U.S. patent application number 09/927576 was filed with the patent office on 2002-02-28 for methods of monitoring glucose levels in a subject and uses thereof.
Invention is credited to Ackerman, Neil.
Application Number | 20020026111 09/927576 |
Document ID | / |
Family ID | 34527757 |
Filed Date | 2002-02-28 |
United States Patent
Application |
20020026111 |
Kind Code |
A1 |
Ackerman, Neil |
February 28, 2002 |
Methods of monitoring glucose levels in a subject and uses
thereof
Abstract
Methods of frequently monitoring glucose amounts and/or
concentrations in a subject who is at risk for hypoglycemia,
hyperglycemia, and/or glucose level fluctuations that put the
subject at risk are provided. Also provided are methods of
monitoring the effects of one or more pharmaceutical compositions
on the levels of glucose in a subject.
Inventors: |
Ackerman, Neil; (San Carlos,
CA) |
Correspondence
Address: |
CYGNUS, INC.
Intellectual Property Dept.
400 Penobscot Drive
Redwood City
CA
94063
US
|
Family ID: |
34527757 |
Appl. No.: |
09/927576 |
Filed: |
August 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60228617 |
Aug 28, 2000 |
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Current U.S.
Class: |
600/347 ;
128/921; 600/300 |
Current CPC
Class: |
A61B 5/413 20130101;
A61B 5/1486 20130101; A61B 5/14532 20130101 |
Class at
Publication: |
600/347 ;
600/300; 128/921 |
International
Class: |
A61B 005/05 |
Claims
What is claimed is:
1. A method for evaluating compliance with a weight management
program in a subject, said method comprising determining a
reference range of glucose amounts or concentrations that
correspond to achieving a weight management goal in the subject,
said range of glucose amounts or concentrations comprising a high
threshold glucose value and a low threshold glucose value,
monitoring glucose amount or concentration in the subject by a
glucose monitoring method comprising transdermally extracting a
sample comprising glucose from the subject using a sampling system
that is in operative contact with a skin or mucosal surface of said
subject, wherein the extracting is carried out using an
iontophoretic system comprising first and second iontophoretic
electrodes; contacting the sample with a sensor element in the
presence of glucose oxidase that reacts with glucose to produce
hydrogen peroxide; detecting the hydrogen peroxide with the sensor
element that reacts electrochemically with the hydrogen peroxide to
produce a detectable signal, wherein said detectable signal is
specifically related to glucose amount or concentration in the
subject; measuring the detectable signal; correlating the signal
measurement to an amount or concentration of glucose in the
subject; and repeating said glucose monitoring method to obtain a
series of glucose amounts or concentrations, in the subject, at
selected time intervals; maintaining a record of caloric intake;
and comparing said series of glucose amounts or concentrations,
said record, and said reference range to evaluate compliance with
the reference range of glucose amounts or concentrations to achieve
the weight management goal of the subject.
2. The method of claim 1, wherein said weight management goal is
selected from the group consisting of weight gain in the subject,
weight reduction in the subject, and weight maintenance in the
subject.
3. The method of claim 1, wherein said maintaining a record further
comprises recording caloric output.
4. The method of claim 1, wherein said monitoring glucose amount or
concentration in the subject by a glucose monitoring method further
comprises providing an alert to the subject when a glucose amount
or concentration, in the subject, at a selected time interval falls
outside of the reference range.
5. A method for monitoring an effect of at least one
non-insulin-containing pharmaceutical composition on glucose levels
in a subject receiving said pharmaceutical composition, the method
comprising, monitoring glucose amount or concentration in the
subject by a glucose monitoring method comprising transdermally
extracting a sample comprising glucose from the subject using a
sampling system that is in operative contact with a skin or mucosal
surface of said subject, wherein the extracting is carried out
using an iontophoretic system comprising first and second
iontophoretic electrodes; contacting the sample with a sensor
element in the presence of glucose oxidase that reacts with glucose
to produce hydrogen peroxide; detecting the hydrogen peroxide with
the sensor element that reacts electrochemically with the hydrogen
peroxide to produce a detectable signal, wherein said detectable
signal is specifically related to glucose amount or concentration
in the subject; measuring the detectable signal; correlating the
signal measurement to an amount or concentration of glucose in the
subject; and repeating said glucose monitoring method to obtain a
series of glucose amounts or concentrations, in the subject, at
selected time intervals; maintaining a record of treatment with the
pharmaceutical composition; and comparing said series of glucose
amounts or concentrations and said record to evaluate the effect of
the pharmaceutical composition on glucose levels in the subject
receiving said pharmaceutical composition.
6. The method of claim 5 further comprising, determining a
reference range of glucose amounts or concentrations that
correspond to maintaining a desired range of glucose amounts or
concentrations in the subject during a treatment course with said
pharmaceutical composition, wherein said reference range comprises
a high threshold glucose value and a low threshold glucose
value.
7. The method of claim 6, wherein said monitoring glucose amount or
concentration in the subject by a glucose monitoring method further
comprises providing an alert to the subject when a glucose amount
or concentration, in the subject, at a selected time interval falls
outside of the reference range.
8. The method of claim 5, wherein the pharmaceutical composition is
pentamidine.
9. The method of claim 5, wherein the pharmaceutical composition is
quinine.
10. The method of claim 5, wherein the pharmaceutical composition
is saquinavir.
11. The method of claim 5, wherein the pharmaceutical composition
is indomethacin.
12. The method of claim 5, wherein the subject is also receiving
insulin.
13. A method for improving prognosis and/or reduction of adverse
side-effects associated with a disease state or condition in a
subject, said method comprising determining a reference range of
glucose amounts or concentrations that correspond to achieving an
improved prognosis or reduction of adverse side-effects associated
with said disease state or condition in the subject, said range of
glucose amounts or concentrations comprising a high threshold
glucose value and a low threshold glucose value, monitoring glucose
amount or concentration in the subject by a glucose monitoring
method comprising transdermally extracting a sample comprising
glucose from the subject using a sampling system that is in
operative contact with a skin or mucosal surface of said subject,
wherein the extracting is carried out using an iontophoretic system
comprising first and second iontophoretic electrodes; contacting
the sample with a sensor element in the presence of glucose oxidase
that reacts with glucose to produce hydrogen peroxide; detecting
the hydrogen peroxide with the sensor element that reacts
electrochemically with the hydrogen peroxide to produce a
detectable signal, wherein said detectable signal is specifically
related to glucose amount or concentration in the subject;
measuring the detectable signal; correlating the signal measurement
to an amount or concentration of glucose in the subject; and
repeating said glucose monitoring method to obtain a series of
glucose amounts or concentrations, in the subject, at selected time
intervals; and comparing said series of glucose amounts or
concentrations and said reference range to evaluate compliance with
the reference range of glucose amounts or concentrations to achieve
an improved prognosis or reduction of adverse side-effects
associated with said disease state or condition in the subject,
wherein said disease state or condition is not type I or type II
diabetes.
14. The method of claim 13, wherein said monitoring glucose amount
or concentration in the subject by a glucose monitoring method
further comprises providing an alert to the subject when a glucose
amount or concentration, in the subject, at a selected time
interval falls outside of the reference range.
15. The method of claim 13, wherein the condition is cancer
remission.
16. The method of claim 13, wherein the disease state is infection
with human immunodeficiency virus (HIV).
17. The method of claim 13, wherein the disease state is infection
with Candida.
18. The method of claim 13, wherein the condition is long distance
driving.
19. The method of claim 13, wherein the condition is organ
transplantation.
20. The method of claim 13, wherein the condition is growth hormone
therapy.
21. The method of claim 13, wherein the disease state is renal
failure.
22. The method of claim 13, wherein the disease state is infection
with malaria.
23. The method of claim 13, wherein the condition is
alcoholism.
24. The method of claim 13, wherein the condition is intense
exercise.
25. The method of claim 13, wherein the disease state is
cardiovascular disease.
26. The method of claim 13, wherein the disease state is cystic
fibrosis.
27. The method of claim 13, wherein the disease state is stroke or
ischemia.
28. The method of claim 13, wherein the disease state is an eating
disorder.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to U.S. Provisional Patent
Application Serial No. 60/228,617, filed Aug. 28, 2000, from which
priority is claimed under 35 USC .sctn.119(e)(1), and which
application is incorporated herein by reference in its
entirety.
TECHNICAL FIELD
[0002] The present invention is in the field of medical devices and
methods of use thereof. More particularly it relates to methods of
using glucose monitoring devices to monitoring glucose amounts
and/or concentrations in a subject who is at risk for hypoglycemia,
hyperglycemia, or fluctuations toward hypoglycemia and/or
hyperglycemia. The methods also include methods of monitoring the
effects of one or more pharmaceutical compositions on the levels of
glucose in a subject.
BACKGROUND OF THE INVENTION
[0003] The level, presence, and/or absence of glucose in a subject
can have a number of consequences. For example, fluctuations of
blood glucose levels can result in one of two physiological states,
hypoglycemia and hyperglycemia. Hypoglycemia is defined as plasma
glucose levels below normal. Hypoglycemia can be symptomatic or
asymptomatic. For example, subjects suffering from postprandial
hypoglycemia generally have symptoms of adrenergic stimulation
including diaphoresis, anxiety, irritability, palpitations, tremor,
and hunger. Such symptoms typically occur from about 2 to 4 hours
postprandially and tend to occur suddenly with symptoms generally
subsiding in about 15 to 20 minutes. Hypoglycemia can be caused by
release of adrenergic and cholinergic hormones. Postprandial
hypoglycemia is often idiopathic, however, it can be caused by
early diabetes, alcohol intake, renal failure, and drug treatments.
In addition, a category of hypoglycemia exists which is designated
as fasting hypoglycemia. Clinically, this form of hypoglycemia may
have symptoms of neuroglycopenia including headache, fatigue, and
mental dullness. In more severe cases, hypoglycemia can progress to
confusion, blurring of vision, seizure, and ultimately loss of
consciousness or seizure. Fasting hypoglycemia can occur with a
fast of greater than 4 hours, and further can be caused by
insulinoma (resulting from self-administered insulin or intake of
other hypoglycemic agents, alcohol abuse, liver disease (e.g.,
decreased gluconeogenesis), pituitary insufficiency, or adrenal
insufficiency).
[0004] Hyperglycemia, on the other hand, refers to excessive levels
of blood glucose in a subject. There are many forms of
hyperglycemia, the primary form being diabetes mellitus (DM) which
is defined as hyperglycemia secondary to decreased insulin
production or an increase in peripheral tissue resistance to the
action of insulin. There are several classifications of DM
including, type 1 DM, type 2 DM, gestational DM, and secondary DM
(which can, for example, be the result of a variety of drug
therapies, disease states (e.g., pancreatitis, Cushing's syndrome),
trauma, surgery, and others causes). Further, in the case of severe
insulin deficiency, a starvation-like state develops resulting in
acidosis (typically referred to as diabetic ketoacidosis). Symptoms
of ketoacidosis can include rapid respiration, acetone breath,
vomiting, dehydration, nausea, abdominal pain and changes in mental
stability.
[0005] Thus, there is a need for frequent monitoring of glucose
levels in many subjects who are at risk for hypogylcemia and
hyperglycemia.
SUMMARY OF THE INVENTION
[0006] The present invention describes methods of monitoring
glucose levels and/or concentration in a subject having a disease
state or condition which puts the subject at risk for hypoglycemia,
hyperglycemia, or fluctuations toward hypoglycemia and/or
hyperglycemia (for example, quickly dropping or increasing glucose
levels). A wide variety of disease states or conditions benefit
from frequent glucose monitoring, such monitoring provides a tool
for the subject, and/or healthcare professional, to develop a
response or plan to assist with management of the disease state or
condition. Methods of monitoring a subject for the effects of at
least one non-insulin containing pharmaceutical composition on
glucose amount or levels in subjects are also described. The
subject being monitored may also be receiving insulin-containing
compositions.
[0007] In one aspect the invention includes, a method for
monitoring an amount or concentration of glucose in a subject
having a disease state or condition, the method comprising:
extracting glucose from the subject having the disease state or
condition into a reservoir to obtain an amount or concentration of
glucose in the reservoir, wherein the extracting is carried out
using an iontophoresis system comprising first and second
iontophoretic electrodes; contacting extracted glucose extracted
with glucose oxidase that reacts with glucose to produce hydrogen
peroxide; detecting the hydrogen peroxide with a sensor element
that reacts electrochemically with the hydrogen peroxide to produce
a detectable signal; measuring the signal produced; correlating the
measured signal with an amount or concentration of glucose in the
subject; and performing the extracting, detecting, and measuring
frequently, and performing the correlating at least periodically to
monitor glucose amount or concentration in the subject in order to
assist in management of the disease state or condition. The methods
are helpful to the subject, and/or healthcare professional, to
provide responses or plans to assist in the management of a wide
variety of disease states and conditions, including, but not
limited to, a weight management regime; cancer remission; infection
with human immunodeficiency virus (HIV); infection with Candida;
long distance driving; organ transplantation; growth hormone
therapy; renal failure; infection with malaria; alcoholism; intense
exercise; cardiovascular disease; cystic fibrosis; or stroke or
ischemia. Further, such methods are helpful in assisting in the
management of diabetic disease states (e.g., gestational diabetes;
fetal or premature-birth neonate (i.e., a neonate born before term)
glucose management).
[0008] In one aspect, the present invention comprises a method for
evaluating compliance with a weight management program in a
subject. In this method a reference range of glucose amounts or
concentrations is determined that correspond to achieving a weight
management goal in the subject. Such range of glucose amounts or
concentrations typically comprises a high threshold glucose value
and a low threshold glucose value. Further, rates of change (or
trends) of glucose amounts or concentrations in the subject may be
determined. In one embodiment of the present invention, monitoring
of glucose amount or concentration in the subject is accomplished
by a glucose monitoring method comprising the following. First a
sample is extracted from the subject, where the sample comprises
glucose. The extraction is carried out, for example, transdermally.
In one embodiment, the transdermal sampling system is in operative
contact with a skin or mucosal surface of the subject, and may be
maintained in contact to obtain a series of samples, for example,
the extracting is carried out using an iontophoretic system
comprising first and second iontophoretic electrodes. The extracted
sample is contacted with a sensor element, for example, in the
presence of glucose oxidase that reacts with glucose to produce
hydrogen peroxide. The hydrogen peroxide is detected by the sensor
element, for example, by an electrochemical reaction between the
sensor element and the hydrogen peroxide, thus a detectable signal
is produced. The detectable signal is specifically related to
glucose amount or concentration in the subject. The detectable
signal is measured and correlated with an amount or concentration
of glucose in the subject. The glucose monitoring method is
typically repeated to obtain a series of glucose amounts or
concentrations, in the subject, at selected time intervals. Glucose
monitoring is usually carried out frequently and periodically.
Exemplary devices for use in glucose monitoring are described
herein. The glucose monitoring device used in the method of the
present invention may have alert means, where an alert is provided
to the subject (for example, an auditory alert) when glucose levels
exceed the predetermined threshold values, when glucose levels
change at a rate faster than a predetermined rate of change, or
when a predicted glucose value for a later time point falls outside
of the predetermined range. The subject typically maintains a
record of caloric intake. Such a record may be inputted into the
glucose monitoring device itself, or a related device (such as a
personal digital assistant, where, for example, the personal
digital assistant is operatively connected, at least periodically,
with the record of glucose values obtained by the glucose
monitoring device). Alternately, such a record may be manually
maintained. In addition to caloric intake, caloric output may be
recorded as well. This record is then compared to the series of
glucose amounts or concentrations and the predetermined reference
ranges to evaluate compliance with the reference range of glucose
amounts or concentrations to achieve the weight management goal of
the subject.
[0009] The weight management goal may be weight gain in the
subject, weight reduction in the subject, and weight maintenance in
the subject.
[0010] A further aspect of the present invention comprises a method
for monitoring an effect of at least one non-insulin-containing
pharmaceutical composition on glucose levels in a subject receiving
the pharmaceutical composition. In the method, glucose monitoring
in the subject may be carried out by the method described above. In
this method a record is maintained of treatment with the
pharmaceutical composition. The series of glucose amounts or
concentrations and the record are compared to evaluate the effect
of the pharmaceutical composition on glucose levels in the subject
receiving the pharmaceutical composition. A reference range of
glucose amounts or concentrations is typically determined that
corresponds to maintaining a desired range of glucose amounts or
concentrations in the subject during a treatment course with the
pharmaceutical composition. The reference range comprises, for
example, a high threshold glucose value, a low threshold glucose
value, a predetermined rate of change (e.g., glucose levels change
at a rate faster than a predetermined rate of change), and/or a
predicted glucose value for a later time point. The glucose
monitoring device may provide an alert corresponding to threshold
values, rate changes, a predicted glucose value that falls outside
of the predetermined range, etc. Such glucose monitoring is useful
when any one or more of a number of pharmaceutical compositions are
being used to treat a subject. Exemplary pharmaceutical
compositions are described herein and include, but are not limited
to, pentamidine, quinine, saquinavir, and/or indomethacin. In
addition, the subject may also be receiving insulin, or another
pharmaceutical directly targeted to maintenance of glucose levels
in the subject.
[0011] Another aspect of the present invention relates to a method
for improving prognosis and/or reduction of adverse side-effects
associated with a disease state or condition in a subject. In this
aspect of the present invention, a reference range of glucose
amounts or concentrations is determined that corresponds to
achieving an improved prognosis or reduction of adverse
side-effects associated with the disease state or condition in the
subject. The reference range comprises, for example, a high
threshold glucose value, a low threshold glucose value, a
predetermined rate of change (e.g., glucose levels change at a rate
faster than a predetermined rate of change), and/or a predicted
glucose value for a later time point. The glucose monitoring device
may provide an alert corresponding to threshold values, rate
changes, a predicted glucose value that falls outside of the
predetermined range, etc. The series of glucose amounts or
concentrations and the reference range are compared to evaluate
compliance with the reference range of glucose amounts or
concentrations to achieve an improved prognosis or reduction of
adverse side-effects associated with the disease state or condition
in the subject. In this aspect of the present invention, the
disease state or condition is not type I or type II diabetes.
[0012] Exemplary disease states or conditions are described herein
and include, but are not limited to, cancer remission, infection
with human immunodeficiency virus (HIV), infection with Candida
and/or other systemic pathogens, long distance driving, organ
transplantation, growth hormone therapy, renal failure, infection
with malaria, alcoholism, intense exercise or training,
cardiovascular disease, cystic fibrosis, stroke or ischemia, and/or
an eating disorder.
[0013] These and other embodiments of the present invention will
readily occur to those of ordinary skill in the art in view of the
disclosure herein.
BRIEF DESCRIPTION OF THE FIGURE
[0014] FIG. 1 presents a schematic of an exploded view of exemplary
components comprising one embodiment of an AutoSensor for use in an
analyte monitoring system.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The practice of the present invention will employ, unless
otherwise indicated, conventional methods and techniques of
chemistry, biochemistry, electrochemisty and pharmacology, within
the skill of the art. Such conventional methods and techniques are
explained fully in the literature.
[0016] All publications, patents and patent applications cited
herein, whether above or below are hereby incorporated by reference
in their entirety.
[0017] 1. Definitions
[0018] It is to be understood that the terminology used herein is
for the purpose of describing particular embodiments only, and is
not intended to be limiting. As used in this specification and the
appended claims, the singular forms "a", "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a reservoir" includes a
combination of two or more such reservoirs, reference to "an
analyte" includes mixtures of analytes, and the like.
[0019] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
other methods and materials similar, or equivalent, to those
described herein can be used in the practice of the present
invention, the preferred materials and methods are described
herein.
[0020] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0021] The term "microprocessor" refers to a computer processor
contained on an integrated circuit chip, such a processor may also
include memory and associated circuits. A microprocessor may
further comprise programmed instructions to execute or control
selected functions, computational methods, switching, etc.
Microprocessors and associated devices are commercially available
from a number of sources, including, but not limited to, Cypress
Semiconductor Corporation, San Jose, Calif.; IBM Corporation, White
Plains, N.Y.; Applied Microsystems Corporation, Redmond, Wash.;
Intel Corporation, Chandler, Ariz.; and, National Semiconductor,
Santa Clara, Calif.
[0022] The terms "analyte" and "target analyte" are used to denote
any physiological analyte of interest that is a specific substance
or component that is being detected and/or measured in a chemical,
physical, enzymatic, or optical analysis. A detectable signal
(e.g., a chemical signal or electrochemical signal) can be
obtained, either directly or indirectly, from such an analyte or
derivatives thereof. Furthermore, the terms "analyte" and
"substance" are used interchangeably herein, and are intended to
have the same meaning, and thus encompass any substance of
interest. In preferred embodiments, the analyte is a physiological
analyte of interest, for example, glucose, or a chemical that has a
physiological action, for example, a drug or pharmacological
agent.
[0023] A "sampling device," "sampling mechanism" or "sampling
system" refers to any device and/or associated method for obtaining
a sample from a biological system for the purpose of determining
the concentration of an analyte of interest. Such "biological
systems" include any biological system from which the analyte of
interest can be extracted, including, but not limited to, blood,
interstitial fluid, perspiration and tears. Further, a "biological
system" includes both living and artificially maintained systems.
The term "sampling" mechanism refers to extraction of a substance
from the biological system, generally across a membrane such as the
stratum corneum or mucosal membranes, wherein said sampling is
invasive, minimally invasive, semi-invasive or non-invasive. The
membrane can be natural or artificial, and can be of plant or
animal nature, such as natural or artificial skin, blood vessel
tissue, intestinal tissue, and the like. Typically, the sampling
mechanism is in operative contact with a "reservoir," or
"collection reservoir," wherein the sampling mechanism is used for
extracting the analyte from the biological system into the
reservoir to obtain the analyte in the reservoir. Nonlimiting
examples of sampling techniques include iontophoresis, sonophoresis
(see, e.g., International Publication No. WO 91/12772, published
Sep. 5, 1991; U.S. Pat. No. 5,636,632), suction, electroporation,
thermal poration, passive diffusion (see, e.g., International
Publication Nos.: WO 97/38126 (published Oct. 16, 1997); WO
97/42888, WO 97/42886, WO 97/42885, and WO 97/42882 (all published
Nov. 20, 1997); and WO 97/43962 (published Nov. 27, 1997)),
microfine (miniature) lances or cannulas, biolistic (e.g., using
particles accelerated to high speeds), subcutaneous implants or
insertions, and laser devices (see, e.g., Jacques et al. (1978) J.
Invest. Dermatology 88:88-93; International Publication WO
99/44507, published Sep. 10, 1999; International Publication WO
99/44638, published Sep. 10, 1999; and International Publication WO
99/40848, published Aug. 19, 1999). Iontophoretic sampling devices
are described, for example, in International Publication No. WO
97/24059, published Jul. 10, 1997; European Patent Application EP
0942 278, published Sep. 15, 1999; International Publication No. WO
96/00110, published Jan. 4, 1996; International Publication No. WO
97/10499, published Mar. 2, 1997; U.S. Pat. Nos. 5,279,543;
5,362,307; 5,730,714; 5,771,890; 5,989,409; 5,735,273; 5,827,183;
5,954,685 and 6,023,629, all of which are herein incorporated by
reference in their entireties. Further, a polymeric membrane may be
used at, for example, the electrode surface to block or inhibit
access of interfering species to the reactive surface of the
electrode.
[0024] The term "physiological fluid" refers to any desired fluid
to be sampled, and includes, but is not limited to, blood,
cerebrospinal fluid, interstitial fluid, semen, sweat, saliva,
urine and the like.
[0025] The term "artificial membrane" or "artificial surface,"
refers to, for example, a polymeric membrane, or an aggregation of
cells of monolayer thickness or greater which are grown or cultured
in vivo or in vitro, wherein said membrane or surface functions as
a tissue of an organism but is not actually derived, or excised,
from a pre-existing source or host.
[0026] A "monitoring system" or "analyte monitoring device" refer
to a system useful for obtaining frequent measurements of a
physiological analyte present in a biological system. Such a device
is useful, for example, for monitoring the amount or concentration
of an analyte in a subject. Such a system may comprise, but is not
limited to, a sampling mechanism, a sensing mechanism, and a
microprocessor mechanism in operative communication with the
sampling mechanism and the sensing mechanism. Such a device
typically provides frequent measurement or determination of analyte
amount or concentration in the subject and provides an alert or
alerts when levels of the analyte being monitored fall outside of a
predetermined range. Such devices may comprise durable and
consumable (or disposable) elements. The term "glucose monitoring
device" refers to a device for monitoring the amount or
concentration of glucose in a subject. Such a device typically
provides a frequent measurement or determination of glucose amount
or concentration in the subject and provides an alert or alerts
when glucose levels fall outside of a predetermined range. One such
exemplary glucose monitoring device is the GlucoWatch.RTM. (Cygnus,
Inc., Redwood City, Calif., US) biographer. The GlucoWatch
biographer comprises two primary elements, a durable element
(comprising a watch-type housing, circuitry, display element,
microprocessor element, electrical connector elements, and may
further comprise a power supply) and a consumable, or disposable,
element (e.g., an AutoSensor component involved in sampling and
signal detection, see, for example, WO 99/58190, published Nov. 18,
1999). This and similar devices is described, for example, in the
following publications: Tamada, et al., (1999) JAMA 282:1839-1844;
U.S. Pat. No. 5,771,890, issued Jun. 30, 1998; U.S. Pat. No. 5,
735,273, issued Apr. 7, 1998; U.S. Pat. No. 5,827,183, issued Oct.
27, 1998; U.S. Pat. No. 5,954,685, issued Sep. 21, 1999; U.S. Pat.
No. 5,989,409, issued Nov. 23, 1999; U.S. Pat. No. 6,023,629,
issued Feb. 8, 2000; EP Pat. Application EP 0 942 278 A2, published
Sep. 15, 1999; PCT International Application WO 96/001100,
published Jan. 4, 1996; PCT International Application WO 99/58190,
published Nov. 18, 1999. The GlucoWatch biographer provides a
device for frequent sampling of glucose from a subject the
application of low intensity electric fields across the skin
(iontophoresis) to enhance the transport of glucose from body
tissues to a sampling chamber. In addition, when the concentration
or amount of glucose has been determined to be outside of a
predetermined range of values (or monitored glucose in the subject
falls too quickly) the GlucoWatch biographer produces an alert or
alarm signal. Such an alert or alarm is a component of the
GlucoWatch biographer.
[0027] A "measurement cycle" typically comprises extraction of an
analyte from a subject, using, for example, a sampling device, and
sensing of the extracted analyte, for example, using a sensing
device, to provide a measured signal, for example, a measured
signal response curve. A complete measurement cycle may comprise
one or more sets of extraction and sensing.
[0028] The term "frequent measurement" refers to a series of two or
more measurements obtained from a particular biological system,
which measurements are obtained using a single device maintained in
operative contact with the biological system over a time period in
which a series of measurements (e.g., second, minute or hour
intervals) is obtained. The term thus includes continual and
continuous measurements.
[0029] The term "subject" encompasses any warm-blooded animal,
particularly including a member of the class Mammalia such as,
without limitation, humans and nonhuman primates such as
chimpanzees and other apes and monkey species; farm animals such as
cattle, sheep, pigs, goats and horses; domestic mammals such as
dogs and cats; laboratory animals including rodents such as mice,
rats and guinea pigs, and the like. The term does not denote a
particular age or sex and, thus, includes adult and newborn
subjects, whether male or female.
[0030] The term "transdermal" includes both transdermal and
transmucosal techniques, i.e., extraction of a target analyte
across skin, e.g., stratum corneum, or mucosal tissue. Aspects of
the invention which are described herein in the context
of"transdermal," unless otherwise specified, are meant to apply to
both transdermal and transmucosal techniques.
[0031] The term "transdermal extraction," or "transdermally
extracted" refers to any sampling method, which entails extracting
and/or transporting an analyte from beneath a tissue surface across
skin or mucosal tissue. The term thus includes extraction of an
analyte using, for example, iontophoresis (reverse iontophoresis),
electroosmosis, sonophoresis, microdialysis, suction, and passive
diffusion. These methods can, of course, be coupled with
application of skin penetration enhancers or skin permeability
enhancing technique such as various substances or physical methods
such as tape stripping or pricking with micro-needles. The term
"transdermally extracted" also encompasses extraction techniques
which employ thermal poration, laser microporation,
electroporation, microfine lances, micro fine cannulas,
subcutaneous implants or insertions, combinations thereof, and the
like.
[0032] The term "iontophoresis" refers to a method for transporting
substances across tissue by way of an application of electrical
energy to the tissue. In conventional iontophoresis, a reservoir is
provided at the tissue surface to serve as a container of (or to
provide containment for) material to be transported. Iontophoresis
can be carried out using standard methods known to those of skill
in the art, for example by establishing an electrical potential
using a direct current (DC) between fixed anode and cathode
"iontophoretic electrodes," alternating a direct current between
anode and cathode iontophoretic electrodes, or using a more complex
waveform such as applying a current with alternating polarity (AP)
between iontophoretic electrodes (so that each electrode is
alternately an anode or a cathode). For example, see U.S. Pat. Nos.
5,771,890 and 6,023,629 and PCT Publication No. WO 96/00109,
published Jan. 4, 1996.
[0033] The term "reverse iontophoresis" refers to the movement of a
substance from a biological fluid across a membrane by way of an
applied electric potential or current. In reverse iontophoresis, a
reservoir is provided at the tissue surface to receive the
extracted material, as used in the GlucoWatch biographer glucose
monitor (Cygnus, Inc., Redwood City, Calif.; see, e.g., Tamada et
al. (1999) JAMA 282:1839-1844).
[0034] "Electroosmosis" refers to the movement of a substance
through a membrane by way of an electric field-induced convective
flow. The terms iontophoresis, reverse iontophoresis, and
electroosmosis, will be used interchangeably herein to refer to
movement of any ionically charged or uncharged substance across a
membrane (e.g., an epithelial membrane) upon application of an
electric potential to the membrane through an ionically conductive
medium.
[0035] The term "sensing device," or "sensing mechanism,"
encompasses any device that can be used to measure the
concentration or amount of an analyte, or derivative thereof, of
interest. Preferred sensing devices for detecting blood analytes
generally include electrochemical devices, optical and chemical
devices and combinations thereof. Examples of electrochemical
devices include the Clark electrode system (see, e.g., Updike, et
al., (1967) Nature 214:986-988), and other amperometric,
coulometric, or potentiometric electrochemical devices, as well as,
optical methods, for example UV detection or infrared detection
(e.g., U.S. Pat. No. 5,747,806).
[0036] A "biosensor" or "biosensor device" includes, but is not
limited to, a "sensor element" that includes, but is not limited
to, a "biosensor electrode" or "sensing electrode" or "working
electrode" which refers to the electrode that is monitored to
determine the amount of electrical signal at a point in time or
over a given time period, which signal is then correlated with the
concentration of a chemical compound. The sensing electrode
comprises a reactive surface which converts the analyte, or a
derivative thereof, to electrical signal. The reactive surface can
be comprised of any electrically conductive material such as, but
not limited to, platinum-group metals (including, platinum,
palladium, rhodium, ruthenium, osmium, and iridium), nickel,
copper, and silver, as well as, oxides, and dioxides, thereof, and
combinations or alloys of the foregoing, which may include carbon
as well. Some catalytic materials, membranes, and fabrication
technologies suitable for the construction of amperometric
biosensors are described by Newman, J. D., et al.(1995) Analytical
Chemistry 67:4594-4599.
[0037] The "sensor element" can include components in addition to
the sensing electrode, for example, it can include a "reference
electrode" and a "counter electrode." The term "reference
electrode" is used to mean an electrode that provides a reference
potential, e.g., a potential can be established between a reference
electrode and a working electrode. The term "counter electrode" is
used to mean an electrode in an electrochemical circuit that acts
as a current source or sink to complete the electrochemical
circuit. Although it is not essential that a counter electrode be
employed where a reference electrode is included in the circuit and
the electrode is capable of performing the function of a counter
electrode, it is preferred to have separate counter and reference
electrodes because the reference potential provided by the
reference electrode is most stable when it is at equilibrium. If
the reference electrode is required to act further as a counter
electrode, the current flowing through the reference electrode may
disturb this equilibrium. Consequently, separate electrodes
functioning as counter and reference electrodes are preferred.
[0038] In one embodiment, the "counter electrode" of the "sensor
element" comprises a "bimodal electrode." The term "bimodal
electrode" typically refers to an electrode which is capable of
functioning non-simultaneously as, for example, both the counter
electrode (of the "sensor element") and the iontophoretic electrode
(of the "sampling mechanism") as described, for example, U.S. Pat.
No. 5,954,685.
[0039] The terms "reactive surface," and "reactive face" are used
interchangeably herein to mean the surface of the sensing electrode
that: (1) is in contact with the surface of an ionically conductive
material which contains an analyte or through which an analyte, or
a derivative thereof, flows from a source thereof; (2) is comprised
of a catalytic material (e.g., a platinum group metal, platinum,
palladium, rhodium, ruthenium, or nickel and/or oxides, dioxides
and combinations or alloys thereof) or a material that provides
sites for electrochemical reaction; (3) converts a chemical signal
(for example, hydrogen peroxide) into an electrical signal (e.g.,
an electrical current); and (4) defines the electrode surface area
that, when composed of a reactive material, is sufficient to drive
the electrochemical reaction at a rate sufficient to generate a
detectable, reproducibly measurable, electrical signal that is
correlatable with the amount of analyte present in the
electrolyte.
[0040] An "ionically conductive material" refers to any material
that provides ionic conductivity, and through which
electrochemically active species can diffuse. The ionically
conductive material can be, for example, a solid, liquid, or
semi-solid (e.g., in the form of a gel) material that contains an
electrolyte, which can be composed primarily of water and ions
(e.g., sodium chloride), and generally comprises 50% or more water
by weight. The material can be in the form of a hydrogel, a sponge
or pad (e.g., soaked with an electrolytic solution), or any other
material that can contain an electrolyte and allow passage of
electrochemically active species, especially the analyte of
interest. Some exemplary hydrogel formulations are described in WO
97/02811, published Jan. 30, 1997. The ionically conductive
material may comprise a biocide. For example, during manufacture of
an AutoSensor assembly, one or more biocides may be incorporated
into the ionically conductive material. Biocides of interest
include, but are not limited to, compounds such as chlorinated
hydrocarbons; organometallics; hydrogen releasing compounds;
metallic salts; organic sulfur compounds; phenolic compounds
(including, but not limited to, a variety of Nipa Hardwicke Inc.
liquid preservatives registered under the trade names
Nipastat.RTM., Nipaguard.RTM., Phenosept.RTM., Phenonip.RTM.,
Phenoxetol.RTM., and Nipacide.RTM.; quaternary ammonium compounds;
surfactants and other membrane-disrupting agents (including, but
not limited to, undecylenic acid and its salts), combinations
thereof, and the like.
[0041] The term "buffer" refers to one or more components which are
added to a composition in order to adjust or maintain the pH of the
composition.
[0042] The term "electrolyte" refers to a component of the
ionically conductive medium which allows an ionic current to flow
within the medium. This component of the ionically conductive
medium can be one or more salts or buffer components, but is not
limited to these materials.
[0043] The term "collection reservoir" is used to describe any
suitable containment method or device for containing a sample
extracted from a biological system. For example, the collection
reservoir can be a receptacle containing a material which is
ionically conductive (e.g., water with ions therein), or
alternatively it can be a material, such as a sponge-like material
or hydrophilic polymer, used to keep the water in place. Such
collection reservoirs can be in the form of a hydrogel (for
example, in the shape of a disk or pad). Hydrogels are typically
referred to as "collection inserts." Other suitable collection
reservoirs include, but are not limited to, tubes, vials, strips,
capillary collection devices, cannulas, and miniaturized etched,
ablated or molded flow paths.
[0044] A "collection insert layer" is a layer of an assembly or
laminate comprising a collection reservoir (or collection insert)
located, for example, between a mask layer and a retaining
layer.
[0045] A "laminate" refers to structures comprised of, at least,
two bonded layers. The layers may be bonded by welding or through
the use of adhesives. Examples of welding include, but are not
limited to, the following: ultrasonic welding, heat bonding, and
inductively coupled localized heating followed by localized flow.
Examples of common adhesives include, but are not limited to,
chemical compounds such as, cyanoacrylate adhesives, and epoxies,
as well as adhesives having such physical attributes as, but not
limited to, the following: pressure sensitive adhesives, thermoset
adhesives, contact adhesives, and heat sensitive adhesives.
[0046] A "collection assembly" refers to structures comprised of
several layers, where the assembly includes at least one collection
insert layer, for example a hydrogel. An example of a collection
assembly as referred to in the present invention is a mask layer,
collection insert layer, and a retaining layer where the layers are
held in appropriate functional relationship to each other but are
not necessarily a laminate (i.e., the layers may not be bonded
together. The layers may, for example, be held together by
interlocking geometry or friction).
[0047] The term "mask layer" refers to a component of a collection
assembly that is substantially planar and typically contacts both
the biological system and the collection insert layer. See, for
example, U.S. Pat. Nos. 5,735,273, 5,827,183, and 6,201,979, all
herein incorporated by reference.
[0048] The term "gel retaining layer" or "gel retainer" refers to a
component of a collection assembly that is substantially planar and
typically contacts both the collection insert layer and the
electrode assembly.
[0049] The term "support tray" typically refers to a rigid,
substantially planar platform and is used to support and/or align
the electrode assembly and the collection assembly. The support
tray provides one way of placing the electrode assembly and the
collection assembly into the sampling system.
[0050] An "AutoSensor assembly" refers to a structure generally
comprising a mask layer, collection insert layer, a gel retaining
layer, an electrode assembly, and a support tray. The AutoSensor
assembly may also include liners where the layers are held in
approximate, functional relationship to each other. Exemplary
collection assemblies and AutoSensor structures are described, for
example, in International Publication WO 99/58190, published Nov.
18, 1999; and U.S. Pat. Nos. 5,735,273 and 5,827,183. The mask and
retaining layers are preferably composed of materials that are
substantially impermeable to the analyte (chemical signal) to be
detected; however, the material can be permeable to other
substances. By "substantially impermeable" is meant that the
material reduces or eliminates chemical signal transport (e.g., by
diffusion). The material can allow for a low level of chemical
signal transport, with the proviso that chemical signal passing
through the material does not cause significant edge effects at the
sensing electrode.
[0051] The terms "about" or "approximately" when associated with a
numeric value refers to that numeric value plus or minus 10 units
of measure (i.e. percent, grams, degrees or volts), preferably plus
or minus 5 units of measure, more preferably plus or minus 2 units
of measure, most preferably plus or minus 1 unit of measure.
[0052] By the term "printed" is meant a substantially uniform
deposition of an electrode formulation onto one surface of a
substrate (i.e., the base support). It will be appreciated by those
skilled in the art that a variety of techniques may be used to
effect substantially uniform deposition of a material onto a
substrate, e.g., Gravure-type printing, extrusion coating, screen
coating, spraying, painting, electroplating, laminating, or the
like.
[0053] The term "physiological effect" encompasses effects produced
in the subject that achieve the intended purpose of a therapy. In
preferred embodiments, a physiological effect means that the
symptoms of the subject being treated are prevented or alleviated.
For example, a physiological effect would be one that results in
the prolongation of survival in a patient. "Parameter" refers to an
arbitrary constant or variable so appearing in a mathematical
expression that changing it give various cases of the phenomenon
represented (McGraw-Hill Dictionary of Scientific and Technical
Terms, S. P. Parker, ed., Fifth Edition, McGraw-Hill Inc., 1994).
In the context of the GlucoWatch biographer, a parameter is a
variable that influences the value of the blood glucose level as
calculated by an algorithm.
[0054] "Decay" refers to a gradual reduction in the magnitude of a
quantity, for example, a current detected using a sensor electrode
where the current is correlated to the concentration of a
particular analyte and where the detected current gradually reduces
but the concentration of the analyte does not.
[0055] The terms "disease state," "condition" and "medical
condition" refer to any physiological or environmental state about
which a subject has concern. Exemplary disease states and
conditions are described extensively herein, for example
hypogylcemia, hyperglycemia, cardiovascular disease, cystic
fibrosis, gestational diabetes, weight management regime, cancer
remission, Candida infection, human immunodeficiency virus (HIV)
infection, long distance driving, organ transplants recipients,
subjects receiving growth hormone therapy, renal failure patients,
malaria infection, alcoholism, etc.
[0056] 2. Modes of Carrying out the Invention
[0057] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
formulations or process parameters as such may, of course, vary. It
is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments of the invention
only, and is not intended to be limiting.
[0058] Although a number of methods and materials similar or
equivalent to those described herein can be used in the practice of
the present invention, the preferred materials and methods are
described herein.
[0059] 2.1.1 Exemplary Monitoring Systems
[0060] Numerous analyte monitoring systems can be used in the
practice of the present invention. Typically, the monitoring system
used to monitor the level of a selected analyte in a target system
comprises a sampling device, which provides a sample comprising the
analyte, and a sensing device, which detects the amount or
concentration of the analyte or a signal associated with the
analyte amount or concentration in the sample.
[0061] One exemplary monitoring system (the GlucoWatch biographer)
is described herein for monitoring glucose levels in a biological
system via the transdermal extraction of glucose from the
biological system, particularly an animal subject, and then
detection of signal corresponding to the amount or concentration of
the extracted glucose. Transdermal extraction is carried out by
applying an electrical current or ultrasonic radiation to a tissue
surface at a collection site. The electrical current is used to
extract small amounts of glucose from the subject into a collection
reservoir. The collection reservoir is in contact with a sensor
element (e.g., a biosensor) which provides for measurement of
glucose concentration in the subject. As glucose is transdermally
extracted into the collection reservoir, the analyte reacts with
the glucose oxidase within the reservoir to produce hydrogen
peroxide. The presence of hydrogen peroxide generates a current at
the biosensor electrode that is directly proportional to the amount
of hydrogen peroxide in the reservoir. This current provides a
signal which can be detected and interpreted (for example,
employing a selected algorithm) by an associated system controller
to provide a glucose concentration value or amount for display.
[0062] In the use of the sampling system, a collection reservoir is
contacted with a tissue surface, for example, on the stratum
corneum of a subject's skin. An electrical current is then applied
to the tissue surface in order to extract glucose from the tissue
into the collection reservoir. Extraction is carried out, for
example, frequently over a selected period of time. The collection
reservoir is analyzed, at least periodically and typically
frequently, to measure glucose concentration therein. The measured
value correlates with the subject's blood glucose level.
[0063] To sample the analyte, one or more collection reservoirs are
placed in contact with a tissue surface on a subject. The ionically
conductive material within the collection reservoir is also in
contact with an electrode (for reverse iontophoretic extraction)
which generates a current sufficient to extract glucose from the
tissue into the collection reservoir. Referring to FIG. 1, an
exploded view of exemplary components comprising one embodiment of
an AutoSensor for use in an iontophoretic sampling system is
presented. The AutoSensor components include two
biosensor/iontophoretic electrode assemblies, 104 and 106, each of
which have an annular iontophoretic electrode, respectively
indicated at 108 and 110, which encircles a biosensor electrode 112
and 114. The electrode assemblies 104 and 106 are printed onto a
polymeric substrate 116 which is maintained within a sensor tray
118. A collection reservoir assembly 120 is arranged over the
electrode assemblies, wherein the collection reservoir assembly
comprises two hydrogel inserts 122 and 124 retained by a gel
retaining layer 126 and mask layer 128. Further release liners may
be included in the assembly, for example, a patient liner 130, and
a plow-fold liner 132. In one embodiment, the electrode assemblies
include bimodal electrodes. A mask layer 128 (for example, as
described in PCT Publication No. WO 97/10356, published Mar. 20,
1997, and U.S. Pat. Nos. 5,735,273, 5,827,183, 6,141,573, and
6,201,979, all herein incorporated by reference) may be present.
Other AutoSensor embodiments are described in WO 99/58190,
published Nov. 18, 1999, herein incorporated by reference.
[0064] The mask and retaining layers are preferably composed of
materials that are substantially impermeable to the analyte (e.g.,
glucose) to be detected (see, for example, U.S. Pat. Nos.
5,735,273, and 5,827,183, both herein incorporated by reference).
By "substantially impermeable" is meant that the material reduces
or eliminates analyte transport (e.g., by diffusion). The material
can allow for a low level of analyte transport, with the proviso
that the analyte that passes through the material does not cause
significant edge effects at the sensing electrode used in
conjunction with the mask and retaining layers. Examples of
materials that can be used to form the layers include, but are not
limited to, polyester, polyester derivatives, other polyester-like
materials, polyurethane, polyurethane derivatives and other
polyurethane-like materials.
[0065] The components shown in exploded view in FIG. 1 (i.e., an
exemplary AutoSensor) are intended for use in a automatic sampling
system which is configured to be worn like an ordinary wristwatch,
as described, for example, in PCT Publication No. WO 96/00110,
published Jan. 4, 1996, herein incorporated by reference. The
AutoSensor in this case is a consumable element. A durable element,
that is the wristwatch housing into which the AutoSensor is
inserted, is also provided. The durable element can further include
suitable electronics (e.g., one or more microprocessor(s), memory,
display and other circuit components) and power sources, for
example, for operating the automatic sampling system. The durable
element also provides means to provide an audible alert when
glucose levels in a subject being monitored are outside of a
predetermined range. Further, such a device may also provide an
audible alert when a trend is identified (for example, using an
algorithm, e.g., U.S. Pat. No. 6,233,471, issued May 15, 2001) that
indicates that glucose levels are dropping too quickly or
increasing too quickly. For example, the GlucoWatch biographer
provides an alert when glucose levels are falling faster than a
predetermined rate. The one or more microprocessors may control a
variety of functions, including, but not limited to, control of a
sampling device, a sensing device, aspects of the measurement cycle
(for example, timing of sampling and sensing, and alternating
polarity between electrodes), connectivity, computational methods,
different aspects of data manipulation (for example, acquisition,
recording, recalling, comparing, and reporting), etc.
[0066] The sensing electrode can be, for example, a Pt-comprising
electrode configured to provide a geometric surface area of about
0.1 to 3 cm.sup.2, preferably about 0.5 to 2 cm.sup.2, and more
preferably about 1 cm.sup.2. This particular configuration is
scaled in proportion to the collection area of the collection
reservoir used in the sampling system of the present invention,
throughout which the extracted analyte and/or its reaction products
will be present. The electrode composition is formulated using
analytical- or electronic-grade reagents and solvents which ensure
that electrochemical and/or other residual contaminants are avoided
in the final composition, significantly reducing the background
noise inherent in the resultant electrode. In particular, the
reagents and solvents used in the formulation of the electrode are
selected so as to be substantially free of electrochemically active
contaminants (e.g., anti-oxidants), and the solvents in particular
are selected for high volatility in order to reduce washing and
cure times. Some electrode embodiments are described in European
Pat. Publication 0 942 278 A2, published Sep. 15, 1999, herein
incorporated by reference.
[0067] The reactive surface of the sensing electrode can be
comprised of any electrically conductive material such as, but not
limited to, platinum-group metals (including, platinum, palladium,
rhodium, ruthenium, osmium, and iridium), nickel, copper, silver,
and carbon, as well as, oxides, dioxides, combinations or alloys
thereof. Some catalytic materials, membranes, and fabrication
technologies suitable for the construction of amperometric
biosensors were described by Newman, J. D., et al. (Analytical
Chemistry 67(24), 4594-4599, 1995, herein incorporated by
reference).
[0068] Any suitable iontophoretic electrode system can be employed,
an exemplary system uses a silver/silver chloride (Ag/AgCl)
electrode system. The iontophoretic electrodes are formulated
typically using two performance criteria: (1) the electrodes are
capable of operation for extended periods, preferably periods of up
to 24 hours or longer; and (2) the electrodes are formulated to
have high electrochemical purity in order to operate within the
present system which requires extremely low background noise
levels. The electrodes must also be capable of passing a large
amount of charge over the life of the electrodes. With regard to
operation for extended periods of time, Ag/AgCl electrodes are
capable of repeatedly forming a reversible couple which operates
without unwanted electrochemical side reactions (which could give
rise to changes in pH, and liberation of hydrogen and oxygen due to
water hydrolysis). The Ag/AgCl electrode is thus formulated to
withstand repeated cycles of current passage in the range of about
0.01 to 1.0 mA per cm.sup.2 of electrode area. With regard to high
electrochemical purity, the Ag/AgCl components are dispersed within
a suitable polymer binder to provide an electrode composition which
is not susceptible to attack (e.g., plasticization) by components
in the collection reservoir, e.g., the hydrogel composition. The
electrode compositions are also typically formulated using
analytical- or electronic-grade reagents and solvents, and the
polymer binder composition is selected to be free of
electrochemically active contaminants which could diffuse to the
biosensor to produce a background current.
[0069] The automatic sampling system can transdermally extract the
sample over the course of a selected period of time using reverse
iontophoresis. The collection reservoir comprises an ionically
conductive medium, preferably the hydrogel medium described
hereinabove. A first iontophoresis electrode is contacted with the
collection reservoir (which is typically in contact with a target,
subject tissue surface), and a second iontophoresis electrode is
contacted with either a second collection reservoir in contact with
the tissue surface, or some other ionically conductive medium in
contact with the tissue. A power source provides an electrical
potential between the two electrodes to perform reverse
iontophoresis in a manner known in the art. As discussed above, the
biosensor selected to detect the presence, and possibly the level,
of the target analyte (for example, glucose) within a reservoir is
also in contact with the reservoir. Typically, there are two
collections reservoirs, each comprising glucose oxidase, and each
in operative contact with iontophoretic electrode and a sensing
electrode. The iontophoretic electrode may be a bimodal electrode
that also serves, non-concurrently, as a counter electrode to the
sensing electrode (see, for example, U.S. Pat. No. 5,954,685,
herein incorporated by reference).
[0070] In practice, an electric potential (either direct current or
a more complex waveform) is applied between the two iontophoresis
electrodes such that current flows from the first electrode through
the first conductive medium into the skin, and back out from the
skin through the second conductive medium to the second electrode.
This current flow extracts substances through the skin into the one
or more collection reservoirs through the process of reverse
iontophoresis or electroosmosis. The electric potential may be
applied as described in PCT Publication No. WO 96/00110, published
Jan. 4, 1996, herein incorporated by reference. Typically, the
electrical potential is alternated between two reservoirs to
provide extraction of analyte into each reservoir in an alternating
fashion (see, for example, U.S. Pat. Nos. 6,023,629, 5,954,685,
both herein incorporated by reference). Analyte is also typically
detected in each reservoir.
[0071] As an example, to extract glucose, the applied electrical
current density on the skin or tissue can be in the range of about
0.01 to about 2 mA/cm.sup.2. In order to facilitate the extraction
of glucose, electrical energy can be applied to the electrodes, and
the polarity of the electrodes can be, for example, alternated so
that each electrode is alternately a cathode or an anode. The
polarity switching can be manual or automatic. A device and method
for sampling of substances using alternating polarity is described
in U.S. Pat. No. 5,771,890, issued Jun. 30, 1998,herein
incorporated by reference.
[0072] When a bimodal electrode is used (e.g., U.S. Pat. No.
5,954,685, issued Sep. 21, 1999, herein incorporated by reference),
during the reverse iontophoretic phase, a power source provides a
current flow to the first bimodal electrode to facilitate the
extraction of the chemical signal into the reservoir. During the
sensing phase, a separate power source is used to provide voltage
to the first sensing electrode to drive the conversion of chemical
signal retained in reservoir to electrical signal at the catalytic
face of the sensing electrode. The separate power source also
maintains a fixed potential at the electrode where, for example
hydrogen peroxide is converted to molecular oxygen, hydrogen ions,
and electrons, which is compared with the potential of the
reference electrode during the sensing phase. While one sensing
electrode is operating in the sensing mode it is electrically
connected to the adjacent bimodal electrode which acts as a counter
electrode at which electrons generated at the sensing electrode are
consumed.
[0073] The electrode subassembly can be operated by electrically
connecting the bimodal electrodes such that each electrode is
capable of functioning as both an iontophoretic electrode and
counter electrode along with appropriate sensing electrode(s) and
reference electrode(s).
[0074] A potentiostat is an electrical circuit used in
electrochemical measurements in three electrode electrochemical
cells. A potential is applied between the reference electrode and
the sensing electrode. The current generated at the sensing
electrode flows through circuitry to the counter electrode (i.e.,
no current flows through the reference electrode to alter its
equilibrium potential). Two independent potentiostat circuits can
be used to operate the two biosensors. For the purpose of the
present invention, the electrical current measured at the sensing
electrode subassembly is the current that is correlated with an
amount of chemical signal corresponding to the analyte.
[0075] The detected current can be correlated with the subject's
blood glucose concentration (e.g., using a statistical technique or
algorithm or combination of techniques) so that the system
controller may display the subject's actual blood glucose
concentration as measured by the sampling system. Such statistical
techniques can be formulated as algorithm(s) and incorporated in
one or more microprocessor(s) associated with the sampling system.
Exemplary signal processing applications include, but are not
limited to, those taught in the following U.S. Pat. Nos. 6,144,869,
6,233,471, 6,180,416, herein incorporated by reference.
[0076] In a further aspect of the present invention, the
sampling/sensing mechanism and user interface may be found on
separate components. Thus, the monitoring system can comprise at
least two components, in which a first component comprises sampling
mechanism and sensing mechanism that are used to extract and detect
an analyte, for example, glucose, and a second component that
receives the analyte data from the first component, conducts data
processing on the analyte data to determine an analyte
concentration and then displays the analyte concentration data.
Typically, microprocessor functions (e.g., control of a sampling
device, a sensing device, aspects of the measurement cycle,
computational methods, different aspects of data manipulation or
recording, etc.) are found in both components. Alternatively,
microprocessing components may be located in one or the other of
the at least two components. The second component of the monitoring
system can assume many forms, including, but not limited to, the
following: a watch, a credit card-shaped device (e.g., a "smart
card" or "universal card" having a built-in microprocessor as
described for example in U.S. Pat. No. 5,892,661, herein
incorporated by reference), a pager-like device, cell phone-like
device, or other such device that communicates information to the
user visually, audibly, or kinesthetically.
[0077] Further, additional components may be added to the system,
for example, a third component comprising a display of analyte
values or an alarm related to analyte concentration, may be
employed. In certain embodiments, a delivery unit is included in
the system. An exemplary delivery unit is an insulin delivery unit.
Insulin delivery units, both implantable and external, are known in
the art and described, for example, in U.S. Pat. Nos. 5,995,860;
5,112,614 and 5,062,841, herein incorporated by reference.
Preferably, when included as a component of the present invention,
the delivery unit is in communication (e.g., wire-like or wireless
communication) with the extracting and/or sensing mechanism such
that the sensing mechanism can control the insulin pump and
regulate delivery of a suitable amount of insulin to the
subject.
[0078] Advantages of separating the first component (e.g.,
including the biosensor and iontophoresis functions) from the
second component (e.g., including some microprocessor and display
functions) include greater flexibility, discretion, privacy and
convenience to the user. Having a small and lightweight measurement
unit allows placement of the two components of the system on a
wider range of body sites, for example, the first component may be
placed on the abdomen or upper arm. This wider range of placement
options may improve the accuracy through optimal extraction site
selection (e.g., torso rather than extremities) and greater
temperature stability (e.g., via the insulating effects of
clothing). Thus, the collection and sensing assembly will be able
to be placed on a greater range of body sites. Similarly, a smaller
and less obtrusive microprocessor and display unit (the second
component) provides a convenient and discrete system by which to
monitor analytes. The biosensor readouts and control signals will
be relayed via wire-like or wireless technology between the
collection and sensing assembly and the display unit which could
take the form of a small watch, a pager, or a credit card-sized
device. This system also provides the ability to relay an alert
message or signal during nighttime use, for example, to a site
remote from the subject being monitored.
[0079] In one embodiment, the two components of the device can be
in operative communication via a wire or cable-like connection.
Operative communications between the components can be wireless
link, i.e. provided by a "virtual cable," for example, a telemetry
link. This wireless link can be uni- or bi-directional between the
two components. In the case of more than two components, links can
be a combination of wire-like and wireless.
[0080] 2.1.2 Exemplary Analytes
[0081] The analyte can be any one or more specific substance,
component, or combinations thereof that one is desirous of
detecting and/or measuring in a chemical, physical, enzymatic, or
optical analysis.
[0082] Analytes that can be measured using the methods of the
present invention include, but are not limited to, amino acids,
enzyme substrates or products indicating a disease state or
condition, other markers of disease states or conditions, drugs of
abuse (e.g., ethanol, cocaine), therapeutic and/or pharmacologic
agents (e.g., theophylline, anti-HIV drugs, lithium, anti-epileptic
drugs, cyclosporin, chemotherapeutics), electrolytes, physiological
analytes of interest (e.g., urate/uric acid, carbonate, calcium,
potassium, sodium, chloride, bicarbonate (CO.sub.2), glucose, urea
(blood urea nitrogen), lactate and/or lactic acid, hydroxybutyrate,
cholesterol, triglycerides, creatine, creatinine, insulin,
hematocrit, and hemoglobin), blood gases (carbon dioxide, oxygen,
pH), lipids, heavy metals (e.g., lead, copper), and the like.
Analytes in non-biological systems may also be evaluated using the
methods of the present invention.
[0083] In preferred embodiments, the analyte is a physiological
analyte of interest, for example glucose, or a chemical that has a
physiological action, for example a drug or pharmacological
agent.
[0084] In order to facilitate detection of the analyte, an enzyme
(or enzymes) can be disposed within the one or more collection
reservoirs. The selected enzyme is capable of catalyzing a reaction
with the extracted analyte to the extent that a product of this
reaction can be sensed, e.g., can be detected electrochemically
from the generation of a current which current is detectable and
proportional to the amount of the analyte which is reacted. In one
embodiment of the present invention, a suitable enzyme is glucose
oxidase, which oxidizes glucose to gluconic acid and hydrogen
peroxide. The subsequent detection of hydrogen peroxide on an
appropriate biosensor electrode generates two electrons per
hydrogen peroxide molecule creating a current that can be detected
and related to the amount of glucose entering the device. Glucose
oxidase (GOx) is readily available commercially and has well known
catalytic characteristics. However, other enzymes can also be used
singly (for detection of individual analytes) or together (for
detection of multiple analytes), as long as they specifically
catalyze a reaction with an analyte or substance of interest to
generate a detectable product in proportion to the amount of
analyte so reacted.
[0085] In like manner, a number of other analyte-specific enzyme
systems can be used in the invention, which enzyme systems operate
on much the same general techniques. For example, a biosensor
electrode that detects hydrogen peroxide can be used to detect
ethanol using an alcohol oxidase enzyme system, or similarly uric
acid with urate oxidase system, cholesterol with a cholesterol
oxidase system, and theophylline with a xanthine oxidase
system.
[0086] In addition, the oxidase enzyme (used for hydrogen
peroxidase-based detection) can be replaced or complemented with
another redox system, for example, the dehydrogenase-enzyme
NAD-NADH, which offers a separate route to detecting additional
analytes. Dehydrogenase-based sensors can use working electrodes
made of gold or carbon (via mediated chemistry). Examples of
analytes suitable for this type of monitoring include, but are not
limited to, cholesterol, ethanol, hydroxybutyrate, phenylalanine,
triglycerides, and urea.
[0087] Further, the enzyme can be eliminated and detection can rely
on direct electrochemical or potentiometric detection of an
analyte. Such analytes include, without limitation, heavy metals
(e.g., cobalt, iron, lead, nickel, zinc), oxygen, carbonate/carbon
dioxide, chloride, fluoride, lithium, pH, potassium, sodium, and
urea. Also, the sampling system described herein can be used for
therapeutic drug monitoring, for example, monitoring anti-epileptic
drugs (e.g., phenytoin), chemotherapy (e.g., adriamycin),
hyperactivity (e.g., ritalin), and anti-organ rejection (e.g.,
cyclosporin).
[0088] Preferably, a sensor electrode is able to detect the analyte
that has been extracted into the one or more collection reservoirs
when present at nominal concentration levels. Suitable exemplary
biosensor electrodes and associated sampling systems as described
in are described in PCT Publication Nos. WO 97/10499, published
Mar. 20, 1997 and WO 98/42252, published Oct. 1, 1998, both herein
incorporated by reference herein.
[0089] A single sensor may detect multiple analytes and/or reaction
products of analytes. For example, a platinum sensor could be used
to detect tyrosine and glucose in a single sample. The tyrosine is
detected, for example, by direct electrochemical oxidation at a
suitable electrode potential (e.g., approximately 0.6V vs.
Ag/AgCl). The glucose is detected, e.g., using glucose oxidase and
detecting the hydrogen peroxide reaction product.
[0090] Different sensing devices and/or sensing systems can be
employed as well to distinguish between signals. For example, a
first gel containing glucose oxidase associated with a first
platinum sensor can be used for the detection of glucose, while a
second gel containing uricase associated with a second platinum
sensor can be used for the detection of urea.
[0091] 2.2.0 Application of Frequent Analyte Monitoring
[0092] Many disease states and conditions will benefit from
frequent monitoring of glucose and, optionally, one or more
additional analytes. Non-limiting examples of such disease states
and conditions that will benefit from frequent monitoring of
glucose levels, include hyperglycemia; hypoglycemia; cystic
fibrosis; AIDS; organic and amino acid disorders; cancer remission;
as well as patients with cardiovascular disease; stroke patients;
gestational diabetes; organ transplant recipients; those infected
with Candida, HIV or malaria; elderly patients; kidney patients;
young children; long-distance drivers; intense exercisers; subjects
on a weight loss program or other special diet; subjects receiving
growth hormone; and alcoholics. Furthermore, monitoring of glucose
levels will also be beneficial in determining the effects of one or
more pharmaceutical compositions on glucose levels or
concentrations in a biological subject. In the present invention,
at least one of the pharmaceutical compositions whose effect on
glucose levels is monitored does not contain insulin.
[0093] 2.2.1 Hyperglycemia
[0094] Hyperglycemia refers to excessive levels of blood glucose in
a subject. The primary form of hyperglycemia is diabetes mellitus
(DM), which is hyperglycemia secondary to decreased insulin where
either production of insulin is decreased or peripheral tissue
resistance to insulin is increased. Insulin-dependent DM (IDDM, or
type I DM) accounts for about 10% of DM cases and usually occurs in
childhood or early adulthood. Type I DM can result in ketoacidosis
when patients are without insulin therapy. Non-insulin dependent DM
(NIDDM, or type II DM) usually occurs in people >40 years of
age, and about 60% of the patients are obese. Type II DM can also
occur in animals, for example, domestic cats. These patients are
not prone to ketosis but may develop it under conditions of stress.
Gestational onset DM (GODM) occurs when diabetes onset is during
pregnancy and resolves with delivery. These patients are at a
higher risk for developing DM at a later date. Secondary DM can be
caused, for example, by steroid therapy, Cushing's syndrome,
pancreatectomy, pancreatic insufficiency secondary to pancreatitis,
or endocrine disorders. The Diabetes Control and Complications
Trial Group reported that the long-term complications of DM appear
to be directly related to control of blood glucose levels. Thus,
the conclusion of the study was that intensive therapy delays the
onset and slows the progression of diabetic retinopathy,
nephropathy, and neuropathy in patients with IDDM. Other studies
have shown the same conclusions in NIDDM. Thus, frequent monitoring
of blood glucose levels is an important tool for both diagnosing
and determining appropriate therapy for many conditions associated
with abnormal glucose levels.
[0095] 2.2.1.1. Dysglycemia and Cardiovascular Disease
[0096] Recent research has found a connection between dysglycemia,
or abnormal glucose levels, and risk factors (e.g., atherosclerosis
and hypertension) for cardiovascular disease (see, for example,
Gerstein H C, Yusuf S (1996) Lancet 347(9006): 949-950; Gerstein H
C, Yusuf S (1998) Diabetes Research and Clinical Practice 40 Suppl:
S9-S14; Meigs J B, Nathan D M et al. (1998) Ann Intern Med 128(7):
524-533; Tsai S T, Li C L et al. (2000) J Clin Epidemiol. 53(5):
505-510). For instance, atherosclerotic changes appear to develop
in non-diabetic individuals with impaired glucose tolerance (see,
e.g., Kawamori, R (1998) Diabetes Res Clin Pract 40 Suppl: S35-S42;
Yamasaki Y, Kawamori R et al. (1995) Diabetologia 38(5):585-591).
Similarly, hypertension is also associated with impaired glucose
tolerance (Vaccaro et al. (1996) Diabetologia 39:70-76). At a
molecular level, studies have shown a connection between a deletion
polymorphism in the antigotensis-converting enzyme (ACE) gene
(which is related to cardiovascular disease) and elevated plasma
glucose levels after oral glucose load (Ohishi et al. (2000) Clin
Exp Pharmacol Physiol 27:483-487). Further, high blood glucose
concentration (in both diabetic and non-diabetic patients)
increases the risk of death and poor outcome after acute myocardial
infarction and significantly increases the mortality rate from
cardiovascular disease (see, e.g., Capes et al. Lancet (2000)
355(9206):773-778; Feskens E J & Kromhout D (1992) J Clin
Epidemiol 45(11): 1327-34 and Bjornholt et al. (1999) Diabetes Care
22(1): 45-49).
[0097] The risk of heart disease associated with hyperglycemia
increases continuously across the spectrum of glucose tolerance
categories, from those that are just barely above normal to those
in the diabetic range. Generally speaking, as blood glucose levels
increase, so does the likelihood that an individual will experience
cardiovascular disease. (see, e.g., Temelkova-Kurktschiev et al.
(2000) Exp Clin Endocrinol Diabetes 108:93-99). This relationship
is similar to the relationship between smoking and blood pressure
to cardiovascular risk.
[0098] Thus, monitoring and controlling blood glucose levels in
individuals with a family or personal history of heart disease
allows these subjects to reduce the risk of cardiovascular
problems. Further, in certain embodiments, it will also be useful
to monitor levels of glucose, cholesterol, triglycerides and/or
therapeutic drugs used to treat high cholesterol, hypertension or
the like.
[0099] 2.2.1.2 Glucose Tolerance, Diabetes Onset and Cystic
Fibrosis
[0100] It is estimated that approximately 50,000 individuals in the
U.S. and Canada suffer from cystic fibrosis. One well-known
complication of this disease is cystic fibrosis-related diabetes
(CFRD) (Finkelstein S M & Wielinski C L (1988) J Pediatr
112(3): 373-377; Handwerger S, Roth J et al. (1969) N Engl J Med
281(9): 451-461). CFRD appears to be grossly underestimated in the
U.S., probably due to the lack of routine oral glucose tolerance
tests (see, e.g., Hardin D S & Moran A (1999) Endocrinol Metab
Clin North Am. 28(4): 787-800). CFRD incidence has also increased
as the life-spans of cystic fibrosis patients increase. In a 10
year study of CFRD, Cucinotta D, De Luca F et al. (1999) Acta
Paediatr 88(4): 389-393 found that impaired glucose tolerance was
the sole predictor of whether patients will develop CFRD.
[0101] Thus, frequent monitoring of blood glucose levels in cystic
fibrosis patients will allow clinicians to detect diabetes earlier
than was previously possible. Moreover, monitoring of trends in
blood glucose levels can help identify groups who are prone to
develop diabetes. In addition to monitoring glucose, the levels of
chloride, sodium, and/or therapeutic drugs used to treat CF may
also be monitored.
[0102] 2.2.1.3 Abnormal Blood Glucose Levels in Stroke, Ischemia,
Brain Injury, Head Injury, and Spinal Cord Injury
[0103] Hyperglycemia following acute stroke is strongly associated
with subsequent mortality, impaired neurological recovery and brain
lesions in diabetic and non-diabetic patients (Sala et al. (1999)
Ann NY Acad Sci 890:133-154; Weir C J, Murray GD et al. (1997) BMJ
314(7090): 1303-1306; Gray C S, Taylor R et al. (1987) Diabet Med
4(3): 237-40; Guyot et al. (2000) Horm Metab Res. 32:6-9; Hayahi
(2000) No To Hattatsu 32:122-131; Rovlias and Kotsou (2000)
Neurosurgery 46:335-342). Furthermore, between 20% and 50% of acute
stroke patients are hyperglycemic at presentation. As a result, it
is of increasing interest to study the effects of modulating blood
glucose levels in stroke patients, for example by administering
glucose potassium insulin (GKI) to these patients (Scott J F,
Robinson G M et al. (1999) Stroke 30(4): 793-799; Scott J F, Gray C
S et al. (1998) Q J Med 91(7): 511-515; Hennes et al. (1999)
Anaesthesist 48:858-870; Schurr et al. (1999) Ann NY Acad Sci
893:386-390).
[0104] Thus, frequent monitoring blood glucose levels in stroke
patients can allow clinicians to detect abnormal glucose levels at
an early time and early treatment may reduce mortality and improve
neurological outcomes.
[0105] 2.2.1.4 Hyperglycemia Associated with Organ
Transplantation
[0106] Impaired glucose tolerance or DM are also frequent
complications after organ transplantation, in both human leukocyte
antigen (HLA) matched and mismatched patients. For example, liver
transplant recipients have been shown to have severe post-prandial
hyperglycemia, which may be attributed to insulinpoenia and a late
increased glucose turnover (Schneiter et al. (2000) Diabetes Metab
26:51-56; Petruzzo et al. (2000) Diabetes Metab 26:215-218).
Similarly, in the context of grafts, Trick et al. (2000) J Thorac
Cardiovasc Surg 119:108-114 report that appropriate control of
preoperative blood glucose levels appears to help prevent deep
sternal site infection after coronary artery bypass graft
operations. Accordingly, frequent monitoring of blood glucose
levels before and after transplant (e.g., organ transplant and
grafts) is part of the present invention. Furthermore, multiple
analytes in these subjects (e.g., glucose, an immunosuppressive
drug, etc.) can also be measured.
[0107] 2.2.1.5 Hyperglycemia Associated with Candida Infection
[0108] Chronic or repeated infection with Candida (e.g.,
vulvovaginal candidiasis and congenital cutaneous candidiaseis in
infants) is a widespread problem in both immunocompetent and
immunosuppressed patients. A known etiology of recurrent
candidiasis is hyperglycermia, see, e.g., Ringdahl (2000) Am Fam
Physician 61:3306-3312. Further, because many patients experience
recurrent Candida infections once prophylaxis is discontinued,
long-term therapy may still be warranted. Therefore, frequent
monitoring of blood glucose level is useful in subjects suffering
from chronic or repeated infection with Candida.
[0109] 2.2.1.6 Diet-induced Hyperglycemia
[0110] Diet can also induce hyperglycemia in certain subjects.
Diets high in carbohydrates and/or fat have been associated with
development of insulin resistance and perturbed carbohydrate and
lipid metabolism and leptin has been proposed as a treatment for
diet induced hyperglycemia and insulin resistance (Buettner et al.
(2000) Am J Physiol Endocrinol Metab 278:E563-9). Thus, in addition
to allowing a subject to quickly and easily monitor blood glucose
levels, the present invention allows for the monitoring of
additional analytes, for example, leptin.
[0111] 2.2.1.7 HIV-related Hyperglycemia
[0112] The present invention will also find use in evaluating and
determining treatment regimes for human immunodeficiency virus
(HIV)-infected patients, particularly those patients currently
receiving protease inhibitors. Although protease inhibitors have
proven to be very useful in treating HIV infection in certain
patients, these drugs often exhibit glucose-related side effects,
including, for example, hyperglycemia, new-onset diabetes mellitus,
lipodystrophic syndrome, central obesity, peripheral fat loss, and
hyperlipidemia, Scevola et al. (2000) AIDS Read 10:365-369;
371-375; Mathe (1999) Biomed Pharmacother 53:449-451. Accordingly,
all patients receiving protease inhibitors should be monitored for
blood glucose levels.
[0113] 2.2.1.8 Geriatric Hyperglycemia
[0114] The prevalence of hyperglycemia in elderly persons (e.g.,
greater than 60 years of age) is high and is significantly
associated with cardiovascular risk factors such as obesity, high
systolic pressure and hypertriglyceridemia, see, above and Lai et
al. (2000) J Gerontol A Biol Sci Med 55:M255-256. Hyperglycemia is
also more common elderly trauma patients and in those elderly
patients exhibit hostility, Frankenfield et al. (2000) J Trauma
48:49-56. Thus, is useful to monitor glucose levels in these in
elderly patients.
[0115] 2.2.1.9 Hyperglycemia in Neonates and Children
[0116] Transient hyperglycemia that occurs as a part of the stress
response in acute illnesses can cause serious complications in
infancy and childhood, Gupta et al. (1997) Indian J Pediatr
64:205-210. For example, non-ketotic hyperglycemia (NKH) in infancy
and childhood can cause serious complications, for example,
hydrocephalus requiring shunting and subsequent brain damage, Van
Hove et al. (2000) Neurol 54:754-756. Thus, frequent monitoring of
glucose (and, optionally, other analytes, such as ketones) is
useful in young children.
[0117] Further, there are numerous reports of transient neonatal
diabetes (Menon, P.S., et al., Indian J Pediatr 67(6):443-448,
2000; Shield, J. P., Horm Res 53(Suppl. 1):7-11, 2000; Stanley, C.
A., Pediatr Clin North Am 44(2):363-374, 1997; Wilson, S., Nurs
Times 87(36):44-45, 1991). There are numerous causes that are
thought to contribute to such transient neonatal diabetes,
including, but not limited to, chromosomal abnormality, genotypic
effects, and/or imprinting (Varrault, A., et al., J Biol Chem
276(22)18653-18656, 2001; Marquis, E., et al., Tissue Antigens
56(3):217-222, 2000; Gardner, R. J., et al., Hum Mol Genet
9(4):589-596, 2000; Kamiya, M., et al., Hum Mol Genet 9(3):453-460,
2000; Shield, J. P., et al., Arch Dis Child Fetal Neonatal Ed
76(1):F39-42, 1997), treatments (e.g., drug treatments to mother
and/or neonate) (Moniaci, V. K., et al., J Perinat Neonatal Nurs
11(4):60-64, 1998; Uhrig, J. D., et al., Can Med Assoc J
128(4):368-371, 1983; Bomba-Opon, D. A., et al., Ginekol Pol
71(8):887-892, 2000; Yunis, K. A., et al., Am J Perinatol
16(1):17-21, 1999), nutrition (Barker, D. J., Nutrition
13(9):807-813, 1997), and disease states (e.g., in the mother
and/or neonate) (Ahlfors, K., et al., Scand J Infect Dis.
31(5):443-457, 1999; Lorenzi, P., et al., AIDS, Dec. 24,
12(18):F241-247, 1998; Cooper, L. Z., Rev Infect Dis 7(Suppl.
1):S2-10, 1985). In addition, babies born before term may have
glucose metabolism abnormalities (Gross, T. L., et al., Am J Obstet
Gynecol 146(3):236-241, 1983; Lackman, F., Am J Obstet Gynecol
184(5):946-953, 2001).
[0118] Thus, frequent monitoring of glucose (and, optionally, other
analytes, such as drug levels) is useful in neonates and premature
neonates to reduce possible short- and/or long-term damage caused
by low, high, or fluctuating glucose levels, as well as to increase
probability of survival.
[0119] 2.2.1.10 Hyperglycemia Associated with Intense Exercise
[0120] During intense exercise, fluctuations in the levels of
various analytes, for example glucose, hormones, etc., has been
shown to occur, Kreisman et al. (2000) Am J Physiol Endocrinol
Metab 278:E7860793. Commonly, subjects who exercise intensely can
become hyperglycemic. Marliss et al. (2000) J Appl Physiol
88:457-66. Accordingly, monitoring the level of glucose and/or
other analytes such as hormones aids in regulating exercise
intensity and/or intake of food or fluids during exercise.
[0121] 2.2.2 Hypoglcemia
[0122] Hypoglycemia refers to decreased levels of glucose in
plasma, or below normal levels. Although hypoglycemic subjects may
be asymptomatic, many exhibit adrenergic stimulation symptoms
including diaphoresis, anxiety, irritability, palpitations, tremor,
and hunger. Hypoglycemic events may also occur during the
night-time (nocturnal hypoglycemia), for example, when a person is
sleeping, thus vulnerable to continuing decreases in levels of
glucose in plasma. Severe hypoglycemia may cause confusion, visual
blurring, loss of consciousness and seizures. Typically,
hypoglycemia occurs about 2 to 4 hours postprandially and generally
subsides in 15 to 20 minutes. The etiology of hypoglycemia is often
idiopathic, but may be caused by early diabetes, malignancies of
the pancreas, benign tumors of the pancreas, general hypertrophy of
the pancreas without evident disease, alcohol intake and liver
disease (decreased gluconeogenesis), gastrectomy, renal failure,
drugs such as salicylates, beta-blockers, pentamidine,
acetylcholine esterase (ACE) inhibitors, excess insulin including
insulinoma, self-administered insulin or oral hypoglycemic agents;
pituitary or adrenal insufficiency.
[0123] Clinicians are generally most concerned with functional or
idiopathic hyperinsulinism, the most common type of which is caused
by excessive intake of refined sugars, caffeine, emotional stress
or a combination of these factors with sugar and caffeine
compounded in their effects through a condition of stress. The
Islets of Langerhans in the pancreas are over-stimulated by
constant bombardment of refined sugar and caffeine producing
greater amounts of insulin than required to metabolize the
circulating blood sugar, thus keeping blood sugar levels lower than
normal except for a very short time after ingestion of food.
Eventually any sugar, good, bad, or indifferent, will trigger the
pancreas to secrete excessive amounts of insulin. The liver is also
heavily involved in this mechanism as it controls reconversion of
stored glycogen into glucose for distribution in the blood stream.
In addition, all the endocrine glands are linked in a dynamic
balance to compensate for any deviation of blood sugar levels so
that the brain and nervous system are never for an instant deprived
of necessary amounts of blood sugar needed for their normal
activity. This balance is upset by stress and symptoms such as
anxiety, irritability, fear, sweating, flushing or pallor,
numbness, chills, headaches, dizziness, weakness and faintness are
common. However, the most obvious symptoms are excessive hunger
just about all the time and great fatigue and weakness. Thus,
hypoglycemia is an important medical issue and frequent monitoring
of glucose levels is useful to a wide variety of subjects.
[0124] 2.2.2.1 Hypoglycemia and Eating Disorders
[0125] Hypoglycemia can occur in individuals with anorexia nervosa
(Alvin et al (1993) Arch Fr Pediatr 50(9): 755-762; Ron Waldrop, M
D "Anorexia Nervosa" From emedicine.com on the Internet and bulimia
nervosa (Johnson et al. (1994) Int J Eat Disord 15(4): 331-341;
Overduin J & Jansen A (1997) Physiol Behav 61(4): 569-575). In
bulimic patients following purging of a meal, there is a dramatic
reduction in insulin and glucose (Johnson et al., above). Because
of the correlation between hypoglycemia and hunger, the
hypoglycemia that results from purging may be partially responsible
for continued binging and purging. Thus, monitoring blood glucose
levels in patients with eating disorders can assist therapists in
treating them, and can also help patients understand physiological
processes that contribute to their problems.
[0126] 2.2.2.2 Hypoglycemia and Pentamidine Therapy
[0127] Pentamidine is an effective agent for treating Pneumocystis
carinii pneumonia in HIV-infected patients, the hemolymphatic stage
of Gambian trypanosomiasis, and antimony-resistant leishmaniasis.
Iatrogenic hypoglycemia occurs in one-quarter to one-third of
HIV-infected patients treated with this drug, and it can become
severe and even life-threatening, Andersen et al. (1986) Drug
Intell Clin Pharm 20(11): 862-868; Stahl-Bayliss et al. (1986) Clin
Pharmacol Ther 39(3): 271-5; Chan et al. (1996) Drug Saf 15(2):
135-157. Thus, frequent monitoring of the levels of blood glucose
and, optionally, other analytes (e.g., pentadiene), in HIV-infected
patients receiving pentamidine therapy will reduce the risk of
nosocomial infections in them, and will reduce the risk of HIV
transmission to needle-stick performing hospital personnel.
[0128] 2.2.2.3 Hypoglycemia and Disease States
[0129] Many organic and amino acid disorders are also correlated
with hypoglycemia, for example acidemias that involve the oxidation
of fatty acids (Ozand et al. (2000) Semin Perinatol 24:172-193);
Beckwith-Wiedemann syndrome (DeBaun et al. (2000) Semin Perinatol
24:164-171); glycogen storage diseases (Wolfsdorf et al. (1999)
Endocrinol Metab Clin North Am 28:801-823; carbohydrate-deficient
glycoprotein syndrome (Babovic-Vuksanovic et al. (1999) J Pediatr
135:775-781; hypopituitarism (Nanao et al. (1999) Acta Paediatr
88:1173; and mitochondrial respiratory chain disorders (Morris
(1999) Liver 19:357-368).
[0130] Glycogen storage diseases (glycogenoses) are a group of
hereditary disorders that result from a lack of at least one enzyme
involved in glycogen synthesis or breakdown. The result is
accumulation of glycogen in tissues. According to the Merck Manual
(16.sup.th edition), hypoglycemia can be a severe problem in some
of these glycogen storage diseases, for example, Type 0 (enzyme
system affected, glycogen synthetase), Type Ia (enzyme system
affected, glucose-6-phosphatase), Type Ib (enzyme system affected,
glucose-6-phosphatase translocase), Type III (enzyme system
affected, debrancher enzyme system), Type VI (enzyme system
affected, liver phosphorylase). Patients with glycogen storage
disorders must follow strict diets (in order to avoid hypoglycemia
and other problems) and must monitor their blood glucose levels
(see, Wolfsdorf, et al., above).
[0131] Thus, frequent monitoring of glucose levels non-invasively
in these patients will likely improve their clinical outcomes and
simplify their lives significantly.
[0132] 2.2.2.4 Hypoglycemia and Alcoholism
[0133] Hypoglycemia is a common adverse effect of alcoholism, and
it occurs in up to 95% of alcoholics, Bunout (1999) Nutrition
15(7-8): 583-589. Hypoglycemia due to excessive alcohol ingestion
can be severe, and alcoholics are usually glucose intolerant as
well, Kearney et al. (2000) J R Soc Med 93:15-17. This condition is
most likely due to an inhibition of glucose-stimulated insulin
secretion. Frequent, non-invasive monitoring of blood glucose
levels and/or other analytes such as alcohol can treat alcoholics
by allowing them to see clinical improvements in their blood sugar
levels, or to allow them to see the extent to which alcohol abuse
has damaged an important metabolic process.
[0134] 2.2.2.5. Hypoglycemia and Long Distance Driving
Performance
[0135] Long distance drivers often experience hypoglycemia.
Further, the fatigue associated with hypoglycemia and the resulting
possibility that these drivers may fall asleep at the wheel is a
potential hazard, Frier (2000) Diabetes Care 23:148-150; Marrero et
al. (2000) Diabetes Care 23:146-147. Long distance driving and
associated risks are most frequently associated with long-haul
trucker drivers (N Engl J Med. 1997 September 11;337(11):755-761).
Long distance driving is, for example, sustained driving with
little or no rest for 5 to 10 hours or more. Typical "long-haul"
trucker drivers may drive from 10 to 15 hours at a time. The
California Department of Motor Vehicles suggests a ten minute rest
after even just two hours of driving. Frequent monitoring of
glucose levels will allow long distance drivers to more adequately
determine food and/or fluid intake. This in turn will decrease the
risks posed by poor driving performance caused by hypoglycemia.
[0136] 2.2.2.6 Hypoglycemia and Renal Failure
[0137] Hypoglycemia and its accompanying complications occur
frequently in both diabetic and non-diabetic end stage renal
failure (ESRF) patients, Haviv et al. (2000) Ren Fail 22:219-223.
Accordingly, using the methods described herein, ESRF patients can
benefit from frequent, periodic monitoring of glucose and/or other
analyte levels (e.g., glucose and liver enzymes).
[0138] 2.2.2.7 Hypoglycemia, Neonates, and Children
[0139] Hypoglycemia can cause severe problems in infants or
children, including for example mild to severe brain damage
(Kinnala et al. (2000) Semin Perinatol 24:116-119;Frey et al.
(2000) Scweiz Zmed Wochenschr 130:151-155; Hawdon (1999) Eur J
Pediatr 158 Suppl 1:S9-S12; see, also, Section 2.2.3 below).
Because hypoglycemia can occur if feeding is postponed more than 12
to 24 hours post-partum, there remains a need for frequent and
close clinical observation of neonates and other vulnerable
children while avoiding excessively invasive management that may
interfere with feeding. Thus, the present invention provides
frequent monitoring of glucose levels and, optionally, the levels
of other analytes which may signal neonatal distress, such as
ketones.
[0140] 2.2.2.8 Hypoglycemia and Growth Hormone Therapy
[0141] Growth hormone (GH) therapy has been recommended for short
stature children and for hypoglycemias due to growth hormone
deficiency. Increasingly, growth hormone therapy is also
recommended for adults with growth hormone deficiency following
pituitary tumor surgery or irradiation (Dash, et al., J. Assoc
Physicians India 47:417-425, 1999). Further, the insulin tolerance
test (ITT) is widely accepted as the method of choice to evaluate
growth hormone secretion capacity in adults with
hypothalamic-pituitary disorders, Hoeck, et al. (2000) J Clin
Endocrinol Metab 85:1467-1472. Thus, the present invention can be
used in both adults and children to monitor the levels of various
analytes (e.g., glucose and/or growth hormone).
[0142] 2.2.2.9 Hypoglycemia and Cancer Remission
[0143] Under most circumstances, tumors growth rapidly when the
blood glucose supply is high and grow slowly when blood glucose
supply is low. In cases of spontaneous remissions, tumors appear to
grow rapidly and steadily despite low blood glucose and,
consequently, the tumor system collapses and is removed by the
immune system. It has been suggested that remission may be induced
if hypoglycemia is initiated just prior to reducing the tumor mass
and then maintaining the hypoglycemic state, Niakan (1999) Cancer
Biother Radiopharm 14:297-298. In such regimes, the present
invention can be used to monitor blood glucose levels to help the
subject remain hypoglycemic during the critical period.
[0144] 2.2.2.10 Hypoglycemia and Malaria
[0145] Severe malaria often presents with hypoglycemia, Agbenyega
et al. (2000) J Clin Endorcrinol Metab 85:1569-1576. Furthermore,
because hypoglycemia is a frequent complication of quinine therapy
for malaria, frequent blood sugar estimations are required in
treating malaria or quinine toxicity, Padmaja et al. (1999) Indian
J Med Sci 53:153-157. Thus, the ability to monitor glucose and/or
quinine levels is useful in relation to diagnosis and treatment of
malaria.
[0146] 2.2.2.11 Drug Treatment Related Hypoglycemia
[0147] As noted above, hypoglycemia is present in many diseases.
One cause of hypoglycemia appears to be related to drug therapy,
Virally et al. (1999) Diabetes Metab 25:477-490. For instance,
saquinavir, a treatment for HIV, induces hypoglycemia in Type II
diabetes (see, Zimhony and Stein (1999) Ann Intern Med 131:980),
while indomethacin, a drug used to arteriosus in premature infants,
also induces hypoglycemia. Consequently, frequent monitoring of
analytes (e.g., glucose and/or the therapeutic drug) in these
individuals is part of the present invention.
[0148] 2.2.2.12 Hypoglycemia, Brain Injury and Stroke
[0149] As noted above, brain injury can be a serious complication
of hypoglycemia. de Courten-Meyers et al. (2000) J Cereb Blood Flow
Metab 20:82-92; Losek (2000) Ann Emerg Med 35:43-46. There is also
strong evidence that severe hypoglycemia can worsen the prognosis
in acute stroke. Nagi et al. (1999) Nervenarzt 70:944-949. To
determine appropriate treatment options, routine and rapid
assessment of analytes such as glucose is recommended.
[0150] 2.2.2.13 Hypoglycemia and Endurance Exercise and
Training
[0151] Performance in endurance events requires an adequate supply
of nutrients such as glucose. Thus, performance is optimized when
training includes monitoring of glucose and other analyte levels
combined with nutritional supplementation to prevent hypoglycemia,
Coyle (1999) J Sci Med Sport 2:181-189.
[0152] 2.2.2.14 Severe Hypoglycemia
[0153] Some individuals may experience recurrent bouts of severe
hypoglycemia. Because such episodes of hypoglycemia may cause
severe complications, it is recommended that individuals with a
recent history of severe hypoglycemia better recognize the
occurrence of low blood glucose. Cox et al. (1999) Diabetes Care
22:2018-2025. The present invention provides a fast and efficient
way for these individuals to monitor glucose levels.
[0154] 2.2.3 Pregnancy and Gestational Diabetes
[0155] Dysglycemia during pregnancy can cause severe problems for
both mother and fetus, see, e.g., Schafer-Graft et al. (1999) Ther
Umsch 56:572-576. For diabetic mothers who become pregnant, close
monitoring and tight control of blood glucose levels during the
first 9 weeks of pregnancy helps reduce the incidence of birth
defects, Schwartz et al. (2000) Semin Perinatol 24:120-135.
[0156] In approximately 4% of women, pregnancy will induce
"gestational diabetes" or "insulin resistance" in women who have
never had diabetes before but who have high blood sugar levels
during pregnancy. Without enough insulin, the mother become
hyperglycemic and is more likely to become hypertensive, Bartha et
al. (2000) Am J Obstet Gynecol 182:346-350. In addition to the
problems this causes the mother, hyperglycemia and hypertension
also place the fetus at risk for serious complications. The high
maternal levels of glucose are able to cross the placenta, which
causes the fetus's pancreas to make extra insulin to metabolize the
blood sugar and can lead to macrosomia (alternately called a "fat"
baby, or a "big bad baby" (BBB)). Babies with macrosomia face
health problems of their own, including damage to their shoulders
during birth; breathing problems and hypoglycemia after birth
because of their own increased insulin production, Schwartz et al.,
above. Further, babies with excess insulin become children who are
at risk for obesity and adults who are at risk for type 2
diabetes.
[0157] Currently, treatment of diabetes during pregnancy is geared
toward keeping blood sugar levels below hyperglycemic levels using
special meal plans, scheduled physical activity and, if necessary,
insulin injections. Monitoring of blood glucose levels after meals
is also recommended. Recently, however, it has been suggested that
overzealous control of hyperglycemia in pregnancy may lead to
hypoglycemic episodes for the mother, Rosenn et al. (2000) J Matern
Fetal Med 9:29-34. As noted above, maternal hypoglycemia is
associated with a variety of problems for the fetus including
intrauterine growth retardation, high rates of gestational
age-specific neonatal mortality, long term cognitive deficits,
increased risk of coronary artery disease, diabetes and
hypertension as an adult, Rosenn et al., above. Thus, ideally,
blood sugar levels during pregnancy are controlled such that the
mother is neither hypoglycemic nor hyperglycemic. Using the methods
described herein, which allow for frequent monitoring of blood
glucose levels, allows for frequent evaluation of blood glucose
levels so that the mother can take appropriate action when either
hyperglycemia or hypoglycemia are imminent.
[0158] 2.2.4 Weight Management
[0159] Obesity is a major health problem in many countries and is
associated with an increased risk for heart disease, certain
cancers and development of Type II diabetes. According to the
Centers for Disease Control's (CDC's) National Center for Health
Statistics, 54% of adult Americans and between 11% and 14% of
children were overweight in 1997, as determined using the Body Mass
Index scale, which defines classes of non-obesity and obesity.
According to guidelines proposed by the World Health Organization,
individuals whose BMI is greater than 25 kg/m.sup.2 are Grade 1
overweight. Those whose BMI is greater than 30 kg/m.sup.2 are Grade
2 overweight, or obese, and individuals with a BMI greater than 40
kg/m.sup.2 are Grade 3 overweight, or morbidly obese (Kopelman
(2000) Nature 404: 635-643).
[0160] According to the CDC, the average American woman is 5'33/4"
tall, weighs 152 pounds, and has a BMI slightly greater than 26. A
woman of the same height, but whose weight was 231 pounds, would
have a BMI of 40 kg/m.sup.2. As a person's body mass index
increases past 30 kg/m.sup.2, the risk of acquiring type 2 diabetes
increases sharply. The relative risk of developing type 2 diabetes
increases with increasing Body Mass Index (BMI). BMI is measured in
kg/m.sup.2. Accordingly to Kopelman (Nature 404:635-643, 2000),
obesity is now so common within the world's population that it is
beginning to replace under-nutrition and infectious diseases as the
most significant contributor to ill health. Obesity is associated
with diabetes mellitus, coronary heart disease, certain forms of
cancer, and sleep-breathing disorders. Obesity is generally defined
by a body-mass index (weight divided by square of the height) of 30
kg/m.sup.-2 or greater. This degree of obesity takes into account
neither the morbidity/mortality associated with more modest degrees
of a person (or animal) being overweight, nor the detrimental
effect of intra-abdominal fat.
[0161] Thus, impaired glucose tolerance is a clear risk factor for
type 2 diabetes. A survey of American adults performed by the World
Health Organization found impaired glucose tolerance in 10%-15% of
the study populations. According to the Merck Manual (17.sub.th
edition), weight loss and exercise are part of the recommended
standard treatment for patients with impaired glucose tolerance or
type 2 diabetes, and the condition can resolve following weight
loss. Furthermore, a recent study correlated weight loss in
patients with impaired glucose tolerance and determined that weight
loss can also prevent type 2 diabetes from developing in the first
place (Eriksson J et al. (1999) Diabetologia 42(7): 793-801).
[0162] One weight loss program involves eating meals that balance
the amounts of protein, fat and carbohydrate. See, e.g. Dr. Barry
Sears, Enter the Zone (1995), Regan Books. This diet, which is
similar to that suggested for diabetic patients, seeks to maintain
blood glucose levels within specified ranges by limiting the amount
of carbohydrate and fat intake and "balancing" fats and
carbohydrates with proteins. Thus, frequent monitoring of blood
glucose levels allows subjects following this diet to determine
which foods (and what combinations of foods) to eat at what times
so they maintain specified blood glucose levels that are neither
hyperglycemic nor hypoglycemic.
[0163] In sum, using the methods described herein provides an
excellent means for (1) demonstrating the need to reduce weight;
(2) providing instant evidence of the deleterious effects of
obesity; and (3) aiding dieters to monitor blood glucose levels and
maintain normal levels by eating appropriately. Isolated finger
stick procedures performed during occasional medical exams will
most likely not have such an impact. Frequent reminders--be they
weekly, monthly, daily or more--of abnormal blood glucose levels,
in addition to a thorough education on the potential complications
of the condition, will stand a greater chance of inspiring change.
The methods described herein can be applied to weight gain, or
weight maintenance as well.
[0164] Accordingly, in one aspect of the present invention a range
of glucose values can be established for a subject based on desired
blood glucose levels directed to the desired goal, for example,
weight management. Alerts can be set in the glucose monitoring
device to be activated when blood sugar levels falls below, or rise
above, lower and upper limits (respectively) of the predetermined
range. Such alerts provide an on-going assessment of the subject's
glucose consumption and production, as well as rates and amounts
thereof. Frequent and periodic monitoring of changes in the plasma
or blood glucose in a subject provides information to the subject
and/or health care profession (e.g., physician, dietician, etc.)
that allows optimization of a food plan to suit the particular
needs of the subject (for example, weight loss or weight gain).
[0165] An appropriate reference range of glucose values (i.e., a
low and high threshold value) is typically determined by a trained,
health-care professional. Such a reference range may also include a
preferred average glucose value, as well as a preferred range of
variation around the average value. Such a determination of
reference glucose range is typically based on current physical
characteristics of the subject (including, but not limited to, body
mass index, percentage body fat, hydration level, etc.) and the
subject's goal for weight management (i.e., gain, loss, or
maintenance). This reference range is then entered into the glucose
monitoring device typically with alerts set at the high and low
threshold values. One or more microprocessor component of the
glucose monitoring device typically includes an algorithm to
maintain a record of all subject glucose values determined by the
glucose monitoring device. A memory component of the glucose
monitoring device may also store related information entered by a
subject, such as, times and amounts of exercise, amounts and types
of food, etc. Alternatively, such information may be entered into a
system that interfaces with the glucose monitoring device, such as,
a personal computer (PC), pocket PC, personal digital assistant
(PDA, e.g., Palm Pilot.TM. (Palm Inc., Santa Clara, Calif.)).
[0166] Accordingly, a record of glucose levels obtained by frequent
sampling (for example, the GlucoWatch biographer provides
approximately 3 glucose readings per hour) is developed. Typically,
a subject enters the time of meals, snacks, or caloric intake
and/or output, in order to keep track of glucose levels relative to
such events. Regardless of the subject's inputted information,
however, the glucose monitoring device alerts the subject to
glucose levels outside of the predetermined range. One set of
distinctive alerts may be associated with a low threshold glucose
level in order to alert the subject to, for example, consume a
snack, and another set of distinctive alerts may be associated with
levels above the high threshold value to warn the subject of
excessive caloric intake. Further, because an ongoing record of
glucose levels is maintained by the glucose monitoring device
(and/or an associated device) the records developed over days,
weeks, months, etc., can be reviewed by a subject and/or a
health-care professional in order to provide appropriate
modifications to the food plan. Accordingly, comparing a series of
glucose amounts or concentrations as determined by the glucose
monitoring device, the record of caloric intake and/or output, and
the predetermined reference range of glucose values allows the
subject (and/or health-care professional) to evaluate compliance
with the reference range of glucose amounts or concentrations that
is being used to achieve the weight management goal of the subject.
Further, glucose level fluctuations that put the subject at risk
can be evaluated and solutions to avoid such fluctuations
proposed.
[0167] A similar approach may be applied to numerous disease states
or conditions, e.g., those described above. For example, a subject
may enter information (e.g., time of dosing) about medications that
are being taken (such as, HIV medications discussed above) and
glucose levels can be evaluated relative to such events, i.e.,
comparing the record of medication to glucose levels. By keeping
track of such information it may be possible to avoid HIV
drug-related hyperglycemia and its attendant health problems by
modifying the subject's dietary intake, perhaps relative to drug
dosing times, in order to maintain glucose values within a
predetermined reference range (i.e., between high and low threshold
values). Accordingly, by comparing a series of glucose amounts or
concentrations in a subject being treated with a pharmaceutical
composition (typically comprising at least one non-insulin
containing pharmaceutical compound, further such pharmaceutical
compounds typically do not comprise pharmaceuticals used for the
treatment of diabetes, rather they are pharmaceutical compounds
with associated side-effects on glucose levels) and a reference
record of dates/times of treatment with the pharmaceutical, it is
possible to evaluate the effect of the pharmaceutical composition
on glucose levels in the subject receiving the pharmaceutical
composition over time. Further, a reference range of glucose
amounts or concentrations that correspond to maintaining a desired
range of glucose amounts or concentrations in the subject during a
treatment course can be determined by the subject typically in
cooperation with a health-care professional. The reference range is
typically defined by a high threshold glucose value and a low
threshold glucose value. Alerts may be set in the glucose
monitoring device to make the subject aware of fluctuations outside
of the reference range.
[0168] In another aspect, the above-described methods can be
applied to a method for improving prognosis and/or reduction of
adverse side-effects associated with a disease state or condition
in a subject. In this aspect, a reference range of glucose amounts
or concentrations is typically determined that corresponds to
achieving an improved prognosis or reduction of adverse
side-effects associated with said disease state or condition in the
subject. The reference range of glucose amounts or concentrations
typically comprises a high threshold glucose value and a low
threshold glucose value, and further may include a desired average
value with a preferred, associated range of variation. The glucose
amount or concentration in the subject is monitored using a glucose
monitoring device, for example, as described above. A series of
glucose values is obtained over a time course. By comparing the
series of glucose amounts or concentrations and the reference range
compliance with the reference range of glucose amounts or
concentrations to achieve an improved prognosis or reduction of
adverse side-effects associated with said disease state or
condition in the subject can be evaluated. Clearly such monitoring
of glucose levels is necessary and useful in diabetic disease, for
example, type I and type II diabetes, however, the method is useful
when applied to monitoring glucose in disease states or conditions
where the primary effect of the disease state or condition is not
directly on glucose levels in the subject, numerous such disease
states and conditions are outlined above, including, but not
limited to cancer remission, infection with human immunodeficiency
virus (HIV), infection with Candida, long distance driving, organ
transplantation, growth hormone therapy, renal failure, infection
with malaria, alcoholism, intense exercise, cardiovascular disease,
cystic fibrosis, stroke, and ischemia.
[0169] As another example, the above-described method of providing
a functional range of glucose values can be extended to endurance
exercise and training. Different ranges of glucose can be
established by the subject and/or a health-care professional
wherein a selected range of glucose values is put into effect in
the glucose monitoring device depending on the activity. For
example, three reference glucose ranges may be established for a
person undertaking an exercise or training program: a resting range
of glucose values, where the high and low glucose threshold values
are determined to maintain a certain weight, an aerobic-exercise
range of glucose values, where the high and low glucose threshold
values are determined to maintain optimum performance during
aerobic exertion, and a training-exercise range, where most of the
activity is not aerobic in nature (e.g., weight training) and the
high and low glucose threshold values are determined to maintain
optimum performance during the training activity. A subject may
activate a selected set of range values in the glucose monitoring
device. A default setting may be selected by the subject to which
settings the glucose monitoring device returns after a specified
amount of time, or another alert may be programmed to remind the
subject to change the selected set of range values after a certain
period of time. In this embodiment of the present invention, a
record of glucose level variation correlated to activities gives
the subject information to evaluate which may reveal particular
issues that need to be addressed. For example, consistently low
glucose levels during sustained aerobic events may indicate to the
subject that such events should be preceded by an increased intake
in carbohydrates/fats/proteins. Further, review and evaluation of
such a record (obtained over, for example, days, weeks, or months)
may allow the subject to modify the intensity, duration, and/or
type of exercise in order to maintain appropriate glucose levels
throughout the subject's training program, thereby preventing
over-exertion and/or reduction of muscle mass.
[0170] In an alternative embodiment, high and low glucose threshold
values may be established for a reference glucose range. The
glucose monitoring device may be worn by the subject in order to
obtain frequent, periodic measurements of glucose amount or
concentration in the subject. An independent record may be kept by
the subject of caloric intake (e.g., meals and snacks) as well as
caloric expenditure (e.g., exercise). This independent record can
then be compared to the record of glucose values provided by the
glucose monitoring device and the reference range of glucose
values. Such comparison may be carried out by hand or by a
computerized algorithm. In this aspect of the invention, trends of
glucose levels can be compared to caloric intake/output and diet
and exercise adjusted accordingly to achieve weight management
goals. Accordingly, comparing a series of glucose amounts or
concentrations as determined by the glucose monitoring device, the
record of caloric intake/output, and the predetermined reference
range of glucose values allows the subject (and/or health-care
professional) to evaluate compliance with the reference range of
glucose amounts or concentrations that is being used to achieve the
weight management goal of the subject. Such independent record
keeping by the subject may be applied to other disease states or
conditions described above (e.g., medications, exercise training,
long distance driving, etc.).
[0171] Although preferred embodiments of the subject invention have
been described in some detail, it is understood that obvious
variations can be made without departing from the spirit and the
scope of the invention as defined by the appended claims.
* * * * *