U.S. patent application number 17/650184 was filed with the patent office on 2022-05-19 for two piece sensor assembly and method of use.
The applicant listed for this patent is MediBeacon Inc.. Invention is credited to Anthony Le, Martin Leugers.
Application Number | 20220153708 17/650184 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-19 |
United States Patent
Application |
20220153708 |
Kind Code |
A1 |
Le; Anthony ; et
al. |
May 19, 2022 |
TWO PIECE SENSOR ASSEMBLY AND METHOD OF USE
Abstract
Disclosed herein is a two-piece sensor assembly that includes an
attachment collar configured to attach to a body surface of a
patient and comprising at least one opening, and a skin sensor
configured to seat into the at least one opening in the attachment
collar. The skin sensor includes at least one radiation source
configured to irradiate the body surface with at least one
interrogation light, at least one detector configured to detect at
least one response light incident from the direction of the body
surface, and a controller communicatively coupled to the skin
sensor, the attachment collar or both, wherein the controller is
programed to transmit information and to receive information
between the controller and the skin sensor and/or the attachment
collar, and to control the at least one radiation source and the at
least one detector.
Inventors: |
Le; Anthony; (St. Louis,
MO) ; Leugers; Martin; (St. Louis, MO) |
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Applicant: |
Name |
City |
State |
Country |
Type |
MediBeacon Inc. |
St. Louis |
MO |
US |
|
|
Appl. No.: |
17/650184 |
Filed: |
February 7, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16552539 |
Aug 27, 2019 |
11261165 |
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17650184 |
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62793000 |
Jan 16, 2019 |
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International
Class: |
C07D 241/28 20060101
C07D241/28; A61K 49/00 20060101 A61K049/00; A61B 5/00 20060101
A61B005/00; A61B 5/1455 20060101 A61B005/1455 |
Claims
1. A two-piece sensor assembly comprising: an attachment collar
configured to attach to a body surface of a patient and comprising
at least one opening, a skin sensor configured to seat into the at
least one opening in the attachment collar and comprising: at least
one radiation source configured to irradiate the body surface with
at least one interrogation light, at least one detector configured
to detect at least one response light incident from the direction
of the body surface, and a controller communicatively coupled to
the skin sensor, the attachment collar or both, wherein the
controller is programed to transmit information and to receive
information between the controller and the skin sensor and/or the
attachment collar, and to control the at least one radiation source
and the at least one detector, wherein the skin sensor and the
attachment collar further comprise a means of authentication
between the skin sensor and the attachment collar.
2. The two-piece sensor assembly according to claim 1, wherein the
means of authentication comprises a pressure sensitive element
configured to provide communication between the attachment collar
and the skin sensor when the skin sensor attaches to the attachment
collar.
3. The two-piece sensor assembly according to claim 2, wherein the
pressure sensitive element provides an indication of secure
attachment of the skin sensor to the body surface of the
patient.
4. The two-piece sensor assembly according to claim 2, wherein the
pressure sensitive element provides an indication that the skin
sensor is no longer securely attached to the body surface of the
patient.
5. The two-piece sensor assembly according to claim 2, wherein the
attachment collar is configured for single use and wherein the
pressure sensitive element is configured to prevent more than a
single use of the attachment collar.
6. The two-piece sensor assembly according to claim 1, wherein the
means of authentication comprises a bar code configured to
authenticate the combination of the skin sensor and the attachment
collar.
7. The two-piece sensor assembly according to claim 1, wherein the
means of authentication comprises an RFID chip on the attachment
collar configured to be detected by the skin sensor in order for
the two-piece sensor assembly to operate.
8. The two-piece sensor assembly according to claim 1, wherein the
means of authentication comprises an identifier tab on the
attachment collar configured to be detected by the skin sensor.
9. The two-piece sensor assembly according to claim 1, wherein the
means of authentication comprises at least one communication port
configured to send and receive information between the skin sensor
and the attachment collar.
10. The two-piece sensor assembly according to claim 9, wherein the
at least one communication port comprises an EEPROM chip configured
to prevent use of the skin sensor unless a connection is made
between the skin sensor and the attachment collar.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/552,539, filed on Aug. 27, 2019, which claims priority
benefit of U.S. Provisional Application Ser. No. 62/793,000, filed
Jan. 16, 2019. Both of these applications are incorporated by
reference herein in their entirety.
FIELD OF INVENTION
[0002] The field of the disclosure relates generally to sensor
systems. More specifically, this disclosure generally relates to a
two-piece sensor assembly where the skin sensor that comprises the
complex electronic components is reusable and the attachment collar
that holds the skin sensor in place on the body of a patient is
either disposable or reusable.
BACKGROUND
[0003] In the clinical and preclinical field, determining various
organ functions is accorded great importance since, for example,
corresponding therapies or medications can be controlled in
accordance with said organ functions. The two-piece sensor assembly
is described hereinafter substantially with regard to kidney
function monitoring. In principle, however, other applications are
also conceivable in which the function of a particular organ can be
detected by means of determining a temporal profile of an indicator
substance.
[0004] The glomerular filtration rate (GFR) is an important
clinical parameter to assess the level of kidney function in a
patient. As shown in the table below, the lower the GFR, the more
serious the kidney impairment for Chronic Kidney Disease (CKD) and
other renal insufficiencies. The GFR can be estimated based on a
blood test measuring the blood creatinine level in the patient in
combination with other factors. More accurate methods involve the
injection of an exogenous substance into a patient followed by
careful monitoring of plasma and/or urine concentration over a
period of time. These are often contrast agents (CA) that can cause
renal problems on their own. Radioisotopes or iodinated aromatic
rings are two common categories of CAs that are used for GFR
determination.
TABLE-US-00001 Stage Description GFR* Increased Increase of risk
factors (e.g., diabetes, high blood >90 risk pressure, family
history, age, ethnicity) 1 Kidney damage with normal kidney
function >90 2 Kidney damage with mild loss of kidney function
60-89 3a Mild to moderate loss of kidney function 44-59 3b Moderate
to severe loss of kidney function 30-44 4 Severe loss of kidney
function 15-29 5 Kidney failure; dialysis required <15 *GFR is
measured in units of mL/min/1.73 m.sup.2.
[0005] With regard to conventional renal function measurement
procedures, an approximation of a patient's GFR can be made via a
24 hour urine collection procedure that (as the name suggests)
typically requires about 24 hours for urine collection, several
more hours for analysis, and a meticulous bedside collection
technique. Unfortunately, patient compliance using this method is
very low, and, as a consequence, is not generally utilized by
clinicians.
[0006] Examples of exogenous substances capable of clearing the
kidney exclusively via glomerular filtration (hereinafter referred
to as "GFR agents") include creatinine, o-iodohippuran, and
.sup.99mTc-DTPA. Examples of exogenous substances that are capable
of undergoing renal clearance via tubular secretion include
.sup.99mTc-MAG3 and other substances known in the art.
.sup.99mTc-MAG3 is also widely used to assess renal function though
gamma scintigraphy as well as through renal blood flow measurement.
One drawback to many indicator substances, such as o-iodohippuran,
.sup.99mTc-DTPA and .sup.99mTc-MAG3, is that they are radioisotopes
and therefore require special handling techniques and are
associated with risks to patient health.
BRIEF DESCRIPTION
[0007] Disclosed here in is a two-piece sensor assembly. The sensor
assembly generally comprises: an attachment collar configured to
attach to a body surface of a patient and comprising at least one
opening, and a skin sensor configured to seat into the at least one
opening in the attachment collar. The skin sensor generally
comprises: at least one radiation source configured to irradiate
the body surface with at least one interrogation light, and at
least one detector configured to detect at least one response light
incident from the direction of the body surface.
[0008] In another aspect, disclosed herein is a method for
determining a glomerular filtration rate (GFR) in a patient in need
thereof. The method generally comprises: applying a two-piece
sensor assembly onto the body surface of the patient, administering
into the body of the patient an indicator substance, said indicator
substance configured to generate an optical response in response to
an interrogation light; detecting said optical response using the
two-piece sensor assembly over a predetermined period of time; and
determining the GFR in said patient based on the detected optical
response.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 illustrates one embodiment of the two-piece sensor
assembly that includes a locking bar on each side of the sensor to
secure it to the attachment collar, a cord management system to
provide strain relief and security from cord pulls, and a pull tab
for easy removal of the attachment collar from skin.
[0010] FIG. 2 illustrates one embodiment of the two-piece sensor
assembly for attaching the skin sensor to the attachment collar
using selectively adhesive surfaces.
[0011] FIG. 3 illustrates one embodiment of the two-piece sensor
that includes a bar code/QR reader.
[0012] FIG. 4 illustrates a torturous light path for the connection
between the skin sensor and the attachment collar to ensure a
light-tight fit.
[0013] FIG. 5 illustrates a cam lock between the skin sensor and
the attachment collar.
[0014] FIG. 6 illustrates one embodiment of the two-piece sensor
assembly that comprises tabs to aid the alignment and positioning
of the skin sensor relative to the attachment collar.
[0015] FIG. 7 illustrates a stretch pocket attachment collar for
the two-piece sensor assembly that provides a slight downward
pressure to the skin sensor onto the skin of the patient.
[0016] FIG. 8 illustrates one embodiment of the two-piece sensor
assembly that includes RFID authentication and grooves within the
attachment collar for the cord to provide security from cord
pulls.
[0017] FIG. 9 illustrates one embodiment of the two-piece sensor
assembly that includes a lock and key type security feature between
the attachment collar and the skin sensor.
[0018] FIG. 10 illustrates one embodiment of the two-piece sensor
assembly that includes a magnetic connection between the attachment
collar and the skin sensor.
[0019] FIG. 11 illustrates one embodiment of the two-piece sensor
assembly that includes an attachment collar that encircles the
sensor, and a cable management system to provide strain relief and
security from cord pulls.
[0020] FIG. 12 illustrates one embodiment of the two-piece sensor
assembly that includes an embedded chemical in the attachment
collar that can be detected by the sensor.
[0021] FIG. 13 illustrates one embodiment of the two-piece sensor
assembly that includes a swivel attachment between the skin sensor
and the attachment collar.
[0022] FIG. 14 illustrates one embodiment of the two-piece sensor
assembly that includes a tab placement port and cord management
system to provide strain relief and security from cord pulls.
[0023] FIG. 15 illustrates one embodiment of the two-piece sensor
assembly that includes fold-over tabs to secure the skin sensor to
the attachment collar.
[0024] FIG. 16 illustrates one embodiment of the two-piece sensor
assembly that includes a communication port (e.g., an EEPROM)
between the skin sensor and the attachment collar.
[0025] FIG. 17 illustrates one embodiment of the two-piece sensor
assembly that includes a cam lock to secure the skin sensor to the
attachment collar, and providing a slight downward pressure to the
skin sensor onto the skin of the patient and visual indication that
the sensor is locked in place.
[0026] FIG. 18 illustrates one embodiment of the two-piece sensor
assembly that includes a wrap mechanism to secure the skin sensor
to the attachment collar, and providing a slight downward pressure
to ensure a light-tight fit.
[0027] FIG. 19 illustrates one embodiment of the two-piece sensor
assembly that includes clips on the skin sensor which secure the
sensor to the attachment collar, a cord management system to
provide strain relief and security from cord pulls, and a pull tab
for easy removal of the attachment collar from the skin when the
session is complete.
[0028] FIG. 20 illustrates one embodiment of the two-piece sensor
assembly that includes a locking mechanism on the skin sensor which
secures the sensor to the attachment collar, a cord management
system to provide strain relief and security from cord pulls, and a
pull tab for easy removal of the attachment collar from the skin
when the session is complete.
[0029] FIG. 21 illustrates one embodiment of the two-piece sensor
assembly that includes an attachment collar that encircles the
sensor to ensure a light-tight fit, a cord management system to
provide strain relief and security from cord pulls, and a pull tab
for easy removal of the attachment collar from the skin when the
session is complete.
[0030] FIG. 22 illustrates one embodiment of the two-piece sensor
assembly that includes clips on the skin sensor which secure the
sensor to the attachment collar, a cord management system to
provide strain relief and security from cord pulls, and a pull tab
for easy removal of the attachment collar from the skin when the
session is complete.
[0031] Unless otherwise indicated, the drawings and figures
provided herein illustrate features of embodiments of the
disclosure or results of representative experiments illustrating
some aspects of the subject matter disclosed herein. These features
and/or results are believed to be applicable in a wide variety of
systems including one or more embodiments of the disclosure. As
such, the drawings are not intended to include all additional
features known by those of ordinary skill in the art to be required
for the practice of the embodiments, nor are they intended to be
limiting as to possible uses of the methods disclosed herein.
DETAILED DESCRIPTION
[0032] In the following specification and the claims, reference
will be made to a number of terms, which shall be defined to have
the following meanings. The singular forms "a," "an," and "the"
include plural references unless the context clearly dictates
otherwise. The terms "comprising," "including," and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements. "Optional" or "optionally"
means that the subsequently described event or a circumstance may
or may not occur, and that the description includes instances where
the event occurs and instances where it does not.
[0033] Approximating language, as used herein throughout the
specification and claims, may be applied to modify any quantitative
representation that could permissibly vary without resulting in a
change in the basic function to which it is related. Accordingly, a
value modified by a term or terms, such as "about,"
"approximately," and "substantially," are not to be limited to the
precise value specified. In at least some instances, the
approximating language may correspond to the precision of an
instrument for measuring the value. Here and throughout the
specification and claims, range limitations may be combined and/or
interchanged; such ranges are identified and include all the
sub-ranges contained therein unless context or language indicates
otherwise.
[0034] As used herein, the term "light-tight" means the interface
between two surfaces does not permit the passage of external light.
For example, when the attachment collar is placed on a body surface
and the skin sensor is operably attached to it, a surface of the
skin sensor faces the body surface. No external light penetrates to
the body surface between the interface of the skin sensor and the
attachment collar to reach the area of the body surface that faces
the skin sensor. Additionally, no external light passes between the
body surface of the patient and the surface or edges of the
attachment collar adhered to or in contact with the body surface.
As such, the only light detected by the skin sensor emanates
directly incident to the body surface of the patient. In some
aspects, the only light detected by the skin sensor emanates from a
response light generated by an indicator substance inside the body
of the patient.
[0035] PCT/EP2009/060785, which is incorporated by reference herein
in its entirety for all purposes, discloses skin sensors that can,
in some aspects, be configured for use in conjunction with an
attachment collar thereby creating a two-piece sensor assembly as
disclosed herein.
[0036] The term "patient" as used herein refers to a warm blooded
animal such as a mammal which is the subject of a medical treatment
for a medical condition that causes at least one symptom. It is
understood that at least humans, dogs, cats, and horses are within
the scope of the meaning of the term. In some aspects, the patient
is human. As used herein, any suitable surface on the body of the
patient may be used as the body surface. Examples include, but are
not limited to, skin surfaces, fingernails or toenails, more
particularly surfaces exposed to the atmosphere. Generally, as used
herein, the term "patient" means a human or an animal on which at
least one of the two-piece sensor assembly may be used,
independently of the health of the patient.
[0037] The skin sensor comprises at least one radiation source. A
radiation source is understood to be any device which can emit
radiation anywhere on the electromagnetic spectrum. In some
aspects, the electromagnetic radiation is in the visible, infrared,
ultraviolet, and/or gamma spectral range. Alternatively or
additionally, other types of radiation can also be used, for
example streams of particles. By way of example and not limitation,
alpha rays and/or beta rays may be used. The radiation source is
configured to generate radiation of the type mentioned. Without
restricting the type of radiation used and for convenience only,
hereinafter radiation is generally designated as "light" whether or
not it is in the visible region of the electromagnetic spectrum,
and the radiation source is described more particularly with
reference to a "light source". However, other configurations of the
radiation source are possible, in some aspects, and it is also
possible, in some aspects, to combine different types of radiation
sources.
[0038] The radiation source can be, for example, an integral
constituent of the skin sensor, for example in the context of a
layer construction of the skin sensor. The radiation source is
therefore designed to generate at least one interrogation light
directly within the skin sensor, in contrast to external generation
of the interrogation light. In this respect, the skin sensor
differs, for example, from the fiber-optic construction in U.S.
Pat. No. 6,995,019 B2, in which an external light source is used.
Instead of an individual light source, in some aspects, it is also
possible to use a plurality of light sources, for example redundant
light sources for emitting one and the same wavelength, and/or a
plurality of different light sources for emitting different
wavelengths. Generally, the at least one light source is designed
to irradiate the body surface with at least one interrogation
light.
[0039] An interrogation light is understood to be a light that can
be used for the detection of an indicator substance as disclosed
elsewhere herein, whose light excites the indicator substance
inside a body tissue and/or a body fluid of the patient, for
example with variable penetration depth, and causing a perceptible
response, more particularly, an optically perceptible response.
This excitation takes place in such a way that a luminescence, a
fluorescence and/or a phosphorescence is initiated in the indicator
substance. In some aspects, other types of excitation occur, for
example scattering of the light at an identical or shifted
wavelength. Generally, at least one response light is generated by
the indicator substance in response to the interrogation light.
[0040] The interrogation light is designed such that the desired
response is excited in a targeted manner in the indicator
substance. Accordingly, by way of example and not limitation, a
wavelength and/or a wavelength range of the interrogation light
and/or some other property of the interrogation light can be
adapted or adjusted based on the identity and properties of the
indicator substance. This can be done directly by the radiation
source, for example, by virtue of the radiation source providing
the interrogation light having a specific wavelength and/or in a
specified wavelength range and/or by the inclusion of at least one
excitation filter being used to filter out the desired
interrogation light from a primary light of the light source. In
some aspects, the skin sensor performs fluorescence measurements on
the indicator substance. Accordingly, the interrogation light can
be adapted to the excitation range of the fluorescence of the
indicator substance.
[0041] The skin sensor further comprises at least one detector
designed to detect at least one response light incident from the
direction of the body surface. The response light can be light in
the sense of the above definition. The detector is also an integral
constituent of the skin sensor. The detector is therefore part of
the skin sensor such that the response light is detected directly
within the skin sensor, in contrast, for example, to the
fiber-optic construction in U.S. Pat. No. 6,995,019 B2, in which an
external detector is required.
[0042] In some aspects, the response light represents an optical
response of the indicator substance to the incidence of the
interrogation light. Accordingly, the detector and/or the detector
in interaction with at least one response filter is configured to
detect in a targeted manner in the spectral range of the response
light. In some aspects, the detector and/or the detector in
interaction with the at least one response filter is configured to
suppress light outside the spectral range of the response light. In
some aspects, the detector and/or the detector in interaction with
the at least one response filter can be designed to suppress the
interrogation light. In yet another aspect, response filters are
designed to suppress the detection of ambient light, particularly
at wavelengths that can travel long distances in tissue prior to
absorption, such as a spectral range of from about 700 to about
1100 nm. The interrogation light and the response light can be
configured such that they are spectrally different or spectrally
shifted relative to one another with regard to their spectral
intensity distribution.
[0043] By way of example and not limitation, in some aspects, the
response light shifts toward longer wavelengths in comparison with
the interrogation light, which generally occurs in a fluorescence
measurement (i.e., the Stokes shift). By way of another example,
the Stokes shift of a peak wavelength of the response light
relative to a peak wavelength of the interrogation light is between
about 10 nm and about 200 nm, more particularly between about 100
nm and about 150 nm, and particularly about 120 nm. The detector
and/or the detector in interaction with the at least one response
filter can be designed to detect such response light. About in this
context means .+-.10 nm.
[0044] The at least one radiation source, more particularly, the at
least one light source, and the at least one detector are designed
to irradiate the body surface with the interrogation light and to
detect at least one response light incident from the direction of
the body surface. The radiation source and the detector are
therefore optically connected to the body surface in such a way
that, through the body surface, for example transcutaneously, the
interrogation light can be radiated into the body tissue or the
body fluid of the patient, and that, likewise through the body
surface, for example transcutaneously, the response light from the
body tissue or the body fluid is observed by the detector.
[0045] In addition to the at least one detector and the at least
one radiation source, the sensor assembly may comprise further
elements. In some aspects, the attachment collar comprises further
elements. In some aspects, the skin sensor comprises further
elements. In some aspects, both the skin sensor and the attachment
collar comprise further elements. Thus, the skin sensor can
comprise, for example, at least one interface for data exchange.
Said data can be, for example, measurement results for intensities
of the response light detected by the detector. Data already partly
processed, filtered or partly or completely evaluated data, can
also be transmitted via said interface. The interface can be
configured as a wireless interface, a cabled interface or a
combination thereof, and can comprise a radiofrequency coil and/or
a cable. In some aspects, transponder technology known in the art
may be used, for example, to initiate a measurement via the skin
sensor and/or to interrogate measurement data from the skin sensor.
In some aspects, corresponding radiofrequency readers such as are
known from RFID technology (radiofrequency identification label
technology), for example, can be used for this purpose.
[0046] In some aspects, the two-piece sensor assembly further
comprises a controller. The controller is programmed to control the
at least one skin sensor comprising the at least one radiation
source and the at least one detector. In some aspects, the
controller is further programmed to receive authentication
information from the skin sensor, the attachment collar or both.
The authentication information can be using techniques known in the
art such as, for example, EPROM or RFID. In some aspects, the
connection between the controller and the skin sensor is cabled,
wireless or a combination thereof. In some aspects, the connection
between the controller and the other components is by a cable. In
some aspects, the connection between the controller and the other
components is wireless. In some aspects, the controller is
contained within the sensor.
[0047] Furthermore, the sensor assembly can comprise at least one
driving or controlling electronic unit. Said driving electronic or
controlling unit can be configured, for example, for driving or
controlling the at least one radiation source and the at least one
detector, for example, for starting an emission of the
interrogation light and/or for initiating a detection of the
response light. For this purpose, the driving or controlling
electronic unit can comprise, for example, corresponding drivers
for the detector and/or the radiation source. A timing for a
measurement can also be predefined, such that, for example, the
driving or controlling electronic unit can predefine a specific
time scheme for the light source and/or the detector, said time
scheme allowing a temporal sequence of the emission of the
interrogation light and the detection of the response light. By way
of example and not limitation, the driving electronic unit can be
designed to carry out or to control a temporally resolved
measurement of the skin sensor. In this case, a measurement
comprises the emissions of at least one interrogation light, more
particularly of at least one pulse of the interrogation light, and
the detection of at least one response light, more particularly of
at least one pulse of the response light. A temporally resolved
measurement can accordingly be understood to be a measurement in
which, in addition, a time of the detection of the response light
also plays a part or is registered. Thus, by way of example and not
limitation, for each value of the response light, it is also
possible to register the corresponding points in time at which this
value is recorded and/or it is possible for the response light only
to be recorded at specific points in time (gating). In this way, by
means of temporally resolved measurements, for example, it is
possible to obtain information about the rate in which an indicator
substance is eliminated from the body of a patient via the kidneys.
In some aspects, the detector is configured to detect the different
time points generated by the interaction of an indicator substance
with a light generated by the light source. In some aspects, the
controller and the driving or controlling electronic unit are the
same device. In some aspects, the driving and controlling
electronic unit is an integrated component in the controller. In
some aspects, the light source is modulated rather than pulsed, and
the detected signal is selectively amplified or digitally
demodulated to selectively detect signals at the frequency of the
source.
[0048] In some aspects, the two-piece sensor assembly further
comprises a cable management system configured to reduce or
eliminate accidental cord pulls that would dislodge or detach the
two-piece sensor assembly from the body of the patient and/or
reduce or eliminate accidental cord pulls that would dislodge or
detach the skin sensor from the attachment collar, said cable
management system is attached to the attachment collar, the skin
sensor or both.
[0049] In order to reduce possible light transmission through the
skin sensor and the attachment collar, in some aspects, one or both
are fabricated out of elastomeric materials. In some aspects, the
elastomer is mixed with graphite and/or carbon black and/or other
light-absorbing materials. In some aspects, an optically
non-transmissive material is included as a layer. In some aspects,
the optically non-transmissive material is mylar. Mylar is highly
absorptive of UV, visible and near infrared light while also being
thin and flexible. In another aspect, the optically
non-transmissive material is aluminum. Aluminum is also highly
absorptive of UV, visible and near infrared light while also being
thin and flexible. This reduces light transmission through the skin
sensor and/or attachment collar. In some aspects, both the skin
sensor and the attachment collar are fabricated from an elastomer
that is mixed with graphite, carbon black or a combination thereof.
A optically non-transmissive material is one that reduces or
eliminates the passage of light therethrough. In some aspects, the
passage of light is entirely eliminated. In some aspects, the
passage of light is reduced by about 99%, by about 98%, by about
97%, by about 96%, by about 95%, or by about 90%. About as used in
this context means .+-.1%. In some aspects, the attachment collar
is disposable.
[0050] In some aspects, the skin sensor and attachment collar are
designed to ameliorate the effects of accumulation of excess fluid
within the skin of the patient beneath the sensor, which could
otherwise have detrimental or undesirable effects on the sensor
measurements. In some aspects, where the rate of elimination of an
exogenous agent is being measured, variation over time in the
fractional volume of interstitial fluid within the measured tissue
volume may result in uncertainty and/or inaccuracy in the
transdermally measured elimination rate. Such may be the case when
the sensor is placed over an area that is locally edematous, or in
patients with whole-body excess fluid build-up ("fluid over-load")
such as is common in patients with, for example, compromised kidney
function or congestive heart failure. Such excess fluid may be
removed from the field of measurement by the application of light
pressure against the skin (e.g., 10-20 mm Hg), without
exsanguinating the skin or shifting the balance of more tightly
bound interstitial fluid. In some aspects, a positive pressure is
exerted on the surface of the skin directly beneath the skin
sensor, while simultaneously applying a negative pressure on the
surrounding skin surface, beneath which the attachment collar is
mounted. In some aspects, this is accomplished by first securely
mounting the attachment collar to the skin, then mounting the skin
sensor into the collar such that the sensor protrudes slightly
beyond the collar, thereby pressing more firmly against the skin
beneath the sensor, with a compensating negative pressure in the
area beneath the attachment collar.
[0051] In some aspects, a 2-sided adhesive is employed within an
aperture inside the attachment collar. The side facing the skin is
selected to adhere reliably to the skin for an extended period of
time (e.g., 24 to 48 hrs.), even in the presence of moisture, such
as sweat. In some aspects, an acrylate-based adhesive is used for
bonding to the skin. In yet another aspect, the skin is pre-treated
with a barrier film, such as by application of rapidly-drying
liquid film that upon drying forms a "second skin". In such aspects
the barrier film aids in the long-term, reliable attachment of the
acrylate-based adhesive to the skin, while also having the benefit
of allowing sensor removal without disruption or removal of the
skin epidermis. In some aspects, the barrier film is CAVILON.TM.
(manufactured by 3M). The second side of the adhesive, which faces
towards the sensor, may be selected to adhere as strongly as
desired to the face of the sensor. In one such aspect the sensor
face is constructed from a polymer material, such as MAKROLON.TM.,
and the adhesive is rubber based. One non-limiting example of an
appropriate 2-sided adhesive is 3M product #2477 (Double-Coated TPE
Silicone Acrylate Medical Tape with Premium Liner).
[0052] In some aspects, the adhesive bond formed between the
attachment collar and sensor is relatively weak or even
non-existent until the adhesive is placed under mild pressure. Such
embodiments have the additional benefit of forming a secure
interface between the sensor and the skin when the sensor is placed
under positive pressure against the skin, but once released, the
sensor is easily removed from the attachment collar without leaving
a residue on the sensor. In some aspects where the sensor is
reusable and the collar is disposable or single use, the sensor
portion never contacts the skin. If the sensor does not come into
direct contact with the skin of the patient, this reduces the
chance of contamination and reduces the cleaning and/or
sterilization needed before the sensor is reused on the same or a
different patient.
[0053] The above-described advantages for the sensor that applies a
small positive pressure over the skin area under measurement may be
combined with the also above-described aspect wherein a small
positive pressure is required to adhere the sensor to the
attachment collar. A nonlimiting example that illustrates these
advantages is shown in in FIG. 17. These same advantages and
features may also be incorporated into other embodiments
illustrated herein.
[0054] In some aspects, it is desirable that a method for reliably
or securely identifying or authenticating the attachment collar is
provided. In some aspects the collar includes an encrypted
identifier or identification tag that prevents the use on
non-approved devices. In some aspects the encryption code is
embedded in an EEPROM chip within the attachment collar. Use of the
sensor is prevented unless a connection is made between the sensor
and collar, and the collar is identified as being valid. In other
aspects, the EEPROM is used to identify a particular product
version, mode of operation, and/or algorithm coefficients for
instrument operation. In this manner, different functions of the
sensor may be enabled through the EEPROM coding.
[0055] In some aspects, the attachment collar further comprises a
pressure sensitive element that communicates with the sensor when
attached. In some aspects, the pressure sensor provides an
indication of secure attachment of the skin sensor to the skin of
the patient. In some aspects, the indication that the sensor is no
longer securely attached is used to discontinue measurement, and/or
to provide feedback to a user.
[0056] In some aspects, the attachment collar is intended for
single use and the pressure sensor is used to enforce this. In some
aspects, the pressure sensor determines that the attachment collar
has been placed on a patient, and then determines that it has been
subsequently removed. Any subsequent attempts to reuse the sensor
with the same attachment collar are prevented.
[0057] With reference to FIG. 1, the two-piece sensor comprises an
attachments collar 110 and a sensor 120. The cable is clipped into
a cable management system 130 to reduce cord pulls and provide
strain relief. Sidebars 140 secure sensor 120 to attachment collar
110, while pull tab 150 allows for easy removal of attachment
collar 110 from the skin of the patient after use.
[0058] With reference to FIG. 2, the two-piece sensor comprises an
attachment collar 210 and a sensor 220. Cable 230 is coupled to a
controller that can send and receive information therebetween. Also
shown and represented by the arrows is a selective adhesive 240
that secures sensor 220 to attachment collar 210.
[0059] With reference to FIG. 3, the two-piece sensor comprises an
attachment collar 310 and a sensor 320. Cable 330 is coupled to a
controller that can send and receive information therebetween. Also
shown is a bar code 340 that is used to authenticate the
combination of sensor 320 and attachment collar 310 thereby
ensuring that a light-tight fit and secure attachment to the
patient's body surface is achieved. Also shown is cable management
groove 350 to help reduce the opportunity for the cable to become
caught and dislodged from the patient.
[0060] With reference to FIG. 4, the two-piece sensor comprises an
attachment collar 410 and a sensor 420. Also shown is one possible
aspect of a light-tight connector 430 between sensor 420 and
attachment collar 410. The non-linear surfaces of light-tight
connector 430 reduces and/or eliminates extraneous light that may
leak through between the interface of sensor 420 and attachment
collar 410.
[0061] With reference to FIG. 5, the two-piece sensor comprises an
attachment collar 510 and a sensor 520. Also shown is one possible
cam locking mechanism 530 that would secure sensor 520 to
attachment collar 510. Sensor 520 would slidably connect tab 550 to
slot 540 and then twist to secure the sensor in place ensuring that
a secure attachment to the patient's body surface is achieved. This
locking mechanism would also be light-tight due to the nonlinear
aspect of the male and female ends of the lock.
[0062] With reference to FIG. 6, the two-piece sensor comprises an
attachment collar 610 and a sensor 620. Cable 630 is coupled to a
controller that can send and receive information therebetween. In
this aspect, tabs 640 fit into slots 650 thereby ensuring proper
alignment of sensor 620 with attachment collar 610 ensuring that a
secure attachment and light-tight fit to the patient's body is
achieved.
[0063] With reference to FIG. 7, the two-piece sensor comprises an
attachment collar 710 and a sensor 720. Cable 730 is coupled to a
controller that can send and receive information therebetween. In
this aspect, attachment collar 710 is a stretchable pocket that
includes an internal cavity 740 therein that receives sensor 720
ensuring a light-tight fit.
[0064] With reference to FIG. 8, the two-piece sensor comprises an
attachment collar 810 and a sensor 820. Cable 830 is coupled to a
controller that can send and receive information therebetween. In
this aspect, slot 840 could receive and secure cable 830 thereby
reducing the incidence of cord-pull by the patient. Also shown is
an RFID chip 850 that includes a security code that must be
detected 860 by the sensor in order for the system to operate. This
RFID code can be used for device security, for ensuring that a
secure attachment and light-tight fit to the patient's body is
achieved, and for inventory control.
[0065] With reference to FIG. 9, the two-piece sensor comprises an
attachment collar 910 and a sensor 920. Cable 930 is coupled to a
controller that can send and receive information therebetween. In
this aspect, slots 940 are present to ensure a proper connection
between sensor 920 and attachment collar 910. The shape of the
slots can be varied in the manner of a lock and key to ensure a
secure attachment and as a form of fraud prevention and quality
control.
[0066] With reference to FIG. 10, the two-piece sensor comprises an
attachment collar 1010 and a sensor 1020. Cable 1030 is coupled to
a controller that can send and receive information therebetween. In
this aspect, magnets 1040 are present to secure sensor 1020 to
attachment collar 1010.
[0067] With reference to FIG. 11, the two-piece sensor comprises an
attachment collar 1110 and a sensor 1120. Cable 1130 is coupled to
a controller that can send and receive information therebetween. In
this aspect, cable clip 1140 is on attachment collar 1110 to secure
cable 1130 to reduce or eliminate the incidence of cord-pull that
would interfere with the use of the system.
[0068] With reference to FIG. 12, the two-piece sensor comprises an
attachment collar 1210 and a sensor 1220. Attachment collar 1210
comprises an embedded chemical 1260 that is detected by sensor 1220
when properly placed to provide a secure connection. Cord 1230
seats into slot 1240 thereby reducing movement and play in the
cord. Also included is identifier tab 1250 that is used to
authenticate the attachment collar 1210 after detection by sensor
1220.
[0069] With reference to FIG. 13, the two-piece sensor comprises an
attachment collar 1310 and a sensor 1320. Cable 1330 is coupled to
a controller that can send and receive information therebetween. In
this aspect, sensor 1320 screws into attachment collar 1310 to
provide a secure connection and light-tight interface between
them.
[0070] With reference to FIG. 14, the two-piece sensor comprises an
attachment collar 1410 and a sensor 1420. Cable 1430 is coupled to
a controller that can send and receive information therebetween. In
this aspect, tab 1440 fits into slot 1450 to secure sensor 1420 to
attachment collar 1410. Cable 1430 fits into cable clip 1460 to
secure the cable and reduce or eliminate the incidence of cord-pull
that would interfere with the use of the system.
[0071] With reference to FIG. 15, the two-piece sensor comprises an
attachment collar 1510 and a sensor 1520. Cable 1530 is coupled to
a controller that can send and receive information therebetween. In
this aspect, tabs 1540 fit through slots 1550 on sensor 1520 and
fold over 1560 to secure sensor 1520 to attachment collar 1510
ensuring that a secure attachment and light-tight fit to the
patient's body is achieved.
[0072] With reference to FIG. 16, the two-piece sensor comprises an
attachment collar 1610 and a sensor 1620. The cable (not shown) is
coupled to a controller that can send and receive information
therebetween. In this aspect, tabs 1630 would insert into holes
1640 thereby ensuring a secure connection between sensor 1620 and
attachment collar 1610. Holes 1640 could also be communication
ports to send and receive information between sensor 1620 and
attachment collar 1610 for both security and inventory purposes.
This would eliminate the need for a wireless authentication thereby
reducing the complexity and electronic components required in the
overall system. In some aspects, communication between sensor 1620
and attachment collar 1610 is via an EPROM type memory ensuring
that a secure attachment and light-tight fit to the patient's body
is achieved.
[0073] With reference to FIG. 17, the two-piece sensor comprises an
attachment collar 1710 and a sensor 1720. Cable 1730 is coupled to
a controller that can send and receive information therebetween. In
this aspect, a cam-lock 1740 secures sensor 1720 to attachment
collar 1710 after engaging locking arm 1750. Simultaneously, when
locking arm 1750 is engaged to secure sensor 1720, it also secures
cable 1730 in a secure configuration 1760 ensuring that a secure
attachment and light-tight fit to the patient's body is
achieved.
[0074] With reference to FIG. 18, the two-piece sensor comprises an
attachment collar 1810 and a sensor 1820. Cable 1830 is coupled to
a controller that can send and receive information therebetween.
Sensor 1820 is securely attached to attachment color 1810 via a
strap 1840 that engages with tab 1850. Engagement 1860, in some
aspects, can be using Velcro, an adhesive, snap, buckle or other
appropriate means ensuring that a secure attachment and light-tight
fit to the patient's body is achieved.
[0075] With reference to FIG. 19, the two-piece sensor comprises an
attachment collar 1910 and a sensor 1920. The cable includes a
cable management clip 1930 to secure the cord and reduce cord pulls
and provide strain relief. Side clips 1940 secure sensor 1920 to
attachment collar 1910 while pull tab 1950 allows for easy removal
from the skin of a patient after use.
[0076] With reference to FIG. 20, the triangular shaped two-piece
sensor comprises an attachment collar 2010 and a sensor 2020. Cable
2040 clips into cable management system 2030 to reduce cord pulls
and provide strain relief. Pull table 2050 allows for easy removal
from the skin of a patient after use.
[0077] With reference to FIG. 21, the two-piece sensor comprises an
attachment collar 2110 and a sensor 2120. Cable 2130 wraps around
skin sensor 2020 and clips into cable management system 2140 to
reduce cord pulls and provide strain relief. Pull table 2150 allows
for easy removal from the skin of a patient after use.
[0078] With reference to FIG. 22, the two-piece sensor comprises an
attachment collar 2210 and a sensor 2220. Sensor 2220 slides under
side table 2250 on the attachment collar 2210 to secure the sensor
in place. Cable 2230 clips into cable management system 2240 to
reduce cord pulls and provide strain relief. Pull table 2150 allows
for easy removal from the skin of a patient after use.
[0079] In some aspects the attachment collar further comprises a
means for securing the skin sensor to the at least one opening of
the attachment collar as illustrated in FIGS. 1 to 22. In some
aspects, the two-piece sensor assembly further comprises a means
for managing a cable attached thereto as illustrated in FIGS. 1 to
22. In some aspects, the means for managing the cable is attached
to the attachment collar, the skin sensor or both as illustrated in
FIGS. 1 to 22. In some aspects, the skin sensor and/or the
attachment collar further comprises a means of authentication
between the skin sensor and the attachment collar as described
elsewhere herein.
[0080] Indicator Substances
[0081] Suitable indicator substances for use with the methods and
devices described herein are disclosed in U.S. 62/577,951, U.S.
Pat. Nos. 8,155,000, 8,664,392, 8,697,033, 8,722,685, 8,778,309,
9,005,581, 9,114,160, 9,283,288, 9,376,399, and 9,480,687 which are
all incorporated by reference in their entirety for all purposes.
In some aspects, the indicator substance is eliminated from the
body of a patient by glomerular filtration. In some aspects, the
indicator substance is eliminated from the body of a patient only
by glomerular filtration. In some aspects, the indicator substance
is a GFR agent.
[0082] In some aspects, the indicator substance is a pyrazine
derivative of Formula I, or a pharmaceutically acceptable salt
thereof,
##STR00001##
wherein each of X.sup.1 and X.sup.2 is independently selected from
the group consisting of --CN, --CO.sub.2R.sup.1,
--CONR.sup.1R.sup.2, --CO(AA), --CO(PS) and --CONH(PS); each of
Y.sup.1 and Y.sup.2 is independently selected from the group
consisting of --NR.sup.1R.sup.2 and
##STR00002##
Z.sup.1 is a single bond, --CR.sup.1R.sup.2--, --O--, --NR.sup.1--,
--NCOR.sup.1--, --S--, --SO--, or --SO.sub.2--; each of R.sup.1 to
R.sup.2 are independently selected from the group consisting of H,
--CH.sub.2(CHOH).sub.aH, --CH.sub.2(CHOH).sub.aCH.sub.3,
--CH.sub.2(CHOH).sub.aCO.sub.2H, --(CHCO.sub.2H).sub.aCO.sub.2H,
--(CH.sub.2CH.sub.2O).sub.cH, --(CH.sub.2CH.sub.2O).sub.cCH.sub.3,
--(CH.sub.2).sub.aSO.sub.3H, --(CH.sub.2).sub.aSO.sub.3.sup.-,
(CH.sub.2).sub.aSO.sub.2H, --(CH.sub.2).sub.aSO.sub.2.sup.-,
--(CH.sub.2).sub.aNHSO.sub.3H, --(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--(CH.sub.2).sub.aNHSO.sub.2H, --(CH.sub.2).sub.aNHSO.sub.2.sup.-,
--(CH.sub.2).sub.aPO.sub.4H.sub.3,
--(CH.sub.2).sub.aPO.sub.4H.sub.2.sup.-,
--(CH.sub.2).sub.aPO.sub.4H.sup.2-,
--(CH.sub.2).sub.aPO.sub.4.sup.3-,
--(CH.sub.2).sub.aPO.sub.3H.sub.2,
--(CH.sub.2).sub.aPO.sub.3H.sup.-, and
--(CH.sub.2).sub.aPO.sub.3.sup.2-; (AA) comprises one or more amino
acids selected from the group consisting of natural and unnatural
amino acids, linked together by peptide or amide bonds and each
instance of (AA) may be the same or different than each other
instance; (PS) is a sulfated or non-sulfated polysaccharide chain
that includes one or more monosaccharide units connected by
glycosidic linkages; and `a` is a number from 0 to 10, `c` is a
number from 1 to 100, and each of `m` and `n` are independently a
number from 1 to 3. In another aspect, `a` is a number from 1 to
10. In still yet another aspect, `a` is 0, 1, 2, 3, 4, 5, 6, 7, 8,
9 or 10.
[0083] (AA) comprises one or more natural or unnatural amino acids
linked together by peptide or amide bonds. The peptide chain (AA)
may be a single amino acid, a homopolypeptide chain or a
heteropolypeptide chain, and may be any appropriate length. In some
embodiments, the natural or unnatural amino acid is an a-amino
acid. In yet another aspect, the a-amino acid is a D-.alpha.-amino
acid or an L-.alpha.-amino acid. In a polypeptide chain that
includes two or more amino acids, each amino acid is selected
independently of the other(s) in all aspects, including, but not
limited to, the structure of the side chain and the
stereochemistry. For example, in some embodiments, the peptide
chain may include 1 to 100 amino acid(s), 1 to 90 amino acid(s), 1
to 80 amino acid(s), 1 to 70 amino acid(s), 1 to 60 amino acid(s),
1 to 50 amino acid(s), 1 to 40 amino acid(s), 1 to 30 amino
acid(s), 1 to 20 amino acid(s), or even 1 to 10 amino acid(s). In
some embodiments, the peptide chain may include 1 to 100
.alpha.-amino acid(s), 1 to 90 .alpha.-amino acid(s), 1 to 80
.alpha.-amino acid(s), 1 to 70 .alpha.-amino acid(s), 1 to 60
.alpha.-amino acid(s), 1 to 50 .alpha.-amino acid(s), 1 to 40
.alpha.-amino acid(s), 1 to 30 .alpha.-amino acid(s), 1 to 20
.alpha.-amino acid(s), or even 1 to 10 .alpha.-amino acid(s). In
some embodiments, the amino acid is selected from the group
consisting of D-alanine, D-arginine D-asparagine, D-aspartic acid,
D-cysteine, D-glutamic acid, D-glutamine, glycine, D-histidine,
D-homoserine, D-isoleucine, D-leucine, D-lysine, D-methionine,
D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan,
D-tyrosine, and D-valine. In some embodiments, the a-amino acids of
the peptide chain (AA) are selected from the group consisting of
arginine, asparagine, aspartic acid, glutamic acid, glutamine,
histidine, homoserine, lysine, and serine. In some embodiments, the
a-amino acids of the peptide chain (AA) are selected from the group
consisting of aspartic acid, glutamic acid, homoserine and serine.
In some embodiments, the peptide chain (AA) refers to a single
amino acid (e.g., D-aspartic acid or D-serine).
[0084] (PS) is a sulfated or non-sulfated polysaccharide chain
including one or more monosaccharide units connected by glycosidic
linkages. The polysaccharide chain (PS) may be any appropriate
length. For instance, in some embodiments, the polysaccharide chain
may include 1 to 100 monosaccharide unit(s), 1 to 90 monosaccharide
unit(s), 1 to 80 monosaccharide unit(s), 1 to 70 monosaccharide
unit(s), 1 to 60 monosaccharide unit(s), 1 to 50 monosaccharide
unit(s), 1 to 40 monosaccharide unit(s), 1 to 30 monosaccharide
unit(s), 1 to 20 monosaccharide unit(s), or even 1 to 10
monosaccharide unit(s). In some embodiments, the polysaccharide
chain (PS) is a homopolysaccharide chain consisting of either
pentose or hexose monosaccharide units. In other embodiments, the
polysaccharide chain (PS) is a heteropolysaccharide chain
consisting of one or both pentose and hexose monosaccharide units.
In some embodiments, the monosaccharide units of the polysaccharide
chain (PS) are selected from the group consisting of glucose,
fructose, mannose, xylose and ribose. In some embodiments, the
polysaccharide chain (PS) refers to a single monosaccharide unit
(e.g., either glucose or fructose). In yet another aspect, the
polysaccharide chain is an amino sugar where one or more of the
hydroxy groups on the sugar has been replaced by an amine group.
The connection to the carbonyl group can be either through the
amine or a hydroxy group.
[0085] Specific examples of indicator substances include, but are
not limited to,
3,6-diamino-N.sup.2,N.sup.2,N.sup.5,N.sup.5-tetrakis(2-methoxyethyl)pyraz-
ine-2,5-dicarboxamide,
3,6-diamino-N.sup.2,N.sup.5-bis(2,3-dihydroxypropyl)pyrazine-2,5-dicarbox-
amide,
(2S,2'S)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))b-
is(3-hydroxypropanoic acid),
3,6-bis(bis(2-methoxyethyl)amino)-N.sup.2,N.sup.2,N.sup.5,N.sup.5-tetraki-
s(2-methoxyethyl) pyrazine-2,5-dicarboxamide bis(TFA) salt,
3,6-diamino-N.sup.2,N.sup.5-bis(2-aminoethyl)pyrazine-2,5-dicarboxamide
bis(TFA) salt, 3,6-diamino-N.sup.2,N.sup.5-bis
(D-aspartate)-pyrazine-2,5-dicarboxamide,
3,6-diamino-N.sup.2,N.sup.5-bis(14-oxo-2,5,8,11-tetraoxa-15-azaheptadecan-
-17-yl)pyrazine-2,5-dicarboxamide,
3,6-diamino-N.sup.2,N.sup.5-bis(26-oxo-2,5,8,11,14,17,20,23-octaoxa-27-az-
anonacosan-29-yl)pyrazine-2,5-dicarboxamide,
3,6-diamino-N.sup.2,N.sup.5-bis(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-d-
odecaoxa-39-azahentetracontan-41-yl)pyrazine-2,5-dicarboxamide,
bis(2-(PEG-5000)ethyl) 6-(2-(3,6-diamino-5-(2-aminoethylcarbamoyl)
pyrazine-2-carboxamido)ethylamino)-6-oxohexane-1,5-diyldicarbamate,
(R)-2-(6-(bis(2-methoxyethyl)amino)-5-cyano-3-morpholinopyrazine-2-carbox-
amido)succinic acid,
(2R,2'R)-2,2'4(3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hy-
droxypropanoic acid),
(2S,2'S)-2,2'43,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hyd-
roxypropanoic acid),
(2R,2'R)-2,2'43,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))
dipropionic acid,
3,3'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))dipropionic
acid,
2,2'4(3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))diacetic
acid,
(2S,2'S)-2,2'4(3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))
dipropionic acid,
2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(2-methylprop-
anoic acid), and
3,6-diamino-N.sup.2,N.sup.5-bis((1R,2S,3R,4R)-1,2,3,4,5-pentahydroxypenty-
l) pyrazine-2,5-dicarboxamide. In some aspects, the indicator
substance is
(2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-h-
ydroxypropanoic acid) (also known as MB-102). In some aspects, the
indicator substance is
(2S,2'S)-2,2'4(3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hy-
droxypropanoic acid).
[0086] In some aspects, the indicator substance is
(2R,2'R)-2,2'-((3,6-diamino-pyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3--
hydroxypropanoic acid) (also known as MB-102 or
##STR00003##
or a pharmaceutically acceptable salt thereof.
[0087] In some aspects, the indicator substance is
(2S,2'S)-2,2'-((3,6-diamino-pyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3--
hydroxypropanoic acid) (also known as
3,6-diamino-N2,N5-bis(L-serine)-pyrazine-2,5-dicarboxamide),
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0088] In still yet another aspect, the indicator substance is
selected from the group consisting of acridines, acridones,
anthracenes, anthracylines, anthraquinones, azaazulenes, azo
azulenes, benzenes, benzimidazoles, benzofurans,
benzoindocarbocyanines, benzoindoles, benzothiophenes, carbazoles,
coumarins, cyanines, dibenzofurans, dibenzothiophenes, dipyrrolo
dyes, flavones, imidazoles, indocarbocyanines, indocyanines,
indoles, isoindoles, isoquinolines, naphthacenediones,
naphthalenes, naphthoquinones, phenanthrenes, phenanthridines,
phenanthridines, phenoselenazines, phenothiazines, phenoxazines,
phenylxanthenes, polyfluorobenzenes, purines, pyrazines, pyrazoles,
pyridines, pyrimidones, pyrroles, quinolines, quinolones,
rhodamines, squaraines, tetracenes, thiophenes, triphenyl methane
dyes, xanthenes, xanthones, and derivatives thereof. In still yet
another aspect, the indicator substance is any compound that is
eliminated from the body of a patient by glomerular filtration. In
still yet another aspect, the indicator substance is any compound
that emits fluorescent energy when exposed to electromagnetic
radiation and is eliminated from the body of the patient by
glomerular filtration.
[0089] In any aspect of the indicator substance, one or more atoms
may alternatively be substituted with an isotopically labelled atom
of the same element. For example, a hydrogen atom may be
isotopically labelled with deuterium or tritium; a carbon atom may
be isotopically labelled with .sup.13C or .sup.14C; a nitrogen atom
may be isotopically labelled with .sup.14N or .sup.15N. An isotopic
label may be a stable isotope or may be an unstable isotope (i.e.,
radioactive). The indicator substance may contain one or more
isotopic labels. The isotopic label may be partial or complete. For
example, an indicator substance may be labeled with 50% deuterium
thereby giving the molecule a signature that can be readily
monitored by mass spectroscopy or other technique. As another
example, the indicator substance may be labeled with tritium
thereby giving the molecule a radioactive signature that can be
monitored both in vivo and ex vivo using techniques known in the
art.
[0090] Pharmaceutically acceptable salts are known in the art. In
any aspect herein, the indicator substance may be in the form of a
pharmaceutically acceptable salt. By way of example and not
limitation, pharmaceutically acceptable salts include those as
described by Berge, et al. in J. Pharm. Sci., 66(1), 1 (1977),
which is incorporated by reference in its entirety for all
purposes. The salt may be cationic or anionic. In some embodiments,
the counter ion for the pharmaceutically acceptable salt is
selected from the group consisting of acetate, benzenesulfonate,
benzoate, besylate, bicarbonate, bitartrate, bromide, calcium
edetate, camsylate, carbonate, chloride, citrate, dihydrochloride,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isethionate, lactate, lactobionate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, pamoate, pantothenate, phosphate,
diphosphate, polygalacturonate, salicylate, stearate, subacetate,
succinate, sulfate, tannate, tartrate, teoclate, triethiodide,
adipate, alginate, aminosalicylate, anhydromethylenecitrate,
arecoline, aspartate, bisulfate, butylbromide, camphorate,
digluconate, dihydrobromide, disuccinate, glycerophosphate,
jemisulfate, judrofluoride, judroiodide, methylenebis(salicylate),
napadisylate, oxalate, pectinate, persulfate,
phenylethylbarbarbiturate, picrate, propionate, thiocyanate,
tosylate, undecanoate, benzathine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, procaine, benethamine,
clemizole, diethylamine, piperazine, tromethamine, aluminum,
calcium, lithium, magnesium, potassium, sodium zinc, barium and
bismuth. Any functional group in the indicator substance capable of
forming a salt may optionally form one using methods known in the
art. By way of example and not limitation, amine hydrochloride
salts may be formed by the addition of hydrochloric acid to the
indicator substance. Phosphate salts may be formed by the addition
of a phosphate buffer to the indicator substance. Any acid
functionality present, such as a sulfonic acid, a carboxylic acid,
or a phosphonic acid, may be deprotonated with a suitable base and
a salt formed. Alternatively, an amine group may be protonated with
an appropriate acid to form the amine salt. The salt form may be
singly charged, doubly charged or even triply charged, and when
more than one counter ion is present, each counter ion may be the
same or different than each of the others.
[0091] In still yet another aspect, disclosed herein is a method
for determining a glomerular filtration rate (GFR) in a patient in
need thereof. The method generally comprises: applying a two-piece
sensor assembly onto the body surface of the patient, administering
into the body of the patient an indicator substance, said indicator
substance configured to generate an optical response in response to
an interrogation light; detecting said optical response using the
two-piece sensor assembly over a predetermined period of time; and
determining the GFR in said patient based on the detected optical
response.
[0092] In some aspects of the method for determining the GFR in a
patient, the two piece-sensor assembly is as described elsewhere
herein. In some aspects of the method for determining the GFR in a
patient, the indicator substance is as described elsewhere herein.
In some aspects of the method for determining the GFR in a patient,
the indicator substance is
(2R,2'R)-2,2'-((3,6-diamino-pyrazine-2,5-dicarbonyl)bis-(azanediyl))bis(3-
-hydroxypropanoic acid) (also known as MB-102 or
3,6-diamino-N2,N5-bis(D-serine)-pyrazine-2,5-dicarboxamide),
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0093] This written description uses examples to disclose the
subject matter herein, including the best mode, and also to enable
any person skilled in the art to practice the subject matter
disclosed herein, including making and using any devices or systems
and performing any incorporated methods. The patentable scope of
the disclosure is defined by the claims, and may include other
examples that occur to those skilled in the art. Such other
examples are intended to be within the scope of the claims if they
have structural elements that do not differ from the literal
language of the claims, or if they include equivalent structural
elements with insubstantial differences from the literal languages
of the claims.
* * * * *