MXPA00012806A - In-vivo determining the effects of a pharmaceutical on blood parameters - Google Patents

Abstract

A blood viscosity measuring system and method that monitors the rising head of a column of fluid (42) representing a living being's blood in-vivo to determine the blood viscosity over a range of shears. The system includes a capillary tube (26), at least a portion of which is located within the vascular system (30) of the being, and a riser tube (44), having a liquid therein coupled to the capillary tube. A sensor (48, 50) and associated microprocessor (52) are provided to determine the change in the height of the liquid in the riser tube (44) at plural points along the length of the tube from which the viscosity is calculated. The system can be utilized to determine the deformability of the red blood cells of a living being's blood and/or the thixotropic properties of a living being's blood. Use of the system enables one to screen a pharmaceutical or other compound on a test subject, such as a living human being or laboratory animal, to determine the likely effect of the pharmaceutical in altering a parameter of the blood, e.g., viscosity, red blood cell deformability, or thixotropic nature, of a living, e.g., human, being to which the pharmaceutical will ultimately be administered.

Description

IN VIVO DETERMINATION OF THE EFFECTS OF A PHARMACEUTICAL IN BLOOD PARAMETERS BACKGROUND OF THE INVENTION This invention relates generally to an apparatus and methods for measuring the viscosity of liquids, and more particularly, to an apparatus and methods for measuring the viscosity of a blood being in vivo and on a large range of cutting forces. The importance of determining the viscosity of blood is well known. Fibrogen, Viscosity and White Blood Cell Count Are Major Risk Factors for Ischemic Heart Disease (Fibroids, viscosity and white blood cell counts are major risk factors for ischemic heart disease), by Yarnell et al., Circulation, Vol. 83, no . 3, March 1991; Postprandial Chanqes in Plasma and Serum Viscosity and Plasma Lipids and Lipoproteins After an Acute Test Meal (Postprandial changes in plasma and serum viscosity and plasma lipids and lipoproteins after an acute test meal), by Tangney, et al., American Journal fer Clinical Nutrition, 65: 36-40, 1997; Studies of Plasma Viscosity in Primary Hyperlipoproteinaemia (Studies of plasma viscosity in primary hyperlipoproteinaemia), by Leonhardt et al., Atherosclerosis 28:, 29-40, 1977; Effects of Lipoproteins on Plasma Viscosity (Effects of lipoproteins in plasma viscosity), by Seplowitz, et al., Atherosclerosis 38, 89-95, 1981; Hyperviscosity Syndrome in a Hypercholesterolemic Patient with Primary Biliary Cirrhosis (hyperviscosity syndrome in a hypercholesterolemic patient with primary biliary cirrhosis), Rosenson, et al., Gastroenterology, vol. 98, No. 5, 1990; Blood Viscosity and Risk of Cardiovascular Events: the Edinburqh Artery Study, (Lowe et al., British Journal of Hematology, 96, 168-171, 1997; Blood Rheology Associated with Cardiovascular Risk Factors and Chronic Cardiovascular Diseases: Results of an Epidemiological Cross-Sectional Study (Blood Rheology Associated with Cardiovascular Risk Factors and Chronic Cardiovascular Disease: Results of a Representative Epidemiological Sample Study), by Koenig, et al. ., Angiology, The Journal of Vascular Diseases, November 1988; Importance of Blood Viscoelasticity in Arteriosclerosis (Importance of blood viscoelasticity in arteriosclerosis), by Hell, et al., Angiology, The Journal of Vascular Diseases, June 1989; Thermal Method for Continuous Blood-Velocity Measurements in Larqe Blood Vessels, and Cardiac-Output Determination (Thermal method for continuous measurements of blood velocity in large blood vessels and determination of cardiac output), by Delanois, Medical and Biological Engineering, vol. 11, no. 2, March 1973; Fluid Mechanics in Atherosclerosis, by Nerem et al., Handbook of Bioengineering, Chapter 21, 1985. Much effort has been made to develop apparatus and methods to determine the viscosity of blood. Theory and Designation of Disposable Clinical Blood Viscometer, (Disposable Clinical Viscometer Theory and Design for Blood), by Litt et al., Biorheology, 25, 697-712, 1988; Automated Measurement of Plasma Viscosity bv Capillary Viscometer (Automated measurement of plasma viscosity by capillary viscometer), by Cooke, et al., Journal of Clinical Pathology 41, 1213-1216, 1988; A Novel Computerized Viscometer / Rheometer (A novel viscometer / computerized rheometer), by Jiménez and Kostic, Rev Scientific Instruments 65, vol. 1, January 1994; A New Instrument for the Measurement of Plasma-Viscosity (A New Instrument for Plasma Viscosity Measurement), by John Harkness, The Lancet. pp 280-281, August 10, 1963; Blood Viscosity and Raynaud's Disease, by Pringle, et al., The Lancet, pp. 1086-1089, May 22, 1965; Measurement of Blood Viscosity Using a Conicylindrical Viscometer, (Measurement of blood viscosity using a conicylindrical viscometer), by Walker et al., Medical and Biological Engineering, p. 551-557, September 1976. In addition, there is a variety of patents that relate to an apparatus and methods for measuring blood viscosity. See, for example, US patents nos. 3,342,063 (Smythe et al); 3.720097 (Kron); 3,999,538 (Philpot, Jr.); 4,083,363 (Philpot); 4,149,405 (Ringrose); 4,165,632 (Weber, et al.); 4,517,830 (Gunn, fined, et al.), 4,519,239 (Kiesewetter, et al); 4,554,821 (Kiesewetter, et al.); 4,858,127 (Kron, et al.); 4,884,577 (Merrill); 4,947,678 (Hori et al.); 5,181,415 (Esvan et al.); 5,257,529 (Taniguchi et al.); 5,271,398 (Schlain et al.); and 5,447,440 (Davis, et al.) The '063 patent of Smythe discloses an apparatus for measuring the viscosity of a blood sample based on the pressure detected in a conduit containing the blood sample. Kron '097 patent describes a method and apparatus for determining blood viscosity using a flow meter, a pressure source and a pressure transducer The' 538 patent of Philpot describes a method for determining the viscosity of blood by removing the blood from the vein at a constant pressure for a predetermined period and the volume of blood withdrawn. The '363 patent of Philpot 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 device that measures negative pressure and a time device. The '405 Ringrose patent describes 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 frequency and amplitude given. Weber's' 632 patent describes an apparatus for determining the fluidity of blood by entraining blood through a capillary tube that measures cells in a reservoir, and then returning the blood back to the tube at a constant flow rate, and being related directly the difference in pressure between the ends of the capillary tube with the viscosity of the blood. Gunn's' 830 patent discloses an apparatus for determining blood viscosity using a transparent hollow tube, a needle at one end, a stopper at the other end to create a vacuum to extract a predetermined amount and an open weight member, which can be moved within the tube, and which can be moved by gravity at a speed that is a function of the viscosity of the blood. The '239 patent of Kiesewetter discloses an apparatus for determining the flow cutoff tension of suspensions, primarily blood, using a measuring chamber comprised of per se.

It is a step configuration that simulates the natural microcirculation of capillary passages in a living being. The '821 patent by Kiesewetter describes another apparatus for determining the viscosity of fluids, particularly blood, which includes the use of two parallel branches of a flow circuit, in combination with a device that measures the flow rate, to measure the flow in one of the branches to determine the viscosity of the blood. The '127 Kron patent describes an apparatus and method for determining the blood viscosity of a blood sample over a wide range of cutting speeds. The '577 patent of Merrill 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 flow velocity of the fluid. blood inside the spine. The '678 patent of Hori discloses a method for measuring the viscosity change in blood, by arranging a temperature sensor in the blood flow and stimulating the blood, in order to cause a change in viscosity. The '415 patent of Esvan discloses an apparatus that detects the change in viscosity of a blood sample, based on a relative slip of an actuating element and a driven element, which holds the blood sample, which rotate. The '529 patent of Taniguchi discloses a method and apparatus for determining the viscosity of liquids, for example, a blood sample, using a pair of vertically aligned tubes coupled together, via thin tubes while using a pressure sensor to measure the change of an internal tube pressure with the passage of time and the change of blood flow velocity. The '323 patent of Bedingham discloses a sensorial system of blood-vascular parameters using a catheter and a probe, having a plurality of sensors (eg, a sensor 02, a CO2 sensor, etc.) to measure the parameters of particular blood in vivo. The '398 patent by Schlam discloses an intra-vessel method and apparatus for detecting an undesirable wall effect in blood parameter sensors and for moving such sensors to reduce or eliminate the effect of the wall. The '440 patent of Davis discloses an apparatus for conducting a variety of assays that respond to a change in the viscosity of a sample fluid, for example, blood. The devices and methods for measuring viscosity for fluids in general are well known. See, for example, US Pat. 1,810,992 (Dallwitz-Wegner), 2,343,061 (Irany); 2,696,734 (Brunstrum et al.); 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. et al.); 3,680,362 (Geerdes et al.); 3,699,804 (Gassmann et al.); 3,713,328 (Aritomi); 3,782,173 (Van Vessem et al.); 3,864,962 (Stark et al.); 3,908,441 (Virloget); 3,952,577 (Hayes et al.); 3,990,295 (Renovanz et al.); 4,149,405 (Ringrose); 4,302,965 (Johnson et al.); 4,426,878 (Pnce et al.); 4,432,761 (Dawe); 4,616,503 (Plungis et al.); 4,637,250 (Irvine, Jr. et al.); 4,680,957 (Dodd); 4,680,958 (Ruelle et al.); 4,750,351 (Ball); 4,856,322 (Langrick et al.); 4,899,575 (Chu et al.); ,142,899 (Park et al); 5,222,497 (Ono); 5,224,375 (You et al.), 5,257,529 (Taniguchi et al); 5,327,778 (Park); and 5,365,776 (Lehmann et al.). The following US patents describe devices for measuring viscosity or flow, or devices that detect the level of liquid using optical monitoring: US Pat. Nos. 3,908,441 (Virloget); 5,099,698 (Kath, et al.); 5,333,497 (Br nd Dag A. et al.). The '441 patent of Virloget discloses a device for use in a viscometer that detects the level of a liquid in a transparent tube using photodetection. The '698 patent of Kath discloses an apparatus for optically scanning a rotameter flow calibrator and determining the position of a float therein. The '497 patent of Br nd Dag A. describes a method and apratus for continuous measurement of the liquid flow velocity of two vertical tubes by means of a coupled charge device (CCD) sensor. U.S. Patent No. 5, 421, 328 (Bedingham) describes a sensor system for intravascular blood parameters. A statutory invention record, H93 (Matta et al.) Discloses an apparatus and method for measuring the elongation viscosity of a test fluid using a video camera or film to monitor a drop of the fluid under test. The following publications discuss the deformability of red blood cells and / or devices used to determine such: Measurement of Human Red Blood Cell Deformability Usinq to Single Micropore on a Thin Si3N Film, (Measurement of the deformability of human red blood cells using a simple micropore in a thin film of Si3N4), by Ogura et al, IEEE Transactions on Biomedical Engineering, vol 38, no. 8, August 1991, The Pall BPF4 Hiqh Efficiency Leukocyte Removal Blood Processing Filter System (Pall BPF4 High Efficiency Blood Purification Blood Filtration System), Pall Biomedical Products Corporation, 1993 Notwithstanding the existence of the prior technology, the need prevails for an apparatus and methods to be used in the classification of a pharmaceutical or other compound, to determine its effect or effectiveness to alter, for example, decrease, the viscosity of the blood of a living being, to alter the deformability of red blood cells in the blood of a living being, and to alter the thixotropic properties of the blood of a living being OBJECTIVES OF THE INVENTION 15 Accordingly, the general objective of the present invention provides an apparatus and methods to be used to meet those needs. A further objective of this invention is to provide in vivo apparatuses and methods for use in the determination of viscosity of the blood of a living being, in order to evaluate the effectiveness of a pharmacist in altering the viscosity of the blood of a living being. . A further objective of this invention is to provide in vivo apparatuses and methods to be used in the determination of the deformability of red blood cells in the blood of a living being, in order to evaluate the t &L * Á < $ »-. The effectiveness of a pharmacist in altering the deformability of the red blood cells of a living organ It is still an additional objective of this invention to provide in vivo devices and methods for use in the determination of the thixotropic properties of the blood of a living being. , in order to evaluate the effectiveness of a pharmacist to alter the thixotropic properties of the blood of a living being.

BRIEF DESCRIPTION OF THE INVENTION These and other objects of this invention are achieved by providing apparatuses and methods for classifying a pharmaceutical, to determine its effectiveness in altering the viscosity of the blood of a living being. The apparatus comprises an in vivo instrument arranged to be coupled to the blood that flows within the vascular system of a living being. According to one aspect of this invention, the method comprises the step of introducing a pharmaceutical (or other compound) into the body of a living being, and using the in vivo instrument to determine the likely effect of the pharmacist introduced on the viscosity of the blood of a living being According to another aspect of this invention, the method comprises the step of introducing a pharmaceutical (or other compound) into the body of a living being, and using the in vivo instrument to determine the likely effect of the introduced pharmaceutical in the deformability of the red blood cells of a living being.

In accordance with yet another aspect of this invention, the method comprises the step of introducing a pharmaceutical (or other compound) into the body of a living being, and using the in vivo instrument to determine the likely effect of the introduced pharmaceutical on the thixotropic properties of the blood of a living being.

DESCRIPTION OF THE DRAWINGS Other objects and many of the intended advantages of this invention will be readily appreciated when they are better understood by reference to the following detailed description when considered in connection with the accompanying drawings in which: FIGS. 1A and 1B form an illustration and functional diagram of one embodiment of a system for measuring in vivo the viscosity of the blood of a living being; Fig. 2A is an isometric view of a portion of the system shown in Fig. 1, namely, an exemplary test station; Fig. 3 is an illustration of the construction and function of the blood receiving means; Fig. 4 is a graph of a parameter measured by the system if Fig. 1, namely, the "head" of the fluid column plotted against time; Figs. 5A-5G are illustrations of a portion of the system shown in Fig. 1, showing the operational sequence thereof; Fig. 6 is an elongated isometric view of a portion of the system, namely, a capillary tube; Fig. 7 is a view similar to Fig. 6, but showing an alternative embodiment of the capillary tube; Fig. 8A is a view similar to fig. 6 and 7, but showing ura alternative modality of the capillary tube; Fig. 8B is a hugely enlarged cross-sectional view taken along line 8B-8B of Fig.8A; Fig. 9 is an enlarged cross-sectional view of yet another alternative embodiment of the capillary tube; Fig. 10 is an enlarged sectional view through a portion of the components shown in Fig. 3 to include means, for example, a shock absorber piston at the blood / fluid or transmission interface to isolate the blood from the of the transmission fluid usaco by the system; Fig. 11 is a block diagram of a portion of the system shown in Fig. 1, namely the sensor means. Fig. 12 is an enlarged cross-sectional view of the sensor means taken along line 12-12 of Fig. 2A; Fig. 13 is an illustration of a test of calibration test equipment for use with the system of Fig. 1; and Fig. 14 is a graph similar to Fig. 4 showing the head of the fluid column plotted versus time to show a thixotropic characteristic of the blood.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Referring now in greater detail to the various figures of the drawings, in which the reference characters refer to similar parts, a liquid viscosity measuring system constructed in accordance with FIGS. 1A and 1B is shown. According to the present invention The system 20 has particular utility for measuring in vivo, the viscosity of the blood of a living being. Although the apparatus 20 has many applications, the preferred embodiment of the apparatus 20 is used to measure the viscosity of the blood in any place of the patient's vascular system, for example, veins, arteries, left chamber pulmonary system, left ventricle, etc. It should be understood that the blood is a non-Newtonian fluid. A Newtonian fluid can be defined as one in which the viscosity does not vary with the cutting speed within the non-turbulent flow range, whereas a non-Newtonian fluid, such as blood, exhibits a viscosity that is variable with the cutting speed in the non-turbulent flow range. As a result, when the viscosity of a non-Newtonian fluid is plotted as a function of the cutting speed, a curve is produced, rather than a straight line. Therefore, to obtain a precise determination of blood viscosity, it is necessary to obtain a viscosity measurement over a range of cuts. The concept of the present invention is to monitor, on a substantially continuous basis, the lifting head of a fluid column located externally coupled to a portion of the patient's body, in which the blood flows, thereby effectively monitoring the blood In vivo patient data The data of this lifting head is used to calculate the viscosity of the blood at a large multiplicity of points during the elevation of the column for yapas different flow rates, thereby providing a viscosity of the blood over a range Of cuts. The monitoring of the lifting column solves the problem of how to generate a range of cuts necessary to obtain an accurate measurement of the viscosity of the blood. As shown in Figs. 1A and 1B, the apparatus 20 basically comprises a blood sampling medium. 22 and a calculation means 24, which are coupled to provide the viscosity measurement. The blood sampling means 22 comprises a catheter 26, which comprises, in a preferred embodiment, a capillary tube. The catheter 26 has an inner diameter D ^ and a length L- ,. The catheter 26 is introduced into the body 28 of the living being (patient) to an internal site 30 (e.g., a vein, artery, etc.) to enable the blood 31 to flow into the catheter 26 Thus, the catheter 26 serves as a blood receptor medium. The catheter 26 is connected via a plug 32 to a conduit means 34 having an inside diameter D2. A first valve means 36 (e.g., a 3-way valve) selectively couples an injector means 38 to the conduit means 34. The injector means 38 comprises a reservoir 40 for containing an indicator or transmission fluid 41 (e.g. liquid such as saline solution, alcohol or any sterile water type liquid) which, when injected into conduit means 34, forms a column of fluid 42 (to be discussed later) that can be monitored (by , 4 * For example, an optically monitored optimal dye can be used to color the transmission fluid to maximize readability by an optical sensor). The other end of the conduit means 34 is coupled to an elevation tube 44 forming a lumen that allows the level of the fluid column 42 to be detected as a function of time. The lifting tube 44 has an inner diameter of D3 The upper end of the lifting tube 44 comprises a second valve means 46 (eg, a 2-way valve) which vents the lifting tube 44 to the atmosphere when the valve 46 The first valve means 36 and the second valve means 46 are open, preferably include hydrophobic vents (not shown) to eliminate blood shedding. It should be understood that the optimum selection of tube sizes for capillary tube 26, conduit means 34 and lifting tube 44 minimizes the viscosity and surface tension effects of transmission fluid 41. It should also be understood that it is preferable having the capillary tube 26 fully inserted into the vascular system, ie, the capillary tube 26 is inserted, so that after the conduit means 34 of diameter D2 is also disposed in the vascular system.

The fluid column 42 is monitored by the monitoring means 48. The monitoring means 48 comprises a sensor means 50 (eg, a coupled charge device, CCD, including the associated electronics, Fig. 11 and an associated power supply). 51) coupled to a microprocessor means 52 (e.g., a personal computer), which further comprises an appropriate diagnostic computing program 54 The monitoring means 48 monitors the height of the fluid column 42 as it rises along the length of the length of the lifting tube 44 during the test or run to determine the viscosity of the patient's blood. Peripheral indicator means 56, for example, a visual display 58, a counter 60, a printer 62, provide data and / or graphics belonging to the viscosity / cutting speed measurements. In addition, a modem 64 may be connected to the monitoring means 48 to provide all pertinent data to some remote location, for example, via the Internet or World Wide Web 66. In accordance with a preferred aspect of this invention, the visual display 58 and / or printer 62 serve to present graphical representations of measured parameters, such as, viscosity vs. cut, or viscosity vs; fluid column height ("head"), or diagnosis. The counter means 60 is used to numerically display such items as viscosity to a particular cut and / or head at which the velocity of the fluid column is zero, for example, the thixotropic point (to be discussed later). The viscosity / cutting speed data can be stored in the microprocessor means 52 and can be compared to databases 54 (on CD-ROMs, diskettes or associated PC cards) to present possible diagnoses to the doctor. Fig.2A shows a portion of the implementation of the system 20. As shown, the injector means 38, a portion of the conduit means 34, the first valve means 36, the lift tube 44 and the second valve means 46 they are mounted on a support plate 68 to form a pipe assembly 69. The pipe assembly 69 is configured to be removably mounted within a housing 70, the one containing the sensor means 50 and the power supply. 51 The support plate 68 is mounted on the locker 70 with the appropriate connections, in order to position the lift tube 44 vertically and directly opposite the sensor means 50 for proper monitoring. Furthermore, during the insertion of the pipe assembly 69, the appropriate valve control connections 72 are made, so that the first valve means 36 and the second valve means 46 can be automatically controlled in sequence in an appropriate manner. The location latches 73 and location holes 75 are provided to ensure that the support plate 68 is properly aligned, thereby arranging the lift tube 44 directly opposite the sensor means 50. The support plate 68 comprises a material transparent that allows the sensor means 50 to optically monitor the fluid column 42. It should be understood that the injector means 38 is pre-loaded with the transmission fluid 41, which is held captive in the reservoir 40 by the valve 3. tracks 36. Only when the valve 36 is properly oriented, the transmission fluid 41 flows out of the injector means 38 and into the conduit means 34. Once the pipe assembly 69 is secured in the seat. 70, a door 74 can be releasably secured to create a sufficiently dark environment to support proper column lighting 76 and level detection by the sensor means 50 during the run. Once a run or viscosity measurement procedure is completed, the pipe assembly 69 is removed, disconnected from the capillary tube 26, and then discarded. To run another test, a new pipe assembly 69 is connected to the capillary tube 26 and it is re-installed in housing 70. It should be understood that it is within the broader scope of this invention, that the first valve means 36 and the second 46 can be manually controlled, that is, the proper operation of the apparatus 20 does not require automatic control of the first valve means 36 and the second 46. An exemplary test station is shown in Fig. 2B. It should be understood that although the apparatus 20 is shown with the capillary 26 inserted into the patient's arm, the apparatus 20 is not limited to use with that portion of the patient's body. Other station configurations could be used where the capillary 26 is inserted into the patient's body. other portions of the patient's body, so that blood flows into the capillary tube 26. With the test station shown in Fig. 2B, the patient 78 is seated with his arm arranged on a horizontal surface 80. The capillary 26 is inserted percutaneously into the the patient's arm until its distal end, and preferably its entire length L ^ is within a desired container, eg, a vein. The conduit means 34 couples the capillary 26 to the housing 70. The housing 70 is releasably disposed on a fixed vertical surface 82. The vertical surface 82 comprises adjustment means 84 which allow the complete housing 70 to be manually moved in a directional direction. vertical, and then be releasably secured to any desired vertical height. The important point is that the operator can change the relative vertical position of the housing 70 with respect to the vertical position of the patient portion, in which the capillary tube 26 has been inserted for reasons that will be understood later. The microprocessor means 52, display 58 and printer 62, are also shown in the station Fig. 3 is a functional diagram of the apparatus 20 With respect to Fig. 3, the basic operation of the apparatus 20 is shown in Fig. 3 As the blood 31 flows towards and through the capillary tube 26 and in the conduit means 34, the blood 31 encounters the transmission fluid 41 and displaces the transmission fluid 41 upwards in the lift tube 44, thereby forming the fluid column 42. The medium sensor 50 (eg, a CCD array) monitors the elevation of fluid column 42 in real time by detecting the interface between the upper part of the transmission fluid column 42 and the gas (for example, air) in the lifting tube above the fluid. This optical interface (e.g., meniscus) is easily detectable by the sensor means 50. The operation of the first valve means 36 and the second valve means 46 is discussed below. If the following considerations are made, in particular, DT is much less than D2; and Di is much smaller than D3 then it can be shown that the viscosity r] - (t)) and the cutting speed (?! (t)) of the blood in the capillary tube 26, are given by: ?? (t) = (sflíD 32L D3 In XX - r? (t) A v? (T) = 8D3 - (?, (ßsg) e), where 4 = 32? 1 (t), D32 where ?? (t) represents the viscosity; ? -? (t) represents the cutting speed; ps represents the density of the indicator or transmission fluid; g represents the gravitational constant; t represents the measurement time, D-i represents the inner diameter of the capillary tube; Li represents the length of the capillary tube; D3 represents the inside diameter of the indicator or transmission fluid column; h8 represents the final height of the indicator or transmission fluid column; and h (t) represents the instantaneous height of the indicator or transmission fluid column. The viscosity,? -, (t), of the blood is plotted as shown in Fig. 4. To increase the range of cuts, a longer capillary tube 26 can be used (i.e., increase L-i). The operation of the apparatus 20 is shown in Figs. 5A-5H and it is as follows.

The portion of the patient's vascular system (eg, vein, artery, etc.) into which the capillary tube 26 is to be inserted is disposed on the hopzonatl surface 80 This entry point in the patient becomes the reference "DATUM" and represents a vertical height reference Figs 5A-5B A guide wire 86 is inserted into the patient's vascular system via a punch 88 The punch 88 is removed, leaving the guidewire 86 in place The following steps are preferably automated, so that once the capillary tube 26 is inserted into the patient, the operator only needs to activate a switch (not shown) of a controller (not shown) that would automatically perform the following steps. FIG. 5C The first valve means 36 is open, of so that the ports A and B are in communication while the ports A to C and B to C are closed, the second valve means 46 is closed The capillary 26 is jet cleaned Fig 5D The first valve means 36 is completely closed and the capillary 26 is screwed onto the guide wire 36, and then it is disposed in the patient's vascular system. The DATUM level is established for the capillary tube 26 and the lifting tube 44. a brand of DATUM on the fixed vertical surface 82. Fig 5E- The guide wire 86 is removed and the DATUM level is set for the capillary tube 26 and the lifting tube 44 A "0" mark is created on the lifting tube 44 that is aligned with the level of DATUM Fig. 5F: The first valve means 36 moves to open communication between ports A and C and the second valve means 46 moves to open communication between ports D and E. The operator then presses the plug 90 in the injection means 38 for filling the lifting tube 44 with the transmission fluid or indicator up to the "0" mark or DATUM. Then both the first valve means 36 and the second valve means 46 are closed. Fig. 5F: Allowing the blood pressure to pressurize the fluid column 42. The operator opens the first valve means 36, so that the ports B and C are in communication, thereby allowing the blood to flow (approximately 0.5 cc of blood) into the middle of conduit 34. The fluid column 42 will rise from the 0 mark to a new level. The operator then manually moves the housing 70 downwards until the new level is aligned with the DATUM mark on the fixed vertical surface 82. This action allows the determination of the static pressure of the blood (for example, the venous) using the Closed lift tube 44 as a "barometer". Fig. 5G: In order to avoid overflowing the lifting tube 44 during the run, it is necessary to calculate the approximate final level or head, h ", of the fluid column 42 and to decrease the housing 70 by that amount. Boyle's law is used to estimate h8 of probable elevation of fluid column 42 in step 5F. The housing 70 is then dropped by the amount of h8. The housing 70 is then secured at that height to prepare the sensor means 50 for monitoring the elevation of the fluid column 42. The second valve means 46 is then opened and the fluid column 42 starts to rise If the test is going to run again, the pipe assembly 69 is discarded and a new pipe assembly 69 is installed in the housing. If the transmission fluid 41 in the injector means 38 is of a biocompatible material, a portion of the transmission fluid 41 can be used to blast clean. the apparatus 20, all the way to the tip of the capillary tube 26, as shown in Fig. 5C. Before making a viscosity measurement run and as part of the automated procedure discussed above, a current barometric pressure reading is obtained (for example, from a barometer not shown, internal to the calculation means 24) and is provided to the microprocessor means 52 Thus, the apparatus 20 calculates the appropriate viscosity / cutting speed graph, based on the existing actual atmospheric pressure. In addition, vents may be provided along the apparatus 20 to minimize the effect on the computed viscosity pres- sure. It should be understood that the process described above could also be achieved with the use of a hemostasis valve (eg, a "Heparin Closure") between the capillary tube 26 and the conduit means 34. This allows the capillary tube 26 to be left in its place, when it is going to make a plurality of runs. Additionally, a hemostasis valve having an accessory "Y" could be disposed near the point where the capillary tube 28 enters the vessel, in order to allow the passage of a guidewire 86, after the apparatus 20 is cleaned at jet without getting air bubbles.

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The capillary tube 26 should be constructed of, or be coated with, a material or materials that prevent blood 31 from adhering to the inner walls of the capillary, for example, an anti-thrombogenic material, such as Heparin, and / or Anti-thrombolytic coatings, for example, phosphoryl choline, etc., can be used to minimize blood coagulation. The phosphoryl choline compounds are available from Biocompatibles, Ltd., Uxbpdge, UK. Such construction or coatings facilitate long-term placement of the capillary tube 26 within the vascular system of the patient. Additionally, as shown more clearly in Fig. 6, the tip of the capillary tube 26 terminates at any portion of the inside of the vessel wall once inserted into the patient's vascular system, the blood flow inlet 94 in the capillary tube 26 will not be obstructed or prevented. An alternative embodiment of the capillary tube 26 is shown in FIG. 7 and includes an intravascular capillary with a controlled lumen or resistor for the function of the viscometer and with another for measuring the pressure. For example, the capillary tube 126 comprises a first lumen 96 for transmitting blood 31 as previously discussed and comprising a second lumen 98, which is coupled to a pressure transducer (not shown) that is coupled to the calculation means 24. Thus, the second lumen 98 provides a continuous reference of the pressure of the blood of the patient to the calculation means 24. Unlike the process described above, whereby the operator determines the blood pressure of the patient before the test is run, using this second lumen 98, the calculation means 24 is provided with a reference of continuous blood pressure throughout the run. In some patients, the actual blood pressure may change during the run. Such variations or pulsations of blood pressure need to be considered to determine the appropriate viscosity / cut versus time curve. Having a continuous blood pressure reference can be compensated for during the blood viscosity / cut determination. Another alternative embodiment of the capillary tube 26 is shown in Figs. 8A-8B and 9. This embodiment includes an intravascular capillary with a controlled lumen or tube with alternative resistance members, such as a variety of small capillary tubes in a bundle (Figs 8A-8B). Alternatively, the tube is filled with very small spheres (Fig 9), or a sintered column (not shown). With respect to the embodiment as shown in Figs. 8A-8B, the capillary tube 226 comprises a plurality of small capillaries 100, each having different internal diameters (d1: d2, d3, etc.). The use of the plurality of small capillaries not only allows the length Li to be smaller, but also allows the achievement of very small cuts. Where these diameters are less than the average diameters of a normal red blood cell, the system 20 can be used to determine the blood pressure at which the blood flow starts. This action provides an indication of the deformability of the red blood cells of the being, because those cells will have to deform to pass through the small capillaries 100. In the alternative embodiment of the capillary tube shown in Fig. 9, the capillary tube 326 includes very small spheres 102 within it to create interstices, which are smaller than the average diameter of a red blood cell, so that such cells will have to deform to pass through it. To eliminate or at least minimize the possible miscibility / contamination problem between the transmission fluid / blood interface in the conduit means 34, a damper piston may be used as shown in Fig. 10. That piston may be of any suitable construction, for example, a carbon post to isolate the blood 31 from the transmission fluid 41 at its interface. In particular, the piston 104, which has a specific gravity of about 1.0, transmits the movement or flow of the blood 31 down the capillary tube to the transmission fluid 41, while isolating or separating these two fluids from each other. Alternatively, although not shown, a buffer fluid could be introduced at the interface between the blood 31 and the transmission fluid 41, to reduce any miscibility / contamination problem. Fig. 11 is a block diagram of the sensor means 50, while Fig. 12 shows its construction, ie, a cross-sectional view thereof taken along line 12-12 of Fig. 2A, but with the support plate 68 already secured to the housing 70. Thus, as can be seen, an exemplary implementation of the sensor means 50 comprises a linear array of illuminators 76 (see Figs 2A and 12), rod lenses 106 and chips sensors 108 mounted on a PCB substrate 110. A particularly useful commercial device, incorporating the components, is Model SV200A4 sold by Sean Vision, Inc of San Jose, CA Sensor means 50 includes a glass cover 112, ending in the lifting tube 44, when the support 68 is installed, as described above. An integrated lens 114 can be arranged on the opposite side of the glass cover 112 to improve the view by the rod lens 106. In order to operate the system 20 appropriately, it is necessary for the calculation means 24 to consider the fluid resistance of the pipe assembly 69, which is mounted in the housing 70. To accomplish this, a test equipment is used. FIG. 13 shows an exemplary test equipment 116 for mounting pipe 69 of the system 20 A bar code 118 is provided on the support plate 68 (Figs. 2A and 13) which contains a calibration factor for that particular pipe assembly 69 Thus, just before a viscosity run is made, an automatic scanner 119, coupled to PC 52, scans bar code 118 and loads PC 52 with the particular calibration factor. To determine the calibration factor, the calibration pipe assembly, A2, is coupled to the calibration equipment. test 116, as shown in Fig 13 An air supply 120 delivers clean dry air at a predetermined pressure, PAS (eg, 703 kg / cm2) which can be regulated (via a REG regulator) up to 7473 Pa The supply of air 120 delivers the flow through a calibrated orifice, A ,, having a known resistance The input of the pipe assembly under the P-2 test is coupled to the output of A ,, and the output of the pipe assembly under the test A2 is ventilated to the atmosphere When the air supply 120 enters the air flow, depending on the internal fluid resistance of the pipe assembly under test A2, a pressure, PTA, appears at the entrance of the pipe assembly under the test , A2. A pair of open ended gauges 122A and 122B are coupled to the input of A, and the output of A1t respectively, to monitor PAs and PTA, respectively. The PAS / PTA ratio represents the calibration factor. This calibration factor is then encoded in the bar code 118. Thus, each time a pipe assembly 69 is mounted in the housing 70 and the bar code reading 118 in the PC 52, the calculation means 24 can make a viscosity determination based on the specific fluid resistance of that mounted pipe assembly 69. In accordance with another aspect of the present invention and to minimize measurement errors, the system 20 includes the means for controlling the formation of a meniscus. (Fig. 3) in the upper part of the transmission fluid column 42. In particular, coatings for the lifting tube 44 can be introduced to control the surface tension, precisely by providing a controlled surface energy, thereby flattening the meniscus. This meniscus 124 can be further controlled by changing the molecular formation of the lifting tube 44, the transmission fluid 41 and the gas above the fluid column 42 being used. Additionally, to make the surface energy repeatable and predictable, the internal surfaces of the lifting tube 44 can be coated by vapor deposition with surfactants, for example, silicone. By including suitable surfactants, such as silicone, in the extrusions, the surfactants migrate to the surfaces in a predictable manner.

Another embodiment (not shown) of the apparatus 20 includes a lifting tube 44 that is inclined to increase sensitivity. In particular, if the lifting tube 44 were bent at an angle away from a vertical orientation, for each millimeter of vertical height elevation of the fluid column 42, there would be more than one millimeter of displacement of the fluid column 42 in the tube Lift 44. In accordance with another aspect of the present invention, means 124 (Fig. 2B) may be provided to apply the vibratory energy to the patient to determine their effect on the blood viscosity of the patient and the developed data may then be used to provide vibrational therapy used to provide beneficial effects. In particular, that aspect of the invention makes use of a vibration source 124 that generates vibratory energy, whose amplitude and frequency can be controlled by the operator. This vibratory energy is applied either before or during a viscosity measurement run. Although the vibratory energy is shown in Fig. 2B as being applied to the patient's arm only, it is within the broader scope of the invention that the vibrational energy can be applied to all or only a portion of the patient's body. The vibration can also be applied to the fluid column 42 and / or the capillary tube 26, to obtain a smoother fluid flow. Another significant feature of the system 20 is its ability to monitor the level of the fluid column 42, in which the velocity becomes zero, i.e., the thixotropic point of the blood flow. The thixotropic point represents a cutting voltage that is supported at speed "I ^ a ^" ^. * Ijasto? S zero, as shown graphically in Fig. 14. The presentation of the cut or head to which the flow is remitted after a zero-adjustment time, provides an indication of the patient's characteristic coagulation. It should be understood that the detailed diagnosis pro- gram 54 allows for the dynamic effects of deceleration of the flow column 42 and the viscous effects of the various diameters of the pipeline, according to figure 31 and the flow of transmission 41 passes through system 20 It should be understood that another implementation of system 20 comprises a molded or engraved channel system, as a substitute for the pipe discussed above. As mentioned before, the apparatus 20 has other applications, such as viscosity measurements of other flowable materials, for example, oils, paints and cosmetics. The in vivo parathion of the present invention can be used to classify or test one or more pharmaceuticals or other compounds to determine its or its likely effects on one or more parameters of the blood of a living being. For example, the apparatus can be used to determine the in vivo viscosity of the blood of a living being to classify a pharmaceutical or other compound in a test subject, e.g., a living human or animal from a laboratory, for the purpose of of predicting the likely effect in altering, for example, the effectiveness in decreasing, the viscosity of the blood of a living, for example, human being, to whom the pharmacist will ultimately be administered. The system can be used to determine the deformability of the red blood cells of a living being to classify the effect of the pharmaceutical or other compound in the test subject, in order to predict its probable effect on the deformability of the red blood cells of the human being. alive to whom the pharmacist will eventually be administered In this way, the system can also be used to determine the thixotropic properties of the blood of a living being to classify the effect of the pharmacist or other compound on the test subject, in order to predict its probable effect on the thixotropic properties of the blood of the living being to whom the pharmacist will finally be administered. Without further elaboration, the foregoing will fully illustrate our invention and others may easily adapt, upon applying current or future knowledge, the same to be used under various conditions of service.

Claims (11)

1. A method for classifying a pharmacist to determine its effectiveness in altering the viscosity of the circulating blood of a living being, characterized by the steps of: (a) introducing the pharmacist into the body of the living being; (b) passing the circulating blood (30) of the living being through a lumen of known dimensions in contact with a second fluid (42) in an elongate container (44), whereby the extension of the fluid changes as a result of the contact, (c) generating a signal by a signal generator means (50) according to the movement of the extension; (d) calculating the viscosity of the circulating blood from the signals generated using calculation means (52); and (e) determining the probable effect of said pharmacist on the viscosity of the circulating blood of the living being from the calculated viscosity.

The method of claim 1, wherein said step for determining the probable effect of said pharmacist comprises determining the pharmaceutical efficacy for decreasing the viscosity of the circulating blood of the living being.

3. A method according to claim 1, wherein said living being to which said pharmacist is to be administered is a living being.

4. A method according to claim 1, wherein said living being is an animal.

The method according to any preceding claim, wherein said step of passing the circulating blood (30) of the living being through the lumen, comprises passing the circulating blood through a capillary tube having a length (L1) and diameter (D1) known

6. A method for classifying a pharmacist to determine its effectiveness in altering the deformability of red blood cells in the circulating blood of a living being, characterized by the steps of: (a) introducing the pharmacist into the body of the being alive; (b) passing the circulating blood (30) of the living being through the blood flow restriction means of known dimensions; (c) monitoring the passage of circulating blood through said means of restricting blood flow; (d) determining the probable effect of said pharmacist on the deformability of the red blood cells of the circulating blood of the living being from the monitored passage of the circulating blood through said means of restriction of blood flow.

7. A method according to claim 6, wherein said living being to which said pharmacist is to be administered is a human being.

8. A method according to claim 6, wherein said living being is an animal.

The method of claim 6. wherein said blood flow restriction means comprises a capillary tube of known length (L1) and diameter (D1), and having a longitudinal axis and further comprising a plurality of capillary tubes smaller ones of varying diameters, said diameters being smaller than said diameter (D1), and wherein each of said smaller capillary tubes is aligned with said longitudinal axis.

The method of claim 6, wherein said blood flow restriction means comprises a capillary tube of known length (L1) and diameter (D1) and further comprises a plurality of spheres disposed within said capillary tube to create interstices , which are smaller than the average diameter of a red blood cell.

11. A method to classify a pharmacist to determine its effectiveness in altering the thixotropic properties of the circulating blood of a living being, characterized by the steps of: (a) introducing the pharmacist to the body of the living being; (b) passing the circulating blood (30) of the living being through a lumen of known dimensions in contact with a second fluid (42) in an elongate container (44), whereby the extension of the fluid changes as a result of the Contact; (c) monitoring the deceleration in the movement of the fluid extension until the fluid reaches a stopped position corresponding to the stopped movement of the circulating blood in the lumen; (d) causing the circulating blood in the lumen to start moving again and monitoring the corresponding movement of fluid from the stopped position; and (e) determining the probable effect of said pharmacist on the thixotropic properties of the circulating blood of the living being, from the monitored deceleration and corresponding movement of the fluid. A method according to claim 11, wherein said living being to which said pharmacist is going to be administered, is a human being 13 A method according to claim 11, wherein said living being is an animal