Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-04-11
2003-05-20
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06566401
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions for the treatment or prevention of drug toxicity in mammals including humans which may result from the administration of therapeutic agents and to methods of treating or preventing such toxicity. The compositions of this invention comprise a toxicity-reducing amount of N-acetylcysteine (NAC) alone or in combination with a therapeutically effective amount or, to achieve its therapeutic advantages, an amount larger than what is customarily given as a therapeutically effective amount, of a therapeutic agent, preferably in combination with a pharmaceutically acceptable carrier. The method of treating or preventing drug toxicity in humans comprises administering a toxicity-reducing amount of NAC alone or in combination with a therapeutically effective amount or, to achieve its therapeutic advantages, an amount larger than what is customarily given as a therapeutically effective amount, of a therapeutic agent, preferably in combination with a pharmaceutically acceptable carrier.
BACKGROUND OF THE INVENTION
Glutathione (GSH), a tripeptide that is normally found in all animal cells and most plants and bacteria at relatively high (1-10 millimolar) concentrations, helps to protect cells against oxidative damage that would otherwise be caused by free radicals and reactive oxidative intermediates (ROIs) produced during cell metabolism or as the results of, for example, drug overdose. Glutathione is itself the major scavenger of reactive oxidative intermediates present in all eukaryotic forms of life and is generally required to protect cells against damage by oxidants. Glutathione reduces (and thereby detoxifies) intracellular oxidants and is consumed by this reaction. Glutathione is oxidized to the disulfide linked dimer (GSSG), which is actively pumped out of cells and becomes largely unavailable for reconversion to reduced glutathione. Thus, unless glutathione is resynthesized through other pathways, utilization of this compound is associated with a reduction in the amount of glutathione available. The antioxidant effects of glutathione are also mediated less directly by the role of this compound in maintaining other antioxidants in reduced form. Thus, pharmaceutical compounds that replenish or elevate glutathione levels work, at least in part, through enhancement of the defense mechanisms seemingly utilized to normally protect tissue from ROI mediated damage.
Glutathione depletion has been implicated in the pathology of a number of diseases including infection by human immunodeficiency virus (HIV). In HIV infection, cysteine/glutathione depletion is known to impair T-cell function and is associated with impaired survival of subjects with less than 200 CD4 T-cells per &mgr;l blood.
Drug toxicity is a very widespread problem. Cysteine/glutathione depletion and oxidative stress (See U.S. Pat. No. 4,757,063) intensify drug toxicity effects and have been implicated in the mechanism of drug toxicity reactions.
For example, acetaminophen is known to act to deplete cysteine/glutathione and cause a variety of drug toxicity symptoms. Acetaminophen, also known as paracetamol and N-acetyl-p-aminophenol, is one of the most widely used pharmaceutical analgesic and antipyretic agents in the world. It is contained in over 100 products and is commonly found in the U.S. as immediate release tablets and as extended-release preparations. Various children's chewable, suspension, and elixir formulations that contain acetaminophen are prevalent. Acetaminophen is also found as a component of combination drugs, such as propoxyphene/acetaminophen and oxycodone/acetaminophen.
Acetaminophen continues to be the most commonly encountered substance in toxic ingestions. In many cases, acetaminophen overdoses are unintentional and are undiagnosed until after substantial damage has already occurred. Repeated administration of acceptable size doses of acetaminophen can produce toxicity symptoms. As discussed by Donovan (1999)
Academic Emergency Med.
6:1079-1082, methods for detecting post-ingestion blood levels of acetaminophen suffer from poor predictive values. Even in the simple case of a single acute ingestion, patients with no discernible risk factors for liver injury and low blood levels of acetaminophen still develop toxicity and even die.
Many companies package acetaminophen under different trade names, resulting in inadvertent overdosing by less sophisticated patients and parents who do not read the information on the packaging. In addition, cold remedies and other over-the-counter preparations often contain acetaminophen, which is listed among a series of generic drug names that are difficult for patients and parents to read. Therefore, patients often are unaware of the amount of acetaminophen that they have received. Children are especially vulnerable to accidental exposure due to their smaller size, the presence of acetaminophen in multiple over-the-counter remedies, and a reluctance to administer aspirin and other NSAIDs to children for fever due to the risk of Reye's Syndrome and renal tubular injury. The antipyretic value of acetaminophen clearly has been demonstrated and hence acetaminophen is widely used in hospitals for this purpose. However, acetaminophen may not be the antipyretic agent of choice under circumstances where renal or hepatic function is in danger of being compromised.
It is well established that large acetaminophen overdose causes hepatotoxicity and, in some cases, nephrotoxicity in humans and in experimental animals. Acute overdosage of acetaminophen results in dose-dependent and potentially fatal hepatic necrosis as well as (in rare cases) renal tubular necrosis and hypoglycemia. Acetaminophen is rapidly absorbed from the stomach and small intestine and is normally metabolized by conjugation in the liver to nontoxic agents, which are then eliminated in the urine. In acute overdoses, or when maximum daily doses are exceeded over a prolonged period, the normal pathways of metabolism become saturated.
Excess acetaminophen is metabolized in the liver via the mixed function oxidase P450 system to a toxic, N-acetyl-p-benzoquinone-Imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPQI formation or reduced glutathione stores, NAPQI is free to bind to vital proteins and the lipid bilayer of hepatocytes. This results in hepatocellular death and subsequent centrilobular liver necrosis. Immumunohistochemical studies have suggested that NAPQI-protein adducts appear even at sub-hepatotoxic acetaminophen doses and before depletion of total hepatic glutathione which may be related to rare cases of hypersensitivity. In addition, decreased intracellular cysteine/glutathione can contribute to cell death via mechanisms that do not involve NAPQI.
The direct cost of acetaminophen overdose has been estimated to be $87 million annually. Effective protocols have been developed and tested to stratify risk and treat patients who present soon after a single large dose of acetaminophen. However, many patients present after a delay long enough to metabolize all the acetaminophen, after two or more ingestions over several hours, or after several days of excessive self-medication. Under these circumstances it is difficult for the clinician to estimate the risk of adverse outcome before hepatic or renal injury occurs. See, for example, Bond and Hite (1999)
Acad. Emerg. Med.
6:1115-1120; and Donovan (1999)
Acad. Emerg. Med.
6:1079-1082. However, early treatment of acetaminophen overdosage is considered to be crucial, and vigorous supportive therapy is essential when intoxication is severe.
Nucleoside reverse transcriptase inhibitors (NRTIs), of which the pyrimidine nucleoside analogue azidothymidine (AZT, zidovudine), is a common example, are often given in combination therapies with other anti-retroviral drugs to treat HIV. Long-term therapy with AZT is commonly associated with dose-dependent hematologic t
Andrus James
De Rosa Stephen C.
Herzenberg Leonard A.
Herzenberg Leonore A.
Greenberg & Traurig, LLP
Lubit Beverly W.
Rzucidlo Eugene C.
The Board of Trustees of the Leland Stanford Junior University
Travers Russell
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