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Clear urine in dogs and cats is a problem that has become widespread in recent years. The problem is particularly prevalent in younger animals. Young animals can often “over hydrate” when they are exposed to extreme temperatures, due to their smaller surface area to body volume ratio, so that they can become dehydrated relatively quickly. Furthermore, the younger the animal, the more susceptible they are to dehydration.
The two most common diseases associated with the inappropriate elimination of urine are known in the art as “distal (or renal) acidification” and “distal (renal) alkalosis” (RAO), respectively. These two conditions represent failure of the kidney to properly acidify the urine (proximal RTA) and failure to properly excrete bicarbonate in the urine (RBBH). Although both of these conditions are recognized in the art, and can be treated to varying degrees of success, current art therapies and methods to prevent them or to treat the consequences of them are suboptimal.
In the art, distal (or renal) acidification is sometimes referred to as “distal renal acidosis” and distal (or renal) alkalosis is sometimes referred to as “distal renal bicarbonate deficiency.” The term distal refers to the fact that it is the kidney that is malfunctioning. The terms alkalosis and acidosis are used to distinguish the conditions from other acid-base conditions, such as mixed acid-base disturbances, that can be present in the body. For example, acidemia is a condition of having an abnormally low or negative pH of the blood. Alkalemia is a condition of having an abnormally high or positive pH of the blood. In other words, alkalemia is a condition in which the blood has a pH that is too alkaline, whereas acidemia is a condition in which the blood has a pH that is too acidic.
It is estimated that distal RTA (dRTA) affects about 1 in 100,000 people. However, there are estimates of the prevalence of other disorders that share some features with dRTA, and it is likely that the total prevalence of renal tubular acidosis is much higher than 1 in 100,000. As a result, a more common cause of an abnormal acid-base profile in a hospitalized or otherwise critically ill patient is an impaired capacity to excrete hydrogen ions and bicarbonate ions from the kidneys, a condition sometimes referred to as respiratory acidosis or renal alkalosis. This condition is sometimes referred to as “acute kidney” (or renal) “acidosis.” It is estimated that respiratory acidosis occurs in as many as 20 to 25 percent of critically ill patients. This is a major cause of morbidity and mortality in patients who are not receiving appropriate therapy.
A number of factors may contribute to respiratory acidosis. It may be a result of inadequate ventilation, which may be a consequence of impaired pulmonary mechanics, or increased dead space ventilation due to lung disease, pneumonia, or even pulmonary edema. Alternatively, an acute and severe respiratory illness such as an infection (i.e., influenza or pneumonia) may cause a marked increase in lung elastance and ventilation/perfusion mismatch, and therefore lead to increased CO2 production. Other factors include diminished respiratory drive, reduced minute ventilation, or even hypovolemia (i.e., decreased intravascular volume).
Acute respiratory acidosis is also common in many acute nonrenal conditions. These include traumatic injury, burns, shock, sepsis, acute and chronic liver failure, and acute gastrointestinal (GI) diseases.
Acute kidney alkalosis (ACK) is often associated with a state of respiratory acidosis. ACK can occur as a consequence of a decreased sodium or water excretion, hyperglycemia, or hypokalemia.
Respiratory acidosis is usually a complication of sepsis, ARDS and septic shock. Respiratory acidosis is characterized by decreased pH, increased partial pressure of carbon dioxide (PCO2), and increased dead space ventilation, and can occur in a variety of clinical conditions such as respiratory disease, pulmonary disease, respiratory failure, cardiac disease, liver disease, and in conditions where there is no pulmonary or cardiac disease. Respiratory acidosis can be a significant problem in patients with severe ARDS, or septic shock. The mortality associated with respiratory acidosis in ARDS is greater than in patients with other causes of ARDS. The prognosis for patients who develop respiratory acidosis from other causes is worse.
Most of the existing therapies for respiratory acidosis either treat respiratory acidosis, improve pulmonary mechanics, or both. There are also some existing therapies that may improve outcome from respiratory acidosis. For example, it has been proposed that acidosis might be treated by administering a non-anionic or anionic carbonic anhydrase inhibitor. U.S. Pat. No. 4,983,599, U.S. Pat. No. 4,804,676, and U.S. Pat. No. 4,798,834. Furthermore, a number of studies have suggested that treatment with 2,3-butanedione monoxime (BDM), an inhibitor of mitochondrial oxidative phosphorylation, might be effective in decreasing the severity of multiple organ failure syndrome (MODS). See, Widdoes, et al., J. Trauma 1992, 42, 915-921, and, Widdoes, et al., Am. Surg. 1988, 154, 485-489.
In contrast, no therapies are currently available for the treatment of metabolic acidosis. It would be desirable to provide methods and compositions for the treatment of both acute and chronic liver failure, and other metabolic acidosis. Such methods should be useful both for reducing morbidity and mortality in liver failure, and for ameliorating the complications that may occur in the course of other types of acute or chronic metabolic acidosis. The present invention is directed to these, as well as other, important ends.