WO2023109825A1 - Use of silver oxide and/or hydrate thereof in preparation of drug - Google Patents

Abstract

The use of silver oxide and/or a hydrate in the preparation of a drug, wherein the drug is used for treating and/or alleviating diseases or conditions related to electrolyte imbalances in a subject. The diseases or conditions include diseases or conditions related to high hydrogen ions (H + ) and/or high chloride ions (Cl -).

Description

Use of silver oxide and/or its hydrate in the preparation of medicine technical field

The present application relates to the use of a silver-containing compound in the preparation of medicines for treating and/or alleviating diseases or conditions related to electrolyte imbalance.

Background technique

Electrolytes in living organisms play an important role in maintaining the body's homeostasis. Electrolytes can regulate heart and nerve functions, transport oxygen, maintain body fluid balance, and acid-base balance. Electrolyte imbalances may cause muscle pain or cramps, heart palpitations, feeling weak, anxiety, etc., which can be serious or even life-threatening. Common electrolyte imbalances include abnormal concentrations of hydrogen ions (H ⁺ ) and/or chloride ions (Cl ^- ) in the blood, for example, some subjects with acidosis may have excessive concentrations of hydrogen ions (H ⁺ ) in their blood , and/or the concentration of chloride ions (Cl ^- ) is too high.

At present, the treatment methods to regulate the human body's hydrogen ion (H ⁺ ) and/or chloride ion (Cl ^- ) levels usually start from the cause, including correcting circulatory disorders, improving tissue perfusion, controlling infection, taking alkaline drugs or supplying sufficient energy, etc. Sodium bicarbonate, sodium lactate, or potassium citrate are commonly used alkaline drugs in clinical practice, but there are still the following problems: (1) introducing unnecessary ions, causing other electrolyte imbalances, and aggravating the burden on organs; (2) poor response Sufficient results in poor efficacy; (3) the degree of correction is unmanageable; and/or (4) subjects usually have significant gastrointestinal symptoms and are not easily absorbed.

Therefore, there is an urgent need for new drugs that are safe, effective and controllable to regulate electrolyte levels in the human body.

Contents of the invention

The present application provides a method for treating and/or alleviating a disease or condition associated with electrolyte imbalance in a subject, especially a disease or condition associated with excessive blood hydrogen ion concentration and/or excessive blood chloride ion concentration, The method comprises administering to a subject in need thereof an effective amount (eg, a therapeutically effective amount) of silver oxide and/or a hydrate thereof. Silver oxide and/or its hydrates of the present application have at least one of the following characteristics: (1) safe and low toxicity, (2) small side effects, (3) will not introduce potentially harmful cations or anions, (4) the product silver chloride is soluble Low, easy to excrete, will not adversely affect the subject, (5) can effectively treat and/or alleviate the disease or condition associated with electrolyte imbalance in the subject, and (6) can effectively treat and/or alleviate A disease or condition associated with an imbalance of hydrogen ions (H ⁺ ) and/or chloride ions (Cl ⁻ ) in a subject.

On the one hand, the application provides the use of silver oxide and/or its hydrate in the preparation of medicine. The medicament is useful for treating and/or alleviating a disease or condition associated with an electrolyte imbalance in a subject.

In certain embodiments, the disease or condition associated with an electrolyte imbalance comprises a disease or condition associated with an imbalance of hydrogen ions (H ⁺ ) and/or chloride ions (Cl ⁻ ).

In certain embodiments, the disease or condition associated with electrolyte imbalance is manifested by high hydrogen ion (H ⁺ ).

In certain embodiments, prior to said treatment and/or remission, said subject had a serum pH of less than about 7.4.

In certain embodiments, the disease or condition associated with electrolyte imbalance is manifested by hyperchloride (Cl ⁻ ).

In certain embodiments, prior to said treatment and/or remission, said subject had a serum ^Cl- concentration of greater than about 106 mEq/L.

In certain embodiments, prior to said treatment and/or remission, said subject had a serum bicarbonate (HCO ₃ ⁻ ) concentration of less than about 24 mEq/L.

In certain embodiments, the disease or condition associated with an electrolyte imbalance comprises acidosis.

In certain embodiments, the acidosis comprises respiratory acidosis and/or metabolic acidosis. In certain embodiments, the acidosis comprises respiratory acidosis. In certain embodiments, the acidosis comprises respiratory metabolic acidosis.

In certain embodiments, the acidosis comprises acute acidosis or chronic acidosis.

In certain embodiments, the acidosis comprises acute respiratory acidosis. In certain embodiments, the acidosis comprises chronic respiratory acidosis.

In certain embodiments, the acidosis comprises acute metabolic acidosis. In certain embodiments, the acidosis comprises chronic metabolic acidosis.

In certain embodiments, the acidosis comprises ketoacidosis, lactic acidosis, salicylates, uremic acidosis, renal tubular acidosis, dilution acidosis and/or drug-induced acidosis poisoned.

In certain embodiments, the disease or condition associated with an electrolyte imbalance comprises hyperchloremia. In certain embodiments, the disease or condition associated with an electrolyte imbalance comprises hyperchloric acidosis. In certain embodiments, the disease or condition associated with an electrolyte imbalance comprises metabolic hyperchloric acidosis.

In certain embodiments, the subject has concurrent kidney disease.

In certain embodiments, the renal disease comprises chronic kidney disease and/or renal failure.

In certain embodiments, the subject has stage 3A chronic kidney disease, stage 3B chronic kidney disease, or stage 4 chronic kidney disease.

In certain embodiments, the silver oxide and/or hydrates thereof are capable of binding Cl ⁻ .

In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of about 5 mmol/g to about 25 mmol/g in a simulated gastric buffer ("SGF") assay. In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 5 mmol/g in a simulated gastric buffer assay.

In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of about 4 mmol/g to about 25 mmol/g in a simulated small intestinal inorganic buffer ("SIB") assay. In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g in a simulated small intestine inorganic buffer assay.

In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of about 4 mmol/g to about 25 mmol/g in a simulated small intestinal organic and inorganic buffer ("SOB") assay. In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g in a simulated small intestinal organic and inorganic buffer assay.

In certain embodiments, the silver oxide and/or hydrates thereof are capable of binding H ⁺ .

In some embodiments, the silver oxide hydrate includes water molecules, or hydrogen and oxygen elements.

In certain embodiments, the silver oxide hydrate has the formula Ag _x O _y (H ₂ O) _z , where x=2y and z is about 0.5-20. In certain embodiments, the value of z is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4. In some embodiments, the value of x is 1-20. In some embodiments, the value of x is 1-4. In some embodiments, the value of y is 0.5-10. In some embodiments, the value of y is 0.5-2.

In some embodiments, the silver oxide and/or its hydrate is silver monoxide Ag ₂ O.

In certain embodiments, the silver oxide or hydrate thereof is silver hydroxide AgOH.

In certain embodiments, administration of the drug increases the subject's serum pH by about 0.05% to about 30% compared to no administration of the drug. In certain embodiments, administration of the drug increases the subject's serum pH by about 0.1% to about 10% compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.5% following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 1% after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 1.5% following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 2% after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 2.5% following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 3% following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 3.5% following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 4% after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 4.5% following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 5% after administration of the drug compared to no administration of the drug.

In certain embodiments, administration of the drug increases the subject's serum pH by about 0.05 to about 1.5 compared to no administration of the drug. In certain embodiments, administration of the drug increases the subject's serum pH by about 0.1 to about 1 compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.05 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.1 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.15 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.2 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.25 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.3 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.35 following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum pH increases by at least about 0.4 following administration of the drug compared to no administration of the drug.

In certain embodiments, the subject's serum pH is substantially controlled or substantially normalized following administration of the drug compared to no administration of the drug.

In certain embodiments, administration of the drug reduces the subject's serum ^Cl- concentration by about 1 mEq/L to about 10 mEq/L compared to no administration of the drug. In certain embodiments, administration of the drug reduces the serum Cl ⁻ concentration in the subject by about 1.5 mEq/L to about 5 mEq/L compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 1 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 1.5 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 2 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 2.5 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 3 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 3.5 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 4 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 4.5 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum ^Cl- concentration is reduced by at least about 5 mEq/L after administration of the drug compared to no administration of the drug.

In certain embodiments, administration of the drug increases the subject's serum HCO ₃ ^{-concentration} by about 1 mEq/L to about 10 mEq/L compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by about 1.5 mEq/L to about 5 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by at least about 1 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} is increased by at least about 1.5 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by at least about 2 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} is increased by at least about 2.5 mEq/L following administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by at least about 3 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by at least about 3.5 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by at least about 4 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} increases by at least about 4.5 mEq/L after administration of the drug compared to no administration of the drug. In certain embodiments, the subject's serum HCO ₃ ^{-concentration} is increased by at least about 5 mEq/L after administration of the drug compared to no administration of the drug.

In certain embodiments, the subject's serum _HCO3 ^- concentration is substantially controlled or substantially normalized after administration of the drug compared to no administration of the drug.

In certain embodiments, the medicament is formulated for oral administration.

In certain embodiments, the medicament is formulated for administration with meals.

In certain embodiments, the medicament is formulated for administration on an empty stomach.

In certain embodiments, the medicament is formulated for administration at a dosage of about 2 mg/k/dg to about 250 mg/kg/d. In certain embodiments, the medicament is formulated for administration at a dosage of about 8 mg/kg/d to about 180 mg/kg/d. In certain embodiments, the medicament is formulated for administration at a dosage of about 16 mg/kg/d to about 150 mg/kg/d. In certain embodiments, the medicament is formulated for administration at a dosage of about 20 mg/kg/d to about 100 mg/kg/d. In certain embodiments, the medicament is formulated for administration at a dosage of about 30 mg/kg/d to about 100 mg/kg/d. In certain embodiments, the medicament is formulated for administration at a dosage of about 30 mg/kg/d to about 80 mg/kg/d. In certain embodiments, the medicament is formulated for administration at a dosage of about 8 mg/kg/d to about 30 mg/kg/d.

In certain embodiments, the medicament is formulated for administration at a dosing frequency of once per day. In certain embodiments, the medicament is formulated for administration at a dosing frequency of 2 times per day. In certain embodiments, the medicament is formulated for administration at a dosing frequency of 3 times per day. In certain embodiments, the medicament is formulated for administration at a dosing frequency of 4 times per day. In certain embodiments, the medicament is formulated for daily administration.

In certain embodiments, the medicament is prepared as a solid. In certain embodiments, the medicament is a capsule, tablet and/or powder.

In certain embodiments, the medicament further comprises one or more other active ingredients.

In certain embodiments, the medicament further comprises one or more pharmaceutically acceptable carriers, adjuvants and/or excipients.

In another aspect, the present application provides a method for treating and/or alleviating a disease or condition related to electrolyte imbalance in a subject, which comprises administering the silver oxide and/or its hydrate described in the present application, or the present application the drug described.

In another aspect, the present application provides a method for treating and/or alleviating a disease or condition associated with an imbalance of hydrogen ions (H ⁺ ) and/or chloride ions (Cl ⁻ ) in a subject, comprising administering silver oxide and / or its hydrate, or the drug described in this application.

In another aspect, the present application provides a pharmaceutical composition comprising silver oxide and/or a hydrate thereof for use in treating and/or alleviating a disease or condition associated with electrolyte imbalance in a subject.

In another aspect, the present application provides a pharmaceutical composition comprising silver oxide and/or hydrate thereof for use in treating and/or alleviating hydrogen ion (H ⁺ ) and/or chloride ion (Cl ⁻ ) in a subject. Imbalance-related diseases or conditions.

Those skilled in the art can easily perceive other aspects and advantages of the present application from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. As those skilled in the art will appreciate, the content of the present application enables those skilled in the art to make changes to the specific embodiments which are disclosed without departing from the spirit and scope of the invention to which this application relates. Correspondingly, the drawings and descriptions in the specification of the present application are only exemplary rather than restrictive.

Description of drawings

The particular features of the invention to which this application relates are set forth in the appended claims. The features and advantages of the invention to which this application relates can be better understood with reference to the exemplary embodiments described in detail hereinafter and the accompanying drawings. A brief description of the accompanying drawings is as follows:

Figure 1 shows the acid binding capacity of each substance under simulated fasting conditions.

Figure 2 shows the acid binding capacity of each substance under simulated meal conditions.

Detailed ways

The implementation of the invention of the present application will be described in the following specific embodiments, and those skilled in the art can easily understand other advantages and effects of the invention of the present application from the content disclosed in this specification.

The methods and/or compositions (eg, pharmaceutical compositions) of the present application may also have one or more of the following beneficial effects: eg, improving or treating metabolic acidosis. These improvements may also include reduced side effects, increased patient compliance, reduced drug load, increased treatment rate, increased treatment intensity, avoidance of unwanted changes to other electrolytes and/or reduced drug-drug interactions. Further improvements may include reducing the patient's anion gap, among others.

Definition of Terms

In this application, the term "non-absorbable" generally means that it is not substantially absorbed through the gastrointestinal tract of an organism (eg, a human being). Those skilled in the art can detect whether a substance can be absorbed by one or more known methods. For example, an organism's body fluids and/or excretions (eg, feces, lymph, blood, and/or interstitial fluid) can be examined to see whether non-absorbable substances are excreted or released after passing through the gastrointestinal tract. For example, at least 80% (such as at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91% , at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) of the non-absorbable substance is excreted or released. For example, it can be obtained by examining the secretion of various organs (for example, pancreas, liver, intestine, etc.) or in each organ (for example, liver, kidney, lung, etc.) Whether or not the content of its metabolites increases. For example, a non-absorbable substance means that the substance does not substantially enter the lymph, blood, interstitial fluid or organs through the main entry points of the human gastrointestinal tract, such as the intercellular entry between intestinal epithelial cells, Uptake by endocytosis by intestinal epithelial cells, entry by M cells, or active or passive transport processes.

In this application, the term "electrolyte imbalance" generally refers to a condition where electrolyte levels in the human body (such as blood, urine, tissues, and other bodily fluids) are too low or too high. Electrolytes may include charged minerals and ions in the human body, such as sodium ions, calcium ions, potassium ions, magnesium ions, chloride ions, phosphates, carbonates, bicarbonates, hydrogen ions, and the like. Electrolytes participate in the regulation of the heart and nerve functions of organisms, body fluid balance, oxygen transport, acid-base balance, transport of nutrients into cells, and transport of metabolites out of cells, etc. Electrolyte imbalances may be related to ingestion of certain medications, vomiting, diarrhea, sweating, and liver or kidney problems. For example, an electrolyte imbalance can refer to an increase in the level of an electrolyte by at least 10% or more (e.g., an increase of at least 20%, 30%, 30%, 50%, 60%, 80%, 99% or more) compared to steady state high), or reduced by at least 10% or more (e.g., reduced by at least 20%, 30%, 30%, 50%, 60%, 80%, 99% or lower). The term "disease or condition associated with electrolyte imbalance" may include one or more diseases or conditions caused by high or low electrolyte levels. "Electrolyte imbalances" may include acid-base disorders, more specifically hydrogen ion (H ⁺ ) imbalances. "Electrolyte imbalance" may include a chloride ion (Cl ⁻ ) imbalance.

In this application, the term "diseases or conditions associated with hydrogen ion (H ⁺ ) imbalance" generally refers to diseases or Conditions, or diseases or conditions caused by low or high levels of hydrogen ions. The hydrogen ion level can be indicated by indicators such as blood pH value, urine pH value, blood hydrogen ion concentration, and urine hydrogen ion concentration. For example, the blood pH value of a normal human body is about 7.35-7.45, corresponding to a hydrogen ion concentration of about 35.48nmol/L-44.67nmol/L; the urine pH value of a normal human body is about 4.5-8.0 (or, 5.0-7.5), The corresponding hydrogen ion concentration is about 10nmol/L-31.62nmol/L. If it is below the bottom of the normal range, or above the top of the normal range, a hydrogen ion (H+) imbalance can be considered. For example, a hydrogen ion (H+) imbalance is also believed to be present when the pH of the blood is below or above about 7.4.

In this application, the term "chloride ion (Cl ^- ) imbalance-associated disease or condition" generally refers to a disease or disorder characterized by low or high levels of chloride ion in the human body (such as blood, urine, tissues, and other bodily fluids). Conditions, or diseases or conditions caused by low or high levels of chloride ions. Chloride levels can be indicated by indicators such as blood chloride concentration, urine chloride concentration, or anion gap (defined as serum Na ⁺ -(Cl ^- +HCO ₃ ^- )]). The serum chloride ion concentration range of normal human body is about 96-106mmol/L. When the serum chloride ion is higher than about 106mmol/L, there may be a disease or disease related to high chloride ion; when the serum chloride ion is lower than about 96mmol/L, there may be a disease or disease related to low chloride ion.

In this application, the term "acidosis" generally refers to a disease or condition in which the concentration of hydrogen ions in the blood increases and the pH decreases. Arterial blood gas and/or blood biochemical indicators can be used to judge whether there is acidosis. The detection indicators and methods of acidosis can include blood pH value, blood hydrogen ion concentration, serum bicarbonate concentration, serum ketone concentration, urine concentration of ketone, serum Creatinine concentration, serum L-lactic acid concentration, serum D-lactic acid concentration, serum osmolarity, serum toxic alcohol concentration, serum organic acid concentration, serum potassium ion concentration, serum anion gap, arterial carbon dioxide partial pressure (PaCO ₂ ), urine electrolyte Concentration, urine osmolality, urine pH, urine anion gap and/or urine osmolality gap. Acidosis can include acute acidosis, which usually lasts from a few minutes to a few days, or chronic acidosis, which usually lasts from a few weeks to several years. Acidosis can include metabolic acidosis and respiratory acidosis.

In the present application, the term "metabolic acidosis" generally refers to a biochemical abnormality of decreased blood bicarbonate (HCO ₃ ⁻ ) concentration, increased blood hydrogen ion (H ⁺ ) concentration, and/or decreased blood pH. Metabolic acidosis occurs when the body accumulates acids produced by metabolic and dietary processes and the excess acid is not completely removed from the body by the kidneys. In chronic kidney disease, acidosis can also be caused by a reduced ability of the kidney to excrete hydrogen ions due to inability to recover filtered bicarbonate (HCO ₃₋ ), ammoniagenesis, and excretion of incrementally increasing acid. In subjects with renal disease, metabolic acidosis may be present when the glomerular filtration rate is less than 30 mL/min/1.73 ^m2 . Arterial blood gases can be used to identify the type of acid-base balance disorder and can be used to determine whether there is a mixed acid-base disorder. In general, arterial blood gas results should be coordinated with the history, physical examination, and routine laboratory data listed above. The indicators of arterial blood gas measurement may include arterial carbon dioxide tension (PaCO ₂ ), acidity (pH) and oxygen tension (PaO ₂ ). The relationship between serum pH and serum bicarbonate is described by the Henderson-Hasselbalch equation: pH=pK'+log[HCO ₃ ⁻ ]/[(0.03×PaCO ₂ )] , where 0.03 is the physical solubility coefficient of _CO2 , [HCO3 ⁻ ] and _PaCO2 are the concentration of bicarbonate and the partial pressure of carbon dioxide, respectively. There are several laboratory tests that can be used to define metabolic acidosis, these tests mainly measure the concentration of bicarbonate (HCO ₃ ^- ) or hydrogen ion (H ⁺ ) in different biological samples, including venous or arterial blood . The diagnostic indicators or methods of metabolic acidosis can be found in Metabolic acidosis: pathophysiology, diagnosis and management, Jeffrey A. Kraut et al., Nature Reviews Nephrology, volume 6, pages 274–285 (2010); "Internal Medicine", Lu Zaiying, Zhong Nanshan, People's Medical Publishing House; "Surgery", Wu Zaide, Wu Zhaohan, People's Medical Publishing House; "Guidelines for Clinical Diagnosis-Surgery Volume", Chinese Medical Association, People's Medical Publishing House, etc.

For example, acidosis can be judged by determination of venous plasma bicarbonate (or total carbon dioxide [tCO ₂ ]), serum electrolytes Cl ⁻ , K ⁺ and Na ⁺ measurements, and/or anion gap. For example, measurements of venous plasma _or serum electrolytes can assess tCO ₂ to reflect the sum of circulating CO ₂ , which is composed of bicarbonate (HCO ₃ ⁻ ), carbonic acid, (H ₂ CO ₃ ), and dissolved O ₂ (0.03 ×P _CO2 ). tCO ₂ can also be related to HCO ₃ ⁻ by using a simplified and normalized form of the Henderson-Hasselbalch equation: tCO ₂ =HCO ₃ ⁻ +0.03 P _{CO 2} , where P _{CO 2} is the measured partial pressure of CO ₂ . Since HCO ₃ ^{-concentrations} are greater than 90% of tCO ₂ , and small amounts of H ₂ CO ₃ are present, venous tCO ₂ is usually used as a reasonable approximation of venous HCO ₃ ^{-concentration} in blood. Especially in the course of chronic kidney disease, plasma HCO ₃ ^-values <24-26 mEq/L generally indicate metabolic acidosis.

Changes in serum ^Cl- concentration can be one of the indicators of acid-base imbalance (eg, acidosis), especially when ^Cl- is not proportional to the change in serum Na ⁺ concentration. Changes in serum Cl ^- concentration can be correlated with reciprocal changes in serum bicarbonate. Thus, in metabolic acidosis with a normal anion gap, serum bicarbonate may decrease to less than about 24-26 mEq/L and serum ^Cl- may increase to greater than about 106 mEq/L.

An anion gap [defined as serum Na ⁺ -(Cl ^- +HCO ₃ ^- )] can also be used as an indicator of metabolic acidosis. Metabolic acidosis can manifest as a normal anion gap or an elevated anion gap. However, an elevated anion gap usually indicates the presence of metabolic acidosis, regardless of changes in serum HCO ₃ ^- . An anion gap greater than 20 mEq/L (normal anion gap is 8-12 mEq/L) can be a classic feature of metabolic acidosis.

In this application, the term "hydrate" generally refers to a compound containing water, wherein water can be linked to other moieties through coordination, and can also be combined with other moieties through covalent bonds. For example, "silver oxide hydrate" generally refers to a compound of silver oxide combined with more than 0 (for example, at least 0.5, at least 1 or more) H ₂ O, and the chemical formula of silver oxide hydrate can be expressed as Ag _x O _y (H ₂ O) _z , wherein each of x, y and z can be independently any positive number (for example, can be an integer or non-integer, and z can be 0.5), and x=2y.

In this application, the term "about" or "approximately" generally means that within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system . For example, "about" can mean within 3 standard deviations or more, as practiced in the art. Alternatively, "about" can mean a range of not more than 20%, such as not more than 10%, not more than 5%, or not more than 1% of a given value.

Detailed description of the invention

In one aspect, the present application provides a use of silver oxide and/or its hydrate in the preparation of medicines. The medicament is for treating and/or alleviating a disease or condition associated with an electrolyte imbalance in a subject.

In another aspect, the present application provides a method of treating and/or alleviating a disease or condition associated with an electrolyte imbalance in a subject. In certain embodiments, the method comprises administering silver oxide and/or a hydrate thereof, or a composition (e.g., a pharmaceutical composition) comprising silver oxide and/or a hydrate thereof to a subject in need thereof.

In another aspect, the present application provides a pharmaceutical composition comprising the silver oxide and/or its hydrate. In certain embodiments, the pharmaceutical composition is used for treating and/or alleviating a disease or condition related to electrolyte imbalance in a subject, or the treatment and/or alleviating method described in this application.

Diseases or conditions associated with electrolyte imbalances

In certain embodiments, in the present application, the diseases or disorders related to electrolyte imbalance include diseases or disorders related to one or more electrolyte imbalances selected from the group consisting of sodium ions, calcium ions, potassium ions , magnesium ions, chloride ions, phosphate, carbonate, bicarbonate and hydrogen ions.

In certain embodiments, the disease or condition associated with an electrolyte imbalance comprises a disease or condition associated with a hydrogen ion (H ⁺ ) imbalance. In certain embodiments, the disease or condition associated with electrolyte imbalance comprises a disease or condition associated with elevated hydrogen ion (H ⁺ ) levels. In certain embodiments, said hydrogen ion (H ⁺ ) level is increased by about 1% in a subject with said disease or condition compared to a normal subject not having said disease or condition to about 1,000%. In certain embodiments, said hydrogen ion (H ⁺ ) level is elevated by at least about 1 in a subject with said disease or condition compared to a normal subject without said disease or condition %, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11 %, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21 %, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 35% %, at least about 40%, at least about 45% or more.

In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.4 but not less than about 6. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.4 but not less than about 6.5. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.4 but not less than about 6.8. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.4. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.38. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.36. For example, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.35. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of about 7.32. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.3. In certain embodiments, the subject suffering from a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.25. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.2. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.15. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum pH of less than about 7.1 or less. In certain embodiments, said serum pH of said subject suffering from a disease or condition associated with an electrolyte imbalance is measured by direct electrode potentiometric method.

In certain embodiments, the subject's serum pH is between several minutes (e.g., at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, or at least 60 minutes) to several days ( Persistently below about 7.4 for at least 1 day, at least 2 days, at least 5 days, at least 10 days, or at least 15 days); or, for several minutes (e.g., at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes , at least 30 minutes, or at least 60 minutes) to several days (at least 1 day, at least 2 days, at least 5 days, at least 10 days, or at least 15 days), the subject's serum pH is below About 7.4. In certain embodiments, the subject's serum pH is within a range of several weeks (e.g., at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, or at least two months) to several years ( For example, consistently less than 7.4 for at least six months, at least one year, at least two years, at least three years, at least four years, at least five years, or at least ten years); or, for several weeks (e.g., at least one week, at least two weeks, At least three weeks, at least four weeks, at least one month, or at least two months) to several years (e.g., at least six months, at least one year, at least two years, at least three years, at least four years, at least five years, or at least ten years) The subject's serum pH was below about 7.4 most of the time.

In certain embodiments, the disease or condition associated with electrolyte imbalance is a disease or condition with elevated blood hydrogen ion (H ⁺ ) concentration. In certain embodiments, the disease or condition associated with an electrolyte imbalance is a blood hydrogen ion (H ⁺ ) concentration greater than about 30 nmol/L but not greater than about 100 nmol/L. In certain embodiments, the disease or condition associated with electrolyte imbalance is a blood hydrogen ion (H ⁺ ) concentration greater than about 30 nmol/L (e.g., greater than about 31 nmol/L, greater than about 32 nmol/L, high At about 33nmol/L, above about 34nmol/L, above about 35nmol/L, above about 36nmol/L, above about 37nmol/L, above about 38nmol/L, above about 39nmol/L, above About 40 nmol/L, above about 41 nmol/L, above about 42 nmol/L, above about 43 nmol/L, above about 44 nmol/L, above about 45 nmol/L, above about 46 nmol/L, above about 47 nmol/L, above about 48 nmol/L, above about 49 nmol/L, above about 50 nmol/L, above about 51 nmol/L, above about 52 nmol/L, above about 53 nmol/L, above about 54 nmol /L, above about 55nmol/L, above about 60nmol/L or higher) diseases or conditions.

In certain embodiments, the disease or condition associated with electrolyte imbalance is a disease or condition associated with chloride ion (Cl ⁻ ) imbalance. In certain embodiments, the disease or condition associated with electrolyte imbalance is a disease or condition associated with elevated chloride (Cl ⁻ ) levels. In certain embodiments, said chloride ion (Cl ⁻ ) level is increased by at least about 1 in a subject with said disease or condition compared to a normal subject without said disease or condition % but not increased by more than about 50%. In certain embodiments, said chloride ion (Cl ⁻ ) level is elevated by at least about 1 in a subject with said disease or condition compared to a normal subject without said disease or condition %, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11 %, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21 %, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 35% %, at least about 40%, at least about 45% or more.

In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum Cl ⁻ concentration of greater than about 100 mEq/L but not greater than about 150 mEq/L. In certain embodiments, the subject having a disease or condition associated with an electrolyte imbalance exhibits a serum Cl ⁻ concentration of greater than about 106 mEq/L but not greater than about 150 mEq/L. In certain embodiments, the subject suffering from a disease or condition associated with an electrolyte imbalance exhibits a serum ^Cl concentration of greater than about 100 mEq/L (e.g., greater than about 101 mEq/L, greater than about 102 mEq/L, greater than About 103 mEq/L, greater than about 104 mEq/L, greater than about 105 mEq/L, greater than about 105.5 mEq/L, greater than about 106 mEq/L, greater than about 106.1 mEq/L, greater than about 106.2 mEq/L, greater than about 106.3 mEq/L , greater than about 106.4 mEq/L, greater than about 106.5 mEq/L, greater than about 106.6 mEq/L, greater than about 106.7 mEq/L, greater than about 106.8 mEq/L, greater than about 106.9 mEq/L, greater than about 107 mEq/L or more high). In some embodiments, the serum Cl ^- concentration of the subject is detected by a biochemical analyzer.

In certain embodiments, the subject's serum chloride ion concentration can be within several minutes (e.g., at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, or at least 60 minutes) ) to several days (at least 1 day, at least 2 days, at least 5 days, at least 10 days, or at least 15 days) of greater than about 100 mEq/L (eg, greater than about 101 mEq/L, greater than about 102 mEq/L, greater than about 103 mEq /L, greater than about 104mEq/L, greater than about 105mEq/L, greater than about 105.5mEq/L, greater than about 106mEq/L, greater than about 106.1mEq/L, greater than about 106.2mEq/L, greater than about 106.3mEq/L, greater than about 106.4 mEq/L, greater than about 106.5 mEq/L, greater than about 106.6 mEq/L, greater than about 106.7 mEq/L, greater than about 106.8 mEq/L, greater than about 106.9 mEq/L, greater than about 107 mEq/L or higher) or, within minutes (e.g., at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, or at least 60 minutes) to several days (at least 1 day, at least 2 days, at least 5 days, at least 10 days or at least 15 days), the subject's serum chloride ion concentration is greater than about 100 mEq/L (e.g., greater than about 101 mEq/L, greater than about 102 mEq/L, greater than about 103 mEq/L, greater than About 104 mEq/L, greater than about 105 mEq/L, greater than about 105.5 mEq/L, greater than about 106 mEq/L, greater than about 106.1 mEq/L, greater than about 106.2 mEq/L, greater than about 106.3 mEq/L, greater than about 106.4 mEq/L L, greater than about 106.5 mEq/L, greater than about 106.6 mEq/L, greater than about 106.7 mEq/L, greater than about 106.8 mEq/L, greater than about 106.9 mEq/L, greater than about 107 mEq/L or higher). In certain embodiments, the subject's serum chloride ion concentration ranges from several weeks (e.g., at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, or at least two months) to several years (e.g., at least six months, at least one year, at least two years, at least three years, at least four years, at least five years, or at least ten years) sustained greater than about 100 mEq/L (e.g., greater than about 101 mEq/L, greater than about 102 mEq/L L, greater than about 103 mEq/L, greater than about 104 mEq/L, greater than about 105 mEq/L, greater than about 105.5 mEq/L, greater than about 106 mEq/L, greater than about 106.1 mEq/L, greater than about 106.2 mEq/L, greater than about 106.3 mEq/L, greater than about 106.4 mEq/L, greater than about 106.5 mEq/L, greater than about 106.6 mEq/L, greater than about 106.7 mEq/L, greater than about 106.8 mEq/L, greater than about 106.9 mEq/L, greater than about 107 mEq/L L or higher); or, within a few weeks (e.g., at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, or at least two months) to several years (e.g., at least half a year, at least a year , at least two years, at least three years, at least four years, at least five years, or at least ten years), the subject has a serum chloride ion concentration greater than about 100 mEq/L (e.g., greater than about 101 mEq/L , greater than about 102 mEq/L, greater than about 103 mEq/L, greater than about 104 mEq/L, greater than about 105 mEq/L, greater than about 105.5 mEq/L, greater than about 106 mEq/L, greater than about 106.1 mEq/L, greater than about 106.2 mEq/L L. Greater than about 106.3 mEq/L, greater than about 106.4 mEq/L, greater than about 106.5 mEq/L, greater than about 106.6 mEq/L, greater than about 106.7 mEq/L, greater than about 106.8 mEq/L, greater than about 106.9 mEq/L , greater than about 107 mEq/L or higher).

In certain embodiments, the disease or condition associated with an electrolyte imbalance is a disease or condition associated with a bicarbonate (HCO ₃ ⁻ ) imbalance. In certain embodiments, the disease or condition associated with electrolyte imbalance is a disease or condition associated with decreased serum bicarbonate (HCO ₃ ⁻ ) levels. In certain embodiments, said serum bicarbonate (HCO ₃ ⁻ ) level is reduced in a subject with said disease or condition compared to a normal subject without said disease or condition by at least About 1% but not reduced by more than about 100%. In certain embodiments, said serum bicarbonate (HCO ₃ ⁻ ) level is reduced in a subject with said disease or condition compared to a normal subject without said disease or condition by at least About 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least About 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least About 35%, at least about 40%, at least about 45% or more.

In certain embodiments, the subject with a disease or ^condition associated with an electrolyte imbalance exhibits a serum HCO ₃ ^{-concentration} (eg, a baseline serum HCO ₃ -concentration) of less than about 27 mEq/L but not less than About 1mEq/L. In certain embodiments, the subject having a disease or ^condition associated with an electrolyte imbalance exhibits a serum HCO ₃ ^{-concentration} (eg, a baseline serum HCO ₃ -concentration) of less than about 24 mEq/L but not less than About 1mEq/L. In certain embodiments, the subject having a disease or ^condition associated with an electrolyte imbalance exhibits a serum HCO ₃ ^{-concentration} (eg, a baseline serum HCO ₃ -concentration) of less than about 27 mEq/L (eg, a low At about 26.5 mEq/L, below about 26 mEq/L, below about 25.5 mEq/L, below about 25 mEq/L, below about 24.5 mEq/L, below about 24 mEq/L, below about 23.5 mEq/L L, less than about 23 mEq/L, less than about 22.5 mEq/L, less than about 22 mEq/L, less than about 21.5 mEq/L, less than about 21 mEq/L, less than about 20.5 mEq/L, less than about 20mEq/L or lower). In certain embodiments, the subject's serum HCO ₃ ^{-concentration} is detected by titration, rate, electrode, and/or chemical colorimetry.

The baseline serum bicarbonate value can be the serum bicarbonate concentration measured at a single time point, or the mean or median of two or more serum bicarbonate concentrations measured at two or more time points. value. In certain embodiments, the baseline serum bicarbonate value is a serum bicarbonate concentration value determined at a single time point, and the baseline serum bicarbonate value is used as the basis for determining an acute acidic condition requiring immediate treatment. In certain embodiments, the baseline serum bicarbonate treatment value is the average of the serum bicarbonate concentrations of serum samples drawn at different time points (eg, different days). In certain embodiments, baseline serum bicarbonate treatment values are drawn on different days (e.g., at least 2, 3, 4, 5 or more days, which may be consecutive or separated by one or more days or even weeks) The mean value of the serum bicarbonate concentration of the serum samples. In certain embodiments, the baseline serum bicarbonate treatment value is the average of the serum bicarbonate concentrations of serum samples drawn on two consecutive days prior to initiation of treatment.

In certain embodiments, a baseline serum bicarbonate value is a serum bicarbonate concentration value determined at a single time point. In certain embodiments, the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations determined at different time points. In certain embodiments, the baseline serum bicarbonate value is the average of at least two serum bicarbonate values from serum samples drawn on different days. In certain embodiments, the baseline serum bicarbonate value is the mean or median of at least two serum bicarbonate concentrations of serum samples drawn on discrete days. In certain embodiments, the discrete days may be separated by at least 2 days. In certain embodiments, the discrete days are at least 1 week apart. In certain embodiments, the discrete days are separated by at least 2 weeks. In certain embodiments, the discrete days are separated by at least 3 weeks.

In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 21 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 20 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 19 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 18 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 17 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 16 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 15 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 14 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 13 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 12 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 11 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 10 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of less than about 9 mEq/L.

In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value of about 9-21 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by baseline serum bicarbonate values in the range of about 12-20 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 12-19 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 12-18 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 12-17 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 12-16 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 9-11 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 12-14 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 15-17 mEq/L. In certain embodiments, the acid-base imbalance to be treated is characterized by a baseline serum bicarbonate value in the range of about 18-21 mEq/L.

In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least about 1 mEq/L over a baseline serum bicarbonate value, but not more than 50 mEq/L. In certain embodiments, oral administration of a pharmaceutical composition comprising silver oxide and/or a hydrate thereof increases the subject's serum bicarbonate value from baseline to an elevated serum bicarbonate value, e.g., which exceeds the baseline serum bicarbonate value Bicarbonate value of at least 1mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 1.5 mEq/L above the baseline serum bicarbonate value. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 2 mEq/L above the baseline serum bicarbonate value. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 2.5 mEq/L above the baseline serum bicarbonate value. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 3 mEq/L above the baseline serum bicarbonate value. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 3.5 mEq/L above the baseline serum bicarbonate value. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 4 mEq/L above the baseline serum bicarbonate value. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 5 mEq/L above the baseline serum bicarbonate value, but not more than 29 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 5 mEq/L above the baseline serum bicarbonate value, but not more than 28 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 5 mEq/L above the baseline serum bicarbonate value, but not more than 27 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 5 mEq/L above the baseline serum bicarbonate value, but not more than 26 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 6 mEq/L above the baseline serum bicarbonate value, but not more than 29 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 6 mEq/L above the baseline serum bicarbonate value, but not more than 28 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 6 mEq/L above the baseline serum bicarbonate value, but not more than 27 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 6 mEq/L above the baseline serum bicarbonate value, but not more than 26 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 7 mEq/L above the baseline serum bicarbonate value, but not more than 29 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 7 mEq/L above the baseline serum bicarbonate value, but not more than 28 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 7 mEq/L above the baseline serum bicarbonate value, but not more than 27 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 7 mEq/L above the baseline serum bicarbonate value, but not more than 26 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 8 mEq/l above the baseline serum bicarbonate value, but not more than 29 mEq/l. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 8 mEq/L above the baseline serum bicarbonate value, but not more than 28 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 8 mEq/L above the baseline serum bicarbonate value, but not more than 27 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 8 mEq/L above the baseline serum bicarbonate value, but not more than 26 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 9 mEq/L above the baseline serum bicarbonate value, but not more than 29 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 9 mEq/L above the baseline serum bicarbonate value, but not more than 28 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 9 mEq/L above the baseline serum bicarbonate value, but not more than 27 mEq/L. In certain embodiments, the treatment increases the subject's serum bicarbonate value to an elevated serum bicarbonate value that is at least 9 mEq/L above a baseline serum bicarbonate value, but not more than 26 mEq/L. In the above exemplary embodiments of the present application, the treatment results in an elevated serum bicarbonate level maintained for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more long time.

In certain embodiments, treatment and/or remission results in a clinically significant improvement (e.g., in measures of any one or more of the conditions, symptoms and/or parameters described above) achieved during less than 1 month of treatment . In certain embodiments, treatment achieves said clinically significant improvement over a 25-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 3-week treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 15-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 2-week treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 10-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 1 week treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 6-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 5-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 4-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 3-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 2-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 1-day treatment period. In certain embodiments, treatment and/or remission achieves said clinically significant improvement achieved within a 12 hour treatment period.

In certain embodiments, treatment and/or remission results in a clinically significant improvement without any change in the subject's diet or eating habits from when treatment began.

In certain embodiments, the subject's serum bicarbonate values return to baseline values ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±1 mEq/L, or ±1 mEq/L within 1 month of cessation of treatment) 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value of ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq/L, within 3 weeks of cessation of treatment) mEq/L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value ± 2.5 mEq/L (e.g., ± 2 mEq/L, ± 1.5 mEq/L, ± 1 mEq/L, or ± 1 mEq/L) within 2 weeks of cessation of treatment. 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq/L) within 10 days of cessation of treatment. /L). In certain embodiments, the subject's serum bicarbonate values return to baseline values ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate value returns to baseline value ± 2.5 mEq/L (e.g., ± 2 mEq/L, ± 1.5 mEq/L, ± 1 mEq/L, or ± 0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate values return to baseline values ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate values return to baseline values ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value of ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value of ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1.0 mEq/L, or ±0.5 mEq/L, within 4 days of cessation of treatment) mEq/L). In certain embodiments, the subject's serum bicarbonate values return to baseline values ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value of ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L). In certain embodiments, the subject's serum bicarbonate value returns to a baseline value of ±2.5 mEq/L (e.g., ±2 mEq/L, ±1.5 mEq/L, ±1 mEq/L, or ±0.5 mEq /L).

In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3.5 mEq/L, within 1 month of cessation of treatment) At least 3 mEq/L, decrease by at least 2.5 mEq/L, decrease by at least 2 mEq/L, decrease by at least 1.5 mEq/L, decrease by at least 1 mEq/L or decrease by at least 0.5 mEq/L). In certain embodiments, the subject's serum bicarbonate value decreases by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3mEq/L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value decreases by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3mEq/L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 10 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 9 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 8 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 7 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject has a decrease in serum bicarbonate value of at least 5 mEq/L (e.g., a decrease of at least 4.5 mEq/L, a decrease of at least 4 mEq/L, a decrease of at least 3.5 mEq/L, a decrease of at least 3 mEq) within 6 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 5 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 4 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject has a decrease in serum bicarbonate value of at least 5 mEq/l (e.g., a decrease of at least 4.5 mEq/l, a decrease of at least 4 mEq/l, a decrease of at least 3.5 mEq/l, a decrease of at least 3 mEq) within 3 days of cessation of treatment /l, decrease by at least 2.5 mEq/l, decrease by at least 2 mEq/l, decrease by at least 1.5 mEq/l, decrease by at least 1 mEq/l or decrease by at least 0.5 mEq/l). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 2 days of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value is reduced by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3 mEq) within 1 day of cessation of treatment /L, decrease by at least 2.5mEq/L, decrease by at least 2mEq/L, decrease by at least 1.5mEq/L, decrease by at least 1mEq/L or decrease by at least 0.5mEq/L). In certain embodiments, the subject's serum bicarbonate value decreases by at least 5 mEq/L (e.g., by at least 4.5 mEq/L, by at least 4 mEq/L, by at least 3.5 mEq/L, by at least 3.5 mEq/L, within 12 hours of cessation of treatment) At least 3 mEq/L, decrease by at least 2.5 mEq/L, decrease by at least 2 mEq/L, decrease by at least 1.5 mEq/L, decrease by at least 1 mEq/L or decrease by at least 0.5 mEq/L).

In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is metabolic acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is respiratory acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is chronic acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is acute acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is chronic metabolic acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is acute metabolic acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is acute respiratory acidosis. In certain embodiments, the disease or condition associated with electrolyte imbalance is chronic respiratory acidosis.

In certain embodiments, the acidosis is ketoacidosis. In certain embodiments, the acidosis is lactic acidosis. In certain embodiments, the acidosis is salicylate poisoning. In certain embodiments, the acidosis is uremic acidosis. In certain embodiments, the acidosis is renal tubular acidosis. In certain embodiments, the acidosis is dilution acidosis. In certain embodiments, the acidosis is drug-induced acidosis.

In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is hyperchloremia. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is chronic hyperchloremia. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is acute hyperchloremia.

In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is hyperchloremic acidosis. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is chronic hyperchloric acidosis. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is acute hyperchloric acidosis.

In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is metabolic hyperchloric acidosis. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is chronic metabolic hyperchloric acidosis. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is acute metabolic hyperchloric acidosis.

In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is respiratory hyperchloric acidosis. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is chronic respiratory hyperchloric acidosis. In certain embodiments, the disease or condition described herein associated with an electrolyte imbalance is acute respiratory hyperchloric acidosis.

In certain embodiments, in the present application, the subject exhibits an electrolyte imbalance and suffers from kidney disease at the same time. In certain embodiments, the renal disease is chronic kidney disease and/or renal failure. In certain embodiments, the renal disease is chronic kidney disease. In certain embodiments, the renal disease is renal failure. In certain embodiments, the subject has stage 3A chronic kidney disease, stage 3B chronic kidney disease, or stage 4 chronic kidney disease. In certain embodiments, the subject has stage 3A chronic kidney disease. In certain embodiments, the subject has stage 3B chronic kidney disease. In certain embodiments, the subject has stage 4 chronic kidney disease. For example, glomerular filtration rate ("GFR") or estimated glomerular filtration rate ("eGFR") is commonly used to characterize renal function and the stage of chronic kidney disease. The five stages of chronic kidney disease and the GFR of each stage can be judged according to the following criteria: stage 1, with normal or high GFR (GFR>90mL/min/1.73m ² ); stage 2, mild chronic kidney disease (GFR=60- 89mL/min/1.73m ² ); stage 3A, moderate chronic kidney disease (GFR=45-59mL/min/1.73m ² ); stage 3B, moderate chronic kidney disease (GFR=30-44mL/min/1.73m ² ) ; stage 4, severe chronic kidney disease (GFR=15-29 mL/min/1.73 m ² ); stage 5, end-stage chronic kidney disease (GFR<15 mL/min/1.73 m ² ). In certain ^embodiments , the subject's _HCO3- is lost renally or extrarenally. In certain embodiments, the subject has decreased tubular secretion of _NH4 ⁺ . In certain embodiments, the subject has concurrent glomerulonephritis, interstitial nephritis and/or renal failure.

For example, a subject with acute or chronic acid-base imbalance may be in any stage of chronic kidney disease. In certain embodiments, the subject with the disease or condition has not yet reached end-stage renal disease ("ESRD"), sometimes referred to as end-stage chronic renal disease, and is not on dialysis (i.e., the subject has at least mGFR (or eGFR) of 15mL/min/ ^1.73m2 ). In certain embodiments, the subject suffering from the disease or disorder is in stage 3B chronic kidney disease (i.e., the subject has an mGFR (or eGFR) of 30-44 mL/min/1.73 ^m for at least three months) . In certain embodiments, the subject with the disease or disorder is in stage 3A chronic kidney disease (i.e., the subject has an mGFR (or eGFR) of 45-59 mL/min/1.73 ^m for at least three months) . In certain embodiments, the subject suffering from the disease or condition has an mGFR or eGFR of less than 60 mL/min/1.73 ^m2 for at least 3 months. In certain embodiments, the subject suffering from the disease or condition has an mGFR or eGFR of less than 45 mL/min/1.73 ^m2 for at least 3 months. In certain embodiments, the subject suffering from the disease or condition has an mGFR or eGFR of less than 30 mL/min/1.73 ^m for at least 3 months. In certain embodiments, the subject suffering from the disease or condition has an mGFR or ^eGFR of at least 3 months.

In certain embodiments, the diseases or conditions associated with electrolyte imbalance described in this application have one or more of the following indicators: (1) serum pH value is less than about 7.4, (2) serum Cl ^- concentration is greater than about 106 mEq/L, and (3) a serum bicarbonate (HCO ₃ ⁻ ) concentration (eg, a baseline serum bicarbonate (HCO ₃ ⁻ ) concentration) of less than about 24 mEq/L.

In certain embodiments, the subject is a subject with acute or chronic acid-base imbalance characterized by a baseline serum bicarbonate value as low as about 22 mEq/L, to which subject the present application may be administered orally. A pharmaceutical composition that is transported through the digestive system, binds a target ion, and removes the bound target ion through normal biological functions (eg, defecation).

In certain embodiments, the subject described herein has an improved serum anion gap following said treatment and/or remission. In certain embodiments, administration of silver oxide and/or hydrate thereof of the present application, or a pharmaceutical composition comprising it (but not accompanied by delivery of sodium or potassium ions) can treat and/or alleviate acid-base imbalance, can increase Serum bicarbonate, but not with an increase in sodium or potassium. In certain embodiments, the serum anion gap can be improved (eg, decreased) by at least 1 mEq/L or more (eg, at least 2 mEq/L) in as little as 2 weeks.

Silver oxide and/or its hydrate

In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g but not greater than about 25 mmol/g in a simulated gastric buffer ("SGF") assay. In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 5 mmol/g but not greater than about 25 mmol/g in a simulated gastric buffer assay. In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g (e.g., at least about 4.5 mmol/g, at least about 5 mmol/g) in a simulated gastric buffer assay. g, at least about 5.5mmol/g, at least about 6mmol/g, at least about 6.5mmol/g, at least about 7mmol/g, at least about 7.5mmol/g, at least about 8mmol/g, at least about 8.1 mmol/g, at least about 8.2 mmol/g, at least about 8.3 mmol/g, at least about 8.4 mmol/g, at least about 8.5 mmol/g, at least about 8.6 mmol/g, at least about 8.7 mmol /g, at least about 9mmol/g, at least about 9.5mmol/g, at least about 10mmol/g, at least about 10.5mmol/g, at least about 11mmol/g or higher).

The "Simulated Gastric Fluid Buffer" or "SGF" assay describes a test for determining the total chloride ion binding capacity of an analyte using a defined buffer that simulates gastric fluid content. For example, simulated gastric fluid (SGF) can consist of 35mM NaCl and 63mM HCl (pH 1.2). In order to carry out the determination, an appropriate amount of the substance to be tested (for example, silver oxide and/or its hydrate) can be added to about 10 mL of SGF buffer to prepare the composition to be tested. The composition to be tested can be incubated overnight at 37°C for about 12-16 hours while stirring on a rotary mixer. The SGF binding data or binding capacity described herein can be determined over a time period of this duration. Following incubation and mixing, the test tubes containing the substance to be tested can be centrifuged at 500-1000Xg for 2 minutes to pellet the test sample. Approximately 750 µl of the supernatant can be removed and filtered using an appropriate filter, such as a 0.45 µm pore size syringe filter or an 800 µl, 1 µm pore size, 96-well, glass filter plate mounted in a 96-well 2 mL collection board. For the latter approach, multiple samples tested in SGF buffer can be prepared for analysis. Samples can be arranged in a filter plate with a collection plate mounted on the bottom, and the unit can be centrifuged at 1000Xg for 1 minute to filter the sample. In the case of small sample sets, a syringe filter can be used instead of a filter plate to recover ~2-4 mL of filtrate into a 15 mL container. After filtration, each filtrate can be diluted 4 times with water, and the chloride ion content of the filtrate can be measured by ion chromatography (IC). The IC method (e.g. Dionex ICS-2100, Thermo Scientific) consists of an AS11 column and a 15 mM KOH mobile phase with an injection volume of about 5 microliters, a run time of about 3 minutes, a wash/flush volume of about 1000 microliters, and a flow rate of about 1.25 mL/min composition.

In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g but not greater than about 25 mmol/g in a simulated small intestinal inorganic buffer ("SIB") assay. In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g (e.g., at least about 4.5 mmol/g, at least about 5 mmol) in a simulated small intestine inorganic buffer assay. /g, at least about 5.5mmol/g, at least about 6mmol/g, at least about 6.5mmol/g, at least about 7mmol/g, at least about 7.5mmol/g, at least about 8mmol/g, at least About 8.1 mmol/g, at least about 8.2 mmol/g, at least about 8.3 mmol/g, at least about 8.4 mmol/g, at least about 8.5 mmol/g, at least about 8.6 mmol/g, at least about 8.7 mmol/g, at least about 9 mmol/g, at least about 9.5 mmol/g, at least about 10 mmol/g, at least about 10.5 mmol/g, at least about 11 mmol/g or higher).

"Simulated Small Intestine Inorganic Buffer" or "SIB" is a test that determines the chloride and phosphate binding capacity of a substance to be tested (eg, silver oxide and/or hydrates thereof) in a Selective Specific Interfering Buffer Assay (SIB). Using the Selective Specific Interference Buffer Assay (SIB), the chloride ion and phosphate binding capacity of the analyte can be determined according to the following steps: The buffer used for the SIB assay can contain 36mM NaCl, 20mM NaH ₂ PO buffered to pH 5.5 ₄ and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES). The SIB buffer may contain the chloride ion, phosphate concentration and pH found in the human duodenum and upper gastrointestinal tract. For example, to carry out the assay, an appropriate amount of the substance to be tested can be added to 10 mL of SIB buffer. The mixture can be incubated at 37°C for about 1 hour while stirring on a rotary mixer. After incubation and mixing, the container containing the substance to be tested can be centrifuged at 1000Xg for 2 minutes to pellet the test sample. Approximately 750 microliters of the supernatant can be removed and filtered using approximately 800 microliters of a 1 micron pore size 96-well glass filter plate that has been assembled into a 96-well 2 mL collection plate. With this arrangement, multiple samples tested in SIB buffer can be prepared for analysis. With samples arrayed in filter plates and bottom fitted collection plates, the device can be centrifuged at 1000Xg for approximately 1 minute to filter the samples. In the case of small sample sets, a syringe filter (0.45 micron) can be used in place of the filter plate to recover -2-4 mL of filtrate into a 15 mL vial. After filtering into a collection plate, each filtrate can be diluted and then measured for chloride or phosphate content. For the measurement of chloride and phosphate, the filtrate to be analyzed is diluted 4-fold with water. The chloride and phosphate content of the filtrate was measured by ion chromatography (IC). An IC method (eg Dionex ICS-2100, Thermo Scientific) may consist of an AS24A column, 45 mM KOH mobile phase, 5 microliter injection volume with about 10 minute run time, 1000 microliter wash/flush volume, and a flow rate of 0.3 mL/min.

In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g but not greater than about 25 mmol/g in a simulated small intestinal organic and inorganic buffer ("SOB") assay . In certain embodiments, the silver oxide and/or hydrate thereof has a chloride ion binding capacity of at least about 4 mmol/g (e.g., at least about 4.5 mmol/g, at least About 5mmol/g, at least about 5.5mmol/g, at least about 6mmol/g, at least about 6.5mmol/g, at least about 7mmol/g, at least about 7.5mmol/g, at least about 8mmol/g, At least about 8.1 mmol/g, at least about 8.2 mmol/g, at least about 8.3 mmol/g, at least about 8.4 mmol/g, at least about 8.5 mmol/g, at least about 8.6 mmol/g, at least about 8.7 mmol/g, at least about 9 mmol/g, at least about 9.5 mmol/g, at least about 10 mmol/g, at least about 10.5 mmol/g, at least about 11 mmol/g or higher).

"Simulated Small Intestinal Organic and Inorganic Buffer" or "SOB" is a test for the determination of chloride ion binding capacity in the presence of organic and inorganic interferents commonly found in the gastrointestinal tract. In the presence of specific organic interfering substances that are common in the gastrointestinal tract, the chloride ion binding capacity and other anion binding capacities of the substance to be tested can be determined as follows: In order to simulate the conditions of the gastrointestinal tract lumen, SOB screening can be used to determine the Chloride binding capacity of a substance when exposed to chloride ions in the presence of other potentially competing anions such as bile acids, fatty acids, phosphate, acetate and citrate. For example, an assay buffer for an SOB assay may contain 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 50 mM sodium acetate, 36 mM sodium chloride, 7 mM sodium phosphate, 1.5 mM Sodium citrate, 30 mM oleic acid and 5 mM sodium taurocholate. Concentrations of potentially competing anions reflect typical gastrointestinal luminal concentrations found at various points in the gastrointestinal tract, and the pH is an average of representative pH values encountered in the duodenum and large intestine. The concentration of chloride ion used was the same as that used in the SIB screening. For this assay, the substance to be tested is accurately weighed into a 16x100 mm glass tube with a liquid-tight screw cap. Add an appropriate amount of SOB buffer to the test tube. The mixture can be incubated at 37°C for about 2 hours while stirring on a rotisserie mixer. After incubation and mixing, approximately 600 microliters of the supernatant was removed and filtered using a 96-well glass filter plate. With the sample lined up in the filter plate and bottom fitted collection plate, centrifuge the device at 1000Xg for 1 minute to filter the sample. In the case of small sample sets, a syringe filter can be used in place of the filter plate to recover ~2-4 mL of filtrate into a 15 mL vial. After filtration into collection plates, each filtrate was diluted appropriately and then assayed for anion content. An IC method (eg Dionex ICS-2100, Thermo Scientific) may consist of an AS24A column, a 20 mM-100 mM KOH gradient, a 5 microliter injection volume with a 30 minute run time, a 1000 microliter wash/rinse volume and a flow rate of 0.3 mL/min. This method is suitable for the quantification of chloride, phosphate and taurocholate.

In certain embodiments, the silver oxide includes or is silver monoxide (AgO). In certain embodiments, the silver oxide includes or is silver monoxide (Ag ₂ O). In certain embodiments, the silver oxide includes or is silver oxide (Ag ^I Ag ^III O ₂ ). In certain embodiments, the silver oxide includes or is tetrasilver tetroxide (Ag ₄ O ₄ ).

In certain embodiments, the silver oxide hydrate has the formula Ag _x O _y (H ₂ O) _z , wherein x, y, and z are each independently any positive number (eg, including integers and non-integers) ), and x=2y. In some embodiments, the value of z is any integer or non-integer between 0.5 and 20. In certain embodiments, the value of z is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20. In some embodiments, the value of x is 1-20. In some embodiments, the value of x is 1-4. In some embodiments, the value of y is 0.5-10. In some embodiments, the value of y is 0.5-2.

In certain embodiments, the silver oxide hydrate has a molecular formula of Ag _x O _y (H ₂ O) _z , wherein the value of x is any positive number between 1 and 20, and the value of y is between 0.5 and Any positive number between 10, and the value of z is any positive number between 0.5 and 4, and x=2y. In certain embodiments, the silver oxide hydrate has a molecular formula of Ag _x O _y (H ₂ O) _z , wherein the value of x is any positive number between 1 and 4, and the value of y is between 0.5 and Any positive number between 2, and the value of z is any positive number between 0.5 and 6, and x=2y. In certain embodiments, the silver oxide hydrate has the formula Ag ₂ O(H ₂ O), Ag ₂ O(H ₂ O) ₂ , Ag ₄ O ₂ (H ₂ O), Ag ₄ O ₂ (H ₂ O) ₂ , Ag ₈ O ₄ (H ₂ O) ₂ . In certain embodiments, the hydrate of silver oxide is silver hydroxide (AgOH).

In one aspect, the present application provides methods of alleviating and/or treating elevated blood hydrogen ion concentrations (eg, pH values below 7.4) using _Ag2O . In another aspect, the present application provides methods of alleviating and/or treating elevated blood hydrogen ion concentrations (eg, pH values below 7.4) using AgOH. In one aspect, the present application provides a method for alleviating and/or treating excessive blood chloride ion concentration (eg, chloride ion concentration greater than 106 mEq/L) using Ag ₂ O. In another aspect, the present application provides methods for alleviating and/or treating excessive blood chloride ion concentration (eg, chloride ion concentration greater than 106 mEq/L) using AgOH.

treatment method

In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively relieves and/or treats the subject Diseases or conditions associated with electrolyte imbalance as described in .

In certain embodiments, the medicament described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively raises the serum pH in experimenter value.

In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively reduces the serum H in the subject. ⁺ Concentration. In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively delays or prevents the Elevation of serum H ⁺ concentration.

In certain embodiments, administration of the drug (for example, silver oxide described herein and/or its hydrate, or a pharmaceutical composition described herein) is administered compared to no administration of the drug described herein The serum pH of the latter subject may be increased by at least about 0.05% but not by more than about 300%. In certain embodiments, administration of the drug (for example, silver oxide described herein and/or its hydrate, or a pharmaceutical composition described herein) is administered compared to no administration of the drug described herein The subject's serum pH is increased by at least about 0.05% (e.g., at least about 0.1%, at least about 0.15%, at least about 0.2%, at least about 0.25%, at least about 0.3%, at least About 0.35%, at least about 0.4%, at least about 0.45%, at least about 0.5%, at least about 0.55%, at least about 0.6%, at least about 0.65%, at least about 0.7%, at least about 0.75% %, at least about 0.8%, at least about 0.85%, at least about 0.9%, at least about 0.95%, at least about 1% or more).

In some embodiments, compared with not administering the drug of the present application, administering the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) The serum pH of the latter subject increases by at least about 0.05 but not more than about 2. In some embodiments, compared with not administering the drug of the present application, administering the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) The serum pH of said subject is increased by at least about 0.05 (e.g., by at least about 0.1, by at least about 0.15, by at least about 0.2, by at least about 0.25, by at least about 0.3, by at least about 0.35, by at least about 0.4, at least about 0.45, at least about 0.5, at least about 0.55, at least about 0.6, at least about 0.65, at least about 0.7, at least about 0.75, at least about 0.8, at least about 0.85, at least about 0.9, at least an increase of about 0.95, at least an increase of about 1 or more).

In some embodiments, compared with no administration of the drug, the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) after the application of the drug The subject's serum pH is substantially controlled or substantially normalized.

In some embodiments, compared with not administering the drug of the present application, administering the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) The subject's serum pH increases to at least about 7.3 (e.g., at least about 7.31, at least about 7.32, at least about 7.33, at least about 7.34, at least about 7.35, at least about 7.36, at least about 7.37, at least about 7.38, At least about 7.39, at least about 7.40, at least about 7.41, at least about 7.42, at least about 7.43, at least about 7.44, at least about 7.45, at least about 7.46, at least about 7.47, at least about 7.48, at least about 7.49, at least about 7.50 or higher ). In some embodiments, the drug (for example, the silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) makes the subject's serum pH return to normal levels, for example back to about 7.35-7.45. In some embodiments, the drug (for example, the silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) makes the subject's serum pH return to normal levels, for example back to about 7.4.

In some embodiments, after applying the drug (for example, silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) for more than about 5 hours (for example, more than about 7 hours) After, after about 12 hours, after about 18 hours, after about 24 hours, after about 2 days, after about 3 days, after about 4 days, after about 5 days, after about 6 days, after about 7 days, After about 8 days, after about 9 days, after about 10 days, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 1.5 months, after about 2 months or longer) , making the subject's serum pH return to a normal level. In certain embodiments, in the present application, the silver oxide and/or hydrate thereof is effective to delay or prevent the decrease of serum pH in the subject.

In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively reduces the serum Cl in the experimenter. ^{-Concentration} .

In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively delays or prevents the Increased serum Cl- concentration.

In some embodiments, compared with no administration of the drug, the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) after the application of the drug The subject's serum ^Cl- concentration is reduced by at least about 1 mEq/L but not by more than about 10 mEq/L. In some embodiments, compared with no administration of the drug, the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) after the application of the drug The subject's serum Cl ^- concentration is reduced by at least about 1 mEq/L (e.g., at least about 1.5 mEq/L, at least about 2 mEq/L, at least about 2.5 mEq/L, at least about 3 mEq/L, at least about 3.5 mEq/L, at least about 4 mEq/L, at least about 4.5 mEq/L, at least about 5 mEq/L, at least about 5.5 mEq/L, at least about 6 mEq/L or more).

In some embodiments, the drug (for example, the silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) makes the experimenter's serum ^Cl concentration substantially controlled or substantially normalized.

In some embodiments, the drug (for example, the silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) makes the subject's serum ^Cl concentration return to Normal levels, such as recovery to about 106mEq/L.

In some embodiments, after applying the drug (for example, silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) for more than about 5 hours (for example, more than about 7 hours) After, after about 12 hours, after about 18 hours, after about 24 hours, after about 2 days, after about 3 days, after about 4 days, after about 5 days, after about 6 days, after about 7 days, After about 8 days, after about 9 days, after about 10 days, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 1.5 months, after about 2 months or longer) , such that the subject's serum Cl ^- concentration is substantially restored to normal levels (eg, to about 106 mEq/L).

In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively improves the serum HCO in the subject. ₃ ^- value.

In some embodiments, the drug described in the application (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) effectively delays or prevents the Decrease in serum HCO ₃ ^{-concentration} .

In some embodiments, compared with no administration of the drug, the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) after the application of the drug The subject's serum HCO ₃ ^{-concentration} increases by at least about 1 mEq/L but does not increase by more than about 10 mEq/L. In some embodiments, compared with no administration of the drug, the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) after the application of the drug The subject's serum HCO ₃ ^{-concentration} increases by at least about 1 mEq/L (e.g., at least about 1.5 mEq/L, at least about 2 mEq/L, at least about 2.5 mEq/L, at least about 3 mEq/L, at least about 3.5 mEq/L , at least about 4 mEq/L, at least about 4.5 mEq/L, at least about 5 mEq/L, at least about 5.5 mEq/L, at least about 6 mEq/L or more).

In some embodiments, compared with no administration of the drug, the drug (for example, the silver oxide described in the application and/or its hydrate, or the pharmaceutical composition described in the application) after the application of the drug The subject's serum _HCO3 ^- concentration is substantially controlled or substantially normalized.

In certain embodiments, the drug (eg, silver oxide and/or hydrates thereof described herein, or the pharmaceutical composition described herein) makes the subject's serum HCO ₃ ^{-concentration} substantially Return to normal levels, for example to about 22-26mEq/L.

In some embodiments, after applying the drug (for example, silver oxide described herein and/or its hydrate, or the pharmaceutical composition described herein) for more than about 5 hours (for example, more than about 7 hours) After, after about 12 hours, after about 18 hours, after about 24 hours, after about 2 days, after about 3 days, after about 4 days, after about 5 days, after about 6 days, after about 7 days, more than about 8 days, more than about 9 days, more than about 10 days, more than about 2 weeks, more than about 3 weeks, more than about 4 weeks, more than about 1.5 months, or more than about 2 months), such that The subject's serum HCO ₃ ^{-concentration} substantially returned to normal levels.

The medicaments of the present application can be administered orally (eg, orally). In certain embodiments, the drug may be administered with a meal. In certain embodiments, the drug may be administered on an empty stomach.

In certain embodiments, in the present application, before eating (for example, at least 1 min before eating, at least 5 min before, at least 10 min before, at least 30 min before, at least 1 h before, at least 2 h before, at least 3 h before, or at least 6 hours before) taking the drug (for example, the silver oxide and/or its hydrate described in this application, or the pharmaceutical composition described in this application).

In certain embodiments, the drug may be taken after eating (e.g., at least 1 min, at least 5 min, at least 10 min, at least 30 min, at least 1 h, at least 2 h, at least 3 h, or at least 6 h after eating). The above-mentioned medicine (for example, the silver oxide and/or its hydrate described in this application, or the pharmaceutical composition described in this application).

In certain embodiments, the therapeutically effective dosage of the silver oxide and/or its hydrate described in the application, or the pharmaceutical composition described in the application is about 2 mg/kg/d to about 250 mg/kg/d (for example , about 3mg/kg/d to about 240mg/kg/d, about 4mg/kg/d to about 230mg/kg/d, about 5mg/kg/d to about 220mg/kg/d, about 6mg/kg/d to about About 210 mg/kg/d, about 7 mg/kg/d to about 200 mg/kg/d, about 8 mg/kg/d to about 190 mg/kg/d, about 9 mg/kg/d to about 180 mg/kg/d, about 10 mg/kg/d to about 170 mg/kg/d, about 11 mg/kg/d to about 160 mg/kg/d, about 12 mg/kg/d to about 150 mg/kg/d, about 13 mg/kg/d to about 140 mg /kg/d, about 14mg/kg/d to about 130mg/kg/d, about 15mg/kg/d to about 120mg/kg/d, about 16mg/kg/d to about 110mg/kg/d, about 17mg/kg/d kg/d to about 100 mg/kg/d, about 18 mg/kg/d to about 90 mg/kg/d, about 19 mg/kg/d to about 80 mg/kg/d, about 20 mg/kg/d to about 70 mg/kg /d, about 21mg/kg/d to about 60mg/kg/d, about 21mg/kg/d to about 50mg/kg/d, about 22mg/kg/d to about 45mg/kg/d, about 23mg/kg/d d to about 40 mg/kg/d, about 25 mg/kg/d to about 35 mg/kg/d or about 26 mg/kg/d to about 30 mg/kg/d). In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 3 mg/kg/d to about 240 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 4 mg/kg/d to about 230 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 5 mg/kg/d to about 220 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 6 mg/kg/d to about 210 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 7 mg/kg/d to about 200 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 8 mg/kg/d to about 190 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 9 mg/kg/d to about 180 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 10 mg/kg/d to about 170 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 11 mg/kg/d to about 160 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 12 mg/kg/d to about 150 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 13 mg/kg/d to about 140 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 14 mg/kg/d to about 130 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 15 mg/kg/d to about 120 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 16 mg/kg/d to about 110 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 17 mg/kg/d to about 100 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 18 mg/kg/d to about 90 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 19 mg/kg/d to about 80 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 20 mg/kg/d to about 70 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 21 mg/kg/d to about 60 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 21 mg/kg/d to about 50 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 22 mg/kg/d to about 45 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 23 mg/kg/d to about 40 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 25 mg/kg/d to about 35 mg/kg/d. In certain embodiments, the therapeutically effective dose of the silver oxide and/or its hydrate described herein, or the pharmaceutical composition described herein is about 26 mg/kg/d to about 30 mg/kg/d).

In some embodiments, it can be performed according to 1 time/day, 2 times/day, 3 times/day, 4 times/day, 5 times/day, 1 time/week, 2 times/week, 3 times/week, 4 times/day times/week, 5 times/week, 6 times/week, 1 time/2 weeks, 1 time/3 weeks, 1 time/month, 1 time/2 months, 1 time/3 months, 1 time/6 The drug (for example, the silver oxide and/or its hydrate described in the present application, or the pharmaceutical composition described in the present application) is administered at a dosing frequency of monthly or 1 time/year. In certain embodiments, the administration can be done daily, every other day, every other day, every week, every month, or every year.

In certain embodiments, the duration of each course of treatment can be at least 1 day, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, At least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 1.5 years, at least 2 years or more.

In certain embodiments, administering a daily dose of a drug described herein (e.g., silver oxide and/or a hydrate thereof described herein, or a pharmaceutical composition described herein) has a removal rate of at least about 5 mEq/ days, but not more than about 100 mEq of target species/ion (eg, hydrogen and/or chloride) capacity. In certain embodiments, administering a daily dose of a drug described herein (e.g., silver oxide and/or a hydrate thereof described herein, or a pharmaceutical composition described herein) has a removal rate of at least about 5 mEq/ day (e.g., at least about 6 mEq/day, at least about 7 mEq/day, at least about 8 mEq/day, at least about 9 mEq/day, at least about 10 mEq/day, at least about 11 mEq/day, at least about 12 mEq/day, at least about 13 mEq/day day, at least about 14 mEq/day, at least about 15 mEq/day, at least about 16 mEq/day, at least about 17 mEq/day, at least about 18 mEq/day, at least about 19 mEq/day, at least about 20 mEq/day, at least about 21 mEq/day, At least about 22 mEq/day, at least about 23 mEq/day, at least about 24 mEq/day, at least about 25 mEq/day, at least about 26 mEq/day, at least about 27 mEq/day, at least about 28 mEq/day, at least about 29 mEq/day, at least about 30 mEq/day, at least about 31 mEq/day, at least about 32 mEq/day, at least about 33 mEq/day, at least about 34 mEq/day, at least about 35 mEq/day, at least about 36 mEq/day, at least about 37 mEq/day, at least about 38 mEq/day day, at least about 39 mEq/day, at least about 40 mEq/day, at least about 41 mEq/day, at least about 42 mEq/day, at least about 43 mEq/day, at least about 44 mEq/day, at least about 45 mEq/day, at least about 46 mEq/day, At least about 47 mEq/day, at least about 48 mEq/day, at least about 49 mEq/day, at least about 50 mEq/day, at least about 51 mEq/day or more) of target substances/ions (e.g., hydrogen ions and/or chloride ions) capacity.

In certain embodiments, in the present application, the administration dose, the administration of the drug of the present application (for example, the silver oxide described in the present application and/or its hydrate, or the pharmaceutical composition described in the present application) Drug interval, dosing frequency, course of treatment, etc. can be adjusted according to the subject's serum pH value, serum hydrogen ion concentration, serum chloride ion concentration and/or serum bicarbonate concentration, so as to control the subject's serum pH value, serum Hydrogen ion concentration, serum chloride ion concentration, and/or serum bicarbonate concentration remain within the normal range.

pharmaceutical composition

In some embodiments, the pharmaceutical composition described in the present application contains the silver oxide described in the present application and/or its hydrate, and one or more pharmaceutically acceptable adjuvants, carriers and/or excipients agent.

In certain embodiments, the pharmaceutical compositions described herein are oral formulations.

In certain embodiments, the pharmaceutical compositions described herein contain about 100 mg to about 5 g (e.g., about 200 mg to about 2.5 g, about 300 mg to about 2.5 g, about 400 mg to about 2.5 g, about 500 mg to about 2.5 g g, from about 500 mg to about 2 g, from about 500 mg to about 1.5 g, or from about 500 mg to about 1 g) of silver oxide and/or its hydrate described herein. In certain embodiments, the pharmaceutical composition described herein contains about 100 mg to about 5 g of the silver oxide described herein and/or its hydrate. In certain embodiments, the pharmaceutical composition described herein contains about 200 mg to about 2.5 g of silver oxide and/or its hydrate described herein. In certain embodiments, the pharmaceutical composition described herein contains about 300 mg to about 2.5 g of the silver oxide described herein and/or its hydrate. In certain embodiments, the pharmaceutical composition described herein contains about 400 mg to about 2.5 g of the silver oxide described herein and/or its hydrate. In certain embodiments, the pharmaceutical composition described herein contains about 500 mg to about 2.5 g of the silver oxide described herein and/or its hydrate. In certain embodiments, the pharmaceutical composition described herein contains about 500 mg to about 2 g of the silver oxide described herein and/or its hydrate. In certain embodiments, the pharmaceutical composition described herein contains about 500 mg to about 1.5 g of the silver oxide described herein and/or its hydrate. In certain embodiments, the pharmaceutical composition described herein contains about 500 mg to about 1 g of the silver oxide described herein and/or its hydrate.

In some embodiments, the pharmaceutical composition of the present application is solid, liquid, emulsion or suspension. In some embodiments, the pharmaceutical composition of the present application is pill, lozenge, sachet, cachet, elixir, suspension, syrup, soft or hard capsule, tablet, Powder, powder, granule, drop pill or film.

In certain embodiments, the pharmaceutical composition of the present application further comprises one or more other active ingredients (eg, one or more other ingredients that can regulate electrolyte balance). In some embodiments, the pharmaceutical composition further comprises potassium ions, phosphorus, sodium, magnesium, vitamins and/or glucose and the like. In certain embodiments, the pharmaceutical compositions described herein comprise one or more inactive ingredients. In certain embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers, stabilizers, excipients, diluents, solubilizers, surfactants, emulsifiers and/or preservatives and other suitable preparations. Acceptable ingredients of the compositions are preferably nontoxic to the subject at the dosages and concentrations employed.

The pharmaceutical compositions of the present application may be co-administered with additional pharmaceutically active agents, depending on the condition to be treated. The co-administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. In certain embodiments, for example, for the treatment of metabolic acidosis, the pharmaceutical compositions described herein may be co-administered with the usual treatments required to treat underlying comorbidities, including but not limited to high Blood pressure, diabetes, obesity, heart failure and complications of chronic kidney disease.

Not intending to be limited by any theory, the following examples are only to illustrate the medicaments, pharmaceutical compositions , methods and uses of the present application, and are not intended to limit the scope of the present invention.

Example

Materials and Methods

1. Preparation of Sevelamer and Its Derivatives

Sevelamer and its derivatives are prepared according to the method described in CN105377270A.

Briefly, put 100 g of sevelamer carbonate (Renvela) resin into a 5 liter beaker, add 2 liters of 1M aqueous sodium hydroxide solution, keep stirring for 30 minutes, vacuum filter, collect the solid, and repeat the sodium hydroxide treatment process 2 times, the solid was collected, and the resin was washed with ultrapure water until the pH of the filtrate was 7 or lower. The wet polymer was transferred to a glass tray, frozen at -40°C for 1 hour, and then freeze-dried for 3-5 days to obtain dry free aminosevelamer resin. Carbonic acid sevelamer resin and free ammonia sevelamer resin will be used as control compounds for performance evaluation experiments.

2. Preparation of quaternary ammonium resin and its derivatives

Put 100 grams of Dowex 1X8 (Cl) resin into a 5-liter beaker, add 2 liters of 1M sodium hydroxide aqueous solution, continue to stir for 30 minutes, vacuum filter, collect the solid, repeat the treatment process of sodium hydroxide 2 times, collect the solid, The resin was washed with ultrapure water until the pH of the filtrate was 7 or lower. The wet polymer was transferred to a glass tray, frozen at -40°C for 1 hour, and then freeze-dried for 3-5 days to obtain a dry quaternary ammonium base Dowex resin.

Put 10 grams of Dowex 1X8 (Cl) quaternary ammonium type anion exchange resin into a 1 liter beaker, add 200 milliliters of 2M sodium bicarbonate aqueous solution, keep stirring for 30 minutes, vacuum filter, collect the solid, repeat the treatment process of sodium bicarbonate 2 Once, the solid was collected, and the resin was washed with ultrapure water until the pH of the filtrate was 7 or lower. The wet polymer was transferred to a glass tray, frozen at -40°C for 1 hour, and then freeze-dried for 3-5 days to obtain dry bicarbonate Dowex resin.

Quaternary ammonium base Dowex resin and bicarbonate Dowex resin were used as control compounds for performance evaluation experiments.

3. Preparation of cholestyramine and its derivatives

Put 100 grams of cholestyramine resin into a 5-liter beaker, add 2 liters of 1M aqueous sodium hydroxide solution, continue to stir for 30 minutes, vacuum filter, collect the solid, repeat the treatment process of sodium hydroxide 2 times, collect the solid, and use The resin was washed with ultrapure water until the pH of the filtrate was 7 or lower. The wet polymer was transferred to a glass tray, frozen at -40°C for 1 hour, and then freeze-dried for 3-5 days to obtain a dry quaternary ammonium base cholestyramine resin. Put 10 grams of cholestyramine resin into a 1-liter beaker, add 200 milliliters of 2M sodium bicarbonate aqueous solution, continue to stir for 30 minutes, vacuum filter, collect the solid, repeat the treatment process of sodium bicarbonate 2 times, collect the solid, and use The resin was washed with ultrapure water until the pH of the filtrate was 7 or lower. The wet polymer was transferred to a glass tray, frozen at -40°C for 1 hour, and then freeze-dried for 3-5 days to obtain a dry cholestyramine bicarbonate resin.

The quaternary ammonium base cholestyramine resin and bicarbonate cholestyramine resin will be used as control compounds for performance evaluation experiments.

4. Preparation of Veverimer (TRC101)

Refer to Gerrit Klaerner et al., 2020, J.Pharmacol.Exp.Ther.375:439–450 and CN105377270A and CN109414453A to prepare and evaluate Veverimer.

Example 1 In vitro performance evaluation

In in vitro tests, the performance of silver oxide (Ag ₂ O) was compared with a control compound.

The gastric acid binding capacity (SGF assay), the chloride ion binding capacity under phosphate competitive conditions (SIB assay), and the chloride ion binding capacity in the presence of inorganic and organic interfering substances (SOB assay) were respectively determined for each substance to be tested. ), binding acid retention (SGF-FASSCoF-SGF assay), hydrochloric acid binding kinetics, hydrochloric acid binding capacity under simulated fasting conditions, hydrochloric acid binding capacity under simulated meal conditions, and chloride ion binding capacity kinetics in various standard simulated gastrointestinal fluids Compare with pill burden.

1.1 Comparison of the chloride ion binding capacity of each test substance in the determination of SGF, SIB and SOB

For the specific experimental method, refer to the method described in CN105377270A. Among them, the chloride ion binding capacity in SGF represents the binding capacity of the test substance to chloride ions in the simulated gastric juice environment. Since there is no competing anion, it can be considered that the determination is the saturated binding capacity of the test substance to chloride ions. The chloride ion binding capacity in SIB is characterized by the binding capacity of the substance to be tested to chloride ions in the simulated intestinal fluid environment, under the condition that only phosphate ions compete. The chloride ion binding capacity in SOB is characterized by the binding capacity of the substance to be tested to chloride ion in the simulated intestinal fluid environment under the condition of competition between phosphate and various organic anions. Since the orally administered substance to be tested passes through the stomach and intestines in sequence in the digestive tract, the adsorption capacity in the intestinal juice environment can better reflect the effect of the substance to be tested on the adsorption of chloride ions in the body. Therefore, the chloride ion in the determination of SIB and/or SOB Binding capacity was used as the main index of this evaluation experiment. The results show (see Table 1), the adsorption capacity of silver oxide to chloride ion in SGF is slightly lower than that of Veverimer and Sevelamer, but it is significantly better than the results of various amino resins in the determination of SIB and SOB. In addition, the adsorption capacity of silver oxide for chloride ions was significantly higher than that of silver carbonate under different conditions.

Table 1

1.2 Binding acid retention performance (SGF-FASSCoF-SGF assay)

Oral administration of the substance to be tested passes through the stomach-small intestine-colorectum sequentially in the digestive tract. The gastric juice has the lowest pH value/the strongest acidity. The test substance passes further through the intestinal tract, and due to the increase in pH/alkalinity, the hydrochloric acid bound to the test substance is partially released.

In this experiment, the substance to be tested is treated with simulated gastric juice SGF and simulated colonic fluid FASSCoF sequentially. In SGF, the substance to be tested is combined with hydrochloric acid to the greatest extent. After the process of the gastrointestinal tract, the test substance is finally treated with SGF, so that the test substance will bind hydrochloric acid again. Thus, through the whole digestive tract, the binding acid retention of the substance to be tested is calculated according to the following formula:

Bound acid retention = Acid binding capacity for first entry into SGF - Acid binding capacity for second entry into SGF

As can be seen from the results in Table 2, the performance of silver oxide in the combined acid retention test is significantly better than that of amino resins (for example, sevelamer carbonate or free ammonia sevelamer), and surprisingly, the performance of silver oxide is also superior to silver carbonate.

Table 2

1.3 Determination of hydrochloric acid binding capacity (pH capacity) under simulated fasting conditions

On an empty stomach, the total amount of hydrochloric acid in the stomach is small, and the binding of the substance to be tested to hydrochloric acid is difficult to reach the saturated binding capacity. Prepare sodium chloride/hydrochloric acid mixed solutions with pHs of 1.2, 1.6, 2.0, 3.0, 4.0, 5.0, and 5.5 respectively, wherein the concentration of sodium chloride is 100 mmol/L. Put 25 mg of the solid substance to be tested into 10 mL of solutions with different pHs, soak for 2 hours, detect the pH change in the solution, and calculate the binding capacity of the substance to be tested to hydrogen ions. From the results in Figure 1, it can be seen that the hydrochloric acid binding capacity of amino resins represented by sevelamer decreases when the pH is high. Similarly, the hydrochloric acid binding capacity of silver carbonate decreases at higher pH. However, silver oxide can maintain a high hydrochloric acid binding capacity at different pH.

1.4 Simulated acid binding capacity under meal conditions

Gastric acid secretion increases after eating, and the binding of the test substance to hydrochloric acid is closer to the saturated binding capacity. Prepare sodium chloride/hydrochloric acid mixed solutions with pHs of 1.5, 3.0, 5.0 and 7.0 respectively, wherein the concentration of sodium chloride is 100mmol/L. Add 400mg solid substance to be tested into 100mL solution, keep stirring for 18 hours, monitor the pH of the solution in real time, maintain the pH of the solution at the initial pH by adding 0.1N hydrochloric acid dropwise, record the total amount of hydrochloric acid added, and calculate the effect of the substance to be tested on Saturation binding capacity of hydrochloric acid. It can be seen from the results (Figure 2) that the saturated binding capacity of silver oxide to hydrochloric acid remains unchanged at different pHs, and is always higher than that of silver carbonate, while the saturated binding capacity of Veverimer to hydrochloric acid decreases with the increase of pH. Silver oxide has a higher saturated acid binding capacity than Veverimer over the intestinal pH range.

1.5 Test the adsorption kinetics of silver oxide on chloride ions in various standard simulated gastrointestinal fluids

Standard simulated gastrointestinal fluids include: FaSSGF (pH = 1.6), FeSSGF (pH = 5), FaSSIF (pH = 6.5), FeSSIF (pH = 5.0), FaSSIF-V2 (pH = 6.5), FeSSIF-V2 (pH = 5.8), FaSSCoF (pH=7.8) and 100mM NaCl, FeSSCoF (pH=6.0) and 100mM NaCl. The results are shown in Table 3. It can be seen from Table 3 that under various standard simulated gastrointestinal fluid conditions, the adsorption rate of silver oxide to chloride ions is fast, and the binding capacity reaches above 8 mmol/g.

table 3

1.6 Comparison of pill burden

The dosage of the drug disclosed in the clinical trials of Veverimer is 3-9 g per day, calculated at a density of 1 g/cm ³ , the volume of the drug is about 3-9 cm ³ , that is, about 10-30 tablets.

Based on the SOB test results, the efficacy of silver oxide is about 2.2 times that of Veverimer, the estimated daily dosage is 1.4-4.1g, the density of silver oxide is 7.5g/cm ³ , and the corresponding number of tablets is 0.6-1.8. Greatly reduces the burden of pills.

From the above experimental results, it can be seen that the drug effect of silver oxide is significantly better than that of amino resins (eg, Veverimer).

In addition, silver oxide has the following advantages over silver carbonate:

Has a higher chlorine binding capacity;

Has a higher hydrogen/acid binding capacity;

Does not produce acidic carbonic acid (H ₂ CO ₃ );

It does not produce a large amount of carbon dioxide gas, thereby avoiding side effects such as abdominal distension and belching.

Example 2 In vivo functional evaluation

In animals, the performance of silver oxide ( _Ag2O ) was compared to a control compound.

Specifically, in healthy rats, chronic metabolic acidosis model rats, and acute metabolic acidosis model rats, the test substance and the control substance were administered, and the test substance combined with chloride ions in the animal body was compared, and the increase in fecal chlorine Ion discharge, increase urine pH, increase blood pH, increase serum bicarbonate concentration, reduce serum chloride ion content, increase serum residual alkali, correct acidosis and other effects.

2.1 Healthy rats

Take 7-8 week male SD rats, 3 in a group, 6 groups in total, respectively: blank group (sterile water), sodium bicarbonate group (2.2mmol Na/kg/day=185mg/kg/day), Silver oxide half dose group (1.1mmol Ag/kg/day＝127mg/kg/day), silver oxide equal dose group (2.2mmol Ag/kg/day＝255mg/kg/day), silver oxide double dose group (4.4mmol Ag/kg/day=510mg/kg/day) and silver oxide triple dose group (6.6mmol Ag/kg/day=765mg/kg/day). From the 1st day to the 7th day, the blank group was gavaged with sterile water every day, and the rest of the administration groups were respectively administered a fixed dose of the test substance solution. On the first day and the seventh day, the blood gas analysis of rats was performed with the Abbott blood gas analyzer i-STAT 300G, and the blood pH, serum bicarbonate, and serum residual alkali were recorded. Blood was collected to make serum, and the serum chlorine content was detected with a blood chlorine kit (results are shown in Table 4). Rats were transferred to metabolic cages with one cage per cage for feeding for 1 day, during which feces were collected for 24 hours, and the feces were freeze-dried and ground into powder, weighed, and the chloride ion content was detected by X-ray fluorescence spectrometer (results are shown in the table 5).

The results in Table 4 show that silver oxide can effectively increase blood pH, increase blood HCO ₃ ^- content, and increase blood residual alkali content. The changes of these indicators are dose-dependent, and the same dose of silver oxide has similar effects to sodium bicarbonate .

Table 4

table 5

The results in Table 5 show that silver oxide reduces blood chlorine content and increases daily fecal chlorine excretion, and the effect increases roughly with dose increase, while sodium bicarbonate does not have the above effects.

2.2 Ammonium chloride induced (acute acidosis) rats

Take 7-8 week male SD rats, 6 in the blank group, drink water normally; add 0.28mol/L ammonium chloride in the drinking water of the acidosis model group, a total of 4 groups, 6 in each group, divided into blank control group , low-dose silver oxide single administration group, medium-dose single-dose silver oxide administration group, middle-dose silver oxide twice-administration group and high-dose silver oxide single administration group. From the first day, the control solution, low-dose silver oxide, medium-dose silver oxide and high-dose silver oxide were used for intragastric administration. Single administration refers to once-a-day administration, and double administration refers to dividing the daily dose into two administrations. Blood was drawn on days 0, 3, 5, and 7, urine was collected, and urine pH, blood pH, blood bicarbonate, and blood chloride were tested.

Results: Silver oxide can effectively correct acidosis, increase blood pH, increase blood HCO ₃ ^- , and lower blood Cl, and the effect is dose-dependent, and the difference in administration times (once or twice a day) has little effect on the effect . Specifically, the results in Table 6 show that in the case where ammonium chloride drinking water significantly reduces blood bicarbonate levels, leading to acute acidosis, administration of silver oxide can reduce the degree of decline in blood bicarbonate and increase blood bicarbonate levels at higher doses. Bicarbonate levels.

Table 6

2.3 Adenine-induced (chronic acidosis) rats

Male SD rats were taken, and chronic kidney disease was induced by an adenine diet (0.75% adenine was added to the casein mouse diet) for the first 2 weeks, and the diet was replaced by a 0.25% adenine diet from the third week. From the 3rd week to the 6th week, the blank group ate a 0.25% adenine diet without drug addition, and the administration groups were divided into low-dose group (0.2% silver oxide in the rat diet), medium-dose group (0.4% silver oxide in the rat diet) silver), high dose group (containing 0.8% silver oxide in rat food). From the 7th week to the 8th week, the low-dose group and the high-dose group were changed to the rat diet without drug, and the middle-dose group continued to use the rat diet mixed with drug. Blood gas analysis was performed at the 2nd week, 6th week and 8th week, and the blood pH, serum bicarbonate and serum residual base of the rats were recorded, and the blood chlorine was tested. In the 4th week and the 6th week, the feces of the rats were collected for 24 hours, and the excretion of chlorine in the feces was tested; the toxic and side effects of the drugs were observed and recorded during the experiment.

For the experimental protocol, refer to the description in Gerrit Klaerner et al., 2020, J.Pharmacol.Exp.Ther.375:439–450.

Results: Low/medium/high doses of silver oxide could correct the pathological indicators of acidosis, and the pathological indicators of acidosis in rats deteriorated again after suspension of administration.

Claims (44)

Use of silver oxide and/or hydrates thereof in the preparation of a medicament, wherein the medicament is used to treat and/or alleviate a disease or condition associated with electrolyte imbalance in a subject. The use according to claim 1, wherein the diseases or conditions associated with electrolyte imbalances include diseases or conditions associated with hydrogen ion (H ⁺ ) and/or chloride ion (Cl ⁻ ) imbalances. The use according to any one of claims 1-2, wherein the disease or condition associated with electrolyte imbalance is manifested by high hydrogen ions (H ⁺ ). The use according to any one of claims 1-3, wherein prior to said treatment and/or remission, said subject has a serum pH value below about 7.4. The use according to any one of claims 1-4, wherein the disease or condition associated with electrolyte imbalance manifests as high chloride ion (Cl ⁻ ). The use according to any one of claims 1-5, wherein prior to said treatment and/or remission, said subject has a serum ^Cl- concentration of about 100 mEq/L to about 150 mEq/L. The use according to any one of claims 1-6, wherein prior to said treatment and/or remission, said subject has a serum bicarbonate (HCO ₃ ⁻ ) concentration of less than about 24 mEq/L. The use according to any one of claims 1-7, wherein the disease or condition associated with electrolyte imbalance comprises acidosis. The use according to claim 8, wherein the acidosis comprises respiratory acidosis. The use according to claim 8, wherein the acidosis comprises metabolic acidosis. Use according to any one of claims 8-10, wherein the acidosis comprises acute acidosis. Use according to any one of claims 8-10, wherein the acidosis comprises chronic acidosis. The use according to any one of claims 8-12, wherein the acidosis comprises ketoacidosis, lactic acidosis, salicylate poisoning, uremic acidosis, renal tubular acidosis, dilution Acidosis and/or drug-induced acidosis. The use according to any one of claims 1-13, wherein the disease or condition associated with electrolyte imbalance comprises hyperchloremia. The use according to any one of claims 1-14, wherein the disease or condition associated with electrolyte imbalance comprises hyperchloric acidosis. The use according to any one of claims 1-15, wherein the disease or condition associated with electrolyte imbalance comprises metabolic hyperchloric acidosis. The use according to any one of claims 1-16, wherein the subject suffers from kidney disease at the same time. The use according to claim 17, wherein the kidney disease comprises chronic kidney disease and/or renal failure. The use according to any one of claims 1-18, wherein the subject has stage 3A chronic kidney disease, stage 3B chronic kidney disease, or stage 4 chronic kidney disease. Use according to any one of claims 1-19, wherein the silver oxide and/or hydrate thereof has a chloride ion binding capacity of about 5 mmol/g to about 25 mmol in a simulated gastric fluid buffer ("SGF") assay /g. Use according to any one of claims 1-20, wherein the silver oxide and/or hydrate thereof has a chloride ion binding capacity of about 4 mmol/g to about 25mmol/g. Use according to any one of claims 1-21, wherein the silver oxide and/or hydrate thereof has a chloride ion binding capacity of about 4 mmol/g in a simulated small intestine organic and inorganic buffer ("SOB") assay to about 25 mmol/g. The use according to any one of claims 1-22, wherein the silver oxide and/or its hydrate is silver monoxide, Ag ₂ O. The use according to any one of claims 1-22, wherein the silver oxide and/or its hydrate is silver hydroxide AgOH. The use according to any one of claims 1-24, wherein the subject's serum pH value is increased by about 0.05% to about 30% after administration of the drug compared to no administration of the drug. The use according to any one of claims 1-25, wherein the subject's serum pH value is increased by about 0.1% to about 10% after administration of the drug compared to no administration of the drug. The use according to any one of claims 1-26, wherein the subject's serum pH value increases by about 0.05 to about 1.5 after administration of the drug compared to no administration of the drug. The use according to any one of claims 1-27, wherein the subject's serum pH value increases by about 0.1 to about 1 after administration of the drug compared to no administration of the drug. The use according to any one of claims 1-28, wherein the subject's serum pH is substantially controlled or substantially normalized after administration of the drug compared to no administration of the drug. The use according to any one of claims 1-29, wherein the subject's serum Cl ^- concentration is reduced by about 1 mEq/L to about 10 mEq/L after administration of the drug compared with no administration of the drug. L. The use according to any one of claims 1-30, wherein the subject's serum Cl ^- concentration is reduced by about 1.5 mEq/L to about 5 mEq after administration of the drug compared to no administration of the drug /L. The use according to any one of claims 1-31, wherein the subject's serum HCO ₃ ^{-concentration} increases from about 1 mEq/L to about 10 mEq after administration of the drug compared to no administration of the drug /L. The use according to any one of claims 1-32, wherein the subject's serum HCO ₃ -concentration increases by about 1.5 mEq/L ^to about 5mEq/L. The use according to any one of claims 1-33, wherein the subject's serum HCO ₃ ^{-concentration} is substantially controlled or substantially normalized after administration of the drug compared to no administration of the drug . The use according to any one of claims 1-34, wherein the medicament is prepared for oral administration. The use according to any one of claims 1-35, wherein the medicament is prepared to be taken with meals. The use according to any one of claims 1-36, wherein the medicament is prepared for administration on an empty stomach. The use according to any one of claims 1-37, wherein the medicament is formulated for administration at a dose of about 2 mg/kg/d to about 250 mg/kg/d. The use according to any one of claims 1-38, wherein the medicament is formulated for administration at a dose of about 20 mg/kg/d to about 100 mg/kg/d. The use according to any one of claims 1-39, wherein the medicament is prepared for administration at a dosing frequency of 1 time/day, 2 times/day, 3 times/day or 4 times/day. The use according to any one of claims 1-40, wherein the medicament is prepared as a solid. The use according to any one of claims 1-41, wherein the medicament is capsule, tablet and/or powder. The use according to any one of claims 1-42, wherein the medicament further comprises one or more other active ingredients. The use according to any one of claims 1-43, wherein the medicament further comprises one or more pharmaceutically acceptable carriers, adjuvants and/or excipients.

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