JP2017151063A - Metabolism state estimation method based on skin gas measurement - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for estimating the metabolism state of a specific material in a subject accurately and conveniently.SOLUTION: The problem is solved by a method for estimating the metabolism state of a specific material in a subject on the basis of skin gas measurement, a method for determining the dosage of an agent on the basis of the estimated metabolism state, and devices that can be used for these methods and the like.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method for estimating a metabolic state based on skin gas measurement, a method for determining a dose of a drug based on the estimated metabolic state, a biomarker for estimating a metabolic state comprising skin gas, and these methods and bio The present invention relates to a device suitable for use of a marker.

  Diabetes is a disease whose diagnostic criterion is that the blood glucose level exceeds a certain reference value. Diabetes is mainly classified into type 1 diabetes, which is mainly caused by the death of β-cells, which are insulin-secreting cells, and type 2 diabetes, which is mainly caused by increased insulin resistance and decreased insulin secretory capacity. Separated. According to a study by the International Diabetes Federation, the diabetes population in 2013 was 382 million worldwide, and the number of patients continues to increase. In order to treat and / or prevent diabetes and diabetic complications, it is important to accurately measure a metabolic state such as a blood glucose level as an index of the degree of the disease, and to administer a drug accordingly.

  Blood glucose measurement devices include a blood collection type called Self Monitoring of Blood Glucose (SMBG) that measures blood glucose levels from blood, and continuous blood glucose measurement (CGMS: Continuous blood glucose measurement from interstitial fluid) There is an interstitial fluid type called Glucose Monitoring. In the measurement by blood collection type, it is not only necessary to collect blood for each measurement and change the blood collection site, but it is limited to at most 7 times (before and after each meal and before going to bed), There is a problem that continuous measurement is difficult. On the other hand, continuous measurement is possible with interstitial fluid type measurement, but puncture with strong pain is required when wearing in the body, and rash and discomfort occur with puncture, and regularly puncture site The burden on patients is large. Furthermore, the interstitial fluid type also has a problem that it can measure only 6 days at the longest.

  As an alternative to blood sampling and interstitial fluid types, blood glucose levels can be estimated based on exhaled gas from type 1 and type 2 diabetics and healthy individuals. It has been reported (Non-Patent Documents 1 to 3). However, exhalation tends to cause problems in accuracy due to the influence of food and the like, and always attaching sensors to the face such as the nose and mouth for continuous monitoring has great resistance to the patient. Furthermore, it is a heavy burden on the patient to consciously measure exhaled gas at regular intervals.

  In order to treat and / or prevent diabetes and diabetic complications, it is important to adjust the drug concentration in the subject to the optimal range in addition to the blood glucose level. The method of measuring is not known so far.

Turner C. et al., J. Breath Res., 2009, 3 (4), 046004 Novak B.J. et al., Proc. Natl. Acad. Sci. USA, 2007, 104 (40), pp. 15613-15618 Righettoni M. et al., J. Breath Res., 2013, 7 (3), 037110

  The present invention provides a method for estimating the metabolic state of a specific substance in a subject in a noninvasive, highly accurate and simple manner, and a method for determining a dose of a drug or the like according to the estimated metabolic state, etc. Let it be an issue.

  Based on the fact that specific skin gas from a subject correlates with the blood glucose level of the subject or blood insulin concentration after administration, and based on the concentration of skin gas, the subject's blood glucose and insulin It was found that the metabolic state such as can be estimated. In addition, the present inventor has developed a method for determining the dose of a drug according to the estimated metabolic state, and has completed the present invention based on these findings.

Accordingly, the present invention includes the following aspects.
(1) collecting one or more skin gases from the subject;
A method for estimating a blood glucose level in a subject, comprising: measuring a concentration of one or more collected skin gases; and estimating a blood glucose level of the subject based on the measured skin gas concentration.
(2) The method according to (1), further comprising a step of concentrating the skin gas before measuring the concentration of the one or more skin gases.
(3) The estimation of the blood glucose level is based on a formula obtained in advance by regression analysis or principal component analysis of the concentration of the one or more skin gases derived from the reference body and the blood glucose level of the reference body (1) or (2 ) Method.
(4) The skin gas is nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol The method in any one of (1)-(3) containing 1 or more selected from the group which consists of cyanocyclohexene and octanal.
(5) The method according to (4), wherein the skin gas includes two or more selected from the group in which acetone is further added to the group.
(6) The method according to any one of (1) to (5), wherein the concentration is measured over time.
(7) collecting one or more skin gases from the subject;
A method for estimating insulin concentration in a subject, comprising: measuring a concentration of one or more collected skin gases; and estimating an insulin concentration in the subject based on the measured skin gas concentration.
(8) The estimation of the insulin concentration is based on a formula obtained in advance by regression analysis or principal component analysis of the concentration of the one or more skin gases derived from the reference body and the insulin concentration in the reference body, according to (7) Method.
(9) The method according to (7) or (8), wherein the skin gas contains acetone and / or hexanal.
(10) The method according to any one of (7) to (9), wherein the concentration is measured over time.
(11) collecting one or more skin gases from the subject;
Measuring the concentration of one or more collected skin gases;
Estimating a metabolic state of a specific substance in a subject based on the measured skin gas concentration, and determining a dose of the drug according to the estimated metabolic state of the specific substance;
A method for determining a dosage of a drug, comprising:
(12) The method according to (11), wherein the specific substance is an endogenous substance of the subject or a substance administered to the subject.
(13) collecting one or more skin gases from the subject;
Measuring the concentration of one or more collected skin gases;
Estimating the metabolic state of the endogenous substance of the subject based on the measured concentration of skin gas,
Estimating the metabolic state of the substance administered to the subject based on the measured skin gas concentration, and the estimated metabolic state of the endogenous substance of the subject and metabolic state of the substance administered to the subject Determining the dose of the drug according to
A method for determining a dosage of a drug, comprising:
(14) The method according to any one of (11) to (13), wherein the concentration is measured over time.
(15) Nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene, and A biomarker for estimating blood glucose level, comprising any one gas selected from the group consisting of octanal.
(16) Acetone, nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene And a biomarker for estimating a blood glucose level, comprising two or more gases selected from the group consisting of octanal.
(17) A biomarker for estimating insulin concentration, which is a gas composed of acetone and / or hexanal.
(18) Collection means for collecting one or more skin gases derived from a subject,
A specific substance in a subject, including a measuring means for measuring the concentration of one or more collected skin gases, and a calculating means for estimating a metabolic state of the specific substance in the subject based on the measured skin gas concentration Estimated unit of metabolic state.
(19) The unit according to (18), wherein the specific substance is an endogenous substance of a subject.
(20) The unit according to (18), wherein the specific substance is a substance administered to a subject.
(21) A mechanism for determining a dose of a drug, comprising: the unit according to (18); and a determination unit that determines the dose of the drug based on information on the estimated metabolic state of the specific substance in the subject.
(22) The unit according to (19),
A determination means for determining a dose of the drug based on the unit according to (20) and the estimated metabolic state of the endogenous substance of the subject and the metabolic state of the substance administered to the subject; Including a mechanism for determining the dose of a drug.
(23) A mechanism for determining a dose of the drug according to (21) or (22),
An automatic drug administration device comprising: a drug storage unit that stores a drug; and an administration unit that administers a drug stored in the drug storage unit to a subject based on the dose of the drug determined by the determination unit.
(24) Concentration measurement is performed over time, the unit according to any one of (18) to (20), the drug dose determination mechanism according to (21) or (22), or (23) The automatic drug delivery device described.

  According to the present invention, the metabolic state of a specific substance in a subject can be estimated with high accuracy and ease. In addition, since the method of the present invention is non-invasive, it places little burden on the subject, and it is easy to measure the metabolic state of a specific substance over time.

FIG. 1 shows the transition of the measured glucose value during the oral glucose tolerance test in rats and the estimated glucose value based on the concentrations of acetone and ethanol released from the skin. Each graph shows the individuals that showed the highest multiple correlation coefficient (No. 1 (A) and No. 11 (C)) in the control group and the obese group, and the individuals that showed the lowest multiple correlation coefficient. The results in (No. 8 (B) and No. 14 (D)) are shown. FIG. 2 shows the relationship between the estimated value of insulin concentration based on multiple regression analysis of acetone and hexanal in rats and the actual measured value of insulin concentration. The horizontal axis represents the measured value (mg / dl) of the insulin concentration, and the vertical axis represents the estimated value (mg / dl) of the insulin concentration. FIG. 3 shows a correlation between an estimated value of blood glucose level based on the skin gas concentration in humans and an actual measured value of glucose using blood. The horizontal axis represents the estimated value from skin gas, and the vertical axis represents the actual measurement value. FIG. 4 shows a correlation between an estimated value of blood glucose level based on skin gas concentration and an actual measured value of glucose using blood after glucose loading in humans. The vertical axis represents the blood glucose level, and the horizontal axis represents the elapsed time after the sugar load. FIG. 5 shows a correlation between an estimated value of blood sugar level based on the concentration of skin gas in humans and an actual measured value of glucose using blood. Correlation was obtained from the data of three persons, an estimated value was calculated from the skin gas concentration based on the correlation, and the relationship with the actual blood glucose level was examined. The horizontal axis represents the estimated value from skin gas, and the vertical axis represents the actual measurement value. FIG. 6 is a diagram showing a correlation between an estimated value obtained by principal component analysis of intensity and blood glucose level for each m / e obtained by GC / MS of human skin gas and an actual measured value of blood glucose level. is there. The horizontal axis represents actual measurement values, and the vertical axis represents estimated values. FIG. 7 shows the contribution of each m / e obtained by GC / MS of skin gas in humans to the blood glucose level. The horizontal axis shows variables (can be converted to actual m / e values by +50), and the vertical axis shows regression coefficients.

<Method for estimating the metabolic state of a specific substance in a subject>
In one aspect, the present invention relates to a method for estimating the metabolic state of a particular substance in a subject.

  As used herein, “subject” refers to an individual subjected to the method of the present invention. The species of the subject is not limited, but mammals, for example, primates such as humans and chimpanzees, laboratory animals such as rats and mice, and livestock animals such as pigs, cows, horses, sheep, and goats. And pets such as dogs and cats, preferably humans.

  In the present specification, the “specific substance” refers to a substance for estimating a metabolic state in a subject in the method of the present invention, and the kind thereof is not particularly limited. The “specific substance” may be an endogenous substance produced in the subject without external administration or a substance administered externally to the subject.

  In the present specification, examples of endogenous substances include sugars, lipids, proteins, reactive oxygen species, antioxidant substances, and intestinal flora.

  As used herein, examples of a substance administered to a subject include a drug administered to the subject, and the concentration of the drug administered to the subject in the subject, for example, blood or plasma, according to the method of the present invention. The concentration can be estimated.

  The type of drug can be selected according to the type of target disease. For example, insulin and insulin derivatives; sulfonylureas such as glyburide, glimepiride, chlorpropamide, and tolbutamide; alpha-glucosidase inhibitors such as acarbose ), Miglitol, and voglibose; and biguanides such as metformin and phenformin. Similarly, as dyslipidemic agents, statins such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; fibrates such as fenofibrate, fenofibric acid, bezafibrate or gemfibrozil; and nicotine Acid derivatives such as niceritrol and collexamine are mentioned. Similarly, examples of hepatitis drugs include ursodeoxycholic acid, glycyrrhizin, aldactone, and lactulose.

  As used herein, “metabolic state” refers to a state such as the presence / absence, concentration, type, and extent of a specific substance in a subject.

  Examples of the metabolic state of the endogenous substance include, for example, blood glucose level, lipid concentration, LDL cholesterol concentration, protein concentration, degree of oxidative stress, and changes in these metabolic states with aging, preferably blood glucose level. In addition, since the intestinal flora also affects the metabolic state of the host, the state of the intestinal flora can also be included in the definition of the “metabolic state of endogenous substances” of the present invention. Since these metabolic states can serve as indicators of diseases such as diabetes, dyslipidemia, hepatitis, and cirrhosis, the present invention can also be used to estimate the degree of the disease.

The method of the present invention comprises (a1) a step of collecting one or more skin gases derived from a subject (hereinafter also referred to as “collecting step”), and (b) a step of measuring the concentration of the collected one or more skin gases. (Hereinafter also referred to as “measurement step”), and (c) a step of estimating the metabolic state of a specific substance in the subject based on the measured concentration of skin gas (hereinafter also referred to as “estimation step”) )including. In addition, the method of the present invention may further include (a2) a step of concentrating skin gas (hereinafter also referred to as “concentration step”) after the collection step and before the measurement step as an optional step.
Each process which comprises the method of this invention is demonstrated in detail below.

(A1) Collection step In this step, one or more skin gases derived from the subject are collected.
In this specification, “skin gas” means a gas released from the skin. Examples of skin gases herein include nitric oxide (NO) and volatile organic compounds. In the present specification, the “volatile organic compound” means a substance that is volatile at room temperature and atmospheric pressure. Examples thereof include acetone (CH ₃ COCH ₃ ), acetaldehyde (CH ₃ CHO), hexanal (C ₆ H ₁₂ O), 6-methyl-5-hepten-2-one (C ₈ H ₁₄ O), acetic acid (CH ₃ COOH), 2-ethylhexanol (C ₈ H ₁₈ O), nonanal (C ₉ H ₁₈ O), 4-cyanohexene, hexadecanal (C ₁₆ H ₃₂ O), toluene (C ₆ H ₅ CH ₃ ), ethanol (C ₂ H ₅ OH), cyanocyclohexene (C ₇ H ₉ N), and And octanal (C ₈ H ₁₆ O).

  In the present specification, the site of the skin from which skin gas is collected is not particularly limited. For example, head, neck, abdomen, chest, back, arms, hands, such as wrists, back of hands, palms, fingers, and legs, feet, such as ankles, insteps, soles, toes Etc. It is preferable to collect skin gas from the abdomen, chest, hands and feet (for example, toes and fingers) from the viewpoint of ease of collecting skin gas and low resistance of the subject to wearing of the collection device. .

  Although the collection method is not limited, for example, it can be performed by covering the part where the skin gas is collected with a container or bag, leaving it for a certain period of time, and collecting the skin gas contained in the container or bag. . In this case, the time to cover the skin is not particularly limited, 5 seconds or more, 10 seconds or more, 30 seconds or more, 1 minute or more, 2 minutes or more, 3 minutes or more, 4 minutes or more, 5 minutes or more, 10 minutes or more, 30 It may be minutes or more, or 1 hour or more, and may be less than 24 hours, less than 12 hours, less than 6 hours, less than 3 hours, less than 2 hours, or less than 1 hour. In addition, skin gas may be directly collected using an instrument, device, container, or the like that collects skin gas.

  In this step, all skin gases may be collected, or some skin gases may be collected. In order to collect a part of the skin gas, a means capable of separating a specific gas from the mixed gas may be used. For example, gas chromatography can be used.

(A2) Concentration step This step is a step that is optionally performed after the collection step and before the measurement step. In particular, the concentration step is preferably performed when the concentration of skin gas measured in the measurement step is low, or when the sensitivity of the measurement is not sufficient.

  The skin gas may be concentrated by using a gas concentration method known to those skilled in the art. For example, the concentration may be performed at a low temperature concentration method (see JP2009-069137, etc.), a concentration method using an adsorbent such as PSA method (see JP2004-148270, etc.), or a solvent such as water. It can be carried out by a method of concentrating gas using solubility (see JP 2008-255209 A).

  The degree of concentration in this step is not limited as long as skin gas can be measured in the measurement step. For example, 1.5 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 10 times or more, 20 times or more, 50 times or more, 100 times or more, 1000 times or less, 500 times or less, 200 times or less It can be concentrated in a range of 100 times or less, 50 times or less, 20 times or less, or 10 times or less.

(B) Measurement step In this step, the concentration of all or part of the skin gas collected in the collection step, preferably a part of it, is measured.

  In the measurement step, the concentration of the skin gas collected in the collection step or the concentration of the skin gas concentrated in the concentration step may be directly measured, or the skin gas is released from the skin using an instrument or device that collects the skin gas. The skin gas may be collected in a container or a bag, and the concentration of the collected skin gas may be measured.

  The type of skin gas whose concentration is to be measured can be appropriately selected according to the substance whose metabolic state is estimated. For example, when the target substance is an endogenous substance such as a blood glucose level, as a skin gas for measuring the concentration, nitric oxide or a volatile organic compound such as acetaldehyde, hexanal, 6-methyl-5-heptene -2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene, octanal, and combinations thereof, preferably nitric oxide, acetaldehyde, hexanal, 6 Skin gas selected from the group consisting of -methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, and combinations thereof. It is preferable to measure the concentration of two or more skin gases from the point of accuracy of estimation. When measuring the density | concentration of two or more skin gases, the two or more skin gases selected from the group which added acetone to said group can be used. As a combination of two skin gases in estimating blood glucose level, combinations shown in Table 1 described in Examples below, that is, nitric oxide and acetaldehyde; nitric oxide and acetone; nitric oxide and hexanal; monoxide Nitrogen and 6-methyl-5-hepten-2-one; acetaldehyde and acetone; acetaldehyde and hexanal; acetaldehyde and 6-methyl-5-hepten-2-one; acetone and hexanal; acetone and 6-methyl-5-heptene- 2-one; hexanal, 6-methyl-5-hepten-2-one and the like.

  When estimating a blood glucose level, it is most preferable to measure the concentration of three skin gases. As combinations of the three skin gases, combinations shown in Table 2 described in Examples below, namely nitric oxide, acetaldehyde, and acetone; nitric oxide, acetaldehyde, and 6-methyl-5-hepten-2-one Nitric oxide, hexanal, and 6-methyl-5-hepten-2-one; nitric oxide, acetone, and hexanal; acetone, hexanal, and 6-methyl-5-hepten-2-one; acetaldehyde, acetone, And hexanal; acetaldehyde, acetone, 6-methyl-5-hepten-2-one, and the like.

  When the target substance is a substance to be administered, for example, insulin in a subject, it is preferable to measure the concentrations of acetone and / or hexanal, preferably both acetone and hexanal.

  The measurement step can be performed by any gas detection or measurement method known to those skilled in the art. For example, the concentration of skin gas may be measured from the intensity of the peak obtained from a TCD detector or FID detector of gas chromatography. Further, the concentration of skin gas can be measured from the intensity of chemiluminescence and the absorbance at a specific wavelength. Moreover, you may measure the density | concentration of skin gas with gas sensors, such as a semiconductor sensor or an electrochemical sensor known to those skilled in the art. It is preferable to use the concentration measured in this step for the following estimation step, but an index indirectly indicating the concentration, for example, peak intensity obtained by gas chromatography, chemiluminescence intensity, absorbance at a specific wavelength, etc. In the estimation step, it may be used directly instead of the concentration.

  The measurement process may be performed over time. In this case, in accordance with the measurement process, other processes, that is, a sampling process, an estimation process, and (and a concentration process when a concentration process is included) are also performed over time. When the measurement process is performed over time, the measurement interval can be set as appropriate. Measurement may be performed continuously, or after 1 to 5 minutes, every 5 to 10 minutes, every 10 to 20 minutes, every 20 to 30 minutes, 30 to 1 hour, and 1 hour to Every 2 hours, every 2 to 4 hours, every 4 to 8 hours, every 8 to 16 hours, every 16 to 24 hours, every day to every few days, or before and after every meal and / or bedtime You can also. By performing the measurement process over time, the metabolic state of the substance in the subject can be monitored.

(C) Estimation Step In this step, the metabolic state of the specific substance in the subject is estimated based on the correlation between the skin gas concentration measured in the measurement step and the metabolic state of the specific substance in the subject.

  Correlation between the concentration of skin gas and the metabolic state of a specific substance in a subject is determined in advance by a statistical method such as regression analysis of the concentration of skin gas from the reference body and the metabolic state of the specific substance or principal component analysis. It is preferable that

  In the estimation step, the concentration of skin gas that is positively correlated with the metabolic state of a specific substance may be used, or the concentration of skin gas that is negatively correlated may be used, or both of them may be used. For example, examples of skin gases that positively correlate with blood glucose levels include acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, 6-methyl-5-hepten-2-one, and acetaldehyde. Examples of skin gases that are negatively correlated with blood glucose levels include toluene, acetone, and ethanol. Similarly, an example of skin gas that is positively correlated with insulin concentration is acetone, and an example of skin gas that is negatively correlated with insulin concentration is hexanal.

  In the present specification, the “reference body” means an individual serving as a reference used for obtaining a correlation between the metabolic state measured by a method other than the method of the present invention and the concentration of skin gas. The reference body may be the same species as the subject. For example, when the subject is a human, the race (including ethnicity), gender, age, weight, height, presence or absence of a disease, etc. may be used. However, it is preferable that these conditions are the same as the subject.

  The metabolic state of a subject's particular substance can be determined, for example, by a single regression analysis based on information about the concentration of one skin gas and the metabolic state of a subject's particular substance, or two or more skin gas concentrations and the subject's metabolic state. It can be estimated by a statistical method such as multiple regression analysis or principal component analysis based on information on the metabolic state of a specific substance. In the case of single regression analysis, the metabolic state of a specific substance in a subject can be determined by the following equation.

（式中、Yは特定の物質の代謝状態、aは係数、Xは皮膚ガスの濃度、bは定数である）

(Where Y is the metabolic state of a specific substance, a is a coefficient, X is the concentration of skin gas, and b is a constant)

  Here, when the concentration of skin gas that is positively correlated with the metabolic state of a specific substance is used, the value of a is positive, and conversely, the concentration of skin gas that is negatively correlated with the metabolic state of a specific substance is When used, the value of a can be negative.

  Similarly, in the case of multiple regression analysis, the metabolic state of a specific substance in a subject can be determined by the following equation.

（式中、Yは特定の物質の代謝状態、a₁〜a_nは係数、x₁〜x_nは皮膚ガスの濃度、nは2以上の整数、bは定数である）

(Wherein, Y is the metabolic state of a particular substance, is a ₁ ~a _n coefficients, the x ₁ ~x _n concentration of skin gases, n represents an integer of 2 or more, b is a constant)

In the case of using the concentration of the skin gas positively correlated with the metabolic state of a specific substance, the value of a ₁ ~a _n is a positive value, which correlates negatively with the metabolic state of a particular substance in the opposite skin when using a concentration of the gas, the value of a ₁ ~a _n may be a negative value.

  The method of the present invention may be performed in a short time such as several hours to several days, several days to several weeks, several weeks to several months, several months to several years, several years to several decades, or It may be done in the medium to long term over a lifetime.

  The method of the present invention is used in combination with a metabolic state estimation method using other markers, for example, gene expression level, protein expression level, blood component concentration, etc. Also good.

<Determination Method of Drug Dose, and Treatment Method for Diseases Including Determining Dosage of Drug>
In one aspect, the invention relates to a method for determining a dosage of a drug. The method comprises (a1) a step of collecting one or more skin gases from the subject (collecting step), (b) a step of measuring the concentration of the collected one or more skin gases (measuring step), and (c) measurement. A step (estimation step) of estimating a metabolic state of a specific substance in a subject based on the concentration of the determined skin gas, and (d) a step of determining a dose of the drug according to the estimated metabolic state (determination) Process). In addition, the method may further include, as an optional step, (a2) a step of concentrating gas (“concentration step”) before measuring the concentration of skin gas. Since the collection process, the measurement process, the estimation process, and the concentration process are as described above, description thereof is omitted here.

(D) Determination step In this step, the concentration of the drug is determined according to the metabolic state of a specific substance in the subject. For example, as the metabolic state of a specific substance in a subject, when blood glucose level, lipid level, LDL cholesterol level, and values that are indicative of the degree of disease such as oxidative stress are estimated, the higher the degree of disease, the more the drug is administered The larger the amount, the lower the degree of disease, the lower the dose of the drug.

  Also, when estimating the drug concentration in the subject as the metabolic state of a specific substance in the subject, the higher the drug concentration in the subject, the lower the dose of the drug, and vice versa. The amount can be increased.

  The type of drug whose dosage is determined in this step is preferably the same as the drug described in the above estimation step, but may be different.

  In the method for determining the dose of the drug of the present invention, it is preferable to estimate the degree of the disease and the drug concentration in the subject, and to determine the dose of the drug in consideration of both. As an example of a method for determining the dose of a drug in this case, (i) when the degree of the disease is high and the drug concentration in the subject is high, the dose of the drug is kept high, and (ii) the degree of the disease is If it is high and the drug concentration in the subject is low, increase the dose of the drug; (iii) if the degree of disease is low and the drug concentration in the subject is high, decrease the dose of the drug; and (iv) When the degree of the disease is low and the drug concentration in the subject is low, the dose of the drug can be maintained at a low level.

  In a preferred embodiment, the disease is diabetes, the severity of the disease is blood glucose, and the drug is insulin.

  A standard amount of drug to be administered to a subject and an actual dose can be selected by those skilled in the art according to the sex, age, weight, height, time after meal, etc. of the subject. . For example, the subject's blood glucose level may be 90 mg / dl or less, 100 mg / dl or less, 110 mg / dl or less, 120 mg / dl or less, 130 mg / dl or less, or 140 mg / dl or less on an empty stomach, When it is in any of these ranges, the dose of a drug such as insulin can be increased, and when it is within any of these ranges, the dose of a drug such as insulin can be decreased. Similarly, the blood insulin concentration may be 0.5 μIU / ml to 20.0 μIU / ml, 1.0 μIU / ml to 15.0 μIU / ml, or 2.0 μIU / ml to 10.0 μIU / ml, and the blood insulin concentration may be When the concentration is lower than this concentration, the insulin dosage can be increased, and when the concentration is higher than this concentration, the insulin dosage can be decreased.

  The method of the present invention allows the optimal dosage for a subject to be determined based on non-invasive and time-measured parameters. The disease can be effectively treated, prevented, and / or alleviated by administering the optimal dose of the drug determined by the method of the present invention over time.

  In one aspect, the present invention relates to a method for treating a disease comprising administering to a subject a dose of a drug determined by a method for determining a dose of a drug of the present invention. The treatment method of the present invention may include administering to the subject a drug other than the drug whose dosage has been determined by the method of the present invention.

<Biomarker>
In one aspect, the invention relates to a biomarker for estimating the metabolic state of a particular substance in a subject. The biomarker of the present invention consists of one or more skin gases. Since the types of skin gas, the subject, the skin site, and the metabolic state are as described in the above <Method for estimating the metabolic state of a specific substance in the subject>, description thereof is omitted here.

  In one embodiment, the present invention relates to a biomarker for estimating blood glucose level consisting of skin gas, wherein the skin gas is nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, Selected from the group consisting of acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene, and octanal. In another embodiment, the present invention relates to a biomarker for estimating a blood glucose level composed of skin gas, wherein the skin gas is acetone, nitric oxide, acetaldehyde, hexanal, 6-methyl-5-heptene- It consists of two or more gases selected from the group consisting of 2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene, and octanal. A preferable combination of two or three skin gases for estimating a blood glucose level is as described above in <Method for estimating metabolic state of a specific substance in a subject>.

  In yet another embodiment, the invention relates to a biomarker for estimating insulin concentration in a subject comprising skin gas, wherein the skin gas is acetone and / or hexanal, preferably a combination of acetone and hexanal. .

  In order to estimate the metabolic state of a specific substance in a subject, only the biomarker of the present invention may be used, or other markers such as gene expression level, protein expression level, and blood components in the subject You may use in combination with a density | concentration etc.

<Unit for estimating metabolic state of a specific substance in a subject>
In one aspect, the invention relates to a unit for estimating the metabolic state of a particular substance in a subject. The estimation unit of the present invention includes (a1) collecting means, (b) measuring means, and (c) calculating means. Further, the estimation unit of the present invention may optionally include (a2) a concentration means. For the method of estimating the metabolic state of a specific substance in a subject based on the measurement of the concentration of the subject, skin gas, skin gas, the metabolic state of a specific substance, and the concentration of skin gas, the above <specific substance in the subject As described in the method for estimating the metabolic state of

(A1) Collecting Means “Collecting means” is means for collecting one or more skin gases from a subject. Examples of the collecting means include a container or a bag that can seal a part from which gas is collected.

(A2) Concentration means The “concentration means” is a concentration means for concentrating the skin gas collected by the collection means before measuring the skin gas concentration. The concentration means is an arbitrary configuration in the estimation unit of the present invention. Examples of the concentration means include a low-temperature concentrator and a gas adsorbent.

(B) Measuring means "Measuring means" is means for measuring the concentration of one or more skin gases collected by the collecting means. Examples of measuring means include gas chromatography and gas sensors such as semiconductor sensors or electrochemical sensors. When the measurement unit includes hardware, the configuration may be the same as the hardware configuration in the following calculation unit.

(C) Calculation means “Calculation means” is means for estimating the metabolic state of a specific substance in a subject from the measurement values obtained by the measurement means. An example of the calculation means is a computer (computer) that automatically calculates the correlation between the skin gas concentration and the metabolic state of a specific substance in the subject.

  In terms of hardware configuration, the calculation means includes a CPU that processes acquired measurement values, a RAM that is a main memory, a non-volatile memory that buffers acquired measurement values and calculation values, and communication of information with external devices. It consists of an interface for making demand for electricity. You may have the display which displays a metabolic state as needed.

  Realization of each device on the hardware configuration is as follows, for example. First, the CPU calls the calculation program from the nonvolatile memory onto the RAM. The calculation program is composed of a correlation formula between the concentration of skin gas and the metabolic state of a specific substance of the subject, and is input in advance into the nonvolatile memory. This correlation equation can be obtained, for example, based on a statistical method such as regression analysis or principal component analysis between the concentration of the skin gas derived from the reference body and the metabolic state of a specific substance of the reference body. Next, the CPU acquires measurement value information from the measurement means, stores it in the RAM, attaches an address, and then buffers it in the nonvolatile memory. Subsequently, the CPU processes, stores, and outputs the stored measurement value information by sequentially executing the programs developed on the RAM. By the above, the metabolic state estimation unit of the present embodiment can be realized.

  In one embodiment, the estimation unit of the present invention may be a unit that estimates the metabolic state of an endogenous substance in a subject, for example, a unit that estimates the degree of a disease such as blood glucose level, lipid concentration, LDL cholesterol level. The estimation unit of the present invention may be a unit that estimates the metabolic state of a substance administered to a subject, for example, a unit that estimates the concentration of a drug such as insulin.

  The size of the estimation unit of the present invention is not limited, but is preferably portable (portable), and it is preferable that the subject can be attached to the test site by himself / herself.

<Determination mechanism of drug dose>
In one aspect, the invention relates to a mechanism for determining the dosage of a drug. The determination mechanism of the dose of the medicine of the present invention includes the above estimation unit and (d) determination means. Preferably, the mechanism for determining the dose of the drug of the present invention includes both a unit for estimating the metabolic state of the endogenous substance of the subject and a unit for estimating the metabolic state of the substance administered to the subject. In the present embodiment, the collecting means and calculating means in the unit for estimating the metabolic state of the endogenous substance of the subject and the unit for estimating the metabolic state of the substance administered to the subject may be common or separately. It may be.

(D) Judgment means The “judgment means” is means for determining an appropriate dose of a drug to a subject based on the estimated information on the metabolic state of a specific substance in the subject. When the mechanism for determining the dose of the drug of the present invention includes both a unit for estimating the metabolic state of the endogenous substance of the subject and a unit for estimating the metabolic state of the substance to be administered to the subject, the judging means comprises: Based on both the estimated metabolic state of the endogenous substance and the metabolic state of the substance administered to the subject, the dosage of the drug is determined.

  In this embodiment, the determination means for determining the dose of the drug may be a computer (computer) having a program for controlling individual means or mechanisms, and may be common to the calculation means or separate. May be.

  Judgment means is hardware configuration, CPU for processing the estimated information acquired, RAM as main memory, non-volatile memory for buffering the acquired estimated values and calculated values, communication of information with external devices It consists of an interface for making demand for electricity. You may have the display which displays a metabolic state as needed.

  To realize each part in the hardware configuration, first, the CPU calls the determination program from the nonvolatile memory onto the RAM. The determination program is a program that compares a reference value as necessary based on the acquired estimated value and determines an appropriate drug dose to the subject, and is preliminarily input to the nonvolatile memory. . Next, the CPU obtains estimated information from the calculation means of each unit through an interface or the like, stores it in its own RAM, attaches an address, and then buffers it in the nonvolatile memory. Subsequently, the CPU sequentially processes the programs developed on the RAM to process, store, and output the stored estimated value information. As described above, the mechanism for determining the dose of the drug of this embodiment can be realized.

  The determination method in the determination means for determining the dose of the drug is as described in the above <Determination method of drug dose, and treatment method of disease including administering the determined dose of drug>. . That is, when there is only an estimation unit of the degree of disease, the higher the degree of disease, the higher the dose of the drug, and conversely, the lower the degree of disease, the lower the dose of the drug. On the other hand, if there is only an estimation unit for the drug concentration in the subject, the higher the drug concentration in the subject, the lower the dose of the drug, and conversely, the higher the drug concentration in the subject, the higher the dose of the drug. be able to. When both the estimation unit for the degree of disease of the subject and the estimation unit for the drug concentration in the subject are included, it is preferable to determine the dose of the drug in consideration of both of them. As an example of a method for determining the dose of a drug in this case, (i) when the degree of the disease is high and the drug concentration in the subject is high, the dose of the drug is kept high, and (ii) the degree of the disease is If it is high and the drug concentration in the subject is low, increase the dose of the drug; (iii) if the degree of disease is low and the drug concentration in the subject is high, decrease the dose of the drug; and (iv) When the degree of the disease is low and the drug concentration in the subject is low, the dose of the drug can be maintained at a low level.

  A standard amount of drug to be administered to a subject and an actual dose can be selected by those skilled in the art according to the sex, age, weight, height, time after meal, etc. of the subject. .

  The size of the mechanism for determining the dose of the drug is not limited, but it is preferably portable, and it is preferable that the subject can attach to the test site by himself / herself.

<Automatic drug administration device>
In one aspect, the present invention relates to an automated drug delivery device. The automatic drug administration device of the present invention is a drug stored in a drug storage means based on a mechanism for determining the dose of the drug, a drug storage means for storing the drug, and a dose of the drug determined by the determination means. Administration means for administering to a subject. The automatic drug administration device of the present invention can be used to effectively treat, prevent, and / or alleviate diseases such as diabetes.

  Examples of the drug storage means include containers, bags, tanks, and the like, and examples of the administration means include a syringe for administering the drug, an inhaler, and a patch means such as a patch. The administration means is preferably controlled so as to administer the dose of the drug determined by the determination means included in the drug dose determination mechanism.

  Although the size of the automatic drug administration device is not limited, it is preferably portable (portable), and it is preferable that the subject can be attached to the test site by himself / herself.

<Example 1: Estimation of blood glucose concentration based on skin gas concentration in rats>
(Method)
1) Experimental animals
We purchased 8 9-week-old Zucker fa / fa rats (obese, impaired glucose tolerance, hypertensive rats) and 8 normal-week-old rats (Zucker + / + rats) (Chubu Science Materials, Nagoya). The experiment was conducted after 7 weeks (16 weeks of age) when fa / fa rats developed obesity and glucose tolerance decreased.

  Rats were raised in a breeding room adjusted to a temperature of 22 ± 1 ° C. and a light / dark cycle every 12 hours. Feed (CE-2 feed) (Nippon Claire Co., Ltd., Tokyo) and water were freely consumed for 24 hours. Food and water intake were measured daily. Immediately after purchase, rats were placed in a fixture for 5 minutes every day to familiarize them with rat fixtures (Kinoshita Rika Co., Ltd., Nagoya). Three types of rat fixtures were prepared: large, medium and small. The largest fixture is 25.5 cm long and 8.5 cm in diameter, the medium fixture is 23 cm long and 8 cm in diameter, and the small one is 23 cm long and 7 cm in diameter, suitable for the size of the rat Experiments were performed using instruments. Furthermore, all fixtures can be adjusted in 3 steps at 1.5 cm intervals.

2) Collection of skin gas from rats (Early feeding box was removed) After rats were fasted for 4 hours, glucose (Wako Pure Chemical Industries, Ltd., Osaka) 2 g / kg body weight was orally administered. Put it in a fixture, wash the tail with distilled water, wipe off the water with Kimwiper (Kimwiper S-200, Nippon Paper Crecia, Tokyo), and then attach a skin gas collection bag made of polyethylene to the tail of the rat. And sealed with parafilm. After sealing, 50 ml of nitrogen gas was injected to clean the inside of the bag. After washing the bag twice, 50 ml of nitrogen gas was injected, and skin gas was collected for 10 minutes. After 10 minutes, 45 ml of collected skin gas was transferred to another analytical bag and used for analysis. Thereafter, the bag was washed twice immediately before collecting the skin gas, and the skin gas was collected at 30, 60, 90, and 120 minutes after glucose administration by the same method.

3) Blood glucose measurement (Early morning food box was removed) After rats were fasted for 4 hours, glucose (Wako Pure Chemical Industries, Ltd., Osaka) 2 g / kg body weight was orally administered. Blood was collected from the tail vein of the rat, and the blood glucose concentration was measured using a blood glucose meter (Glutest Every, Sanwa Chemical, Nagoya). The rat entered the fixture and did not move violently. Blood was collected 5 times before administration of glucose and 30, 60, 90 and 120 minutes after administration.

4) Skin gas analysis The concentration of nitric oxide among the skin gas components was measured using a nitric oxide measuring device (ppb-NO, manufactured by Pico Devices, Nagoya). The skin gas nitric oxide concentration was calibrated and measured using known standard nitric oxide gases of 5, 10, 15, and 20 ppb. Acetaldehyde, acetone, hexanal, and 6-methyl-5-hepten-2-one in skin gas were calculated using the Cold-trap gas chromatographic system (Yamane et al. 2006; Naitoh et al. 2000). This system consists of a concentrator (NIT-3; manufactured by Pico Devices, Nagoya) and a gas chromatograph (GC-2010; Shimadzu, Kyoto). The gas chromatograph detector is FID (flame ion detector), the column is DB-WAXETR (length 30 m, inner diameter 0.32 mm; Agilent Technology, J & W, USA), and the injection temperature and detector temperature are At 150 ° C, the column temperature was initially set at 40 ° C for 3 minutes, then increased by 20 ° C per minute over 8 minutes, increased to 200 ° C, maintained at that temperature for 5 minutes, and measured. . Helium is used for the carrier gas and makeup gas, and the flow rates are 12.0 ml / min for carrier gas, 20 ml / min for makeup gas, 25.0 ml / min for hydrogen gas, and 250.0 ml / min for air. It was. Standard gases of 50, 100, and 150 ppb concentrations of acetaldehyde (AA), acetone (A), hexanal (H), and 6-methyl-5-hepten-2-one (M) were prepared and the concentrations were calculated.

5) Statistical analysis Values were expressed as mean ± standard deviation or standard error. Significance test, regression analysis and multiple regression analysis were performed using Excel, and the significance level was p <0.05.

(result)
When the body weight, food, and water intake were compared between the obesity group and the control group, all the results were significantly higher in the obesity group (data not shown). In addition, changes in blood glucose during the oral glucose tolerance test (OGTT, Oral Glucose Tolerance Test) in the obese group and the control group were examined. As a result, no significant difference was observed between the two groups before glucose administration. After glucose administration, the blood glucose level in the obese group showed a significant increase at 30 and 60 minutes, but there was no significant change in blood glucose level in the control group, and any time between 30, 60, 90, and 120 minutes Also showed a significant difference between the two groups (p <0.0001) (data not shown).

  Multiple correlation coefficients between blood glucose concentration in each rat and the concentration of two gases of nitric oxide, acetaldehyde, acetone, hexanal, and 6-methyl-5-hepten-2-one in skin gas When the average value and the standard deviation of the multiple correlation coefficient were examined, the results shown in Table 1 were obtained.

  In the table, 1 to 16 in the second column from the left indicate each individual rat, and the top row shows two combinations of skin gases used for multiple regression analysis (N is nitric oxide, AA is acetaldehyde, A is acetone) , H represents hexanal, and M represents 6-methyl-5-hepten-2-one).

  When the two kinds of skin gases shown in Table 1 were used, an average multiple correlation coefficient of about 0.5 to 0.7 was obtained.

  Similarly, the concentration of the blood glucose concentration in each rat and the concentration of three gases among nitric oxide, acetaldehyde, acetone, hexanal, and 6-methyl-5-hepten-2-one contained in skin gas. When the correlation coefficient, the average value of the multiple correlation coefficient, and the standard deviation were examined, the results shown in Table 2 were obtained.

  In the table, 1 to 16 in the second column from the left indicate the individual rats, and the top row shows the three combinations of skin gases used in the multiple regression analysis (N is nitric oxide, AA is acetaldehyde, and A is acetone. , H represents hexanal, and M represents 6-methyl-5-hepten-2-one).

  When the three types of skin gas shown in Table 2 were used, a multiple correlation coefficient of about 0.7 to 0.9 was obtained on average, and the overall high-phase relationship was higher than when two types of skin gas were used. Number showed.

  Table 2 suggests that the glucose concentration can be estimated with the highest accuracy when three types of skin gases, acetaldehyde, acetone, and hexanal, are used.

  Table 3 shows the individual having the highest multiple correlation coefficient in each of the control group and the obesity group (No. 1) when the glucose level was estimated using three types of skin gases, acetaldehyde, acetone, and hexanal. And No. 11), the measured glucose value during the oral glucose tolerance test, the estimated glucose value, and the error between the estimated value and the measured value in the individuals (No. 8 and No. 14) that showed the lowest multiple correlation coefficient Indicates. In addition, FIGS. 1A to D show the transition of the measured values and estimated values of glucose concentrations in Nos. 1, 8, 11, and 14 during the oral glucose tolerance test.

  Relatively large errors were observed at 0 minutes for No. 8, 0 minutes for No. 14, and 60 minutes for No. 14, but all other errors were within ± 15%.

<Example 2: Estimation of insulin concentration based on skin gas concentration in rats>
Plasma insulin concentration and acetone as a skin gas before (0 minutes) and after (60 minutes) administration of glucose (2 g / kg body weight) to healthy rats and obese rats with reduced glucose tolerance described in Example 1 And the concentration of 1-hexanal was measured. Plasma insulin concentration was measured using a “Rat Insulin ELISA kit” (AKRIN-010T) (Shibagaki, Gunma) measurement kit, and acetone and 1-hexanal were measured by the same method as in Example 1.

  As a result, there was a positive correlation between the plasma insulin concentration and the acetone concentration released from the skin (r = 0.566 (p <0.05, n = 16)), and a negative correlation between the plasma insulin concentration and the hexanal concentration released from the skin. (R = 0.523 (p <0.05, n = 16)) was observed. Subsequently, multiple regression analysis was performed using Excel with the values of acetone and hexanal, which were correlated with the insulin concentration, as explanatory variables and the plasma insulin concentration as an objective variable. As a result, when the correlation between the insulin concentration estimated by multiple regression analysis and the actual insulin concentration was determined, a high correlation of r = 0.750 (n = 16, p <0.001) was observed (FIG. 2).

<Example 3: Estimation of blood glucose concentration based on skin gas concentration in human>
1) Correlation between skin gas and blood glucose concentration Using a skin gas from a finger and using an “acetone / ethanol detector” (Picodevices, Nagoya), a preliminary test was conducted with the cooperation of three concerned parties. It was. In this preliminary test, blood glucose level measured by Medisafefit (Terumo Co., Ltd., Tokyo) according to the manufacturer's instructions using blood from the fingertip by puncture, and skin gas concentration measured by the acetone / ethanol detector. The correlation with was investigated.

  Specifically, a finger was used as a skin gas collection site, and the surface of the finger was lightly wiped with dry paper, and then the acetone / ethanol detector was used. When the measurement was repeated three times in the same subject, the first was excluded. The left hand was used when both left and right hands were used. Using the measured 25 points, preliminary software (primary) showing a correlation with blood glucose was prepared. The results are shown in FIG. As shown in FIG. 3, a certain degree of correlation was observed between skin gas and blood glucose concentration.

2) Acquisition of test data using the prototype A blood glucose measurement prototype including a total of six sensors (semiconductor sensor, electrochemical sensor, and moisture sensor) was prepared.

  The basic data was acquired using a prototype equipped with the preliminary software. That is, in the same manner as described above, the correlation between the measured value of glucose using blood by puncturing the finger and the blood glucose level displayed by the measuring instrument incorporating the first preliminary software was examined.

  In 4 subjects, under the fasting conditions without meals, glucose tolerance test was conducted according to the manufacturer's instructions using 75 g of Tralan G solution (sugar solution for oral glucose tolerance test) (Japanese standard product classification number 87729) did.

  The results of this test are shown in FIG. FIG. 4 shows a value close to the actually measured value and the estimated value as a whole in the primary blood glucose software.

  In addition, a new software (secondary blood sugar software) was created from the data of three people, and the relationship between the measured value and the value measured by the skin gas blood glucose meter of one person who performed the same day using the software was examined. Figure 5 shows the results. Regarding the correlation between skin gas and blood glucose level, there is generally a correlation between the measured value by blood and the measured value by skin gas.

3) Search by GC / MS for components in skin gas related to blood glucose level Changes in blood glucose levels during the blood glucose tolerance test of 3 subjects were examined. The glucose tolerance test was performed according to the manufacturer's instructions using 75 g of Toleran G solution (sugar solution for oral glucose tolerance test) (Japanese standard product classification number 87729) (Ajinomoto Co., Inc., Tokyo). At that time, the skin gas of the subject was collected, and at the same time, the blood glucose level was measured by Medisafe Fit (manufactured by Terumo Corporation, Kyoto Prefecture) according to the manufacturer's instructions. GC / MS using the GC / MS 2010 (Shimadzu Corporation, Kyoto Prefecture) connected to a low-temperature concentrator (NIT-P type, Pico Device, Nagoya) while keeping the obtained skin gas in a sample storage bag Carried out. The GC conditions were in accordance with Example 1. As data, the correlation between blood glucose levels of 6 subjects, total of 18 points, and GC / MS after 2 and a half hours of blood glucose load of 3 subjects was examined.

  As a result of examining changes in the obtained chromatogram and blood glucose level over time, it was found that acetaldehyde and acetic acid increased with an increase in blood glucose level and decreased with a decrease in blood glucose level (data not shown). ).

  Next, data processing software was applied to the obtained chromatogram to convert it into intensities for each m / e (mass / electric number) so that it could be used for statistical analysis. Next, statistical processing was performed using multivariate analysis software (Partial Least Square Regression Analysis) created with a pico device. This software is linked to PLS statistical processing software as multivariable analysis software.

  The results of carrying out the treatment in the range of m / e 50 to 250 are shown in FIG. As shown in FIG. 6, the measured value and the estimated value showed a very good relationship. As a result, it was found that the blood glucose level can be estimated using the GC / MS result of skin gas.

4) Contribution information on blood sugar level of the obtained mass fragment Since the relationship between blood sugar level and skin gas component was found by multivariable analysis, the contribution of m / e, which is a variable factor, was calculated using the above multivariable analysis software. This is shown in FIG. In FIG. 7, the horizontal axis represents the m / e value (can be converted to an actual value by +50), and the vertical axis represents the regression coefficient. FIG. 7 shows the presence of substances having a large positive contribution in the vicinity of 60, 70, 80, 110, and 230 (m / e) values of the fragments. The m / e 60 fragment corresponds to acetic acid, the m / e 70 fragment corresponds to 2-ethylhexanol, and the m / e 110 fragment corresponds to nonanal. In addition, the m / e 80 fragment was considered to correspond to 4-cyanohexene, and the m / e 230 fragment was considered to correspond to hexadecanal. In addition, FIG. 7 reveals the existence of substances having a large negative contribution in the vicinity of 73, 78, 90, and 130. The m / e 90 fragment corresponds to toluene. From the above, it was found that there are substances in skin gas that are positively and negatively involved in blood glucose levels, and it was suggested that blood glucose levels can be estimated using the concentrations of these skin gases.

Claims (24)

Collecting one or more skin gases from the subject;
A method for estimating a blood glucose level in a subject, comprising: measuring a concentration of one or more collected skin gases; and estimating a blood glucose level of the subject based on the measured skin gas concentration.   The method of claim 1, further comprising concentrating the skin gas prior to measuring the concentration of the one or more skin gases.   The method according to claim 1 or 2, wherein the estimation of the blood glucose level is based on a formula obtained in advance by regression analysis or principal component analysis of the concentration of the one or more skin gases derived from the reference body and the blood glucose level of the reference body. .   The skin gas is nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene. And the method according to any one of claims 1 to 3, comprising one or more selected from the group consisting of octanal.   The method according to claim 4, wherein the skin gas includes two or more selected from the group obtained by further adding acetone to the group.   The method according to any one of claims 1 to 5, wherein the concentration is measured over time. Collecting one or more skin gases from the subject;
A method for estimating insulin concentration in a subject, comprising: measuring a concentration of one or more collected skin gases; and estimating an insulin concentration in the subject based on the measured skin gas concentration.   The method according to claim 7, wherein the estimation of the insulin concentration is based on a formula obtained in advance by regression analysis or principal component analysis of the concentration of the one or more skin gases derived from the reference body and the insulin concentration in the reference body.   The method according to claim 7 or 8, wherein the skin gas comprises acetone and / or hexanal.   The method according to claim 7, wherein the concentration is measured over time. Collecting one or more skin gases from the subject;
Measuring the concentration of one or more collected skin gases;
Estimating a metabolic state of a specific substance in a subject based on the measured skin gas concentration, and determining a dose of the drug according to the estimated metabolic state of the specific substance;
A method for determining a dosage of a drug, comprising:   The method according to claim 11, wherein the specific substance is an endogenous substance of a subject or a substance administered to the subject. Collecting one or more skin gases from the subject;
Measuring the concentration of one or more collected skin gases;
Estimating the metabolic state of the endogenous substance of the subject based on the measured concentration of skin gas,
Estimating the metabolic state of the substance administered to the subject based on the measured skin gas concentration, and the estimated metabolic state of the endogenous substance of the subject and metabolic state of the substance administered to the subject Determining the dose of the drug according to
A method for determining a dosage of a drug, comprising:   The method according to any one of claims 11 to 13, wherein the concentration is measured over time.   Nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene, and octanal A biomarker for estimating blood glucose level, comprising any one gas selected from a group.   Acetone, nitric oxide, acetaldehyde, hexanal, 6-methyl-5-hepten-2-one, acetic acid, 2-ethylhexanol, nonanal, 4-cyanohexene, hexadecanal, toluene, ethanol, cyanocyclohexene, and octanal A biomarker for estimating blood glucose level, comprising two or more gases selected from the group consisting of:   A biomarker for estimating insulin concentration, which is a gas composed of acetone and / or hexanal. A means for collecting one or more skin gases from the subject;
A specific substance in a subject, including a measuring means for measuring the concentration of one or more collected skin gases, and a calculating means for estimating a metabolic state of the specific substance in the subject based on the measured skin gas concentration Estimated unit of metabolic state.   The unit according to claim 18, wherein the specific substance is an endogenous substance of a subject.   The unit according to claim 18, wherein the specific substance is a substance to be administered to a subject. A unit for determining a dose of a drug, comprising: the unit according to claim 18; and a determination unit that determines the dose of the drug based on information on the estimated metabolic state of the specific substance in the subject. Unit according to claim 19,
21. A determination means for determining a dose of a drug based on the unit according to claim 20 and information on the estimated metabolic state of the endogenous substance of the subject and the metabolic state of the substance administered to the subject. Including a mechanism for determining the dose of a drug. A mechanism for determining the dose of the drug according to claim 21 or 22,
An automatic drug administration device comprising: a drug storage unit that stores a drug; and an administration unit that administers a drug stored in the drug storage unit to a subject based on the dose of the drug determined by the determination unit.   The unit according to any one of claims 18 to 20, the dose determination mechanism of the drug according to claim 21 or 22, or the automatic drug administration according to claim 23, wherein the concentration is measured over time. apparatus.

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