Patent Application
20220153708
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.
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.
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.
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.
Examples of exogenous substances capable of clearing the kidney exclusively via glomerular filtration (hereinafter referred to as “GFR agents”) include creatinine, o-iodohippuran, and 99mTc-DTPA. Examples of exogenous substances that are capable of undergoing renal clearance via tubular secretion include 99mTc-MAG3 and other substances known in the art. 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, 99mTc-DTPA and 99mTc-MAG3, is that they are radioisotopes and therefore require special handling techniques and are associated with risks to patient health.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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™ (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™, 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).
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.
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
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.
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.
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.
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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
Indicator Substances
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.
In some aspects, the indicator substance is a pyrazine derivative of Formula I, or a pharmaceutically acceptable salt thereof,
wherein each of X1 and X2 is independently selected from the group consisting of —CN, —CO2R1, —CONR1R2, —CO(AA), —CO(PS) and —CONH(PS); each of Y1 and Y2 is independently selected from the group consisting of —NR1R2 and
Z1 is a single bond, —CR1R2—, —O—, —NR1—, —NCOR1—, —S—, —SO—, or —SO2—; each of R1 to R2 are independently selected from the group consisting of H, —CH2(CHOH)aH, —CH2(CHOH)aCH3, —CH2(CHOH)aCO2H, —(CHCO2H)aCO2H, —(CH2CH2O)cH, —(CH2CH2O)cCH3, —(CH2)aSO3H, —(CH2)aSO3−, (CH2)aSO2H, —(CH2)aSO2−, —(CH2)aNHSO3H, —(CH2)aNHSO3−, —(CH2)aNHSO2H, —(CH2)aNHSO2−, —(CH2)aPO4H3, —(CH2)aPO4H2−, —(CH2)aPO4H2−, —(CH2)aPO43−, —(CH2)aPO3H2, —(CH2)aPO3H−, and —(CH2)aPO32−; (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.
(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-α-amino acid or an L-α-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 α-amino acid(s), 1 to 90 α-amino acid(s), 1 to 80 α-amino acid(s), 1 to 70 α-amino acid(s), 1 to 60 α-amino acid(s), 1 to 50 α-amino acid(s), 1 to 40 α-amino acid(s), 1 to 30 α-amino acid(s), 1 to 20 α-amino acid(s), or even 1 to 10 α-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).
(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.
Specific examples of indicator substances include, but are not limited to, 3,6-diamino-N2,N2,N5,N5-tetrakis(2-methoxyethyl)pyrazine-2,5-dicarboxamide, 3,6-diamino-N2,N5-bis(2,3-dihydroxypropyl)pyrazine-2,5-dicarboxamide, (2S,2′S)-2,2′-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hydroxypropanoic acid), 3,6-bis(bis(2-methoxyethyl)amino)-N2,N2,N5,N5-tetrakis(2-methoxyethyl) pyrazine-2,5-dicarboxamide bis(TFA) salt, 3,6-diamino-N2,N5-bis(2-aminoethyl)pyrazine-2,5-dicarboxamide bis(TFA) salt, 3,6-diamino-N2,N5-bis (D-aspartate)-pyrazine-2,5-dicarboxamide, 3,6-diamino-N2,N5-bis(14-oxo-2,5,8,11-tetraoxa-15-azaheptadecan-17-yl)pyrazine-2,5-dicarboxamide, 3,6-diamino-N2,N5-bis(26-oxo-2,5,8,11,14,17,20,23-octaoxa-27-azanonacosan-29-yl)pyrazine-2,5-dicarboxamide, 3,6-diamino-N2,N5-bis(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-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-carboxamido)succinic acid, (2R,2′R)-2,2′4(3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hydroxypropanoic acid), (2S,2′S)-2,2′43,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hydroxypropanoic 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-methylpropanoic acid), and 3,6-diamino-N2,N5-bis((1R,2S,3R,4R)-1,2,3,4,5-pentahydroxypentyl) 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-hydroxypropanoic 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-hydroxypropanoic acid).
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
or a pharmaceutically acceptable salt thereof.
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),
or a pharmaceutically acceptable salt thereof.
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.
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 13C or 14C; a nitrogen atom may be isotopically labelled with 14N or 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.
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.
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.
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),
or a pharmaceutically acceptable salt thereof.
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.
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.
| Number | Date | Country | |
|---|---|---|---|
| 62793000 | Jan 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16552539 | Aug 2019 | US |
| Child | 17650184 | US |
