,978.

The term lower alkyl as used throughout this specification includes both straight and branched chain alkyl groups having from one to seven carbon atoms such as methyl, ethyl, propyl, isopropyl and the like. The term lower alkanoyloxy" refers to both straight chain and branched chain aliphatic carboxylic acid moieties such as acetoxy, propionyloxy, butyryloxy and the like. The term halogen includes bromine, chlorine, fluorine and iodine. Also included within-the purview of the present invention are the water soluble acid addition salts of the compounds of formula I above. Any conventional water soluble acid addition salts of the compounds of formula I above may be utilized in the process of this invention to quantitatively determine the iron content of aqueous solutions. Among the acid addition salts which can be utilized in accordance with this invention, includes salts of compounds of the formula I with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid, ptoluenesulfonic acid and the like.

The color differentiation with varying concentrations of ferrous ions produced by the compound of formula I above is such that the concentration of ferrous ions produced by the instant diagnostic reagent composition in situ can easily be determined by standard colorimetric instruments. Furthermore, the compounds of formula I are not sensitive to extraneous sources and therefore are not affected by trace contaminants. The method of this invention provides a simple colorimetric means for quantitatively determining the glucose content of blood plasma and serum.

In accordance with the present invention the glucose content of blood plasma or serum can be determined by first heating a deproteinized sample with an aqueous solution containing ferricyanide ions to form an aqueous solution containing gluconic acid and ferrocyanide ions, cooling the solution and adding an aqueous solution containing ferric ions and a compound of formula I above wherein ferricyanide and ferrous ions are formed and the ferrous ions thus produced react with the compound of formula I, preferably in the presence of a buffer, to produce a brilliant deep purple color and colorimetrically quantitating the amount of glucose present in the sample. This procedure provides a simple and quick method for quantitatively determining the glucose content of a blood sample which is ideally suited for routine diagnostic use.

In accordance with the present invention, the specimen to be tested is initially treated with a conventional neutral deproteinizing agent such as, for example, an aqueous solution of either sodium or barium hydroxide and zinc sulfate, or an acidic deproteinizing agent such as, for example, tungstic acid or trichloroacetic' acid. Of these, tungstic acid or an aqueous solution of barium hydroxide and zinc sulfate are preferred. The specimen is well mixed with the deproteinizing agent and centrifuged at high speed to obtain a clear supemate. A 0.1 ml. aliquot of the superna'te is then heated to from 90 C. to about 100 C. preferably about 95 C. with 2.0 ml. of an aqueous alkaline solution containing ferricyanide ions. The mixture is rapidly cooled after about 5 minutes heating and treated with 2.0 ml. of an aqueous solution containing ferric ions such as, for example, ferric chloride, and 2.0 ml. of an aqueous solution of a compound of the formula I. The solutions are mixed and the absorbance of the violet blue color which develops over about 10 minutes is measured at 580 nm against both a standard glucose solution similarly treated and a reagent blank.

The solution containing ferricyanide ions can be made from any water soluble ferricyanide salt which does not otherwise interfere with the reaction such as, for example, potassium ferricyanide and sodium ferricyanide. Potassium ferricyanide is preferred in the practice of the present invention. This reagent may be made in quantity if so desired and used as needed. The

appropriate amount of potassium ferricyanide is dissolved in an aqueous alkaline medium'such as, for example, a 2 percent sodium carbonate solution. The quantity of ferricyanide salt utilized in preparing the reagent is variable. However, a sufficient quantity must be utilized to react with all the glucose in the specimen to furnish a positive indication of elevated glucose blood levels when the diagnostic method of the present invention is being utilized as a diagnostic or a mass screening tool.

Generally, it is preferred that for each ml. of blood plasma or serum tested, the reagent solution contain from about l.8 x 10" moles to about 7.0 X 10 moles of ferricyanide salt, preferably from about 3.5 X 10" moles to about 5.0 X 10" moles per ml. of plasma or serum utilized.

The quantity of ferric ions added to the sample ferricyanide ion mixture is again variable. However, it is preferred to utilize a quantity of ferric ion slightly in excess of the molar quantity of ferricyanide ions added to the sample. The utilization of such an excess insures that there will be sufficient ferric ions present to react with the ferrocyanide ions generated by the initial reaction between the ferricyanideions and the glucose in the sample. The ferric ions may be supplied as any water soluble ferric salt which does not interfere with the diagnostic determination such as, for example, ferric chloride, ferric nitrate, ferric sulfate and the like. Of these, ferric chloride is preferred.

The quantity of the compound of formula I which is added to the aqueous mixture is variable. In all instances, however, there must be a sufficient quantity of the compound of formula I present to react with all of the ferrous ions generated bythe reaction between the ferric ions and the ferrocyanide ions. This quantity is most conveniently determined by equating the quantity of the compound of formula I with that of the ferric ions to insure the stoichiometry of the chelation reaction.

It is preferred to maintain the test medium at a pH of about 4.0 to about 5 .0, preferably about 4.5. This can most easily be accomplished by adding suitable buffers to the ferric ion reagent and the reagent containing the compound of formula I. Buffering these reagents also makes them stable in aqueous solution when they are made up in quantity for large scale laboratory testing.

In general, any recognized buffer pair suitable for the maintenance of such a pH range as described above can be utilized.

Preferably, there can be utilized as a buffer pair a water soluble salt of acetic acid and acetic acid. Of the water soluble salts of acetic acid sodium acetate is preferred. However, ammonium acetate, potassium acetate or other water soluble salt of acetic acid can be used, if desired. Although the quantities of the buffer pair comprising a water soluble acetic acid salt and acetic acid are variable, the present invention contemplates the use of a sufficient quantity of the acidcomponent, e.g. acetic acid, to provide a final test sample having a pH in the range of from about 4.5 to about 5.5. By final test sample is meant a solution containing the ferricyanide ions, the ferric ions and the benzodiazepine color reagent. In general, there is contemplated the preparation of a solution of both the ferric ions and the benzodiazepine color former which contains per liter about 1.0 mole of a water soluble salt of acetic acid to about 1.0 to about 2.0 moles of acetic acid.

From the foregoing description it is evident that thecompositions of the present invention may be utilized or handled as prepared aqueous stock solutions, aqueous concentrates or in a dry powder form. In either the concentrate or the powder form, sufficient buffering agents are added to stabilize the compositions when the working dilutions are made and maintain the pH of the reaction mixture at between 4.5 and 5.5 preferably about 4.8.

In utilizing the compositions of the present invention, the addition of the compound of formula I to the test system immediately produces the desired purple coloration. The color deepens as the reaction proceeds to completion. The reaction mixture ceases to undergo anycolor changes discernible to the naked eye after it has been allowed to stand for a short time at room temperature. Accordingly, in order to insure uniform coloring, the aqueous solution should be aliowed to stand until its color appears to have become constant. In general, it has been found that the full development of the purple color will occur over a period of from about 5 to minutes after the addition of the compound of formula I. In most cases 10 minutes is a sufficient period of time to allow for full color development.

The quantitation of the glucose in the colored sample can be carried out by any conventional colorimetric method utilizing standard spectrophotometers such as a Beckman Spectrophotometer, Coleman Spectrophotometer and the like.

The principle of the diagnostic method according to the present invention is based on a series of coupled reactions. Initially, glucose present in the sample undergoing analysis reduces the ferricyanide ion in the added first reagent to ferrocyanide ions, in turn form ferricyanide ions and ferrous ions with the addition of the second reagent which comprises a source of ferric ions such as, for example, ferric chloride, a buffer and a compound of the formula I. The ferrous ions thus generated react with the compound of the formula I to produce a brilliant deep purple color. The purple color is thereafter colorimetrically measured and the glucose content of the sample quantitatively determined.

The quantitative determination of the glucose content in a specimen is carried out as follows: the optical density of the purple color developed in the sample by the method of the present invention is measured against a reagent blank at 580 nm utilizing a standard spectrophotometer such as, for example, a Coleman Spectrophotometer, employing a cuvette with a 19 mm. light path. The quantity of glucose in the specimen is determined in the conventional manner from the absorbance of the specimen with reference to the absorbance of the color produced by a glucose standard similarly treated. The glucose content of the specimen is calculated in accordance with the following formula:

Glucose content of specimen (mg./ 100 ml.)

Absorbance of specimen Absorbance of standard As indicated heretofore, the present invention provides an extremely important diagnostic tool. In addition, the method of the present invention affords a rapid and accurate determination of the glucose content of body fluids such as plasma or serum with results that are characterized by a high degree of reproducibility.

In another aspect of the present invention, the analytical compositions as described are utilized in a method of analyzing the glucose content of body fluids automatically by discrete sequential sampling or by continuous flow apparatus. The latter method consists essentially of mixing specimens in continuous flow with normal saline, dialyzing the mixture to produce an aqueous protein-free solution containing the glucose, mixing the aqueous solution with an aqueous alkaline solution containing ferricyanide ions, passing the resulting mixture through a heating bath to raise the temperature thereof to about95 C., mixing the heated aqueous solution with an aqueous solution of a ferric salt and a compound of the formula I at a constant pH of from about 4.5 to about 5.5 and passing the resulting solution through an apparatus which quantitatively determines the glucose content thereof photometrically.

FIG. 1 is a schematic flow diagram illustrating a continuous flow automated system for analyzing glucose in biological fluids utilizing the diagnostic composition of the present invention.

FIG. 2 is a recording of the photometric response obtained when utilizing the automated system of FIG. 1.

FIG. 3 is a plot in terms of absorbance of the photometric response illustrated in FIG. 2.

In FIG. 1, a continuous flow automated testing system is,

showriglgrnati cally wherein a specimen sample to be tested, i.e. serum or plasma, is drawn up in sequence from separate sample cups in thesample plate which rotates at a constant speed to provide the system with 20-60 specimen samples with a 2:1 wash ratio per hour. A sample, so drawn, is mixed in flow with normal saline and passed through a glass mixing coil of conventional design. After the mixture has passed through the mixing coil, it is next pumped through a dialyzer module that is provided with a cellophane membrane or the like through which the glucose passes in aqueous solution by dialysis. The dialyzer module is maintained at a constant temperature of 37 C. The residual, non-diffusable portion of the sample is discarded. As the aqueous glucose solution passes through the dialyzer module membrane it is admixed with an aqueous alkaline solution containing ferricyanide ions, preferably in the form of potassium ferricyanide, the glucose and the ferricyanide ions are passed in solution through a heating bath which raises the temperature of the mixture to C. As this passage takes place the glucose and ferricyanide ions are reacting to form gluconic acid and ferrocyanide ions. The heated aqueous stream is then mixed in continuous flow with an aqueous solution containing ferric ions, preferably in the form of ferric chloride, and a reagent stream comprising the 5-(2-pyridyl)-2H-l ,4-benzodiazepine color reagent of formula I. The color reagent, preferably 7-bromo-l,3-dihydro-l- 3-dimethylaminopropyl)-5-( 2-pyridyl)-2I-I- l ,4- benzodiazepine-2-one is maintained at a pH of about 4.5 to 5.5, preferably at about 5.0. The mixture is then passed through a second mixing coil. As the mixture is in transit through this coil, the ferric ions and ferrocyanide ions react to form ferricyanide ions and ferrous ions which in turn react with the benzodiazepine color reagent to form a brilliant purple coloration. Photometric measurements are then performed at 580 nm in a 15 mm. flow-cell colorimeter, i.e., the absorbance of the solution to be tested is measured at 580 nm in a flow-cell colorimeter using a 580 nm filter. The results of the colorimetric readings are recorded on a conventionalrecording mechanism.

The continuous flow system illustrated in FIG. 1 aspirates at a rate of 20 to 60 specimens/hour. The rate of flow in ml./min. of the materials entering the system according to a preferred technique is illustrated in FIG. 1. The materials entering the system are pumped into it by any suitable pumping means adjusted to maintain the rate of flow illustrated in FIG. 1. The mechanism for the system of the present invention can be conveniently provided by a manifold assembly prepared in accordance with the system illustrated in FIG. 1 adaptable to the Technicon Autoanalyzer.

In FIG. 2 the absorbance of solutions containing graduated amounts of glucose, e.g. 50 mg./ ml., 100 mg./ 100 ml. etc. are plotted as a graph against concentration.

In FIG. 3 the photometric response of solutions containing different concentrations of glucose is demonstrated. The drawing illustrates four separate experiments, each of which represents passage through the automated system of FIG. 1 of a sequence of at least three solutions having glucose concentrations in the order of low to high to low, such as, for example, 50 mg. per 100 ml. to 400 mg. per 100 ml. to 50 mg. per 100 ml. These experiments were conducted to illustrate the sensitivity of the automated system. The difference in the response curve for similar concentration sequences represents a variance in the speed with which they were passed through the system.

The reagents utilized in connection with the automated procedure of glucose determination comprise aqueous solutions of a ferricyanide reagent, a ferric ion containing reagent and and the buffered color forming reagent. The ferricyanide reagent comprises sufficient ferricyanide to react with all the glucose in the sample, for example, 0.1 I5 g. potassium ferricyanide dissolved in 1 liter of 0.05 percent sodium hydroxide and 0.9 percent sodium chloride. The ferric ion containing solutions comprises suflicient ferric ions to react with all the ferrocyanide ions formed in the initial reaction, for example, 0. 2 7 g. ferric chloride dissolved in 1 liter of distilled water and buffered to a pH of about 4.5 with a sodium acetate/acetic acid buffer couple. The color-forming reagent comprises sufficient color-forming compound to react with the ferrous in the ions formed by the reaction of the ferric ions and the ferrocya nide ions, for'example, 2.0 g. of a compound of formula I, 82.0 g. of ammonium acetate and approximately 60.0 ml. of glacial acetic acid in a liter of distilled water. The pH of the solution is maintained between about 4.4 and 4.6.

In the practice of the invention according to the automated procedure, iron-free distilled water is pumped through the system for 10 minutes. The system is then switched to reagent and the pumping is continued until a steady base line is obtained on the recorder chart. The base line is set to 0.01A (95 percent transmission).

The standards in the sample tray are aspirated at a rate of 20 to 60' (2:1 wash ratio) samples per hour. The specimens to be analyzed are then sampled, with a standard glucose specimen which is aspirated intermittently to insure qualitative control. p The glucose content of each specimen is determined by reference to a calibration curve prepared by plotting the corrected absorbances of the glucose standards against concentrations in mg./ 100 ml. Table l sets forth a comparison of results obtained when 10 randomly selected plasma specimens were analyzed utilizing the automated and manual glucose procedures of the present invention.

TABLE I Comparison of Manual and Automated Glucose Analysis (mg/100 ml.)

Specimen No. Manual Automated Difference In Table II, the recovery of glucose added to pooled serum aliquots is given. An average recovery of 99.3 percent (range 94.2-l03.5 percent was realized.)

TABLE II.--RECOVERY OF GLUCOSE ADDED TO SERUM For a fuller understanding of the nature and objects of the present invention, reference may be had to the following examples which are given merely as further illustrations of the invention and are not to be construed in a limiting sense.

EXAMPLE 1 To a stirred solution off 22.0 g. of 7-bromo-l,3-dihydro-5- (2-pyridyl)-2H l,4-benzodiazepin 2-one in 55.0 ml. of dry N,N-dimethylformamide was treated with 11.0 ml. of a methanolic solution of sodium methoxide (0.0835 mole of 75 4 EXAMPLE 2 The 7-bromol ,3-dihydrol-( 3-dimethylaminopropyl )-5 2 was dissolved in sufficient methanol to provide a 10 percent solution. This solution was then saturated with hydrogen chloride. A sufficient amount of ether was added to cause turbidity. The resultant mixture was allowed to cool for several hours. 7-Bromol ,3-dihydrol 3-dimethylaminopropyl)-5-( 2 9y y 2H 1L .-.l2=nm iiaz9p n: 1e d ydr9.h. 2n'ds precipitated out on standing and was separated by filtration. The salt was recrystallized from a methanol-ether mixture as pale yellow prisms, MP. l8l-l 83 dec.

EXAMPLE 3 This example demonstrates the applicability of the test method to either blood serum or plasma.

In the method, aliquots of plasma or serum were added in 0.1 ml. quantities to 2.4 ml. of a tungstic acid solution prepared by mixing one volume 10 percent sodium tungstate and 8 volumes N/ l2 sulfuric acid. Each mixture was well mixed and then centrifuged at 2,500 rpm. for IS minutes. A 0.1 ml. aliquot of the clear supernatant liquid was treated with 2.0 ml. of a ferricyanide solution which had been prepared by dissolving 0.1 15 g. of potassium ferricyanide in one liter of a 2 percent aqueous solution of sodium carbonate. ,The deproteinized fluid ferricyanide mixture was heated for 5 minutes in a boiling water bath, rapidly cooled to about 25 C. and treated with 2.0 ml. of a ferric ion reagent prepared by dissolving 0.27 g. ferric chloride hexahydrate in one liter of an acetate buffer comprising 272.0 g. sodium acetate and 294.0

- ml. glacial acetic acid, and 2.0 ml. of a solution prepared by dissolving 2.0 g. of the compound produced in Example 2 in one liter of 1M acetate bufl'er. The solutions were thoroughly mixed and the absorbance of the violet blue color that develops was measured after about 10 minutes against a reagent blank at 580 nm in a Coleman Spectrophotometer using a cuvette with a 19 mm. light path.

The glucose content of the specimens was obtained by reference to a calibration curve prepared by plotting the absorbances (A) given by standard glucose solutions treated in the same manner against concentration or by the Beer-Lambert formula. Utilizing 4.0 mcg. glucose/0.1 ml. as a standard, the concentration of the specimen was calculated according to the formula:

(Absorbance of Specimen/Absorbance of Standard) x l00 mg. glucose/ ml.

For comparative purposes, glucose analyses were also conducted on a like number of samples utilizing a modified Folin- Wu procedure as described by B D. Tonks in American Journal of Clinical Pathology, 22:1009, (l952).

The results obtained utilizing the aforesaid two techniques 2? 595.1%?! thef ll w s il Benzediazeplne test Folin-Wu Difference Specimen (mg. glucose/ (mg. glucose] (mg. glucose] Difference,- number 100 ml.) 100 ml.) 100 ml.) percent The comparative data obtained utilizing plasma specimens was completely analogous to that with serum.

Utilizing similar reagents and quantities as were employed in Example 3, tests were conducted utilizing the compound prepared in Example 2 and comparing the results with the glucose content deproteinized plasma prepared as described in B. Klein in Clinical Chemistry, 5; 62, (1959) and designated Somogyi filtrates.

The results obtained are set forth in the following table:

In an analogous manner to that employed in Examples 3 and 4, serum specimens from 20 randomly selected blood samples obtained from healthy individuals and hospitalized patients were tested for glucose content. For comparative purposes, the glucose content of the same blood sample was also determined utilizing a standard glucose oxidase procedure. The glucose oxidase procedure employed herein is described in detail by R. Richterich and J. P. Colombo in Klin. Woch., 40, 1208, (1962) and A. Saifer and S. Gerstenfeld in J. Lab. Clin. Med., 51, 448, (1958).

The results obtained utilizing the two techniques are set forth in the following table:

Comparison of Glucose Analyses (milligrams glucose/100 ml.)

1. A process for quantitating the glucose content of blood serum or plasma comprising:

a. treating a deproteinized sample of blood serum or plasma with an aqueous alkaline solution containing a source of ferricyanide ions;

b. heating the mixture from step (a) to a temperature of from about 90C. to about l00C.;

c. adding to the mixture from step (b) a source of ferric iron ions;

d. reacting the mixture of step (c) with a benzodiazepine compound selected from the group of the compounds of the formula wherein A is selected from the group consisting of and B is selected from the group of hydrogen, lower alkyl and C uHzn rt is an integer from 2 t o 7 R3 is selected from the group consisting of hydrogen, hydroxy, lower alkylIlower allioxy a nd lower alkanoyloxy; R is Z-pyridyl; R is selected from the group consisting of lower alkyl, hydrogen,

and

GEN

gnd R and "R6, where taken together with their attached nitrogenatom, from a radical selected from the group consisting of piperazinyl, lower alkyl substituted piperazinyl, pyrrolidinyl, lower alkyl substituted pyrrolidinyl, piperidinyl, and lower alkyl substituted piperidinyl; R is lower alkyl; and R is selected from the group consisting of lower alkyl and hydrogen, and water soluble acid addition salts thereof; and

e. colorimetrically quantitating the glucose present by means of said color.

2. The process in accordance with claim 1 wherein said source of ferric ions consists essentially of an aqueous solution of ferric chloride buffered to a pH of between from about 4.0 to about 5.0.

3. The process in accordance with claim 1 wherein said benzodiazepine compound is added as an aqueous solution buffered to a pH of from about 4.0 toabout 5.0.

4. The process in accordance with claim 1 wherein said benzodiazepine compound is selected from the group consisting of 7-bromo-l ,3-dihydro-l-( 3-dimethylaminopropyl)-5-(2- pyridyl)-2H-l,4-benzodiazepin-2-one and water soluble acid addition salts thereof.

1 1 l2 5. A process for quantitating the glucose content of blood 7. The process in accordance with claim 5 wherein said j serum or plasma comprising: buffer present in the aqueous solution containing ferric a. treating a deproteinized sample of blood serum or plasma chloride and the aqueous solution containing the with an aqueous alkaline solution containing a source of benzodiazepine compound is a buffer pair comprising a water ferricyanide ions; 5 soluble salt of acetic acid and acetic acid.

b. heating the mixture from step (a) to a temperature of 8 A method for the quantitative analysis of the glucose confrom about 90C. to about 100C; tent of blood plasma or serum consisting essentially of providc. adding tov the mixture of step (b) an aqueous solution ing in continuous flow, the sequential steps comprising:

containing ferric chloride and abuffer; a. combining in continuous flow a measured specimen of d. adding to the mixture of step (c) an aqueous solution 10 plasma or serum with an isotonic solution of sodium containing a buffer and a benzodiazepine compound chloride; selected from the group consisting of compounds of the b. passing said mixture through a separating zone, thereby formula separating by dialysis in said zone from said mixture a clear aqueous solution; c. mixing said clear aqueous solution with a reagent com- N-B H prising an alkaline aqueous solution of a water soluble ferricyanide salt; R, d. passing said aqueous mixture through heating means thereby raising the temperature thereof to from about A I 95C. to about iooc.;'

e. mixing said heated aqueous mixture by concurrent flow h i A i selected from the group consisting of with a first reagent comprising a buffered aqueous solution of a ferric iron salt and a second reagent comprising a buffered, aqueous solution of a color-forming compound \m selected from the group consisting of compounds of the i l formula and R2 N-B H R; 0 B is selected from the group consisting of A/ 3 o wt, I wherein A is selected from the group consisting of and Cl-l,; R is selected from the group consisting of 1 halogen, hydrogen, trifluoromethyl, nitro, and amino; R, is selected from the group consisting of 40 and H C='N r; R1 Rs 4 \O r H B is selected from the group consisting of hydrogen, lower alkyl and 0 Rs -H o HhN and --CH,--; R, is selected from the group consisting of RB halogen, hydrogen, trifluoromethyl, nitro, and amino; R, is

selected from'the group consisting of n is an integer from 2 to 7; R; is selected from t h e group consisting of hydrogen, hydroxy, lower alkyl, lower allioxy and H lower alkanoyloxy; R, is 2-pyridyl; R is selected from the group consisting of lower alkyl; hydrogen,

fiNH2 hydrogen, lower alkyl and and s GEN CnH2nN jl ld R and R where taken together with their attached nitrogen atom, fonn a radical selected from the group consist- M ing of piperazinyl, lower alkyl substituted piperazinyl, pyrn is an integer from 2 to 7; R is selected from the gr o gn rolidinyl, lower alkyl substituted pyrrolidinyl, piperidinyl, and sisting of hydrogen, hydroxy, lower alkyl, lower alkoxy and lower alkyl substituted piperidinyl; R is lower alkyl; and R, is lower alkanoyloxy; R is 2-pyridyl; R is selected from the selected from the group consisting of lower alkyl and group consisting of lower alkyl; hydrogen, hydrogen and water soluble acid addition salts thereof; and

e. colorimetrically quantitating the glucose present by means of said color.

6. The process in accordance with claim 5 wherein said source of ferricyanide ions is potassium ferricyanide. and

GEN

; and R and R;, where taken together with their attached nitrogen atom, form a radical selected from the group consisting of piperazinyl, lower alkyl substituted piperazinyl, pyrrolidinyl, lower alkyl substituted pyrrolidinyl, piperidinyl, and

lower alkyl substituted piperidinyl; R is lower alkyl; and R is selected from the group consisting of lower alkyl and hydrogen thereof and water soluble acid addition salts thereof thereby forming a colored solution; and

f. flowing said colored solution to an analyzing zone and photometrically determining quantitatively the amount of glucose present during the flow of said colored solution through said analyzing zone.

9. The method in accordance with claim 8 wherein said first reagent and said second reagent are buffered to a pH of from about 4.0 to about 5.0 with a buffer pair comprising a water soluble salt of acetic acid and acetic acid.

10. The method in accordance with claim 8 wherein said colorforming compound is selected from the group consisting of 7-bromo-l ,3-dihydrol 3-dimethylaminopropyl)-5-( 2- pyridyl)-2H-1,4-benzodiazepin-2-one and water soluble acid addition salts thereof.

11. The method in accordance with claim 8 wherein said water soluble ferricyanide salt is potassium ferricyanide and said ferric iron salt is ferric chloride.

Claims (10)

  1. 2. The process in accordance with claim 1 wherein said source of ferric ions consists essentially of an aqueous solution of ferric chloride buffered to a pH of between from about 4.0 to about 5.0.
  2. 3. The process in accordance with claim 1 wherein said benzodiazepine compound is added as an aqueous solution buffered to a pH of from about 4.0 to about 5.0.
  3. 4. The process in accordance with claim 1 wherein said benzodiazepine compound is selected from the group consisting of 7-bromo-1,3-dihydro-1-(3-dimethylaminopropyl)-5-(2-pyridyl)-2H-1, 4-benzodiazepin-2-one and water soluble acid addition salts thereof.
  4. 5. A process for quantitating the glucose content of blood serum or plasma comprising: a. treating a deproteinized sample of blood serum or plasma with an aqueous alkaline solution containing a source of ferricyanide ions; b. heating the mixture from step (a) to a temperature of from about 90* C. to about 100*C.; c. adding to the mixture of step (b) an aqueous solution containing ferric chloride and a buffer; d. adding to the mixture of step (c) an aqueous solution containing a buffer and a benzodiazepine compound selected from the group consisting of compounds of the formula wherein A is selected from the group consisting of and B is selected from the group consisting of and -CH2-; R1 is selected from the group consisting of halogen, hydrogen, trifluoromethyl, nitro, and amino; R2 is selected from the group consisting of , hydrogen, lower alkyl and ; n is an integer from 2 to 7; R3 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy and lower alkanoyloxy; R4 is 2-pyridyl; R5 is selected from the group consisting of lower alkyl; hydrogen, and ; and R5 and R6, where taken together with their attached nitrogen atom, form a radical selected from the group consisting of piperazinyl, lower alkyl substituted piperazinyl, pyrrolidinyl, lower alkyl substituted pyrrolidinyl, piperidinyl, and lower alkyl substituted piperidinyl; R7 is lower alkyl; and R8 is selected from the group consisting of lower alkyl and hydrogen and water soluble acid addition salts thereof; and e. colorimetrically quantitating the glucose present by means of said color.
  5. 6. The process in accordance with claim 5 wherein said source of ferricyanide ions is potassium ferricyanide.
  6. 7. The process in accordance with claim 5 wherein said buffer present in the aqueous solution containing ferric chloride and the aqueous solution containing the benzodiazepine compound is a buffer pair comprising a water soluble salt of acetic acid and acetic acid.
  7. 8. A method for the quantitative analysis of the glucose content of blood plasma or serum consisting essentially of providing in continuous flow, the sequential steps comprising: a. combining in continuous flow a measured specimen of plasma or serum with an isotonic solution of sodium chloride; b. passing said mixture through a separating zone, thereby separating by dialysis in said zone from said mixture a clear aqueous solution; c. mixing sAid clear aqueous solution with a reagent comprising an alkaline aqueous solution of a water soluble ferricyanide salt; d. passing said aqueous mixture through heating means thereby raising the temperature thereof to from about 95* C. to about 100* C.; e. mixing said heated aqueous mixture by concurrent flow with a first reagent comprising a buffered aqueous solution of a ferric iron salt and a second reagent comprising a buffered, aqueous solution of a color-forming compound selected from the group consisting of compounds of the formula wherein A is selected from the group consisting of and ; B is selected from the group consisting of and -CH2-; R1 is selected from the group consisting of halogen, hydrogen, trifluoromethyl, nitro, and amino; R2 is selected from the group consisting of , hydrogen, lower alkyl and ; n is an integer from 2 to 7; R3 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy and lower alkanoyloxy; R4 is 2-pyridyl; R5 is selected from the group consisting of lower alkyl; hydrogen, and ; and R5 and R6, where taken together with their attached nitrogen atom, form a radical selected from the group consisting of piperazinyl, lower alkyl substituted piperazinyl, pyrrolidinyl, lower alkyl substituted pyrrolidinyl, piperidinyl, and lower alkyl substituted piperidinyl; R7 is lower alkyl; and R6 is selected from the group consisting of lower alkyl and hydrogen thereof and water soluble acid addition salts thereof thereby forming a colored solution; and f. flowing said colored solution to an analyzing zone and photometrically determining quantitatively the amount of glucose present during the flow of said colored solution through said analyzing zone.
  8. 9. The method in accordance with claim 8 wherein said first reagent and said second reagent are buffered to a pH of from about 4.0 to about 5.0 with a buffer pair comprising a water soluble salt of acetic acid and acetic acid.
  9. 10. The method in accordance with claim 8 wherein said colorforming compound is selected from the group consisting of 7-bromo-1,3-dihydro-1-(3-dimethylaminopropyl)-5-(2-pyridyl)-2H-1,4 -benzodiazepin-2-one and water soluble acid addition salts thereof.
  10. 11. The method in accordance with claim 8 wherein said water soluble ferricyanide salt is potassium ferricyanide and said ferric iron salt is ferric chloride.
US3653841A 1969-12-19 1969-12-19 Methods and compositions for determining glucose in blood Expired - Lifetime US3653841A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US88653869 true 1969-12-19 1969-12-19

Publications (1)

Publication Number Publication Date
US3653841A true US3653841A (en) 1972-04-04

Family

ID=25389219

Family Applications (1)

Application Number Title Priority Date Filing Date
US3653841A Expired - Lifetime US3653841A (en) 1969-12-19 1969-12-19 Methods and compositions for determining glucose in blood

Country Status (1)

Country Link
US (1) US3653841A (en)

Cited By (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920969A (en) * 1974-01-31 1975-11-18 Robert E Berglas Digital glucose analyzer
DE2658101A1 (en) * 1975-12-31 1977-07-14 Gambro Ag A method for measuring the concentration of low molecular weight compounds in complex media, preferably in medical treatments, and apparatus for carrying out the method
US4095948A (en) * 1973-10-19 1978-06-20 Hoffmann-La Roche Inc. Determination of uric acid
US4319883A (en) * 1979-03-30 1982-03-16 Atto Corporation Method for determining catecholic compounds and their related compounds
US4645742A (en) * 1981-12-23 1987-02-24 Baker John R Materials for determining fructosamine levels in blood samples
US4953552A (en) * 1989-04-21 1990-09-04 Demarzo Arthur P Blood glucose monitoring system
US5571723A (en) * 1991-02-07 1996-11-05 Evans; Cody A. Method of testing for diabetes that reduces the effect of interfering substances
US6103033A (en) * 1998-03-04 2000-08-15 Therasense, Inc. Process for producing an electrochemical biosensor
US6120676A (en) * 1997-02-06 2000-09-19 Therasense, Inc. Method of using a small volume in vitro analyte sensor
US6134461A (en) * 1998-03-04 2000-10-17 E. Heller & Company Electrochemical analyte
US6162611A (en) * 1993-12-02 2000-12-19 E. Heller & Company Subcutaneous glucose electrode
US6175752B1 (en) 1998-04-30 2001-01-16 Therasense, Inc. Analyte monitoring device and methods of use
US6251260B1 (en) 1998-08-24 2001-06-26 Therasense, Inc. Potentiometric sensors for analytic determination
US6299757B1 (en) 1998-10-08 2001-10-09 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US20020053523A1 (en) * 1999-11-04 2002-05-09 Therasense, Inc. Small volume in vitro analyte sensor and methods
US6591125B1 (en) 2000-06-27 2003-07-08 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US6654625B1 (en) 1999-06-18 2003-11-25 Therasense, Inc. Mass transport limited in vivo analyte sensor
US20050058873A1 (en) * 2003-09-12 2005-03-17 Arthur Alan R. Integral fuel cartridge and filter
US20060091006A1 (en) * 1999-11-04 2006-05-04 Yi Wang Analyte sensor with insertion monitor, and methods
US20070106135A1 (en) * 2005-11-04 2007-05-10 Abbott Diabetes Care, Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US20080004512A1 (en) * 2002-11-05 2008-01-03 Funderburk Jeffery V Sensor inserter assembly
US20080041506A1 (en) * 2006-08-19 2008-02-21 Aijun Huang Alloy and method of treating titanium aluminide
US20080076997A1 (en) * 1998-04-30 2008-03-27 Abbott Diabetes Care, Inc. Analyte monitoring device and methods of use
US20080139798A1 (en) * 2002-11-14 2008-06-12 Dharmacon, Inc. siRNA targeting myeloid cell leukemia sequence 1
US20090137889A1 (en) * 1991-03-04 2009-05-28 Adam Heller Subcutaneous Glucose Electrode
US20090171182A1 (en) * 2004-12-29 2009-07-02 Abbott Diabetes Care Inc. Method and apparatus for mounting a data transmission device in a communication system
US7620438B2 (en) 2006-03-31 2009-11-17 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US20100087721A1 (en) * 2005-12-28 2010-04-08 Abbott Diabetes Care Inc. Method and Apparatus for Providing Analyte Sensor Insertion
US20100185066A1 (en) * 2001-04-27 2010-07-22 Eyesense Ag Apparatus for measuring blood glucose concentrations
US20100213082A1 (en) * 2009-02-26 2010-08-26 Benjamin Feldman Self-Powered Analyte Sensor
US7811231B2 (en) 2002-12-31 2010-10-12 Abbott Diabetes Care Inc. Continuous glucose monitoring system and methods of use
US20110060196A1 (en) * 2009-08-31 2011-03-10 Abbott Diabetes Care Inc. Flexible Mounting Unit and Cover for a Medical Device
US7920907B2 (en) 2006-06-07 2011-04-05 Abbott Diabetes Care Inc. Analyte monitoring system and method
US7928850B2 (en) 2007-05-08 2011-04-19 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US7976778B2 (en) 2001-04-02 2011-07-12 Abbott Diabetes Care Inc. Blood glucose tracking apparatus
US8066639B2 (en) 2003-06-10 2011-11-29 Abbott Diabetes Care Inc. Glucose measuring device for use in personal area network
US8103456B2 (en) 2009-01-29 2012-01-24 Abbott Diabetes Care Inc. Method and device for early signal attenuation detection using blood glucose measurements
US8112240B2 (en) 2005-04-29 2012-02-07 Abbott Diabetes Care Inc. Method and apparatus for providing leak detection in data monitoring and management systems
US8123686B2 (en) 2007-03-01 2012-02-28 Abbott Diabetes Care Inc. Method and apparatus for providing rolling data in communication systems
US8149117B2 (en) 2007-05-08 2012-04-03 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8226891B2 (en) 2006-03-31 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring devices and methods therefor
US8287454B2 (en) 1998-04-30 2012-10-16 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8333714B2 (en) 2006-09-10 2012-12-18 Abbott Diabetes Care Inc. Method and system for providing an integrated analyte sensor insertion device and data processing unit
US8346337B2 (en) 1998-04-30 2013-01-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8456301B2 (en) 2007-05-08 2013-06-04 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8465425B2 (en) 1998-04-30 2013-06-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8512243B2 (en) 2005-09-30 2013-08-20 Abbott Diabetes Care Inc. Integrated introducer and transmitter assembly and methods of use
US8545403B2 (en) 2005-12-28 2013-10-01 Abbott Diabetes Care Inc. Medical device insertion
US8602991B2 (en) 2005-08-30 2013-12-10 Abbott Diabetes Care Inc. Analyte sensor introducer and methods of use
US8612159B2 (en) 1998-04-30 2013-12-17 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8613703B2 (en) 2007-05-31 2013-12-24 Abbott Diabetes Care Inc. Insertion devices and methods
US8652043B2 (en) 2001-01-02 2014-02-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8665091B2 (en) 2007-05-08 2014-03-04 Abbott Diabetes Care Inc. Method and device for determining elapsed sensor life
US8688188B2 (en) 1998-04-30 2014-04-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8732188B2 (en) 2007-02-18 2014-05-20 Abbott Diabetes Care Inc. Method and system for providing contextual based medication dosage determination
US8764657B2 (en) 2010-03-24 2014-07-01 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
US8771183B2 (en) 2004-02-17 2014-07-08 Abbott Diabetes Care Inc. Method and system for providing data communication in continuous glucose monitoring and management system
US8930203B2 (en) 2007-02-18 2015-01-06 Abbott Diabetes Care Inc. Multi-function analyte test device and methods therefor
US8974386B2 (en) 1998-04-30 2015-03-10 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8993331B2 (en) 2009-08-31 2015-03-31 Abbott Diabetes Care Inc. Analyte monitoring system and methods for managing power and noise
US9066695B2 (en) 1998-04-30 2015-06-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9226701B2 (en) 2009-04-28 2016-01-05 Abbott Diabetes Care Inc. Error detection in critical repeating data in a wireless sensor system
US9259175B2 (en) 2006-10-23 2016-02-16 Abbott Diabetes Care, Inc. Flexible patch for fluid delivery and monitoring body analytes
US9314195B2 (en) 2009-08-31 2016-04-19 Abbott Diabetes Care Inc. Analyte signal processing device and methods
US9320461B2 (en) 2009-09-29 2016-04-26 Abbott Diabetes Care Inc. Method and apparatus for providing notification function in analyte monitoring systems
US9351669B2 (en) 2009-09-30 2016-05-31 Abbott Diabetes Care Inc. Interconnect for on-body analyte monitoring device
US9398882B2 (en) 2005-09-30 2016-07-26 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor and data processing device
US9402570B2 (en) 2011-12-11 2016-08-02 Abbott Diabetes Care Inc. Analyte sensor devices, connections, and methods
US9402544B2 (en) 2009-02-03 2016-08-02 Abbott Diabetes Care Inc. Analyte sensor and apparatus for insertion of the sensor
US9521968B2 (en) 2005-09-30 2016-12-20 Abbott Diabetes Care Inc. Analyte sensor retention mechanism and methods of use
US9572534B2 (en) 2010-06-29 2017-02-21 Abbott Diabetes Care Inc. Devices, systems and methods for on-skin or on-body mounting of medical devices
US9743862B2 (en) 2011-03-31 2017-08-29 Abbott Diabetes Care Inc. Systems and methods for transcutaneously implanting medical devices
US9788771B2 (en) 2006-10-23 2017-10-17 Abbott Diabetes Care Inc. Variable speed sensor insertion devices and methods of use
US9931066B2 (en) 2017-05-31 2018-04-03 Abbott Diabetes Care Inc. Analyte sensor devices, connections, and methods

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3098717A (en) * 1959-04-27 1963-07-23 Technicon Instr Fluid treatment method and apparatus with double-flow colorimeter
US3449081A (en) * 1965-03-29 1969-06-10 Electronic Instr Co Test kit
US3506404A (en) * 1967-12-19 1970-04-14 Hoffmann La Roche Colorimetric method for determining iron in blood

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3098717A (en) * 1959-04-27 1963-07-23 Technicon Instr Fluid treatment method and apparatus with double-flow colorimeter
US3449081A (en) * 1965-03-29 1969-06-10 Electronic Instr Co Test kit
US3506404A (en) * 1967-12-19 1970-04-14 Hoffmann La Roche Colorimetric method for determining iron in blood

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Aloe Scientific Co., Catalog 103, p. 1011, 1041, 1065, 1073 *
Hawk et al., Practical Physiological Chemistry, 13th ed., McGraw Hill Co., QP514H4, 1954, p. 567, 575 *

Cited By (315)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4095948A (en) * 1973-10-19 1978-06-20 Hoffmann-La Roche Inc. Determination of uric acid
US3920969A (en) * 1974-01-31 1975-11-18 Robert E Berglas Digital glucose analyzer
DE2658101A1 (en) * 1975-12-31 1977-07-14 Gambro Ag A method for measuring the concentration of low molecular weight compounds in complex media, preferably in medical treatments, and apparatus for carrying out the method
US4319883A (en) * 1979-03-30 1982-03-16 Atto Corporation Method for determining catecholic compounds and their related compounds
US4645742A (en) * 1981-12-23 1987-02-24 Baker John R Materials for determining fructosamine levels in blood samples
US4953552A (en) * 1989-04-21 1990-09-04 Demarzo Arthur P Blood glucose monitoring system
US5571723A (en) * 1991-02-07 1996-11-05 Evans; Cody A. Method of testing for diabetes that reduces the effect of interfering substances
US8741590B2 (en) 1991-03-04 2014-06-03 Abbott Diabetes Care Inc. Subcutaneous glucose electrode
US6514718B2 (en) 1991-03-04 2003-02-04 Therasense, Inc. Subcutaneous glucose electrode
US20070215491A1 (en) * 1991-03-04 2007-09-20 Abbott Diabetes Care, Inc. Subcutaneous Glucose Electrode
US8414750B2 (en) 1991-03-04 2013-04-09 Abbott Diabetes Care Inc. Subcutaneous glucose electrode
US7462264B2 (en) 1991-03-04 2008-12-09 Abbott Diabetes Care Inc. Subcutaneous glucose electrode
US6881551B2 (en) 1991-03-04 2005-04-19 Therasense, Inc. Subcutaneous glucose electrode
US20060003398A1 (en) * 1991-03-04 2006-01-05 Therasense, Inc. Subcutaneous glucose electrode
US8414749B2 (en) 1991-03-04 2013-04-09 Abbott Diabetes Care Inc. Subcutaneous glucose electrode
US20030134347A1 (en) * 1991-03-04 2003-07-17 Therasense, Inc. Subcutaneous glucose electrode
US20110021895A1 (en) * 1991-03-04 2011-01-27 Abbott Diabetes Care Inc. Subcutaneous Glucose Electrode
US8588881B2 (en) 1991-03-04 2013-11-19 Abbott Diabetes Care Inc. Subcutaneous glucose electrode
US20090137889A1 (en) * 1991-03-04 2009-05-28 Adam Heller Subcutaneous Glucose Electrode
US20070151869A1 (en) * 1991-03-04 2007-07-05 Abbott Diabetes Care, Inc. Subcutaneous Glucose Electrode
US6284478B1 (en) 1993-12-02 2001-09-04 E. Heller & Company Subcutaneous glucose electrode
US6329161B1 (en) 1993-12-02 2001-12-11 Therasense, Inc. Subcutaneous glucose electrode
US6162611A (en) * 1993-12-02 2000-12-19 E. Heller & Company Subcutaneous glucose electrode
US8142643B2 (en) 1997-02-06 2012-03-27 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US8142642B2 (en) 1997-02-06 2012-03-27 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US6551494B1 (en) 1997-02-06 2003-04-22 Therasense, Inc. Small volume in vitro analyte sensor
US8105476B2 (en) 1997-02-06 2012-01-31 Abbott Diabetes Care Inc. Integrated lancing and measurement device
US9234864B2 (en) 1997-02-06 2016-01-12 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US6576101B1 (en) 1997-02-06 2003-06-10 Therasense, Inc. Small volume in vitro analyte sensor
US8808531B2 (en) 1997-02-06 2014-08-19 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US20080194990A1 (en) * 1997-02-06 2008-08-14 Abbott Diabetes Care, Inc. Integrated Lancing And Measurement Device And Analyte Measuring Methods
US8114271B2 (en) 1997-02-06 2012-02-14 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US8114270B2 (en) 1997-02-06 2012-02-14 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US7909984B2 (en) 1997-02-06 2011-03-22 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US8118992B2 (en) 1997-02-06 2012-02-21 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US20030201194A1 (en) * 1997-02-06 2003-10-30 Therasense, Inc. Small volume in vitro analyte sensor
US7906009B2 (en) 1997-02-06 2011-03-15 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US6143164A (en) * 1997-02-06 2000-11-07 E. Heller & Company Small volume in vitro analyte sensor
US20080277292A1 (en) * 1997-02-06 2008-11-13 Therasense, Inc. Small Volume In Vitro Analyte Sensor
US8123929B2 (en) 1997-02-06 2012-02-28 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US7988845B2 (en) 1997-02-06 2011-08-02 Abbott Diabetes Care Inc. Integrated lancing and measurement device and analyte measuring methods
US6120676A (en) * 1997-02-06 2000-09-19 Therasense, Inc. Method of using a small volume in vitro analyte sensor
US6484046B1 (en) 1998-03-04 2002-11-19 Therasense, Inc. Electrochemical analyte sensor
US7996054B2 (en) 1998-03-04 2011-08-09 Abbott Diabetes Care Inc. Electrochemical analyte sensor
US7861397B2 (en) 1998-03-04 2011-01-04 Abbott Diabetes Care Inc. Method of making an electrochemical sensor
US7721412B2 (en) 1998-03-04 2010-05-25 Abbott Diabetes Care Inc. Method of making an electrochemical sensor
US6973706B2 (en) 1998-03-04 2005-12-13 Therasense, Inc. Method of making a transcutaneous electrochemical sensor
US8117734B2 (en) 1998-03-04 2012-02-21 Abbott Diabetes Care Inc. Method of making an electrochemical sensor
US7003340B2 (en) 1998-03-04 2006-02-21 Abbott Diabetes Care Inc. Electrochemical analyte sensor
US20060042080A1 (en) * 1998-03-04 2006-03-02 Therasense, Inc. Method of making an electrochemical sensor
US8168051B2 (en) 1998-03-04 2012-05-01 Abbott Diabetes Care Inc. Sensor for determination of glucose
US20030088166A1 (en) * 1998-03-04 2003-05-08 Therasense, Inc. Electrochemical analyte sensor
US8463351B2 (en) 1998-03-04 2013-06-11 Abbott Diabetes Care Inc. Electrochemical analyte sensor
US8273227B2 (en) 1998-03-04 2012-09-25 Abbott Diabetes Care Inc. Sensor for in vitro determination of glucose
US8136220B2 (en) 1998-03-04 2012-03-20 Abbott Diabetes Care Inc. Method of making an electrochemical sensor
US6134461A (en) * 1998-03-04 2000-10-17 E. Heller & Company Electrochemical analyte
US6103033A (en) * 1998-03-04 2000-08-15 Therasense, Inc. Process for producing an electrochemical biosensor
US8706180B2 (en) 1998-03-04 2014-04-22 Abbott Diabetes Care Inc. Electrochemical analyte sensor
US20080281175A1 (en) * 1998-03-04 2008-11-13 Therasense, Inc. Method of making an electrochemical sensor
US20080281176A1 (en) * 1998-03-04 2008-11-13 Therasense, Inc. Method of making an electrochemical sensor
US20080276455A1 (en) * 1998-03-04 2008-11-13 Therasense, Inc. method of making an electrochemical sensor
US20080281177A1 (en) * 1998-03-04 2008-11-13 Therasense, Inc. method of making an electrochemical sensor
US20080275423A1 (en) * 1998-03-04 2008-11-06 Therasense, Inc. Method of making an electrochemical sensor
US7879213B2 (en) 1998-03-04 2011-02-01 Abbott Diabetes Care Inc. Sensor for in vitro determination of glucose
US8275439B2 (en) 1998-04-30 2012-09-25 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8273022B2 (en) 1998-04-30 2012-09-25 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US20080076997A1 (en) * 1998-04-30 2008-03-27 Abbott Diabetes Care, Inc. Analyte monitoring device and methods of use
US8287454B2 (en) 1998-04-30 2012-10-16 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9326714B2 (en) 1998-04-30 2016-05-03 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8306598B2 (en) 1998-04-30 2012-11-06 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8346336B2 (en) 1998-04-30 2013-01-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8346337B2 (en) 1998-04-30 2013-01-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8353829B2 (en) 1998-04-30 2013-01-15 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8265726B2 (en) 1998-04-30 2012-09-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8357091B2 (en) 1998-04-30 2013-01-22 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US20090216102A1 (en) * 1998-04-30 2009-08-27 James Say Analyte Monitoring Device and Methods of Use
US8366614B2 (en) 1998-04-30 2013-02-05 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8260392B2 (en) 1998-04-30 2012-09-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8255031B2 (en) 1998-04-30 2012-08-28 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8235896B2 (en) 1998-04-30 2012-08-07 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8738109B2 (en) 1998-04-30 2014-05-27 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8231532B2 (en) 1998-04-30 2012-07-31 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8226555B2 (en) 1998-04-30 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9072477B2 (en) 1998-04-30 2015-07-07 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8226558B2 (en) 1998-04-30 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8226557B2 (en) 1998-04-30 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8734346B2 (en) 1998-04-30 2014-05-27 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8224413B2 (en) 1998-04-30 2012-07-17 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9066694B2 (en) 1998-04-30 2015-06-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8372005B2 (en) 1998-04-30 2013-02-12 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9066695B2 (en) 1998-04-30 2015-06-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9066697B2 (en) 1998-04-30 2015-06-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9042953B2 (en) 1998-04-30 2015-05-26 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8734348B2 (en) 1998-04-30 2014-05-27 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9011331B2 (en) 1998-04-30 2015-04-21 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US20100312078A1 (en) * 1998-04-30 2010-12-09 Abbott Diabetes Care Inc. Analyte Monitoring Device and Methods of Use
US7860544B2 (en) 1998-04-30 2010-12-28 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8380273B2 (en) 1998-04-30 2013-02-19 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US7869853B1 (en) 1998-04-30 2011-01-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US20050121322A1 (en) * 1998-04-30 2005-06-09 Therasense, Inc. Analyte monitoring device and methods of use
US8391945B2 (en) 1998-04-30 2013-03-05 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8409131B2 (en) 1998-04-30 2013-04-02 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9014773B2 (en) 1998-04-30 2015-04-21 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8688188B2 (en) 1998-04-30 2014-04-01 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8672844B2 (en) 1998-04-30 2014-03-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8974386B2 (en) 1998-04-30 2015-03-10 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8880137B2 (en) 1998-04-30 2014-11-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8840553B2 (en) 1998-04-30 2014-09-23 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8465425B2 (en) 1998-04-30 2013-06-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8473021B2 (en) 1998-04-30 2013-06-25 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8670815B2 (en) 1998-04-30 2014-03-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8177716B2 (en) 1998-04-30 2012-05-15 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8175673B2 (en) 1998-04-30 2012-05-08 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US6565509B1 (en) 1998-04-30 2003-05-20 Therasense, Inc. Analyte monitoring device and methods of use
US8162829B2 (en) 1998-04-30 2012-04-24 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8480580B2 (en) 1998-04-30 2013-07-09 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8666469B2 (en) 1998-04-30 2014-03-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8660627B2 (en) 1998-04-30 2014-02-25 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8649841B2 (en) 1998-04-30 2014-02-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8641619B2 (en) 1998-04-30 2014-02-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8774887B2 (en) 1998-04-30 2014-07-08 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8622906B2 (en) 1998-04-30 2014-01-07 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8617071B2 (en) 1998-04-30 2013-12-31 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8744545B2 (en) 1998-04-30 2014-06-03 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US6175752B1 (en) 1998-04-30 2001-01-16 Therasense, Inc. Analyte monitoring device and methods of use
US7885699B2 (en) 1998-04-30 2011-02-08 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8597189B2 (en) 1998-04-30 2013-12-03 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8612159B2 (en) 1998-04-30 2013-12-17 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US6251260B1 (en) 1998-08-24 2001-06-26 Therasense, Inc. Potentiometric sensors for analytic determination
US8377378B2 (en) 1998-10-08 2013-02-19 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8087162B2 (en) 1998-10-08 2012-01-03 Abbott Diabetes Care Inc. Methods of making small volume in vitro analyte sensors
US8083924B2 (en) 1998-10-08 2011-12-27 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8153063B2 (en) 1998-10-08 2012-04-10 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8163164B2 (en) 1998-10-08 2012-04-24 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8083928B2 (en) 1998-10-08 2011-12-27 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8083929B2 (en) 1998-10-08 2011-12-27 Abbott Diabetes Care Inc. Small volume in vitro sensor and methods of making
US8118993B2 (en) 1998-10-08 2012-02-21 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8091220B2 (en) 1998-10-08 2012-01-10 Abbott Diabetes Care Inc. Methods of making small volume in vitro analyte sensors
US8182670B2 (en) 1998-10-08 2012-05-22 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8182671B2 (en) 1998-10-08 2012-05-22 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8187895B2 (en) 1998-10-08 2012-05-29 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US6299757B1 (en) 1998-10-08 2001-10-09 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US8186044B2 (en) 1998-10-08 2012-05-29 Abbott Diabetes Care Inc. Method of manufacturing small volume in vitro analyte sensors
US8192611B2 (en) 1998-10-08 2012-06-05 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8211363B2 (en) 1998-10-08 2012-07-03 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US6338790B1 (en) 1998-10-08 2002-01-15 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US8221685B2 (en) 1998-10-08 2012-07-17 Abbott Diabetes Care Inc. Small volume in vitro sensor and methods of making
US20100015692A1 (en) * 1998-10-08 2010-01-21 Feldman Benjamin J Small Volume In Vitro Sensor and Methods of Making
US20100012526A1 (en) * 1998-10-08 2010-01-21 Feldman Benjamin J Small Volume In Vitro Sensor and Methods of Making
US20100012519A1 (en) * 1998-10-08 2010-01-21 Feldman Benjamin J Small Volume In Vitro Sensor and Methods of Making
US8226815B2 (en) 1998-10-08 2012-07-24 Abbott Diabetes Care Inc. Small volume in vitro sensor and methods of making
US8650751B2 (en) 1998-10-08 2014-02-18 Abbott Diabetes Care Inc. Methods of making small volume in vitro analyte sensors
US6461496B1 (en) 1998-10-08 2002-10-08 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US8262996B2 (en) 1998-10-08 2012-09-11 Abbott Diabetes Care Inc. Small volume in vitro sensor and methods of making
US9234863B2 (en) 1998-10-08 2016-01-12 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US6592745B1 (en) 1998-10-08 2003-07-15 Therasense, Inc. Method of using a small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US7563350B2 (en) 1998-10-08 2009-07-21 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US7550069B2 (en) 1998-10-08 2009-06-23 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US20090014328A1 (en) * 1998-10-08 2009-01-15 Abbott Diabetes Care Inc. Small Volume in vitro Analyte Sensor and Methods of Making
US8268163B2 (en) 1998-10-08 2012-09-18 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8728297B2 (en) 1998-10-08 2014-05-20 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US8268144B2 (en) 1998-10-08 2012-09-18 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US6618934B1 (en) 1998-10-08 2003-09-16 Therasense, Inc. Method of manufacturing small volume in vitro analyte sensor
US20030199744A1 (en) * 1998-10-08 2003-10-23 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US9291592B2 (en) 1998-10-08 2016-03-22 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US8273241B2 (en) 1998-10-08 2012-09-25 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8272125B2 (en) 1998-10-08 2012-09-25 Abbott Diabetes Care Inc. Method of manufacturing in vitro analyte sensors
US9316609B2 (en) 1998-10-08 2016-04-19 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US8449758B2 (en) 1998-10-08 2013-05-28 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US8425758B2 (en) 1998-10-08 2013-04-23 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US9341591B2 (en) 1998-10-08 2016-05-17 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US7225535B2 (en) 1998-10-08 2007-06-05 Abbott Diabetes Care, Inc. Method of manufacturing electrochemical sensors
US20040054267A1 (en) * 1998-10-08 2004-03-18 Therasense, Inc. Small volume in vitro analyte sensor
US7058437B2 (en) 1998-10-08 2006-06-06 Therasense, Inc. Methods of determining concentration of glucose
US8701282B2 (en) 1998-10-08 2014-04-22 Abbott Diabetes Care Inc. Method for manufacturing a biosensor
US20040060818A1 (en) * 1998-10-08 2004-04-01 Therasense, Inc. Small volume in vitro analyte sensor and methods of making
US8372261B2 (en) 1998-10-08 2013-02-12 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US9891185B2 (en) 1998-10-08 2018-02-13 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor
US20100076287A1 (en) * 1998-10-08 2010-03-25 Feldman Benjamin J Small Volume In Vitro Analyte Sensor and Methods of Making
US8425743B2 (en) 1998-10-08 2013-04-23 Abbott Diabetes Care Inc. Small volume in vitro analyte sensor and methods of making
US6654625B1 (en) 1999-06-18 2003-11-25 Therasense, Inc. Mass transport limited in vivo analyte sensor
US6975893B2 (en) 1999-06-18 2005-12-13 Therasense, Inc. Mass transport limited in vivo analyte sensor
US20020148739A2 (en) * 1999-11-04 2002-10-17 Therasense, Inc. Small Volume in Vitro Analyte Sensor and Methods
US8066858B2 (en) 1999-11-04 2011-11-29 Abbott Diabetes Care Inc. Analyte sensor with insertion monitor, and methods
US20020157948A2 (en) * 1999-11-04 2002-10-31 Therasense, Inc. Small Volume in Vitro Analyte Sensor and Methods
US20080021295A1 (en) * 1999-11-04 2008-01-24 Yi Wang Sample Acquisition and Analyte Measurement Device
US20020053523A1 (en) * 1999-11-04 2002-05-09 Therasense, Inc. Small volume in vitro analyte sensor and methods
US20060091006A1 (en) * 1999-11-04 2006-05-04 Yi Wang Analyte sensor with insertion monitor, and methods
US20020084196A1 (en) * 1999-11-04 2002-07-04 Therasense, Inc. Small volume in vitro analyte sensor and methods
US20080283396A1 (en) * 1999-11-04 2008-11-20 Abbot Diabetes Care, Inc. Analyte Sensor with Insertion Monitor, and Methods
US6616819B1 (en) 1999-11-04 2003-09-09 Therasense, Inc. Small volume in vitro analyte sensor and methods
US20040225230A1 (en) * 1999-11-04 2004-11-11 Therasense, Inc. Small volume in vitro analyte sensor and methods
US20090260986A1 (en) * 1999-11-04 2009-10-22 Abbott Diabetes Care Inc. Analyte sensor with insertion monitor, and methods
US20090260985A1 (en) * 1999-11-04 2009-10-22 Abbott Diabetes Care Inc. Analyte sensor with insertion monitor, and methods
US6749740B2 (en) 1999-11-04 2004-06-15 Therasense, Inc. Small volume in vitro analyte sensor and methods
US6942518B2 (en) 1999-11-04 2005-09-13 Therasense, Inc. Small volume in vitro analyte sensor and methods
US6591125B1 (en) 2000-06-27 2003-07-08 Therasense, Inc. Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator
US9271669B2 (en) 2000-06-27 2016-03-01 Abbott Diabetes Care Inc. Method for integrated sample acquisition and analyte measurement device
US20080027302A1 (en) * 2000-06-27 2008-01-31 Therasense, Inc. Integrated Sample Acquisition and Analyte Measurement Device
US8795176B2 (en) 2000-06-27 2014-08-05 Abbott Diabetes Care Inc. Integrated sample acquisition and analyte measurement device
US9017259B2 (en) 2000-06-27 2015-04-28 Abbott Diabetes Care Inc. Integrated sample acquisition and analyte measurement device
US9662057B2 (en) 2000-06-27 2017-05-30 Abbott Diabetes Care Inc. Integrated sample acquisition and analyte measurement method
US20090270764A1 (en) * 2000-06-27 2009-10-29 Abbott Diabetes Care Inc. Methods of determining concentration of ketone bodies
US8532731B2 (en) 2000-06-27 2013-09-10 Abbott Diabetes Care Inc. Methods of determining analyte concentration
US8652043B2 (en) 2001-01-02 2014-02-18 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9011332B2 (en) 2001-01-02 2015-04-21 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9498159B2 (en) 2001-01-02 2016-11-22 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9610034B2 (en) 2001-01-02 2017-04-04 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8668645B2 (en) 2001-01-02 2014-03-11 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8765059B2 (en) 2001-04-02 2014-07-01 Abbott Diabetes Care Inc. Blood glucose tracking apparatus
US8236242B2 (en) 2001-04-02 2012-08-07 Abbott Diabetes Care Inc. Blood glucose tracking apparatus and methods
US8268243B2 (en) 2001-04-02 2012-09-18 Abbott Diabetes Care Inc. Blood glucose tracking apparatus and methods
US9477811B2 (en) 2001-04-02 2016-10-25 Abbott Diabetes Care Inc. Blood glucose tracking apparatus and methods
US7976778B2 (en) 2001-04-02 2011-07-12 Abbott Diabetes Care Inc. Blood glucose tracking apparatus
US20100185066A1 (en) * 2001-04-27 2010-07-22 Eyesense Ag Apparatus for measuring blood glucose concentrations
US20080064941A1 (en) * 2002-11-05 2008-03-13 Funderburk Jeffery V Sensor inserter methods of use
US7381184B2 (en) 2002-11-05 2008-06-03 Abbott Diabetes Care Inc. Sensor inserter assembly
US7582059B2 (en) 2002-11-05 2009-09-01 Abbott Diabetes Care Inc. Sensor inserter methods of use
US20080004512A1 (en) * 2002-11-05 2008-01-03 Funderburk Jeffery V Sensor inserter assembly
US8029442B2 (en) 2002-11-05 2011-10-04 Abbott Diabetes Care Inc. Sensor inserter assembly
US20080139798A1 (en) * 2002-11-14 2008-06-12 Dharmacon, Inc. siRNA targeting myeloid cell leukemia sequence 1
US7811231B2 (en) 2002-12-31 2010-10-12 Abbott Diabetes Care Inc. Continuous glucose monitoring system and methods of use
US8187183B2 (en) 2002-12-31 2012-05-29 Abbott Diabetes Care Inc. Continuous glucose monitoring system and methods of use
US8622903B2 (en) 2002-12-31 2014-01-07 Abbott Diabetes Care Inc. Continuous glucose monitoring system and methods of use
US8647269B2 (en) 2003-06-10 2014-02-11 Abbott Diabetes Care Inc. Glucose measuring device for use in personal area network
US9730584B2 (en) 2003-06-10 2017-08-15 Abbott Diabetes Care Inc. Glucose measuring device for use in personal area network
US8512239B2 (en) 2003-06-10 2013-08-20 Abbott Diabetes Care Inc. Glucose measuring device for use in personal area network
US8066639B2 (en) 2003-06-10 2011-11-29 Abbott Diabetes Care Inc. Glucose measuring device for use in personal area network
US20050058873A1 (en) * 2003-09-12 2005-03-17 Arthur Alan R. Integral fuel cartridge and filter
US8771183B2 (en) 2004-02-17 2014-07-08 Abbott Diabetes Care Inc. Method and system for providing data communication in continuous glucose monitoring and management system
US20090171182A1 (en) * 2004-12-29 2009-07-02 Abbott Diabetes Care Inc. Method and apparatus for mounting a data transmission device in a communication system
US8571624B2 (en) 2004-12-29 2013-10-29 Abbott Diabetes Care Inc. Method and apparatus for mounting a data transmission device in a communication system
US8112240B2 (en) 2005-04-29 2012-02-07 Abbott Diabetes Care Inc. Method and apparatus for providing leak detection in data monitoring and management systems
US8602991B2 (en) 2005-08-30 2013-12-10 Abbott Diabetes Care Inc. Analyte sensor introducer and methods of use
US9480421B2 (en) 2005-09-30 2016-11-01 Abbott Diabetes Care Inc. Integrated introducer and transmitter assembly and methods of use
US9521968B2 (en) 2005-09-30 2016-12-20 Abbott Diabetes Care Inc. Analyte sensor retention mechanism and methods of use
US9775563B2 (en) 2005-09-30 2017-10-03 Abbott Diabetes Care Inc. Integrated introducer and transmitter assembly and methods of use
US9398882B2 (en) 2005-09-30 2016-07-26 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor and data processing device
US8512243B2 (en) 2005-09-30 2013-08-20 Abbott Diabetes Care Inc. Integrated introducer and transmitter assembly and methods of use
US9326716B2 (en) 2005-11-01 2016-05-03 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8915850B2 (en) 2005-11-01 2014-12-23 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US8920319B2 (en) 2005-11-01 2014-12-30 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9078607B2 (en) 2005-11-01 2015-07-14 Abbott Diabetes Care Inc. Analyte monitoring device and methods of use
US9669162B2 (en) 2005-11-04 2017-06-06 Abbott Diabetes Care Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US7766829B2 (en) 2005-11-04 2010-08-03 Abbott Diabetes Care Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US8585591B2 (en) 2005-11-04 2013-11-19 Abbott Diabetes Care Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US9323898B2 (en) 2005-11-04 2016-04-26 Abbott Diabetes Care Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US20070106135A1 (en) * 2005-11-04 2007-05-10 Abbott Diabetes Care, Inc. Method and system for providing basal profile modification in analyte monitoring and management systems
US9795331B2 (en) 2005-12-28 2017-10-24 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor insertion
US9332933B2 (en) 2005-12-28 2016-05-10 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor insertion
US8852101B2 (en) 2005-12-28 2014-10-07 Abbott Diabetes Care Inc. Method and apparatus for providing analyte sensor insertion
US8545403B2 (en) 2005-12-28 2013-10-01 Abbott Diabetes Care Inc. Medical device insertion
US20100087721A1 (en) * 2005-12-28 2010-04-08 Abbott Diabetes Care Inc. Method and Apparatus for Providing Analyte Sensor Insertion
US7620438B2 (en) 2006-03-31 2009-11-17 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US8226891B2 (en) 2006-03-31 2012-07-24 Abbott Diabetes Care Inc. Analyte monitoring devices and methods therefor
US8597575B2 (en) 2006-03-31 2013-12-03 Abbott Diabetes Care Inc. Analyte monitoring devices and methods therefor
US9039975B2 (en) 2006-03-31 2015-05-26 Abbott Diabetes Care Inc. Analyte monitoring devices and methods therefor
US9380971B2 (en) 2006-03-31 2016-07-05 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US9743863B2 (en) 2006-03-31 2017-08-29 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US8933664B2 (en) 2006-03-31 2015-01-13 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US8593109B2 (en) 2006-03-31 2013-11-26 Abbott Diabetes Care Inc. Method and system for powering an electronic device
US9625413B2 (en) 2006-03-31 2017-04-18 Abbott Diabetes Care Inc. Analyte monitoring devices and methods therefor
US7920907B2 (en) 2006-06-07 2011-04-05 Abbott Diabetes Care Inc. Analyte monitoring system and method
US20080041506A1 (en) * 2006-08-19 2008-02-21 Aijun Huang Alloy and method of treating titanium aluminide
US8333714B2 (en) 2006-09-10 2012-12-18 Abbott Diabetes Care Inc. Method and system for providing an integrated analyte sensor insertion device and data processing unit
US9808186B2 (en) 2006-09-10 2017-11-07 Abbott Diabetes Care Inc. Method and system for providing an integrated analyte sensor insertion device and data processing unit
US8862198B2 (en) 2006-09-10 2014-10-14 Abbott Diabetes Care Inc. Method and system for providing an integrated analyte sensor insertion device and data processing unit
US9788771B2 (en) 2006-10-23 2017-10-17 Abbott Diabetes Care Inc. Variable speed sensor insertion devices and methods of use
US9259175B2 (en) 2006-10-23 2016-02-16 Abbott Diabetes Care, Inc. Flexible patch for fluid delivery and monitoring body analytes
US8930203B2 (en) 2007-02-18 2015-01-06 Abbott Diabetes Care Inc. Multi-function analyte test device and methods therefor
US8732188B2 (en) 2007-02-18 2014-05-20 Abbott Diabetes Care Inc. Method and system for providing contextual based medication dosage determination
US8123686B2 (en) 2007-03-01 2012-02-28 Abbott Diabetes Care Inc. Method and apparatus for providing rolling data in communication systems
US9801545B2 (en) 2007-03-01 2017-10-31 Abbott Diabetes Care Inc. Method and apparatus for providing rolling data in communication systems
US9095290B2 (en) 2007-03-01 2015-08-04 Abbott Diabetes Care Inc. Method and apparatus for providing rolling data in communication systems
US7928850B2 (en) 2007-05-08 2011-04-19 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US9649057B2 (en) 2007-05-08 2017-05-16 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8665091B2 (en) 2007-05-08 2014-03-04 Abbott Diabetes Care Inc. Method and device for determining elapsed sensor life
US9314198B2 (en) 2007-05-08 2016-04-19 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US9177456B2 (en) 2007-05-08 2015-11-03 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US9000929B2 (en) 2007-05-08 2015-04-07 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8149117B2 (en) 2007-05-08 2012-04-03 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8593287B2 (en) 2007-05-08 2013-11-26 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US9035767B2 (en) 2007-05-08 2015-05-19 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8461985B2 (en) 2007-05-08 2013-06-11 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8456301B2 (en) 2007-05-08 2013-06-04 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US9574914B2 (en) 2007-05-08 2017-02-21 Abbott Diabetes Care Inc. Method and device for determining elapsed sensor life
US8362904B2 (en) 2007-05-08 2013-01-29 Abbott Diabetes Care Inc. Analyte monitoring system and methods
US8613703B2 (en) 2007-05-31 2013-12-24 Abbott Diabetes Care Inc. Insertion devices and methods
US8676513B2 (en) 2009-01-29 2014-03-18 Abbott Diabetes Care Inc. Method and device for early signal attenuation detection using blood glucose measurements
US9066709B2 (en) 2009-01-29 2015-06-30 Abbott Diabetes Care Inc. Method and device for early signal attenuation detection using blood glucose measurements
US8103456B2 (en) 2009-01-29 2012-01-24 Abbott Diabetes Care Inc. Method and device for early signal attenuation detection using blood glucose measurements
US8473220B2 (en) 2009-01-29 2013-06-25 Abbott Diabetes Care Inc. Method and device for early signal attenuation detection using blood glucose measurements
US9402544B2 (en) 2009-02-03 2016-08-02 Abbott Diabetes Care Inc. Analyte sensor and apparatus for insertion of the sensor
US9636068B2 (en) 2009-02-03 2017-05-02 Abbott Diabetes Care Inc. Analyte sensor and apparatus for insertion of the sensor
US20100213057A1 (en) * 2009-02-26 2010-08-26 Benjamin Feldman Self-Powered Analyte Sensor
US20100213082A1 (en) * 2009-02-26 2010-08-26 Benjamin Feldman Self-Powered Analyte Sensor
US9668684B2 (en) 2009-02-26 2017-06-06 Abbott Diabetes Care Inc. Self-powered analyte sensor
US9226701B2 (en) 2009-04-28 2016-01-05 Abbott Diabetes Care Inc. Error detection in critical repeating data in a wireless sensor system
US20110060196A1 (en) * 2009-08-31 2011-03-10 Abbott Diabetes Care Inc. Flexible Mounting Unit and Cover for a Medical Device
US8993331B2 (en) 2009-08-31 2015-03-31 Abbott Diabetes Care Inc. Analyte monitoring system and methods for managing power and noise
US9314195B2 (en) 2009-08-31 2016-04-19 Abbott Diabetes Care Inc. Analyte signal processing device and methods
US9750439B2 (en) 2009-09-29 2017-09-05 Abbott Diabetes Care Inc. Method and apparatus for providing notification function in analyte monitoring systems
US9320461B2 (en) 2009-09-29 2016-04-26 Abbott Diabetes Care Inc. Method and apparatus for providing notification function in analyte monitoring systems
US9750444B2 (en) 2009-09-30 2017-09-05 Abbott Diabetes Care Inc. Interconnect for on-body analyte monitoring device
US9351669B2 (en) 2009-09-30 2016-05-31 Abbott Diabetes Care Inc. Interconnect for on-body analyte monitoring device
US9215992B2 (en) 2010-03-24 2015-12-22 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
US9186098B2 (en) 2010-03-24 2015-11-17 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
US9265453B2 (en) 2010-03-24 2016-02-23 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
US9687183B2 (en) 2010-03-24 2017-06-27 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
US8764657B2 (en) 2010-03-24 2014-07-01 Abbott Diabetes Care Inc. Medical device inserters and processes of inserting and using medical devices
US9572534B2 (en) 2010-06-29 2017-02-21 Abbott Diabetes Care Inc. Devices, systems and methods for on-skin or on-body mounting of medical devices
US9743862B2 (en) 2011-03-31 2017-08-29 Abbott Diabetes Care Inc. Systems and methods for transcutaneously implanting medical devices
US9693713B2 (en) 2011-12-11 2017-07-04 Abbott Diabetes Care Inc. Analyte sensor devices, connections, and methods
US9402570B2 (en) 2011-12-11 2016-08-02 Abbott Diabetes Care Inc. Analyte sensor devices, connections, and methods
US9931066B2 (en) 2017-05-31 2018-04-03 Abbott Diabetes Care Inc. Analyte sensor devices, connections, and methods

Similar Documents

Publication Publication Date Title
Kessler et al. An automated procedure for the simultaneous determination of calcium and phosphorus
Hill Automated fluorometric method for determination of serum calcium
Babson et al. The use of a diazonium salt for the determination of glutamic-oxalacetic transaminase in serum
Amador et al. Serum lactic dehydrogenase activity: an analytical assessment of current assays
Willis Determination of calcium and magnesium in urine by atomic absorption spectroscopy
Morgenstern et al. Automated determination of NAD-coupled enzymes. Determination of lactic dehydrogenase
Ohnishi et al. A simplified method of quantitating protein using the biuret and phenol reagents
Estabrook et al. [74] The fluorometric determination of mitochondrial adenine and pyridine nucleotides
Noto et al. Simple, rapid spectrophotometry of urinary N-acetyl-beta-D-glucosaminidase, with use of a new chromogenic substrate.
Bronstein et al. Chemiluminescent assay of alkaline phosphatase applied in an ultrasensitive enzyme immunoassay of thyrotropin.
Wybenga et al. Direct manual determination of serum total cholesterol with a single stable reagent
Kageyama A direct colorimetric determination of uric acid in serum and urine with uricase-catalase system
Teppo Immunoturbidimetry of albumin and immunoglobulin G in urine.
US4396579A (en) Luminescence detection device
US5232835A (en) Qualitative immunochromatographic method and device
Evans Manual and automated methods for measuring urea based on a modification of its reaction with diacetyl monoxime and thiosemicarbazide.
US4302534A (en) Chemiluminescent enzyme immunoassay
US3791988A (en) Diagnostic test for glucose
Pearlman et al. Detection and measurement of total bilirubin in serum, with use of surfactants as solubilizing agents
US4766083A (en) Method for the photometric determination of biological agglutination
US3973129A (en) Fluorimetric apparatus and method for analysis of body fluid
Christopoulos et al. Enzymically amplified time-resolved fluorescence immunoassay with terbium chelates
Rosenthal Determination of urea in blood and urine with diacetyl monoxime
Lanzetta et al. An improved assay for nanomole amounts of inorganic phosphate
Macpherson Modified procedures for the colorimetric estimation of arginine and histidine