WO2002079778A2 - Methodes d'administration in vivo et compositions - Google Patents

Methodes d'administration in vivo et compositions Download PDF

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Publication number
WO2002079778A2
WO2002079778A2 PCT/US2002/003984 US0203984W WO02079778A2 WO 2002079778 A2 WO2002079778 A2 WO 2002079778A2 US 0203984 W US0203984 W US 0203984W WO 02079778 A2 WO02079778 A2 WO 02079778A2
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WO
WIPO (PCT)
Prior art keywords
blood
viscosity
agents
agent
flavor
Prior art date
Application number
PCT/US2002/003984
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English (en)
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WO2002079778A3 (fr
Inventor
Kenneth Kensey
Original Assignee
Rheologics, Inc.
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
Priority claimed from US09/819,924 external-priority patent/US20010044584A1/en
Application filed by Rheologics, Inc. filed Critical Rheologics, Inc.
Priority to AU2002306461A priority Critical patent/AU2002306461A1/en
Publication of WO2002079778A2 publication Critical patent/WO2002079778A2/fr
Publication of WO2002079778A3 publication Critical patent/WO2002079778A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6866—Extracorporeal blood circuits, e.g. dialysis circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/02028—Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
    • A61B5/02035—Determining blood viscosity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3607—Regulation parameters
    • A61M1/3609—Physical characteristics of the blood, e.g. haematocrit, urea
    • A61M1/361—Physical characteristics of the blood, e.g. haematocrit, urea before treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3672—Means preventing coagulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026—Measuring blood flow
    • A61B5/029—Measuring or recording blood output from the heart, e.g. minute volume
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/04—Heartbeat characteristics, e.g. ECG, blood pressure modulation

Definitions

  • This invention relates generally to apparatus and methods for determining and utilizing the viscosity of the circulating blood of a living being for diagnostics and treatment, and more particularly, apparatus and methods for detecting/reducing blood viscosity, work of the heart, contractility of the heart, for detecting/reducing the surface tension of the blood, for detecting plasma viscosity, for explaining/countering endothelial cell dysfunction, for providing high and low blood vessel wall shear stress data, red blood cell deformability, lubricity of blood, and for treating different ailments, such as peripheral arterial disease.
  • the Goldman Algorithm Revisited Prospective Evaluation of a Computer-Derived Algorithm Versus Unaided Physician Judgment in Suspected Acute Myocardial Infarction, by Qamar, et al., Am Heart J 138(4):705-709, 1999, discusses the use of the Goldman algorithm for providing an indicator to acute myocardial infarction.
  • the Goldman algorithm basically utilizes facts from a patient's history, physical examination and admission (emergency room) electrocardiogram to provide an AMI indicator.
  • the Smythe '063 patent discloses an apparatus for measuring the viscosity of a blood sample based on the pressure detected in a conduit containing the blood sample.
  • the Kron '097 patent discloses a method and apparatus for determining the blood viscosity using a flowmeter, a pressure source and a pressure transducer.
  • the Philpot '538 patent discloses a method of determining blood viscosity by withdrawing blood from the vein at a constant pressure for a predetermined time period and from the volume of blood withdrawn.
  • the Philpot '363 patent discloses an apparatus for determining blood viscosity using a hollow needle, a means for withdrawing and collecting blood from the vein via the hollow needle, a negative pressure measuring device and a timing device.
  • the Ringrose '405 patent discloses a method for measuring the viscosity of blood by placing a sample of it on a support and directing a beam of light through the sample and then detecting the reflected light while vibrating the support at a given frequency and amplitude.
  • the Weber '632 patent discloses a method and apparatus for determining the fluidity of blood by drawing the blood through a capillary tube measuring cell into a reservoir and then returning the blood back through the tube at a constant flow velocity and with the pressure difference between the ends of the capillary tube being directly related to the blood viscosity.
  • the Gunn '830 patent discloses an apparatus for determining blood viscosity that utilizes a transparent hollow tube, a needle at one end, a plunger at the other end for creating a vacuum to extract a predetermined amount and an apertured weight member that is movable within the tube and is movable by gravity at a rate that is a function of the viscosity of the blood.
  • the Kiesewetter '239 patent discloses an apparatus for determining the flow shear stress of suspensions, principally blood, using a measuring chamber comprised of a passage configuration that simulates the natural microcirculation of capillary passages in a being.
  • the Kiesewetter '821 patent discloses another apparatus for determining the viscosity of fluids, particularly blood, that includes the use of two parallel branches of a flow loop in combination with a flow rate measuring device for measuring the flow in one of the branches for determining the blood viscosity.
  • the Kron '127 patent discloses an apparatus and method for determining blood viscosity of a blood sample over a wide range of shear rates.
  • the Merrill '577 patent discloses an apparatus and method for determining the blood viscosity of a blood sample using a hollow column in fluid communication with a chamber containing a porous bed and means for measuring the blood flow rate within the column.
  • the Hori '678 patent discloses a method for measurement of the viscosity change in blood by disposing a temperature sensor in the blood flow and stimulating the blood so as to cause a viscosity change.
  • the Esvan '415 patent discloses an apparatus that detects the change in viscosity of a blood sample based on the relative slip of a drive element and a driven element, which holds the blood sample, that are rotated.
  • the Taniguchi '529 patent discloses a method and apparatus for determining the viscosity of liquids, e.g., a blood sample, utilizing a pair of vertically-aligned tubes coupled together via fine tubes while using a pressure sensor to measure the change of an internal tube pressure with the passage of time and the change of flow rate of the blood.
  • the Bedingham '328 patent discloses an intravascular blood parameter sensing system that uses a catheter and probe having a plurality of sensors (e.g., an O 2 sensor, CO 2 sensor, etc.) for measuring particular blood parameters in vivo.
  • the Schlain '398 patent discloses a intra-vessel method and apparatus for detecting undesirable wall effect on blood parameter sensors and for moving such sensors to reduce or eliminate the wall effect.
  • the Davis '440 patent discloses an apparatus for conducting a variety of assays that are responsive to a change in the viscosity of a sample fluid, e.g., blood.
  • Viscosity measuring methods and devices for fluids in general are well-known. See for example, U.S. Patent Nos.: 1 ,810,992 (Dallwitz-Wegner); 2,343,061 (lrany); 2,696,734 (Brunstrum etal.); 2,700,891 (Shafer); 2,934,944 (Eolkin); 3,071 ,961 (Heigl et al.); 3,116,630 (Piros); 3,137,161 (Lewis et al.); 3,138,950 (Welty et al.); 3,277,694 (Cannon et al.); 3,286,511 (Harkness); 3,435,665 (Tzentis); 3,520,179 (Reed); 3,604,247 (Gramain et al.); 3,666,999 (Moreland, Jr.
  • U.S. patents disclose viscosity or flow measuring devices, or liquid level detecting devices using optical monitoring: U.S. Patent Nos. 3,908,441 (Virloget); 5,099,698 (Kath, et. al.); 5,333,497.
  • the Virloget '441 patent discloses a device for use in viscometer that detects the level of a liquid in a transparent tube using photodetection.
  • the Kath '698 patent discloses an apparatus for optically scanning a rotameter flow gauge and determining the position of a float therein.
  • U.S. Patent No. 5,333,497 (Br nd Dag A. et al.) discloses a method and apparatus for continuous measurement of liquid flow velocity of two risers by a charge coupled device (CCD) sensor.
  • CCD charge coupled device
  • U.S. Patent No.5,421 ,328 (Bedingham) discloses an intravascular blood parameter sensing system.
  • a statutory invention registration, H93 discloses an apparatus and method for measuring elongational viscosity of a test fluid using a movie or video camera to monitor a drop of the fluid under test.
  • Hevimet 40 A device called the "Hevimet 40" has recently been advertised at www.hevimet.freeserve.co.uk.
  • the Hevimet 40 device is stated to be a whole blood and plasma viscometer that tracks the meniscus of a blood sample that falls due to gravity through a capillary. While the Hevimet 40 device may be generally suitable for some whole blood or blood plasma viscosity determinations, it appears to exhibit several significant drawbacks. For example, among other things, the Hevimet 40 device appears to require the use of anti-coagulants. Moreover, this device relies on the assumption that the circulatory characteristics of the blood sample are for a period of 3 hours the same as that for the patient's circulating blood. That assumption may not be completely valid. Also, due to surface alteration, the device requires cleaning after each test.
  • compositions pharmaceutically effective to regulate blood viscosity comprising at least two agents selected from the group consisting of intravenous diluents, red blood cell deformability agents, antiurea agents, oral contraceptives, anti- diabetic agents, antiarrythmics, antihypertensives, antihyperlipidemics, antiplatelet agents, appetite suppressants, antiobesity agents, blood modifiers, smoking deterrent agents, nutritional supplements, endocrine agents, gastrointestinal agents, anti- neoplastic agents, CNS agents, anti-infective agents, anti-asthmatic and pulmonary agents, opthalmic agents, chelating agents and granulocyte colony stimulating factors.
  • compositions pharmaceutically effective to regulate plasma viscosity comprising at least two agents selected from the group consisting of anti-diabetics, intravenous solutions, cholesterol-lowering agents, triglyceride-lowering agents, lubricants, homocysteine-reducing agents, and vitamin supplements. It is still further another object of the present invention to provide a composition pharmaceutically effective to regulate the work of the heart, said composition comprising at least two agents selected from the group consisting of beta- blockers, calcium channel blockers, ACE inhibitors, ACE-II inhibitors, vasodilators, blood pressure reducing agents, viscosity reducing agents and anti-diabetic agents.
  • compositions pharmaceutically effective to regulate low shear stress comprising at least two agents selected from the group consisting of beta blockers, calcium channel blockers, ACE inhibitors, ACE-II inhibitors, vasodilators, blood pressure reducing agents, viscosity reducing agents, contractility reducing agents, anti-diabetics, and anti-obesity agents.
  • compositions pharmaceutically effective to regulate high shear stress comprising at least two agents selected from the group consisting of intravenous solutions, anti-diabetics, hemodilution agents, anti-platelet agents, lubricity enhancing agents and adhesiveness minimizing agents.
  • compositions pharmaceutically effective to regulate the contractility of the heart comprising at least two agents selected from the group consisting of beta- blockers, calcium channel blockers, and peripheral antiadrenergic/sympatholytics.
  • compositions pharmaceutically effective to regulate the thrombogenicity of the heart comprising at least two agents selected from the group consisting of anti-thrombogenic agents.
  • compositions pharmaceutically effective to regulate platelet aggregation comprising at least two agents selected from the group consisting of warfarin, heparin, and anti-platelet agents.
  • composition pharmaceutically effective to regulate lubricity said composition comprising at least two agents selected from the group consisting of intravenous fluids, lubricants, anti-adhesives, surfactants, and saponifying agents. It is still yet another object of the present invention to provide a composition pharmaceutically effective to regulate thixotropy, said composition comprising at least two agents selected from the group consisting of sodium bentonite magma, colloidal clays, colloidal silicon dioxide, and microcrystalline cellulose.
  • compositions pharmaceutically effective to regulate yield stress comprising at least two agents selected from the group consisting of gels of colloidal clays, such as sodium bentonite, gels of organic polymers, such as gelatin, agar, pectin, methylcellulose, and high-molecular-weight polyethylene glycol.
  • compositions pharmaceutically effective to regulate endothelial shear injury comprising at least two agents selected from the group consisting of beta- blockers and viscosity reducing agents.
  • compositions pharmaceutically effective to regulate coagulability comprising at least two agents selected from the group consisting of anti-thrombogenics, anti-platelets, heparin, and anti-coagulants.
  • compositions pharmaceutically effective to regulate coagulation time comprising at least two agents selected from the group consisting of anti-thrombogenics and anti-platelets, heparin, and anti-coagulants.
  • compositions pharmaceutically effective to regulate agglutination comprising at least two agents selected from the group consisting of anti-platelets and anti-coagulants.
  • compositions pharmaceutically effective to regulate clot retraction comprising at least two agents selected from the group consisting of anti-thrombogenics and anti-platelets, and anti-coagulants.
  • compositions pharmaceutically effective to regulate clot lysis time comprising at least two agents selected from the group consisting of anti-thrombogenics, anti-platelets, and anti-coagulants.
  • compositions pharmaceutically effective to regulate prothrombin rates comprising at least two agents selected from the group consisting of heparin, warfarin and anti-coagulants.
  • a method for distributing and administering a substance through a bloodstream of an organism comprising: monitoring at least one blood flow parameter of said bloodstream, said at least one blood flow parameter being selected from the group consisting of circulating blood viscosity, absolute viscosity, effective viscosity, low shear viscosity, high shear viscosity, shear rate of circulating blood, work of heart, contractility of heart, thrombogenicity, platelet aggregation, lubricity, red blood cell deformability, thixotropy, yield stress, coagulability, coagulation time, agglutination, clot retraction, clot lysis time, sedimentation rate and prothrombin rate; administering said substance to said organism such that an amount of said substance enters said bloodstream; and distributing at least a portion of said amount of said substance to at least one target within said organism, wherein a distribution parameter of said distributing
  • compositions for administration to an organism having a circulatory system comprising: a pharmaceutically active agent; and a distribution agent effective to increase or decrease distribution of said pharmaceutically active agent through said circulatory system by increasing or decreasing at least one blood flow parameter selected from the group consisting of circulating blood viscosity, absolute viscosity, effective viscosity, low shear viscosity, high shear viscosity, shear rate of circulating blood, work of heart, contractility of heart, thrombogenicity, platelet aggregation, lubricity, red blood cell deformability, thixotropy, yield stress, coagulability, coagulation time, agglutination, clot retraction, clot lysis time, sedimentation rate and prothrombin rate, wherein said distribution agent is not a diluent.
  • a method for reducing endothelial cell dysfunction in a living being which is caused by oscillating flow of the circulating blood of the living being.
  • the method comprises the step of reducing the viscosity of the circulating blood of the living being.
  • a method for reducing endothelial cell dysfunction in a living being which is caused by oscillating flow of the circulating blood of the living being.
  • the method comprises the steps of reducing the rate of ejection of the blood from the heart and reducing the viscosity of the circulating blood of the living being.
  • the method comprises the step of administering the combination of ⁇ -blocker, ACE inhibitor and blood viscosity reducing drugs together to a living being experiencing hypertension.
  • the method comprises the step of administering a blood viscosity reducing drug, including but not limited to intravenous diluents, red blood cell deformability agents, antiurea agents, oral contraceptives, anti-diabetic agents, antiarrythmics, antihypertensives, antihyperlipidemics, antiplatelet agents, appetite suppressants, anti-obesity agents, blood modifiers, smoking deterrent agents, nutritional supplements, endocrine agents, gastrointestinal agents, anti- neoplastic agents, CNS agents, anti-infective agents, anti-asthmatic and pulmonary agents, opthalmic agents, chelating agents and granulocyte colony stimulating factors, and any derivatives and/or combinations thereof to a living being.
  • a blood viscosity reducing drug including but not limited to intravenous diluents, red blood cell deformability agents, antiurea agents, oral contraceptives, anti-diabetic agents, antiarrythmics, antihypertens
  • an apparatus for determining the hematocrit of the circulating blood of a living being without having to separate red blood cells from the plasma of the circulating blood comprises an optical analysis means.
  • a method for analyzing the viscosity of the circulating blood of a living being comprises the steps of: (a) determining viscosity data of the living being's circulating blood for a plurality of shear rates over a test run time; (b) segmenting the test run time into a plurality of time segments; and (c) generating a blood viscosity profile for each of the time segments from the beginning of the test run until the end of each of the time segments.
  • the apparatus comprises a blood column height determinator based on capillary rise.
  • a method for determining whether a drug reduces or increases the surface tension of the circulating blood of a living being comprising the steps of: (a) determining the surface tension of the circulating blood of a living being utilizing a blood column height determinator based on capillary rise; (b) administering a drug to the living being; and (c) re-determining the surface tension of the circulating blood of the living being utilizing the blood column height determinator to see the change in the surface tension.
  • a method for improving blood perfusion to the lower extremities of a living being experiencing peripheral arterial disease comprises the steps of: (a) determining the viscosity of the circulating blood of the living being over a range of shear rates; (b) reducing the viscosity of the circulating blood by administering a substance to the living being or by blood letting; and (c) re-determining the viscosity of the circulating blood of the living being over the range of shear rates to verify the reduction in the viscosity.
  • the apparatus comprises a plurality of tubes closely adjacent one another and each having an inner diameter different from its neighbor. Furthermore, each of the plurality of tubes has an opening exposed to a flow of circulating blood and each of the tubes being closed at its other end for collecting red blood cells therein.
  • an apparatus for detecting the lubricity of the circulating blood of a living being as the blood travels through the vascular system of the living being comprises: a transparent tube for passing a falling column of the circulating blood of the living being; an illuminator for directing light at a portion of the transparent tube that contains a residue left by the falling column; a detector for detecting any light that passes through the transparent tube and residue and generating corresponding detection data; and calculation means for receiving the detection data and generating a lubricity value based on the detection data.
  • prophylactic and therapeutic compositions and methods for controlling at least one property of blood measured by the apparatus and methods of the invention are also achieved by prophylactic and therapeutic compositions and methods for controlling at least one property of blood measured by the apparatus and methods of the invention.
  • a method for administering a medication to a living being comprising: (a) providing an apparatus according to the invention, which is adapted to measure at least one blood flow parameter of the living being selected from the group consisting of circulating blood viscosity, absolute viscosity, effective viscosity, low shear viscosity, high shear viscosity, shear rate of circulating blood, work of heart, contractility of heart, thrombogenicity, platelet aggregation, lubricity, red blood cell deformability, thixotropy, yield stress, coagulability, coagulation time, agglutination, clot retraction, clot lysis time, sedimentation rate and prothrombin rate; (b) supplying a sample of the living being's blood to the at least one apparatus; and (c) measuring the at least one blood flow parameter to determine whether and how to administer the medication to the living being, wherein the apparatus is at least one member selected from the group
  • Fig. 1 is a block diagram of a dual riser/single capillary (DRSC) viscometer;
  • Fig. 1A is a functional diagram of the first embodiment of the DRSC viscometer during the viscosity test run;
  • DRSC dual riser/single capillary
  • Fig. 2 is a block diagram of another DRSC viscometer
  • Fig. 2A is a functional diagram of the second embodiment of the DRSC viscometer during the viscosity test run;
  • Fig. 3A is the graphical depiction of the cardiac output of the heart of a living being
  • Fig. 3B is a graphical depiction of the pressure pulse of the heart of a living being
  • Fig. 3C is a blood viscosity vs. time plot for a living being
  • Fig. 3D is a graphical depiction of the pressure pulse of the heart of a living being having a first contractility, and another pressure pulse of the heart having a second increased contractility;
  • Fig. 3E is a graphical depiction of how the contractility of the heart of a living being can be determined from the pressure pulse curve
  • Fig. 4 is a flow diagram of a portion of an artery showing a bifurcation
  • Fig. 5A is an enlarged view of healthy, normal endothelial cells located along a portion of an arterial wall;
  • Fig. 5B is an enlarged view of dysfunctional endothelial cells, e.g., endothelial cells located along a portion of an arterial wall opposite a bifurcation;
  • Fig. 6 is a functional diagram of a hematocrit analyzer of the present invention.
  • Fig. 7 is an enlarged view of a portion of the hematocrit analyzer showing a predetermined window used in the hematocrit analysis
  • Fig. 8 is an alternative lumen for use in the hematocrit analyzer
  • Figs. 9A-9C together constitute the plasma viscosity analyzer
  • Fig. 10 depicts a graphical representation of the respective columns of fluid in the riser tubes of either the first or second embodiment of the DRSC viscometer during the viscosity test run;
  • Fig. 11 depicts a graphical representation of the absolute viscosity profile versus the effective viscosity profile corresponding to Fig. 10
  • Fig. 12A depicts a typical graphical representation of the absolute viscosity profile versus the effective viscosity profile for a living being
  • Fig. 12B depicts a graphical representation of the absolute viscosity profile versus the effective viscosity profile for a healthy living being
  • Fig. 12C depicts a graphical representation of the effective viscosity profile for a living being under test versus the effective viscosity profile of a normal, healthy individual;
  • Fig. 13 is a table for presenting blood pressure and blood viscosity parameters in a matrix fashion for indicating both high and low blood vessel wall shear stress data;
  • Fig. 14A is an enlarged view of the top of the riser having a falling blood column showing a meniscus
  • Fig. 14B depicts a blood lubricity detector used in conjunction with the riser tube of Fig. 14A;
  • Fig. 14C depicts blood lubricity plots for several living beings under test
  • Fig. 15 depicts a red blood cell deformability analyzer
  • Figs. 16A-16B depict a surface tension analyzer
  • Fig. 17 depicts a graphical representation of the respective columns of fluid in the riser tubes of either the first or second embodiment of the DRSC viscometer during the viscosity test run wherein the height vs. time data is segmented into a plurality of shear rate regions;
  • Figs. 18A and 18B are blood viscosity profiles for a patient A and a patient B, respectively, based on the various shear rate regions depicted in Fig. 17;
  • Fig. 19 depicts one full blood viscosity profile including the extreme high and low shear rate ranges
  • Fig. 20 depicts a method for improving blood profusion in the lower extremities of a living being
  • Fig. 21 depicts a method for treating low shear injury through the use of a surface tension analyzer
  • Fig. 22 depicts red blood cell bonding at both a high shear and low shear conditions.
  • the apparatus disclosed in A.S.N. 09/439,795 comprises a first embodiment of a dual riser/single capillary (DRSC) viscometer shown in Figs. 1 and 1A, and a second embodiment of the DRSC viscometer shown in Figs. 2 and 2A, each of which measures the viscosity of circulating blood, including whole blood, of a living being.
  • DRSC viscometers 20 (Fig.1 ) and 120 (Fig. 2) comprise a blood receiving means 22 and 122, respectively, and an analyzer/output portion 24.
  • the patient is coupled to the DRSC viscometers 20/120 through a circulating blood conveying means 26, e.g., a needle, an IV needle, an in-dwelling catheter, etc., or any equivalent structure that can convey circulating blood from a patient to the DRSC viscometers 20/120.
  • the analyzer/output portion 24 includes a microprocessor 58 that, among other things, calculates the circulating blood viscosity based on the information that it receives from the blood receiving means 22/122.
  • a display 28 is also provided for presenting the viscosity information, as well as other information to the operator.
  • the analyzer/output portion 24 may also provide this information to other suitable output means 30, such as a datalogger 32, other computer(s) 34, a printer 36, a plotter 38, remote computers/storage 40, to the Internet 42 or to other on-line services 44.
  • suitable output means such as a datalogger 32, other computer(s) 34, a printer 36, a plotter 38, remote computers/storage 40, to the Internet 42 or to other on-line services 44.
  • the blood receiving means 22/122 basically comprises a valve mechanism 46 coupled between a first riser tube R1 and a second riser tube R2 (Figs. 1-2), or coupled to one end of one of the riser tubes (Figs. 3-4), for controlling the input circulating blood flow into the DRSC viscometers 20/120.
  • a capillary tube 52 of known dimensions is coupled to one of the riser tubes (e.g., as shown in Fig. 2), or is coupled between the riser tubes (e.g., as shown in Fig. 4).
  • the valve mechanism 46 in both embodiments establishes a first initial position, h 1i( of a column of blood (h.,) in one of the riser tubes (e.g., R1 ) and a second initial position, h 2i , of another column of blood (h 2 ) in the other of the riser tubes (e.g., R2).
  • the valve mechanism 46 then isolates these columns of blood from the input circulating blood flow, resulting in the oppositely-moving columns of blood away from their initial positions as shown in Figs. 1A and 2A.
  • each column of blood is monitored by a respective column level detector 54 and 56 which send their data to the microprocessor 58.
  • the column level detectors 54/56 collect data (h ⁇ t) and h 2 (t)) regarding the movement of these respective columns of blood, which can also be plotted (Fig. 10) and then displayed on the display screen 28.
  • time data for the other column of blood can be generated by using a single height point from that column.
  • it is only necessary to monitor the change in position of one of the columns of blood in either riser tube R1 or riser tube R2 and to detect only one point from the other column of blood.
  • the preferred method/means is to monitor the rising column of blood 84 which occurs in riser tube R2 and to detect the initial viscosity test run level (i.e., h 1i; as discussed in A.S.N. 09/439,795) of the column of blood 82 in riser tube R1.
  • a monitor that monitors either one of the moving columns of blood (which also includes methodologies known in the art such as monitoring the change in position, column height, weight, volume, mass, etc.) but not both columns (as is disclosed in A.S.N. 09/439,795) and a single point detector for detecting one point from the other moving column of blood.
  • a blood column movement indicator is also provided.
  • This indicator provides either a visual and/or audible indication of the blood column movement. For example, as either the falling column moves downward or the rising column moves upward, the indicator provides a flashing light whose flash rate is proportional to the speed of either the falling or rising column movement. Alternatively, or in addition, the indicator provides a continuous beeping sound whose beeping rate is proportional to the speed of either the falling or rising column.
  • the indicator flashes and/or beeps at a high rate; near the end of the viscosity test run when the falling and rising columns are moving very slowly, the indicator flashes very slowly and/or beeps a slow rate.
  • the blood column movement indicator comprises including a sound card (e.g., Sound Blaster AWE64 manufactured by Creative) and speaker (not shown) in the display 28.
  • the processor 58 activates the speaker card which causes the speaker to emit a sound whose intensity varies with the speed of the blood column.
  • the graphical depiction of the two height vs. time plots in the graphical display 61 can flash at a rate that varies with the speed of the column movement.
  • a hematocrit analyzer 300 plasma viscosity analyzer 400, surface tension analyzer 500, and red blood cell deformability analyzer 600. The details of each of these will be discussed in below.
  • a valve 700 is used which permits a predetermined amount of blood to enter the respective analyzer and then closes off the path to these means.
  • WOH can be estimated from the following equation:
  • P(t) is the pressure pulse curve of the heart (Fig. 3B);
  • T represents the period of one cardiac cycle.
  • the flow resistance comes from the piping arrangement and the type of fluids.
  • the flow rate i.e., cardiac output
  • the Poiseuille flow describes the flow rate (Q) in terms of the viscosity ( ⁇ ) of the fluid, the length (L) of the tube, the inside diameter (d) of the tube and the pressure drop ( ⁇ P) across the length of the tube, and is given as:
  • the WOH is given as:
  • ⁇ P(t) represents the pressure difference between the ends of a blood vessel of a fixed diameter and length.
  • the vascular system between the heart (aorta) and vein is composed of blood vessels having different diameters and corresponding lengths which are known in the art. Since the pressure at the capillary bed can be approximated to be zero, the term, ⁇ P(t), can be approximated with the pressure pulse term, P(t), such that the equation for WOH is defined as:
  • d and “L” represent average diameter and length of the entire vascular system of a living being.
  • the pressure pulse of the heart, P(t) can be detected by conventional medical equipment using, e.g., skin sensors and a digital storage oscilloscope.
  • the viscosity ⁇ (t) of the circulating blood of a living being can be determined (Fig. 3C) using the viscometers 20/120, it is now possible to determine the WOH of the living being.
  • the contractility of the heart is the rate of ejection of blood by the left ventricle of the heart (Fig. 3D). The faster the heart squeezes blood out of the left ventricle, the greater is the contractility of the heart. In particular, as the contractility of the heart increases (from the dotted line 250 which indicates a first lower COH to the solid line 252 which indicates a second higher COH in the direction of the arrow 254), the pressure pulse wave becomes steeper during systole. Another term for COH is the "pulsatility" of the heart.
  • the contractility can be measured from the pressure pulse curve (Fig. 3E).
  • the slope of the pressure pulse curve in the beginning of systole represents how fast the left ventricle of the heart ejects blood. Hence, the slope represents the contractility of the heart.
  • Arterial disease often occurs at bifurcations (Fig. 4), but not in straight vessels. Hence, it is often called site-specific disease.
  • blood flow recirculation occurs on the wall 256 opposite the flow divider 255 but has heretofore not been explained.
  • One of the reasons may be hemodynamics.
  • a recirculation flow in an unsteady, pulsatile blood flow means that the wall shear stress between LC1 and LC2 is alternating between a negative value (e.g., - 5 dyne/cm 2 ) and a positive value (i.e., +5 dyne/cm 2 ).
  • This same type of pressure differential also occurs at the proximal side 265 of the flow divider 255.
  • a recirculation flow in an unsteady, pulsatile blood flow also occurs between location LC3 and location LC4 wherein P LC4 > P LC3 . This pressure differential forces some fluid elements to move upstream, producing a recirculation flow in the branch flow 258.
  • the wall shear stress between LC3 and LC4 is alternating between a negative value (e.g., - 5 dyne/cm 2 ) and a positive value (i.e., +5 dyne/cm 2 ).
  • This alternating wall shear stress can be viewed as a sandpaper or abrading effect.
  • the effect of this alternating shear on endothelial cells is very serious and the key to the arterial disease.
  • endothelial cells 266 (Fig. 5B) become more rounded, forming dysfunctional endothelial cells which expose leaky sites, whereas normal, healthy endothelial cells 264 are elongated and contiguous (Fig. 5A).
  • E-cells endothelial cells in a recirculating area become more rounded than elongated along the flow direction.
  • Rounded E-cells are more permeable so that lipid and other macromolecules can move through the endothelial cell layer from blood to arterial wall 267 via the gaps, i.e., leaky sites 268.
  • the E-cells do not perform their normal function and are called dysfunctional E-cells.
  • E-cells become rounded, the life of the cells become short, i.e., the cell turnover becomes high.
  • E-cells become dysfunctional this causes a series of biological responses, including the production of nitric oxide (NO).
  • NO nitric oxide
  • E-cells become dysfunctional due to oscillating/alternating wall shear stress in the low shear zones (1 ) at the wall 256 opposite the flow divider 255 and (2) at the proximal side 265 of the branch vessel 255.
  • the wall shear stress at the opposite wall 256 may vary from -10 to +10 dyne/cm 2 .
  • the contractility of the heart by reducing the contractility of the heart one can normalize the E-cell, reduce the number of dysfunctional E-cells, reduce cell turnover, reduce leaky sites, and reduce permeability of E-cells.
  • the benefit of reducing contractility is to reduce the transport of lipids and other macromolecules across the E-cell layer, thus preventing the initiation and progression of arterial disease or atherosclerosis.
  • drugs such as beta-blockers
  • Smoking is known to increase the contractility of the heart, thus accelerating the progress of atherosclerosis.
  • Alcohol is well-known to relax the muscle of the left ventricle of the heart, thus decreasing the contractility of the heart.
  • Caffeine can increase the contractility of the heart.
  • risk factors such as those addressed above, can be correlated to the contractility of the heart of a living being.
  • Blood viscosity affects the global hemodynamics at arterial vessels, particularly at arterial bifurcation 255, thus affecting E-cells.
  • the flow separation zone increases and the magnitude of the alternating wall shear stress (i.e., the positive and negative values) is amplified.
  • the magnitude (or level) of the alternating wall shear stress decreases, resulting in more healthy E-cells, i.e., less dysfunctional E-cells.
  • the shape of the E- cells is less round and the E-cell turnover decreases.
  • the reduced blood viscosity can reduce the transport of lipids and macromolecules across the E-cell layer (i.e., intima). Therefore, any drug compositions reducing blood viscosity can reduce the number of dysfunctional E-cells which are often called intimal injury at the early stage of atherosclerosis.
  • drugs known to reduce viscosity include, but are not limited to, intravenous diluents, red blood cell deformability agents, antiurea agents, oral contraceptives, anti-diabetic agents, antiarrythmics, antihypertensives, antihyperlipidemics, antiplatelet agents, appetite suppressants, antiobesity agents, blood modifiers, smoking deterrent agents, nutritional supplements and any derivatives and/or combinations thereof.
  • oral contraceptives, antiplatelet agents and antihyperlipidemics are preferred.
  • oral contraceptives consisting essentially of levonorgestrel, estrogen, progestin, estradiol, ethinyl estradiol, ethynodiol, medroxyprogesterone, desogestrel, cyproterone, norethindrone, gestodene, norgestrel, mestranol, or norgestimate, including their salts, derivatives and any combinations thereof, antihypieripidemic agents, and abciximab which is commercially available from Eli Lilly & Co. as the prescription product ReoPro ® .
  • Suitable intravenous diluents include, but are not limited to, saline, deionized water, and any derivatives and/or combinations thereof.
  • Suitable antidiabetic agents include, but are not limited to, metformin, acarbose, insulins including all salts and crystalline forms, chlorpropamide, glipizide, glyburide, tolazamide, glimepiride, troglitazone, pioglitazone, repaglinide, losartan potassium, candesartan cilexetil, irbesartan, mitiglinide, trendolapril/verapamil, nateglinide, repaglinide, and any derivatives and/or combinations thereof.
  • Suitable antihypertensive agents include, but are not limited to, nifedipine, nisoldipine, nicardipine , bepridil, isradipine, nimodipine, felodipine, amlodipine, diltiazem, verapamil, isosorbide mononitrate, isosorbide dinitrate, nitroglycerin, hydralazine, minoxidil, hydrochlorothiazide, chlorothiazide, indapamide, metolazone, furosemide, bumetanide, ethacrynic acid, torsemide, spironolactone, triamterene, acetazolamide, mannitol, atenolol, bisoprolol, pindolol, metoprolol, timolol, nadolol, propanolol, carvedilol, captopril, fo
  • Suitable distribution agents and pharmaceutical agents include the vasoconstrictor, sumatriptan, and the vasodilator, milrinone, and derivatives of them.
  • Suitable antihypieripidemic agents include, but are not limited to, lovastatin, atorvastatin, cerivastatin, simvastatin, fluvastatin, cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate, pamaqueside, pitavastatin, and any derivatives and/or combinations thereof.
  • Suitable appetite suppressants and anti-obesity agents include, but are not limited to, phentermine, phendimetrazine, sibutramine, orlistat and any derivatives and/or combinations thereof.
  • Suitable blood modifiers include, but are not limited to, aspirin, warfarin, enoxaparin, heparin, low molecular weight heparin, cilostazol, clopidogrel, ticlopidine, tirofiban, abciximab, dipyridamole, plasma protein fraction, human albumin, low molecular weight dextran, hetastarch, reteplase, alteplase, streptokinase, urokinase, dalteparin, filgrastin, immunoglogulin, ginkolide B, clopidogrel, hirudins, foropafant, rocepafant, bivalirudin, dermatan sulfate mediolanum, eptilibatide, tirofiban, thrombomodulin, abcxmab, low molecular weight dermatan sulfate-opocrin, eptacog al
  • distribution agents and blood modifiers can be selected from the following list, and titrated for optimal concentrations based on the information and techniques described elsewhere herein: acacia; acacia mucilage; acetic acid; acetic acid, glacial; acetic anhydride; acetone sodium bisulfite; acetyl tributyl citrate; acetylated monoglycerides; acetylcysteine; acrylates copolymer; adcote 72A103; aerosil 380; aerosil-200; aerotex resin 3730; air; albumin aggregated; albumin colloidal; albumin human; alcohol (especially ethanol); alcohol, dehydrated; alcohol, denatured; alcohol, diluted; alginic acid; alkyl ammonium sulfonic acid betaine; alkyl aryl sodium sulfonate; allantoin; althea; aluminum acetate; aluminum hydroxide; aluminum hydroxide-sucrose, hydrated;
  • flavor cherry EP- 3699 flavor cherry F-232; flavor cherry FMC 8513; flavor cherry IFF 13530912; flavor cherry maraschino S-3531 ; flavor cherry mint; flavor cherry N-2755; flavor cherry R- 6556; flavor cherry raspberry; flavor cherry WL-1093; flavor cherry WL-18022; flavor cherry WL-4658; flavor cherry 11539; flavor cherry 181612; flavor cherry 3321 ; flavor cherry 338614; flavor cherry 349; flavor cherry 500910U; flavor cherry 594 S.D.; flavor cherry-anise; flavor cherry-anise PFC 9758; flavor chocolate; flavor chocolate cream; flavor chocolate P727; flavor citrus; flavor citrus mint; flavor citrus-vanilla; flavor cocoa; flavor coconut custard; flavor cola FMC 1574; flavor cough syrup 110257; flavor cream; flavor creme de menthe; flavor creme de menthe 14677; flavor creme de vanilla 28156; flavor curacao 50.397A; flavor custard;
  • silastic brand medical grade tubing silastic medical adhesive, silicone type a; silica gel; silica, diatomaceous; silicon; silicon dioxide; silicone; silicone emulsion; silicone/polyester film strip; simethicone; simethicone emulsion; simethicone MDX4- 4036; soap; soap, eiderdown; sodium acetate; sodium acetate, anhydrous; sodium acid pyrophosphate; sodium alginate; sodium alkyl sulfate; sodium aminobenzoate; sodium ascorbate; sodium benzoate; sodium bicarbonate; sodium bilsulfate; sodium bisulfite; sodium borate; sodium borate decahydrate; sodium carbonate; sodium carbonate; sodium carbonate hydrate; sodium carragenate; sodium cellulose; sodium chlorate; sodium chloride; sodium chloride injection; sodium chloride injection, bacteriostatic; sodium citrate; sodium citrate anhydrous; sodium citrate dihydrate; sodium desoxycholate; sodium dithi
  • N-(9,10-dihydro- 9,10-dioxo-1 ,5-anthracenediyl) bisbenzamide 7,16-dichloro-6,15-dihydro-5,9,14,19- anthrazinetetrone; 15,17- or 16,17- dimethoxdinaptho[1 ,2,3-CD, 3',2',1' IM] perylene -5,10, dione; 2- ⁇ [2,5-diethoxy-4[(4methylphenyl) thiol]phenyl] azo]- ,3,5-benzenetriol; 1 ,4 - BIS[(2-methylphenyl)amino]- 9,10-anthracenedione.
  • distribution agents and blood modifiers can be selected from the following functional categories, and titrated for optimal concentrations based on the information and techniques described elsewhere herein: acidifying agents (acidulants); additives color (coloring agents);adsorbents; aerosol propellants; air displacement agents; alkalizing agents; anticaking agents; anticoagulants; antimicrobial preservatives/ antiseptics/disenfectants; antioxidants; bases; binders; buffering agents; lubricants (for capsule/tablet); chelating agents; coating agents; controlled release vehicles; dessicants; detergents; diluents (for capsule/tablet); disintegrants (for capsule/tablet); dispersing agents; dissolution enhancing agents; drug deliver systems; dusting powders; dyes (coloring agents); emolients; emulsifying agents; emulsion stabilizers; extened release agents; fillers; film forming agents; flavor enhancers (flavoring agents); flow enhancers; gelling agents; gli
  • Lubricants include, but are not limited to, calcium stearate; canola oil; glyceryl palmitostearate; hydrogenated vegetable oil, type I; magnesium oxide; mineral oil; poloxamer; polyethylene glycol; polyvinyl alcohol; sodium benzoate; sodium lauryl sulfate; sodium stearyl fumarate; stearicacid; talc; zinc stearate.
  • Surfactants include, but are not limited to anionic (ocusate sodium;sodium lauryl sulfate), cationic: (certrimide), and nonionic ⁇ polyoxyethylene fatty acid esters (polysorbates) (polysorbate 20, 40, 60 used orally); sorbitan ester (sorbitan fatty acid esters) ⁇ .
  • Wetting agents include, but are not limited to, benzalkonium chloride; castor oil, polyethoxylated; docusate sodium; ether, polyoxethylene; poloxamer; polyoxethylene esters; polyoxyethylene fatty acid ether (polysolbrate); polyoxyethylenes, stearates; sodium lauryl sulfates; sorbitan esters (sorbitan fatty acid esters).
  • Solubllizing agents include, but are not limited to, benzalkonium chloride; castor oil, polyethoxylated; cyclodextrins; ethers, polyoxyethylene; glyceryl monostearate; lecithin; poloxamer; polysorbates; polyoxyethylene stearates; sorbitan esters (sorbtitan fatty acid esters); stearic acid,.
  • Water miscible cosolvents include, but are not limited to, propylene glycol.
  • Suitable smoking deterrent agents include, but are not limited to, nicotine, buprorion, fasudil, ziconotide, RSR13, and any derivatives and/or combinations thereof.
  • Suitable nutritional supplements include, but are not limited to, amino acid preparations, minerals, electrolytes, vitamins, calcitriol, and any derivatives and/or combinations thereof.
  • Suitable anti-infective agents include, but are not limited to, terbinafine, ticarcillin disodium, cefixime, meropenem, cefprozil, levofloxacin, cefpodoxime proxetil, imipenem, cefuroxime axetil, trovafloxacin, mupirocin, stavudine, didanosine, nevirapine, lamivudine, zidovudine, valcyclovir, ganciclovir, nefiracetam, and any derivatives and/or combinations thereof.
  • Suitable central nervous system agents include, but are not limited to, remifentanil, sevoflurane, tiagabine, topiramate, lamotrigine, naratriptan, bromocriptine, tolcapone, oxaprozin, diclofenac and misoprostol, nabumetone, granisetron, fasudil, dotarizine, ziconotide, RSR13, zonisamide, BMS204352, foropatant, oxcarbazepine, tropisetron and any derivatives and/or combinations thereof.
  • Suitable anti-neoplastic agents include, but are not limited to, irinotecan, topetecan, anastrozole, nilutamide, cladribine, gemcitabine, letrozole, vinorelbine, epirubicin, and any derivatives and/or combinations thereof.
  • Suitable endocrine agents include, but are not limited to, raloxifene, calcitonin, somatotropin, recombinant somatropin, tolterodine, temiverine, meluadrine tartrate, and any derivatives and/or combinations thereof.
  • Suitable gastrointestinal agents include, but are not limited to, lansoprazole, misoprostol, ropivacaine, and any derivatives and/or combinations thereof.
  • Suitable anti-asthmatic and pulmonary agents include, but are not limited to, bambuterol, israpafant, foropatant, rupatadine, levosalbutamol, ARC68397AA, salbutamol (powder) (Chiesi & Astra Zeneca), salbutamol (inhalation) (Astra Zeneca & Aventis), salbutamol (oral), salbutamol (powder inhilation) (Astra Medici & IVAX), formoterol, salmeterol/fluticasone propionate, salmeterol MDI dose counter, salmeterol (inhilation) (GSK), salmeterol hydrofluoroalkane, budesonide/formoterol, olopatadine, and any derivatives and/or combinations thereof.
  • Suitable opthalmic agents include, but are not limited to, levobetaxolol, levobunolol, latanoprost/timolol, ketotifen, and any derivatives and/or combinations thereof.
  • Suitable chelating agents include, but are not limited to, desferoxamine, and any derivatives, and/or combinations thereof.
  • Suitable granulocyte colony stimulating factors include, but are not limited to, leukine, sargramostin, GM-CSF, and any derivatives and/or combinations thereof.
  • Reduced viscosity can reduce the permeability of leaky junctions, thus reducing intimal injury. It should be noted that enhanced permeability of E-cells causes influx of lipids and macromolecules. Reduced viscosity does reduce the magnitude of high shear stress at the flow divider 255 of an arterial bifurcation because wall shear stress is proportional to blood viscosity.
  • thrombosis there is also a relationship between blood viscosity and thrombosis. Thrombosis often occurs in the later stages of the arterial disease. Blood viscosity may be indirectly related to thrombogenesis. By reducing blood viscosity, the occurrence of thrombosis can be reduced because reduced blood viscosity increases flow velocity. Coagulability or thrombogenicity of blood indicates the blood's tendency to coagulate, form thrombi, aggregate platelets or clot. Thus, as shown in Fig. 11 , by measuring both the absolute and effective blood viscosity profiles and monitoring the angle between the two profiles, ⁇ , one can quantitatively evaluate the blood's tendency to form thrombi, as discussed in A.S.N. 09/501,856.
  • hematocrit analyzer 300 plasma viscosity analyzer 400, surface tension analyzer 500 and red blood cell deformability analyzer 600.
  • Each of these analyzers operate independently of the blood viscometers 20/120 but take advantage of sharing the single intubation of the living being via circulating blood conveying means 26.
  • hematocrit analyzer 300 (Figs. 6-8), there is a need to monitor the level (percentage) of hematocrit of blood on a real time base. As blood is drawn out of a living being, if one can measure or monitor the hematocrit, it can improve health care quality, diagnostic capability and treatment.
  • hematocrit (which is defined as the volume percentage of red blood cells in whole blood wherein the hematocrit of a normal healthy individual is approximately 40% - 45% ) is measured using a small capillary tube where a small amount of blood is filled from one end, and the end is closed by an amorphous, dough-like material.
  • hematocrit is measured using a small capillary tube where a small amount of blood is filled from one end, and the end is closed by an amorphous, dough-like material.
  • hematocrit Using a (micro) centrifuge, cells from blood are separated from plasma and the volume of the cells is read in terms of percentage, called hematocrit.
  • the present invention implements a hematocrit analyzer 300 which utilizes an optical non-contact method.
  • Blood is diverted from the circulating blood conveying means 26, through the valve 700 and into the hematocrit analyzer 300.
  • the blood sample flows through a transparent capillary tube 302 of approximately 20-50 m ID.
  • a pulsing light 304 e.g., a strobe light
  • a red blood cell detector 305 is used to count the red blood cells and may comprise a CCD camera microscope 306 and an image processing means 308.
  • Imaging frames can be captured by the CCD (charge coupled device) camera/microscope 306 (e.g., a CCD having 300 dpi- 83 ⁇ pixel resolution available from ScanVision Inc. of San Jose, CA) and processed through the image processor 308 which includes image processing software (e.g., conventional CCD acquisition software available with the ScanVision Inc. CCD mentioned previously).
  • the image processor 308 identifies cells and counts the number of cells in a given window 310 (Fig. 7).
  • the given window has a predetermined volume. Since one can calculate the total volume and cells from cell count, one can estimate the volume percentage of cells, thus hematocrit.
  • the total volume and cell count can then be transmitted to a computer 312, or to the microprocessor 58 (Figs. 1 and 2) in the viscometer 20/120.
  • the new method utilized by the hematocrit analyzer 300 can easily be validated by comparing the hematocrit data generated from the analyzer 300 with those obtained from the conventional method such as the microcentrifuge method described earlier.
  • Fig. 8 depicts an alternative lumen to the capillary tube 302.
  • a rectangular glass tube or lumen 314, which is readily available off-the-shelf, can be used and a predetermined window 316 can be established for conducting the total volume and cell count.
  • Figs. 9A-9C depict portions of the plasma viscosity analyzer 400 which basically comprises a first vacutainer 402, an optional high pressure source 404, a second vacutainer 406 and an automated volume reader 408.
  • a portion of the circulating blood is diverted therein from the living being using the single intubation of the living being via the circulating blood conveying means 26.
  • circulating blood is diverted to the plasma viscosity analyzer 400 via the valve 700.
  • a lumen 410 (e.g., a 21 gauge needle) releasably fits into the valve 700.
  • the other end of the lumen 410 passes through a rubber membrane or plug 412 in the top portion of a first vacutainer 402.
  • a porous medium e.g., a membrane filter 414, which separates the vacutainer 402 into an upper chamber 416 for collecting the circulating blood 15 therein and a lower chamber 418 that initially comprises a vacuum.
  • the membrane filter 414 separates cells only, but not fibrinogen.
  • a filter membrane used for ultra-filtration with a pore size of approximately 0.1 ⁇ m should be suitable for this purpose.
  • the circulating blood conveying means 26 is in fluid communication with the plasma viscosity analyzer 400 via valve 700, blood 15 flows into the upper chamber 416. Under the influence of gravity and the pressure differential, the red blood cells are separated from the plasma 17 (Fig. 9B) via the membrane filter 414, i.e., the red blood cells remain in the upper chamber 416, with the plasma 17 being collected in the lower chamber 418.
  • the first vacutainer 402 can be disengaged from the valve 700 and coupled to a high pressure source 404 (Fig. 9B, e.g., compressed air).
  • the high pressure source 404 forces the collected blood 15 against the porous membrane 414 and thereby separates the plasma 17 much more quickly.
  • plasma 17 is a Newtonian fluid, therefore the viscosity thereof does not vary with shear rate.
  • shear rate i.e., it is not necessary to monitor the change in height of a column of plasma.
  • the first vacutainer 402 is disengaged from the valve 700 (or from the high pressure source 404, if used).
  • a second vacutainer 404 having graduations indicating different volume levels, is coupled to the first vacutainer 402.
  • a lower rubber membrane or plug 420 of the first vacutainer 402 is pierced by another lumen 422 (e.g., a 21 gauge needle).
  • the other end of the lumen 422 is disposed through a rubber membrane plug 424 of the second vacutainer 404.
  • atmosphere i.e., zero gauge pressure
  • the pressure above the plasma 17 is atmospheric pressure; furthermore, the second vacutainer 404 comprises a predetermined vacuum level. Because of this pressure differential ( ⁇ p) between the two vacutainers 402/404, when the second lumen 422 punctures the membrane/plug 420, the plasma 17 is forced down out of the first vacutainer 402 down into the second vacutainer 404 via the lumen 422.
  • plasma viscosity can be determined from a single shear rate, according to the equation: ⁇ d 4 ⁇ P ⁇ US P L
  • L second lumen 422 length
  • d second lumen 422 inside diameter
  • ⁇ P pressure difference between the two vacutainers 402/404 as shown in Fig. 9C (i.e, pressure levels are predetermined and vary depending on the accumulated plasma amount, thus mathematically estimated, no need to measure)
  • the plasma viscosity can be calculated.
  • Fig. 13 shows both high and low wall shear stress that is based on computational fluid dynamic (CFD) modeling of the coronary bifurcation flow.
  • BPN blood pressure number
  • BVP blood viscosity parameter
  • the table (Fig. 13) provides the high and low shear data as soon as the BPN and BVP data become available. For example, if a patient has a BVP III level and BPN5 level, one can read from the table the corresponding values of high wall shear stress (high ⁇ w ) and low wall shear stress (low ⁇ w ).
  • the objective of any drug administration and clinical treatment is to move a patient condition from the lower right corner (i.e., the worst wall shear stress conditions) to the upper left corner (i.e., the ideal wall shear stress conditions).
  • BVP and BPN are discussed next. To understand the definition of BVP, it is necessary to discuss the absolute viscosity profile and the effective viscosity profile in view of Figs. 10-12B. As disclosed in A.S.N. 09/501 ,856, once the height vs. time data is collected from changing column levels in the riser tubes R1 and R2, that data can be segmented into a first shear rate range A (e.g., 320s "1 to 1s "1 ) and a second shear rate range B (e.g., 1s "1 to 0.02s "1 ).
  • A e.g., 320s "1 to 1s "1
  • B e.g., 1s "1 to 0.02s "1
  • shear rate selected to define the end of range A and the beginning of range B e.g., 1s "1
  • 1s "1 is by way of example only and not limitation; thus, it is within the broadest scope of this invention to cover any number of shear rates that define the end of range A and the beginning of range B.
  • the viscosity profile over the first shear rate range (A) is called the “absolute viscosity profile” and the viscosity profile over the first and second shear rate ranges (A+B) is called the “effective viscosity profile” (see Fig. 11 ).
  • the angle ⁇ (Fig. 12A) formed between the absolute viscosity profile and the effective viscosity profile can be used as an indicator of blood parameters.
  • the blood viscosity parameter is a value that is determined from comparing the effective viscosity profile 800 of the living being under test (UT) to the effective viscosity profile 802 of a normal healthy living being, e.g., a healthy young boy, as shown in Fig. 12C.
  • BVP varies between approximately 5 -10 and is defined as:
  • ⁇ absolute is the absolute viscosity profile and the effective viscosity profile 802 of a normal healthy person, in a log-log graph;
  • ⁇ 15Q is the living being UT's circulating blood viscosity measured at ⁇ - 150 s "1 ;
  • the first term • 50 is known as the "effective/absolute
  • the denominators of the high shear effect term and the low shear effect term are used as references and are the viscosity values (4 and 8 centipoise) from a healthy young boy at the shear rates of 150 s "1 and 1 s "1 , respectively (see Fig. 12C).
  • the high shear effect term can be much greater.
  • a weighting factor of "3" is used with the low shear effect term because the low shear viscosity is often a direct cause of arterial disease.
  • ⁇ 1 for the subject is often much greater than 8 centipoise for most adults, the low shear effect term can be the largest contributor among the three terms.
  • a weighting factor of "2" is used with the high shear effect term since the effect of high shear on atherosclerosis is less than that of low shear viscosity.
  • the BPN can be defined as an average blood pressure term (i.e., the average value of the systole and diastole) and a contractility of the heart (COH) term.
  • an average blood pressure term i.e., the average value of the systole and diastole
  • COH contractility of the heart
  • a BVP and a BPN are determined for any particular living being, these values can be immediately referenced according to the table shown in Fig. 13 and the high and low wall shear stress indicated.
  • the physician and/or specialist can then devise a regimen of drugs and/or lifestyle changes (as mentioned previously) to move the patient's cardiovascular system toward the upper left corner of the table in Fig. 13.
  • the h n (t) and h 2 (t) data/curves of the viscometers 20/120 can be segmented into two shear rate regions (A and B) and from which an absolute viscosity profile and an effective viscosity profile can be obtained.
  • These h ⁇ t) and h 2 (t) data/curves can be further segmented into a plurality of regions (see Fig. 17), resulting in a plurality of viscosity profiles (see Fig. 18A), and two of which are the absolute viscosity profile (III, in Figs. 12A and 18A) and the effective viscosity profile (VI, in Figs. 12A and 18A).
  • the h ⁇ t) and h 2 (t) data/curves have been segmented into six regions.
  • the blood viscosity calculated using the data 0 ⁇ t ⁇ t 1 is a freshly shed, high shear blood viscosity. It is also desirable to obtain viscosity data in a shear rate range > 100 s "1 . It should also be noted that the blood viscosity calculated using Region VI data contains the most significant effect of coagulation/clotting because while the columns of blood in riser tubes R1 and R2 fall and rise, respectively, the blood is exposed to air. Thus, the h.,(t) and h 2 (t) data/curves contain information about the blood's coagulability characteristics. This segmentation of these data/curves and the subsequent analysis helps further define these coagulability characteristics of the blood.
  • Figs. 18A and 18B provide the various blood viscosity profiles (in a log viscosity vs. log shear rate plot) over the six regions, for two hypothetical patients: patient A (Fig. 18A) and patient B (Fig. 18B).
  • patient A shows almost Newtonian type high shear viscosity (Region I viscosity profile is substantially horizontal, i.e., the viscosity in that region does not vary over shear rate).
  • Regular I viscosity profile is substantially horizontal, i.e., the viscosity in that region does not vary over shear rate.
  • Fig. 19 confirms that the plurality of blood profiles depicted in Figs. 18A and 18B form the central portion of the log viscosity vs. log shear rate plots, i.e., the extreme ends, both extreme high shear rates and extreme low shear rates, are not plotted or used.
  • the surface tension analyzer 500 (Figs. 16A-16B) provides a measurement of the surface tension of a liquid; in the preferred embodiment blood is the liquid whose surface tension is being determined.
  • surface tension is measured using a bubble-blowing method; however, this method is labor-intensive and a time-consuming procedure.
  • liquid becomes hazardous to handle e.g., human blood, it is desirable to have a fully automated procedure.
  • the surface tension of a liquid is being determined using a cylindrical capillary tube
  • the surface tension is defined as that upward vertical force which balances the weight of the liquid element.
  • a contact angle, ⁇ is formed between the liquid and the capillary tube, such as that depicted in Fig. 14A.
  • the contact angle ⁇ 0° and therefore the vertical component of surface tension, namely, ⁇ d ⁇ cos ⁇ which counteracts the weight of the liquid, is simply ⁇ d ⁇ .
  • the surface tension, ⁇ is calculated based on the following:
  • the surface tension analyzer 500 provides a unique manner for accurately determining the height of the liquid element in the surface tension analysis using capillary rise, as is discussed below.
  • the surface tension analyzer 500 comprises a conduit 502 from the valve 700, a stopcock 504, a capillary tube 506, a CCD sensor array 508, an elbow 509, a mini-reservoir 510 and an adjacent overflow chamber 512.
  • An aperture 514 is provided in one of the walls of the mini-reservoir 510 adjacent the overflow chamber 512.
  • the aperture 514 controls the blood level 516 in the mini- reservoir 510, i.e., as the collected blood level 516 rises to or above the aperture 514, blood flows into the overflow chamber 512. As a result, the exact level of blood in the mini-reservoir 510 is maintained.
  • the CCD sensor array 508 is positioned at a predetermined height, h r above the aperture 514.
  • the predetermined height, h r can be programmed into the CCD sensor array 508 as an offset such the height necessary for the surface tension calculation, namely, h f , is sent to the processor 58.
  • the predetermined height, h r can already be stored in the processor 58 and only the final position of the column in the capillary tube 508 is detected and transmitted by the CCD sensor array 508 to the processor 58; the processor 58 then adds the value h r to the final position of the column height to arrive at h f . In either case, the processor 58 calculates the surface tension according to the above equation.
  • the surface tension analyzer 500 operates as follows: Before the test is run, the inside of the capillary tube 506 is wetted by the blood of the living being as it flows from the valve 700. In particular, with the stopcock valve 504 in its initial position as shown in Fig. 16A, the blood flows upward into the capillary tube 506, whose top (not shown) is vented to atmosphere. When the CCD sensor array 508 detects a predetermined level (not shown) of the column of blood 513 in the capillary tube 506, the stopcock valve 504 is rotated to isolate the capillary tube 506 from the conduit 502 and to couple the tube 506 to the elbow 509 and mini-reservoir 510.
  • h f is the distance between the blood level in the capillary tube 506 and the level 516 in the mini-reservoir 510 and therefore represents the height of the liquid element required for determining the surface tension, ⁇ , as discussed above.
  • the aperture 514 on the side wall of the mini- reservoir 510 controls the blood level 516 in the reservoir 510. Blood from the reservoir 510 flows into the overflow chamber 512 if the fluid level 516 rises above the aperture 514. Using this level-control aperture, the exact level of blood 516 in the mini-reservoir 510 is known.
  • ⁇ is related to yield stress, ⁇ Q , (as discussed in A.S.N. 09/501 ,856) which is related to RBC (red blood cell) agglomeration (see Fig. 22 where at high shear conditions, the blood cells bonds are evenly spaced allowing these bonds to be easily severed versus low shear conditions where the cells are closely stacked, known as a Rouleaux formation, and where the yield stress/RBC agglomeration causes thrombosis), using the surface tension analyzer 500, it is now possible to determine whether a drug reduces or increases the surface tension of whole blood.
  • Fig.21 depicts a method for treating low shear injury through the use of surface tension analyzer 500.
  • the determination of the surface tension of blood can be of great assistance to pharmaceutical companies in their quest to manufacture drugs that reduce the surface tension of whole blood.
  • One of the benefits of reducing the surface tension of blood is to reduce blood viscosity and the work of the heart. For example, saline IV solution and distilled water reduces surface tension and blood viscosity, thus reducing the work of the heart.
  • blood letting can reduce the surface tension.
  • PVR peripheral vascular resistance
  • the reduction of blood viscosity can be accomplished by blood letting or the injection of distilled water (i.e., saline IV solution) or mechanical vibration.
  • distilled water i.e., saline IV solution
  • mechanical vibration By improving circulation and reducing PVR, one can reduce pain while increasing walking distance, as well as quality of life in individuals with intermittent claudication.
  • Diuretics - removes water from blood - but actually increases blood viscosity.
  • a new method of treating hypertension is to apply ⁇ -blocker/calcium-channel blocker, ACE inhibitor (including the vasodilator and blood pressure lowering drugs), and blood viscosity reducing drugs in combination to effectively reduce hypertension.
  • the combined use of certain pharmaceutical agents may regulate (ie. alter or maintain) various blood parameters.
  • the combination of at least two pharmaceutical agents selected from the group consisting of intravenous diluents, red blood cell deformability agents, antiurea agents, oral contraceptives, anti-diabetic agents, antiarrythmics, antihypertensives, antihyperlipidemics, antiplatelet agents, appetite suppressants, anti-obesity agents, blood modifiers, smoking deterrent agents, and nutritional supplements may regulate blood viscosity.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-diabetics, intravenous solutions, cholesterol-lowering agents, triglyceride-lowering agents, lubricants, homocysteine-reducing agents, and vitamin supplements may be used to regulate plasma viscosity.
  • the combination of at least two pharmaceutical agents selected from the group consisting of beta-blockers, calcium channel blockers, ACE inhibitors, ACE-II inhibitors, vasodilators, blood pressure reducing agents, viscosity reducing agents and anti-diabetic agents may regulate the work of the heart.
  • the combination of at least two pharmaceutical agents selected from the group consisting of beta blockers, calcium channel blockers, ACE inhibitors, ACE-II inhibitors, vasodilators, blood pressure reducing agents, viscosity reducing agents, contractility reducing agents, anti-diabetics, and anti-obesity agents may regulate low shear stress.
  • the combination of at least two pharmaceutical agents selected from the group consisting of intravenous solutions, anti-diabetics, hemodilution agents, anti-platelet agents, lubricity enhancing agents and adhesiveness minimizing agents may regulate high shear stress.
  • the combination of at least two pharmaceutical agents selected from the group consisting of beta-blockers, calcium channel blockers, and peripheral antiadrenergic/sympatholytics may regulate the contractility of the heart.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-thrombogenic agents may regulate the thrombogenicity of the heart.
  • the combination of at least two pharmaceutical agents selected from the group consisting of warfarin, heparin, and anti-platelet agents may regulate platelet aggregation.
  • the combination of at least two pharmaceutical agents selected from the group consisting of intravenous fluids, lubricants, anti-adhesives, surfactants, and saponifying agents may regulate lubricity.
  • the combination of at least two pharmaceutical agents selected from the group consisting of sodium bentonite magma; colloidal clays (such as magnesium bentonite and attapulgite), colloidal silicon dioxide, and microcrystalline cellulose may regulate thixotropy.
  • the combination of at least two pharmaceutical agents selected from the group consisting of gels of colloidal clays, such as sodium bentonite, gels of organic polymers, such as gelatin, agar, pectin, methylcellulose, and high- molecular-weight polyethylene glycol may regulate yield stress.
  • the combination of at least two pharmaceutical agents selected from the group consisting of beta-blockers and viscosity reducing agents may regulate endothelial shear injury.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-thrombogenics and anti-platelets may regulate coagulability.
  • anti-thrombogenics and anti-platelets e.g., aspirin
  • heparin e.g., aspirin
  • anti-coagulants may regulate coagulability.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-thrombogenics and anti-platelets may regulate coagulation time.
  • anti-thrombogenics and anti-platelets e.g., aspirin
  • heparin e.g., aspirin
  • anti-coagulants may regulate coagulation time.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-platelets and anti-coagulants may regulate agglutination.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-thrombogenics and anti-platelets (e.g., aspirin), and anticoagulants may regulate clot retraction.
  • the combination of at least two pharmaceutical agents selected from the group consisting of anti-thrombogenics and anti-platelets (e.g., aspirin), and anti-coagulants may regulate clot lysis time. Also, the combination of at least two pharmaceutical agents selected from the group consisting of heparin, warfarin and anti-coagulants may regulate prothrombin rates.
  • embodiments of the present method enable adjusting the distribution of a substance through a bloodstream of an organism by altering at least one blood flow parameter of the bloodstream.
  • the substance being distributed is not particularly limited, but includes, e.g., pharmaceutically active agents.
  • the method is suitable for use in any organism, including, e.g., single- celled organisms, and multicellular organisms, such as humans and other mammals.
  • the substance being distributed is suitably administered in any way in which at least some (preferably about 1 wt.% to about 100 wt.%) of the substance reaches the bloodstream of the organism.
  • the substance can be administered enterally (via the alimentary canal) or parenterally (via any route other than the alimentary canal, such as, e.g., through intravenous injection, subcutaneous injection, intramuscular injection, inhalation percutaneous application, etc.).
  • Suitable targets for the substance being distributed include, e.g., cells, tissues, organs or systems.
  • the ultimate effects of such adjustments are not limited to the bloodstream specifically or the circulatory system in general. That is, the target for the substance need not be part of the circulatory system, as long as some amount of the substance (in certain embodiments, about 1 wt.% to about 100 wt.% of the substance in the bloodstream) in the bloodstream reaches its intended target.
  • a distribution parameter for distributing the substance is adjusted, up and/or down, or simply maintained at a desired value, preferably through the use of an agent such as, e.g., levonorgestrel, estrogen, progestin, estradiol, ethinyl estradiol, ethynodiol, medroxyprogesterone, desogestrel, cyproterone, norethindrone, gestodene, norgestrel, mestranol, norgestimate, metformin, acarbose, insulin, chlorpropamide, glipizide, glyburide, tolazamide, glimepiride, troglitazone, pioglitazone, repaglinide, losartan potassium, candesartan cilexetil, irbesartan, mitiglinide, tr endolapril/ verapamil, nateglinide, nifedipine, n
  • fenofibrate pamaqueside, pitavastatin, phentermine, phendimetrazine, sibutramine, orlistat, aspirin, warfarin, enoxaparin, heparin, low molecular weight heparin, cilostazol, clopidogrel, ticlopidine, tirofiban, abciximab, dipyridamole, plasma protein fraction, human albumin, low molecular weight dextran, hetastarch, reteplase,reteplase, streptokinase, urokinase, dalteparin, filgrastin, immunoglogulin, ginkolide B, hirudins, foropafant, rocepafant, bivalirudin, dermatan sulfate mediolanum, eptilibatide, thrombomodulin, low molecular weight dermatan sulfate-opocr
  • the distribution parameter can be any such parameter used to evaluate distribution of the substance in an organism. Suitable parameters include, but are not limited to distribution rate and bioavailability.
  • the distribution rate is decreased, it is particularly preferred to hinder the distribution of a substance, such as a psychoactive ingredient in an addictive product.
  • a substance such as a psychoactive ingredient in an addictive product.
  • Another example of such an embodiment is comprises hindering the distribution of toxins and other substances in cigarettes and other tobacco products.
  • Fig. 15 depicts the red blood cell deformability analyzer 600.
  • the analyzer 600 comprises a plurality of tubes 602 having various inner diameters in the range from 1 ⁇ m to 10 ⁇ m and with each tube 602 being in contact with its neighboring tube 602.
  • each RBC will either (1 ) enter that tube 602 which is large enough for the RBC to pass through, or (2) enter that tube 602 for which the RBC is able to deform without rupturing.
  • a light source 604 illuminates the plurality of tubes 602.
  • the light passing through the tubes 602 having varying degrees of "redness” is detected by a red color detector 606 (e.g., light source 604/color detector 606 can be implemented by the CS64A color sensor manufactured by Delta Computer Systems, Inc. of Vancouver, WA which comprises both a light generation system and a light receiving system for detecting color; a digital/analog converter is used to make the output of the CS64A compatible for computer processing).
  • the higher degree of redness the higher the RBC content in the tube 602.
  • the red color detector 606 collects the redness information along with the corresponding tube 602 and then passes this information to the processor 58.
  • Figs. 14A-14B depict another blood characteristic detector: a blood lubricity detector 800.
  • lubricity is known by those skilled in the mechanical arts as describing the slipperyness between two solids
  • lubricity refers to the “slipperyness" of the blood flow with respect to the vessel wall, i.e., the slipperyness between a liquid (blood) and a solid (the vessel wall).
  • the blood's "adhesiveness” refers to the property of the blood which causes it to cling to the vessel walls.
  • the lubricity and the adhesiveness of the blood are inversely related, namely, as adhesiveness increases the lubricity decreases, and vice versa.
  • a meniscus 802 forms at the top of the column of blood as it falls down the riser tube R1.
  • a thin residue of blood of varying thickness is left on the inside surface of the riser tube R1 ; this is indicated by the reference numbers 804A and 804B.
  • the residue has a minimum thickness at the higher elevations 806 of the riser tube R1 and maximum thickness closest to the meniscus 802 itself, as indicated by the reference number 808.
  • the amount of this residue is indicative of the lubricity of the blood and is exemplary of the lubricity of the blood as it travels through the vascular system of a living being.
  • the lubricity detector 800 is used.
  • the detector 800 comprises a light source 810 located on one side of the riser tube R1 near its top portion.
  • the detector 800 also comprises a light detector 812 located on the opposite side of the top portion of the riser tube R1 , directly opposite the light source 810.
  • light rays 814 emanating from the light source will pass through the riser tube R1 wall, a portion of the film of blood on one side of the tube R1 , the other thin layer of blood on the opposite side of the tube R1 and through the other side of the riser tube R1 to be detected by the light detector 812.
  • the light detector 812 is a CCD having a vertical array of pixels (or an active-pixel sensor (APS) comprising rows/columns of pixels).
  • APS active-pixel sensor
  • Fig. 14C depicts such plots for different living beings.
  • the processor 58 determines the slope of each curve which is an indicator of the lubricity of a particular living being's blood.
  • An alternative indicator of lubricity may comprise the sum of Gray scale values over a specified vertical length; the higher the sum value, the greater the lubricity since there is little or no blood residue blocking the light rays 814. In a normal healthy living being the lubricity should be high so that a minimum amount of residue, having a minimum thickness, would be left on the inside of the riser tube RL
  • blood pressure monitors such as the implantable blood pressure monitors disclosed in U.S. Patent No. 6,015,386 (Kensey et al.), whose entire disclosure is incorporated by reference herein, or any other type of blood pressure monitor, can be used in combination with the viscometers 20/120 as shown in Figs. 1 and 2 to accomplish the methods described herein.
  • the implantable blood pressure monitors of U.S. Patent No. 6,015,386 can be implanted in the living UT and can be used in determining the COH and/or generating the BPN, both of which are discussed above.
  • the above-described apparatuses and diagnostic methods enable the practice of a variety of prophylactic and/or therapeutic methods using a variety of prophylactic and/or therapeutic compositions to control at least one property of blood measured by the apparatus and methods of the invention.
  • Table 1 below, provides examples of preferred pharmaceuticals for adjusting blood flow parameters.

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Abstract

L'invention concerne diverses méthodes de détermination et d'utilisation de la viscosité du courant sanguin d'un être humain se trouvant au-dessus d'une gamme de taux de cisaillement à des fins diagnostiques et thérapeutiques, servant par exemple à détecter/réduire la viscosité sanguine, le travail du coeur, la contractilité du coeur, à détecter/réduire la tension de surface du sang, à détecter la viscosité plasmatique, à expliquer/estimer le dysfonctionnement des cellules endothéliales, à générer des données de force de cisaillement des parois des vaisseaux sanguins basses et élevées, des données de déformabilité des globules rouges, de lubrification sanguine, et à traiter différentes maladies telles que les maladies artérielles périphériques. Ces méthodes sont utilisées en combinaison avec l'administration d'au moins un agent acceptable d'un point de vue pharmaceutique. Des agents efficaces d'un point de vue pharmaceutique servant à réguler au moins un des paramètres sanguins mentionnés ci-dessus sont utilisés pour ajuster la distribution d'une substance dans le courant sanguin.
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WO2021092057A1 (fr) * 2019-11-04 2021-05-14 The Regents Of The University Of California Contrôle de l'hémodynamique activé par l'intelligence artificielle chez des patients en chirurgie
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WO2005112762A1 (fr) * 2004-05-14 2005-12-01 Florida Atlantic University Dispositif et procedes permettant de controler de reguler un traitement anticoagulant
US10004703B2 (en) 2006-10-12 2018-06-26 Biogen Chesapeake Llc Treatment of alzheimer's disease using compounds that reduce the activity of non-selective CA++ activated ATP-sensitive cation channels regulated by SUR1 channels
US8277845B2 (en) 2007-12-04 2012-10-02 Remedy Pharmaceuticals, Inc. Formulations and methods for lyophilization and lyophilates provided thereby
US8858997B2 (en) 2007-12-04 2014-10-14 Remedy Pharmaceuticals, Inc. Formulations and methods for lyophilization and lyophilates provided thereby
US10869835B2 (en) 2007-12-04 2020-12-22 Biogen Chesapeake Llc Formulations and methods for lyophilization and lyophilates provided thereby
US10688111B2 (en) 2008-01-29 2020-06-23 Biogen Chesapeake Llc Liquid formulations of compounds active at sulfonylurea receptors
WO2009097443A2 (fr) * 2008-01-29 2009-08-06 Remedy Pharmaceuticals, Inc. Formulations liquides de composés actifs au niveau des récepteurs des sulfonylurées
WO2009097443A3 (fr) * 2008-01-29 2009-12-10 Remedy Pharmaceuticals, Inc. Formulations liquides de composés actifs au niveau des récepteurs des sulfonylurées
CN101869708A (zh) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 含有钙通道阻滞剂和双胍类降糖药物的药物组合物及其用途
US10028858B2 (en) 2011-07-11 2018-07-24 Medicines360 Intrauterine systems, IUD insertion devices, and related methods and kits therefor
US11090186B2 (en) 2011-07-11 2021-08-17 Medicines360 Methods for using intrauterine systems and IUD insertion devices
US12004992B2 (en) 2011-07-11 2024-06-11 Medicines360 Kits for intrauterine systems and IUD insertion devices
CN106501127B (zh) * 2016-10-17 2019-04-12 大港油田集团有限责任公司 调剖用凝胶动态性能评价方法及装置
CN106501127A (zh) * 2016-10-17 2017-03-15 大港油田集团有限责任公司 调剖用凝胶动态性能评价方法及装置
WO2021092057A1 (fr) * 2019-11-04 2021-05-14 The Regents Of The University Of California Contrôle de l'hémodynamique activé par l'intelligence artificielle chez des patients en chirurgie
WO2023158789A1 (fr) * 2022-02-17 2023-08-24 Woolsey Pharmaceuticals, Inc. Formulations orales de fasudil avec résine échangeuse d'ions
US11944633B2 (en) 2022-02-17 2024-04-02 Woolsey Pharmaceuticals, Inc. Oral formulations of fasudil with ion exchange resin

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