Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-09-02
2002-10-22
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S409000, C514S443000, C514S211120, C514S411000, C514S213010, C514S225500, C514S224800, C514S225800, C514S015800
Reexamination Certificate
active
06468971
ABSTRACT:
TECHNICAL FIELD
This invention pertains to diuretics, particularly to diuretics that are used during surgery or severe trauma under general anesthesia.
This is the United States national stage of International Application PCT/US97/03439, filed Mar. 5, 1997; which claims the priority of the filing date of the United States patent application Ser. No. 08/615,531, filed Mar. 11, 1996, now converted to provisional application Ser. No. 60/040,272.
BACKGROUND ART
During surgery or severe trauma, gaseous (volatile) general anesthetics such as isoflurane, enflurane, desflurane, nitrous oxide, halothane, ethylene, cyclopropane, sevoflurane and methoxyflurane cause an undesirable side effect on the kidneys: the use of gaseous general anesthetics during the stress of surgery or severe trauma causes acute renal failure and the nearly complete shutdown of urine production. There are profound and sustained reductions in urine output (antidiuresis), urinary sodium excretion (antinatriuresis), and urinary potassium excretion (antikaluresis). When renal function is thus impaired, the kidneys do not produce normal amounts of urine. Water then accumulates in the vascular and interstitial compartments of the body, leading to fluid overload and electrolyte imbalance. In a healthy surgical patient with normal cardiovascular function, the fluid retention and electrolyte imbalance do not necessarily present complications. But potentially life-threatening complications can develop if the same amount of fluid is retained, or if the same electrolyte imbalance occurs in a surgical patient with a preexisting cardiovascular or renal condition, such as hypertension, angina, hepatic cirrhosis, congestive heart failure, renal failure, myocardial infarction, or arrhythmia. Potentially life-threatening conditions that can develop during or after surgery under general anesthesia include pulmonary edema, seizures, angina, myocardial infarction, cardiac arrhythmia, heart failure, renal failure, renal tubular necrosis, sepsis, gastrointestinal hemorrhage, and central nervous system edema or dysfunction.
Drugs that function as diuretics in conscious patients often do not function at all, or do not function in the same manner when used during general anesthesia. There are a few drugs that have been used to increase urine output and to try to protect the kidneys from damage during anesthesia and surgery, but the existing drugs have complications. Drugs that have been used as diuretics during major operations and treatments for severe trauma include the following: high ceiling loop diuretics such as furosemide, bumetanide, and ethacrynic acid: mannitol, an osmotic diuretic; dopamine, a dopaminergic agonist; and clonidine, an alpha-2 adrenoceptor agonist. These drugs have significant limitations in that either they have a limited ability to increase urine output during anesthesia and surgery, or they cause excessive loss of water and electrolytes. Moreover, in surgical patients with a reduced kidney perfusion pressure (e.g. patients with a preexisting renal disease, or patients suffering from shock or hypotension), these drugs are largely ineffective as diuretics. In cases where these agents do produce a diuretic response during anesthesia and surgery, the level of water output can be exceedingly high. In addition, these agents can cause adverse, potentially life-threatening electrolyte imbalances such as hyponatremia (low plasma sodium) or hyperkalemia (high plasma potassium). Disturbances of electrolyte concentration during the peri- or post-operative periods can severely impair cerebral, neuromuscular, respiratory, and cardiac function. The likelihood that an electrolyte imbalance will cause cardiovascular and renal complications greatly increases in elderly patients, patients with a reduced cardiovascular or renal reserve, and patients being treated with certain other drugs such as cardiac glycosides, corticosteroids, amphotericin B, or other diuretics.
Furosemide, bumetanide and ethacrynic acid are short acting loop diuretics (none of which are opioid agonists). Furosemide is currently one of the drugs most frequently selected for increasing urine output during surgery under general anesthesia. Furosemide has been used to treat fluid overload and hypertension in the following settings: (1) following renal transplant, (2) as an adjunct in reducing intracranial pressure in patients undergoing surgery for intracranial hematomas, (3) for the treatment of edema associated with renal failure, and (4) as an adjunct in treating acute pulmonary edema. Furosemide is administered during a surgical procedure, but not before. Adverse effects related to fluid or electrolyte disturbances can include hyperglycemia, hyperuricemia, hypokalemia, hyponatremia, hypovolemia, hypochloremic alkalosis, tachycardia, oliguria (diminished output of urine), and arrhythmias. Furosemide can also cause acute hypotensive episodes during rapid diuresis that can then lead to further impairment of renal function. Moreover, furosemide can cause excessive losses of water, sodium, potassium, and calcium that can lead to life-threatening complications as severe as those caused by renal shutdown. For example, the marked rise in urine output caused by furosemide can cause renal failure by inducing hypovolemia (abnormally decreased volume of circulating blood). Hypovolemia is a particular problem in patients who are only minimally euvolemic (normal blood volume).
Y. Hamaya et al., “Diuretic Effect of Clonidine during Isoflurane, Nitrous Oxide, and Oxygen Anesthesia,” Anesthesiology, vol. 81, pp. 811-819 (1994) discussed the diuretic effect of clonidine (not an opioid agonist) during general anesthesia and surgery in human patients. When clonidine was administered 90 minutes before anesthesia it caused significant diuresis during surgery, but also produced substantial losses of sodium and potassium. Clonidine also produced a substantial decrease in mean arterial pressure and heart rate in these patients. Further, clonidine can alter the pharmacological action of other drugs that are frequently co-administered during various surgical operations. For example, the heart rate response to intravenous administration of atropine is attenuated. Moreover, the pressor response to intravenous ephedrine is augmented by clonidine pretreatment.
Mannitol (not an opioid agonist) is extensively employed as an osmotic diuretic. Mannitol is sometimes used to decrease intracranial pressure and fluid volume. Mannitol has also been used for prophylaxis and the treatment of acute renal failure during cardiovascular operations and in treating severe traumatic injury. However, mannitol causes extracellular (e.g., intravascular and interstitial) volume expansion, and it can precipitate congestive heart failure and pulmonary edema in patients with limited cardiac reserve. Mannitol can cause other major adverse reactions including hypernatremia, hyperkalemia, hyperosmolality, circulatory overload, renal failure, allergic reactions, and seizures. Mannitol's effects on plasma potassium and sodium can produce potentially life-threatening complications in surgical patients with underlying conditions such as cardiac or renal disease, or in patients with preexisting electrolyte abnormalities.
Dopamine is an inotropic agent that stimulates dopaminergic and alpha-adrenergic receptors. Dopamine is sometimes used in surgical settings to improve renal blood flow in an attempt to augment urine flow. Dopamine is also a natriuretic agent; it produces an increase in urine sodium excretion. Adverse effects of dopamine infusion in surgical patients can include hypotension, hypertension, tachycardia, hyponatremia, and cardiac arrhythmias. Dopamine can also cause renal artery vasoconstriction, thereby reducing urinary sodium and water excretion. Dopamine is contraindicated in patients receiving cyclopropane or halothane anesthesia.
There is a continuing, unfilled need for improved diuretic compounds that may be used during surgery or treatment for severe trauma under a general, gaseous anesthetic.
Board of Supervisors of Louisiana State University and Agricultu
Reamer James H.
Runnels John H.
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