Acetaminophen and NSAID Toxicity

Acetaminophen and NSAID Toxicity

1 Overview

Summary and Quick Facts

  • Acetaminophen accounts for up to 50% of all adult cases of acute liver failure in the U.S. Other potential consequences of this over-the-counter analgesic include increased fracture risk, inhibition of testosterone production and kidney toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin also relieve pain, but chronic use is associated with gastrointestinal bleeding.
  • This protocol describes possible adverse effects of some common pain relievers. It also describes nutritional and other therapies to help prevent and reduce toxicity.
  • For those who are in need of these non-addictive pain relievers, the addition of a few nutritional supplements can improve the relative safety of acetaminophen and NSAIDs.

What is Acetaminophen and NSAID Toxicity?

Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) (eg, aspirin, ibuprofen) are widely used as analgesics and antipyretics (fever-reducers). Overdosing on acetaminophen is not uncommon, and acetaminophen accounts for up to 50% of all adult cases of acute liver failure in the United States.

Acetaminophen can be toxic to the liver and kidneys. Excess levels overwhelm the liver’s innate detoxification system by depleting levels of glutathione, the ubiquitous cellular antioxidant. Acetaminophen overdose can cause acute liver failure, and in some cases, renal failure.

NSAIDs can cause toxicity in the gastrointestinal tract, kidneys, and cardiovascular system. Their risk profiles vary depending on their cellular targets.

Natural interventions such as N-acetylcysteine and silymarin may help prevent acetaminophen and NSAID toxicity.

What are Risk Factors for Acetaminophen and NSAID Toxicity?

  • Aging
  • Renal or hepatic impairment (and other pre-existing medical conditions)
  • Alcohol use
  • Concurrent use of certain medications
  • Malnutrition

Note: Always read dosing instructions and warnings on every medication. For an adult, the maximum recommended single dose of acetaminophen is 1 gram and the maximum dose in a 24-hour period is 4 grams. Pay specific attention if you are taking more than one medication—many contain acetaminophen and inadvertent combination can easily cause an overdose.

What are Signs and Symptoms of Acetaminophen and NSAID Toxicity?

Acetaminophen:

  • Nausea, vomiting
  • Tenderness/pain in upper right abdomen
  • Jaundice
  • Impaired consciousness

Note: If you suspect an acetaminophen overdose immediately call 911 or the National Poison Control Center (1-800-222-1222).

NSAIDs:

  • Heartburn
  • Nausea
  • Abdominal pain

What are Conventional Medical Treatments for Acetaminophen and NSAID Toxicity?

Acetaminophen overdose:

  • N-acetylcysteine, administered either intravenously or orally, to restore glutathione levels
  • Activated charcoal to absorb excess drug
  • If acute liver failure occurs, intensive supportive therapy or liver transplantation may be required

NSAID toxicity:

  • Gastroprotective agents to prevent or treat gastric ulcers (eg, proton pump inhibitors [eg, omeprazole])

What are Emerging Therapies for Acetaminophen and NSAID Toxicity?

  • Combining NSAIDs with gastroprotective agents in single-tablet formulations
  • Topical NSAIDs

What Natural Interventions May Be Beneficial for Acetaminophen and NSAID Toxicity?

  • N-acetylcysteine (NAC). High dose NAC is a conventional treatment for acetaminophen overdose. Taking at least 600 mg NAC anytime acetaminophen is used may help prevent liver toxicity.
  • Methionine. Methionine, a precursor to glutathione and other cellular antioxidants, may be used as an alternative to NAC.
  • S-adenosylmethionine (SAMe). Levels of SAMe, a derivative of methionine, are decreased in the presence of acetaminophen. One animal study showed comparable efficacy of SAMe and NAC after acetaminophen overdose.
  • Selenium. Selenium is a cofactor for enzymes that synthesize glutathione and detoxify acetaminophen. Selenium deficiency may decrease the acetaminophen dose necessary to produce toxicity, and coadministration with NAC may be more effective than NAC alone.
  • Carotenoids. Several carotenoids, including lutein and lycopene, have been shown in animal models to exert protective effects against acetaminophen toxicity.
  • Silymarin. Silymarin, a mixture of compounds from milk thistle, has been shown to protect against acetaminophen toxicity and may be more effective than NAC if treatment is delayed after overdose.
  • Other natural interventions that may protect against acetaminophen toxicity include curcumin, polyphenols such as resveratrol and green tea extract, coenzyme Q10, several botanicals such as Ginkgo biloba and garlic, and others.
  • Natural interventions such as zinc-carnosine, licorice, and Boswellia serrata may protect against the gastrointestinal side effects of NSAIDs.

2 Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are a diverse group of drugs with analgesic, anti-inflammatory, and antipyretic (fever-reducing) properties. NSAIDs are typically used to relieve mild to moderate pain related to a variety of conditions (Conaghan 2012; Goldman 2011; Mayo Clinic 2011).

Acetaminophen, also called paracetamol, is not an NSAID, but a distinct analgesic and fever reducing drug with a similarly broad usage (Amar 2007; Harvard Medical School 2006).

Acetaminophen overdose is the leading cause of acute liver failure in the developed world (Larson 2005; Craig 2010), accounting for more than 56,000 emergency room visits, 26,000 hospitalizations, and 450 deaths per year in the U.S. (Amar 2007). Acetaminophen can also contribute to kidney toxicity (Bessems 2001).

Although the “safe” dose of acetaminophen is up to 4 grams daily, chronic daily ingestion of this dose has been shown to cause elevations of liver enzymes, even in healthy people (Watkins 2006). Since alcohol, especially when consumed chronically, augments the toxic potential of acetaminophen, many people unknowingly put themselves at risk of significant liver damage by consuming acetaminophen and alcohol together (Sharma 2009; van Mil 2001).

Aspirin and NSAID usage has been associated with gastrointestinal toxicity including bleeding ulcer (Singh 1998; Vonkeman 2010). Certain NSAIDs (e.g., selective COX-2 inhibitors) have been linked to an increased risk of cardiovascular events, in particular heart attack. In addition, chronic use of some types of NSAIDs has been associated with kidney damage that may persist even after drug withdrawal in some cases (Trelle 2011; Back 2011; Moodley 2008; Ejaz 2004).

This protocol discusses the mechanisms of acetaminophen and NSAID function and toxicity, and outlines dietary and lifestyle approaches for minimizing their toxic potential.

3 Acetaminophen & NSAIDs - Background and Overview

Acetaminophen has been available as an over-the-counter analgesic and antipyretic for over 50 years. More than 100 million people use acetaminophen each year in the U.S. alone, with up to 50 million Americans using acetaminophen-containing products in a given week (Amar 2007). While generally considered a safe therapy when taken below the recommended maximum daily dose of 4 grams, acetaminophen overdoses are not uncommon (Ferner 2011; Amar 2007).

Although most patients recover spontaneously from an acetaminophen overdose, the drug can cause life-threatening liver injury. Acetaminophen accounts for up to 50% of all adult cases of acute liver failure in the U.S. (Craig 2010; Amar 2007). Even in the absence of overt overdose symptoms, therapeutic acetaminophen dosages can still increase the blood concentrations of liver enzymes (markers of liver damage) (Watkins 2006). Other potential negative consequences of acetaminophen include increased fracture risk (Vestergaard 2012), inhibition of testosterone production (Kristensen 2011; Kristensen 2012), and kidney toxicity (Bessems 2001).

NSAIDs are among the most widely used of all drugs, with 20 to 30 billion tablets sold each year in the U.S. alone (Peura 2002; Dal Pan 2009). The prototypical member, aspirin, is one of the oldest analgesics, in use as an anti-inflammatory therapy long before the molecular mechanics of inflammation had been discovered. Low-dose aspirin (e.g. 75-100 mg) is often used to reduce the risk of cardiovascular events in high-risk patient populations (Mills 2012). Regular use of aspirin has also been associated with a significantly reduced risk of several cancers (see below) (Algra 2012).

The anti-inflammatory properties of NSAIDs are due to their inhibition of the cyclooxygenase (COX) enzymes, which catalyze the synthesis of localized pro-inflammatory signaling molecules called prostaglandins (Toussaint 2010).

The two COX enzymes with well-defined roles in humans are COX-1 and COX-2. COX-2 is normally inactive, but can be turned on during inflammation to produce pro-inflammatory prostaglandins. In contrast, COX-1 is normally active in many tissues, where it has roles unrelated to inflammation (e.g., clotting function in blood platelets, mucus production from cells lining the GI tract) (Toussaint 2010; Conaghan 2012). The inhibition of prostaglandins in the central nervous system also raises the pain threshold and acts on the hypothalamus to reduce body temperature (Amar 2007).

Non-selective NSAIDs (aspirin, naproxen [e.g., Aleve®], ibuprofen [e.g., Advil®], diclofenac [e.g., Cambia®], and indomethacin [Indocin®]) inhibit the activity of both COX enzymes (Conaghan 2012). COX-2 selective NSAIDs (i.e., COX-2 inhibitors or coxibs) inhibit COX-2 more strongly than COX-1, resulting in less gastrointestinal side effects, but potential cardiovascular complications, most notably an increase in the risk of heart attack due to increased blood clotting propensity (see below) (Conaghan 2012).

4 Mechanisms of Acetaminophen & NSAID Toxicity

Despite similarities in activity, the potential toxicities of acetaminophen and NSAIDs arise from different mechanisms.

Acetaminophen is toxic to the liver and kidneys primarily through its ability to overwhelm the liver’s innate detoxification systems (See Life Extension’s Metabolic Detoxification protocol for a review of this system) (Bessems 2001; Moyer 2011).

The liver uses multiple enzyme systems to metabolize acetaminophen; at low doses, these systems are able to remove excess acetaminophen from the body. However, if the acetaminophen dosage is increased, some of these enzyme systems may become overwhelmed.

The majority of acetaminophen is first converted into the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) by phase I CYP (cytochrome P450) enzymes; and then conjugated with glutathione using the phase II enzyme glutathione-S-transferase (GST). As acetaminophen detoxification proceeds in this fashion, glutathione, a ubiquitous cellular antioxidant, eventually becomes depleted (Moyer 2011), and NAPQI can no longer be sufficiently detoxified (James 2003). Rising levels of NAPQI in the liver cause widespread damage, including lipid peroxidation, inactivation of cellular proteins, and disruption of DNA metabolism (Bessems 2001). Furthermore, the loss of cellular glutathione leads to increased oxidative damage, the inability of mitochondria to produce cellular energy (ATP), and eventual cell death (Hinson 2010). The outcome of excessive acetaminophen is liver toxicity which, if left untreated, can lead to liver failure (Buckley 2007). Similarly, toxicity can be observed in the kidneys and may lead to acute renal failure (Bessems 2001; Ozkaya 2010).

NSAID Toxicity. In contrast to the liver toxicity of acetaminophen, NSAIDs exhibit varying degrees of gastrointestinal, cardiovascular, and kidney toxicity.

NSAID COX-1 and COX-2 Selectivity

It should be noted that even non-selective NSAIDs have different degrees of selectivity toward COX-1 and COX-2 enzymes (Fitzgerald 2001). For example, diclofenac, while considered a non-selective NSAID, may inhibit COX-2 significantly more than COX-1; naproxen inhibits COX-1 more readily than COX-2 (Fitzgerald 2001). These differences may partially explain why various NSAIDs carry different cardiovascular and gastrointestinal risk profiles.

NSAIDs - COX-1 Inhibition and Gastrointestinal Toxicity. Cyclooxygenases and the prostaglandins they form also have roles beyond inflammation. In the gastrointestinal tract, COX-1-derived prostaglandins function to increase production of the thick mucus/bicarbonate layer that coats gastric surfaces and buffers them against stomach acid (Vonkeman 2010). Inhibition of COX-1 activity by non-selective NSAIDs (such as aspirin or ibuprofen) results in degradation of the protective mucus layer (Vonkeman 2010). Damage to the lining of the stomach and small intestine results in symptoms that range from relatively minor heartburn, nausea, and abdominal pain (affecting 15-40% of NSAID users) to the life-threatening ulceration, perforation, and bleeding (affecting 1-2% of chronic NSAID users) (Vonkeman 2010).

NSAIDs - COX-2 Inhibition and Cardiovascular Toxicity. While inhibition of COX-1 can have serious gastrointestinal consequences, selective inhibition of COX-2 carries cardiovascular risks. Blood platelets express a blood clotting, vessel-constricting compound called thromboxane A2 or TXA2, which is synthesized by COX-1. Blood vessels produce an anti-clotting compound called prostaglandin I2 or PGI2. During blood vessel injury, the relative ratios of TXA2 and PGI2 are controlled by COX enzymes to balance the opposing actions of clotting and blood flow. COX-2 specific inhibitors (e.g., coxibs) preferentially reduce amounts of PGI2, tipping the balance toward thrombosis (Vonkeman 2010). The increased risk of thrombosis and heart attack observed in some studies of COX-2 inhibitors may result from this mechanism (Conaghan 2012). Increases in blood vessel constriction by COX-2 inhibition can also lead to the hypertension and renal failure seen in some studies of non-selective and COX-2 selective NSAIDs (Conaghan 2012). COX-2 inhibitors may also impair the removal of excess cholesterol from blood vessel walls, a process known as reverse cholesterol transport (Reiss 2009). Moreover, COX-2 inhibitors can cause metabolic imbalances that result in over production of two toxic cytokines, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) (Takahashi 1998; Jeng 1995).

NSAIDs - Kidney Toxicity. An underappreciated side effect of NSAID use is kidney toxicity. Long-term use of NSAIDs can lead to impaired glomerular filtration, renal tubular necrosis, and ultimately chronic renal failure by disrupting prostaglandin synthesis, which can impair renal blood flow (Weir 2002). This is because prostaglandins, which are blocked by COX inhibition, are important for proper blood vessel function within the kidneys (Ejaz 2004).

In a study involving more than 10,000 elderly individuals, long-term, high-dose NSAID therapy was associated with a significantly increased risk of progression of chronic kidney disease (Gooch 2007). Even in NSAID users with healthy kidneys, subclinical irregularities in kidney function are sometimes observed (Ejaz 2004). Other consequences of kidney toxicity related to NSAID use include high blood pressure, salt and water retention, and electrolyte imbalances (Ejaz 2004).

NSAIDs - Mitochondrial dysfunction and oxidative stress. An underappreciated side effect of NSAIDs is their contribution to mitochondrial dysfunction, thereby causing the formation of highly reactive free radicals. Free radicals cause tissue damage and may contribute to toxicity associated with NSAIDs (Sandoval-Acuña 2012; Patel 2012).

Mitochondria generate energy for cells in the form of adenosine triphosphate (ATP). A byproduct of this metabolically intensive process is creation of free radicals. When mitochondria are functioning normally, they generate minimal oxidative products and the body’s antioxidant defense systems keep them in check. However, when toxins, in this case NSAIDs and/or their metabolites, interfere with the efficiency of this process, the amount of free radical products generated can increase considerably (van Leeuwen 2012; Watanabe 2011). This mechanism has been associated with NSAID-related gastrointestinal (Watanabe 2011) and liver toxicity (Doi 2010; O’Connor 2003). NSAIDs have also been shown to cause oxidative stress via a mitochondria-independent mechanism in vascular tissue (Li 2008).

Daily Low Dose (75-100mg) Aspirin: Life Saving Benefits with Manageable Risk

Life Extension originally began recommending low dose aspirin for the prevention of cardiovascular events in the early 1980s. This was based upon evidence for reduction in the risk of certain cardiovascular events such as heart attack and ischemic stroke.

Today, the role of daily low dose aspirin therapy in reducing the risk of cardiovascular events is well known (Bartolucci 2011).

However, there is another emerging benefit of this low cost drug – cancer prevention.

In a landmark study published in early 2011 in The Lancet, Oxford University researchers found that daily low-dose aspirin therapy reduces overall risk of cancer death by 20% and colorectal cancer death risk by nearly 40%, proving especially effective in populations 55 and older (Rothwell 2010). Subsequently, additional evidence corroborated these findings (Mills 2012).

Aspirin, like other NSAIDs, inhibits COX-2, which is one way it combats cancer. However, aspirin has several other anti-cancer mechanisms. It inhibits signaling through the nuclear factor kappa B (Nf-kB) pathway, which is involved in inflammation and carcinogenesis (Dolcet 2005). Other anti-cancer mechanisms of aspirin include COX-1 inhibition, inhibition of platelet aggregation, and induction of apoptosis (Thun 2002; Stark 2007; Schrör 2011).

Many important decisions in medicine are based upon careful consideration of the potential risk vs. potential benefit of using or not using a drug or therapy. Aspirin is associated with peptic ulcer and, less commonly, hemorrhagic stroke. For these reasons, individuals should discuss the risks and benefits of low-dose aspirin with their healthcare practitioners prior to initiating an aspirin regimen (Lanas 2011; Garcia Rodríguez 2001; Derry 2000; De Berardis 2012). In addition, those using daily low-dose aspirin are encouraged to consider the suggestions in this protocol for protecting against gastrointestinal damage related to COX-1 inhibition.

5 Causes and Risk Factors for Acetaminophen & NSAID Toxicity

Acetaminophen

Liver necrosis, the primary outcome of acetaminophen toxicity in humans, is predominantly a function of overdose (Hinson 2010). For an adult, the maximum recommended single dose is 1 gram and the maximum dose in a 24-hour period is 4 grams (Ferner 2011). Acetaminophen overdose has occurred over a wide range of daily intakes. Acute toxicity studies in animals, if extrapolated to humans, implicate a single dose of 10-15 grams necessary to produce significant liver toxicity, although several human case reports have shown toxicity at doses less than 4 grams per day (likely due to having one or more risk factors for sensitivity to toxicity) (Amar 2007). Accidental overdose (taking an over-the-counter acetaminophen-containing product concurrently with a prescription acetaminophen-containing therapy) represents a significant number of acetaminophen toxicities.

Factors that can lower the threshold for overdose or increase the likelihood of liver failure include:

Delays in treatment. Delays in treatment following overdose are associated with increased mortality. The conventional antidote for acetaminophen toxicity, N-acetyl cysteine (NAC), begins to lose efficacy if administered more than 8-10 hours following overdose (Smilkstein 1988; Buckley 2007).

Alcohol use. Chronic alcohol use lowers the threshold for acetaminophen toxicity by induction of CYP enzymes and depletion of glutathione stores (Amar 2007).

Medications. Anticonvulsants, antibiotics, antivirals, anti-gout, and anti-GERD treatments can increase the toxicity of an acetaminophen dose by induction of CYP enzymes, depletion of glutathione stores, or saturation of other liver detoxification systems (Amar 2007).

Starvation and Malnutrition. Starvation can increase the toxicity of an acetaminophen dose. It may also be responsible for toxicity and liver failure seen at lower doses (Amar 2007). Starvation may deplete liver glutathione stores, as well as precursors for other acetaminophen detoxification pathways. Malnourishment, eating disorders, and cachexia (muscle wasting) can also increase the risk of liver injury following overdose (Ferner 2011). Animal models have demonstrated a protective effect of caloric restriction with optimal nutrition against experimentally induced acetaminophen toxicity (Johnson 2009; Harper 2006). Low dietary protein (a source of sulfur-containing amino acids used in glutathione synthesis) has been associated with increased sensitivity to acetaminophen toxicity in animals (Hwang 2009).

Age and Gender. Acetaminophen toxicity, more common in women than men, is most common in people aged 30-40 years. Note that these observations are based on case reports, and do not necessarily reflect susceptibility of these demographics to toxicity (Amar 2007).

Genetics. Several mutations have been identified in the phase I and II detoxification genes required for acetaminophen metabolism, which may affect the rate of acetaminophen clearance or production of the toxic metabolite NAPQI (Zhao 2011).

NSAIDs

NSAID use is associated with significant adverse effects such as gastrointestinal bleeding, peptic ulcer disease, high blood pressure, edema (i.e., swelling), and kidney disease (Peterson 2010).

There are several factors that influence risk of toxicity due to NSAID use (Chen 2006; Vonkeman 2010):

Age. Individuals over 60 are 5-6 times more likely to develop NSAID-related ulcers. Because older people generally have greater cardiovascular risk than younger people, their risk of NSAID-related cardiovascular events may also be elevated.

Medical conditions. Prior history of ulcer or other gastrointestinal complications increase risk of NSAID ulcers 4- to 5-fold. Cardiovascular or respiratory disease, renal or hepatic impairment, diabetes, Helicobacter pylori infection, rheumatoid arthritis, and hypertension are also associated with increased risk. Individuals with cardiovascular risk factors such as hypertension, high cholesterol, or history of heart attack or bypass surgery are at increased risk of having an NSAID-related cardiovascular event (Conaghan 2012).

Dose and Duration of treatment. Use of high dose or multiple NSAIDs increase the risk of gastrointestinal complications up to 10-fold. Cardiovascular risk appears to increase in tandem with duration of NSAID use (Conaghan 2012).

Medications. Simultaneous use of NSAIDs with corticosteroids, anticoagulants, aspirin, platelet inhibitors, and serotonin re-uptake inhibitors can increase gastrointestinal toxicity up to 15-fold.

NSAID selection. As mentioned above, different NSAIDs carry different risks of either gastrointestinal or cardiovascular toxicity. While COX-2 selective inhibitors and diclofenac are associated with greater cardiovascular but lower gastrointestinal risks than non-selective NSAIDs, non-selective NSAIDs demonstrate the opposite effect. NSAIDs with longer half-lives, such as piroxicam (Feldene®), are associated with greater risk of gastrointestinal bleeding than those metabolized more quickly (Roth 2011). For people with high cardiovascular risk, the NSAID naproxen is typically recommended because it has been associated with fewer cardiovascular events compared with other NSAIDs in several studies (Conaghan 2012).

Avoiding Unintentional Toxic Overdose

Most cases of unintentional acetaminophen overdose result from either failure to follow dosing instructions, or inadvertently combining multiple acetaminophen-containing products (such as “cold medicines” with analgesics). In one study, nearly one quarter of adults surveyed reported that they were likely to take more than the maximum 4 grams of acetaminophen in a 24 hour period, while just over 5% (in error) were likely to take more than 6 grams in the same period (Wolf 2012). Therefore, strict attention to dosing instructions for all medications is imperative.

Avoiding the potential gastrointestinal and cardiovascular risk(s) of sustained NSAID usage necessitates the recognition of risk factors for each, as well as choosing an appropriate treatment strategy (e.g., reduced dosage or pairing with a gastroprotective agent) (Vonkeman 2010).

6 Diagnosis and Treatment of Acetaminophen/NSAID Toxicity

Acetaminophen overdose

Within a few hours of acetaminophen overdose, typical symptoms include nausea and vomiting. Tenderness and pain in the upper right abdomen may be present. Initial signs of liver failure (e.g., jaundice, impaired consciousness, and hemorrhage) can begin within 24 hours of ingestion, but may be delayed for two or three days. Very large doses can result in lactic acidosis (a drop in pH of the blood) and coma (Ferner 2011; Hinson 2010).

Several additional tests can support a diagnosis of acetaminophen overdose. Elevated levels of liver enzymes gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) can indicate liver damage, as can elevated serum bilirubin (a breakdown product of the red blood cell component hemoglobin normally cleared by a healthy liver). Increased prothrombin time (determined by a PTT test) also indicates liver dysfunction. Recovery from acetaminophen overdose is less favorable if these tests are abnormal by the time medical treatment is initiated. Blood levels of acetaminophen are also determined to guide treatment (Ferner 2011; Hinson 2010).

A mainstay of conventional treatment for acetaminophen overdose is N-acetyl cysteine (NAC). NAC, a therapeutic form of the conditionally essential amino acid cysteine, is the rate-limiting reagent for the production of glutathione (Bessems 2001). Health care practitioners prescribe NAC either orally (1330 mg/kg of body weight, given over 72 hours) or intravenously (300 mg/kg of body weight, given over 20 hours) (Amar 2007). At these doses, the most common side effects of NAC are nausea and vomiting, although severe allergic reactions can occur in susceptible individuals (Ferner 2011). NAC should be given relatively quickly after an overdose, as its efficacy begins to decline 8-10 hours following intoxication (Smilkstein 1988; Buckley 2007). If administered within this window, however, NAC is very effective at mitigating toxicity. In a study of cancer patients taking high dose acetaminophen (an average dose of 400 mg/kg/day, up to a maximum of 1 gram/kg/day), a rescue dose of NAC within 8 hours of acetaminophen dosing prevented severe liver toxicity (Kobrinsky 1996).

If taken within two hours of acetaminophen overdose, activated charcoal may absorb excess drug (Buckley 2007). Once acute liver failure has occurred or seems likely, however, the course of action is intensive supportive therapy or liver transplantation (Ferner 2011).

NSAID toxicity

Gastrointestinal NSAID toxicity is managed by minimizing NSAID exposure, or pairing the NSAIDs with drugs that protect the integrity of the GI tract. The American College of Rheumatology has recommended acetaminophen as first line analgesic therapy for arthritis pain; if other NSAIDs are used, then the lowest effective dose for the shortest possible duration is recommended (Peura 2002). For individuals at moderate risk of gastrointestinal complications, combined therapy of NSAIDs with a gastroprotective agent should be considered. Conventional gastroprotective drugs commonly prescribed to minimize NSAID toxicity or heal NSAID-induced ulcers include H2-receptor antagonists (cimetidine, ranitidine, famotidine), proton pump inhibitors (omeprazole, lansoprazole, esomeprazole), and misoprostol (a synthetic prostaglandin analog) (Vonkeman 2010).

7 Novel and Emerging Therapies

One approach to avoiding gastrointestinal toxicity of NSAIDs is to pair them with fixed doses of gastroprotective agents in single-tablet formulations. For example, Arthrotec®, a combination product of diclofenac and misoprostol, is approved for use in osteoarthritis or rheumatoid arthritis patients at high risk of gastrointestinal disorders. A single-tablet combination of naproxen and esomeprazole is available by prescription under the brand name Vimovo®, and HZT-501 (a combination product of ibuprofen and famotidine) is being developed under the brand name Duexa® (Laine 2012; Conaghan 2012). In two multicenter studies of over 1,500 patients requiring NSAID therapy, HZT-501 demonstrated a ~55% reduction in the risk of ulcer (determined by endoscopy) compared to ibuprofen alone over 24 weeks (Laine 2012). Single tablet preparations may also help overcome poor compliance to prescription NSAID/gastroprotectant regimens (reported at only 68% in one survey) (Goldstein 2006).

Topical NSAIDs, unlike oral NSAIDs, deliver the drug directly to the target tissue, resulting in significantly lower systemic concentrations (<10% of an equivalent oral dose) and reduced gastrointestinal symptoms. Therefore, topical NSAIDs may have advantages over oral NSAIDs in some cases (e.g., osteoarthritis). In the US, only topical diclofenac (solution and gel) has been FDA approved for use in osteoarthritis patients; its efficacy is comparable to oral diclofenac (Roth 2011).

8 Avoiding Acetaminophen/NSAID Toxicity

The most effective approach to minimizing acetaminophen and NSAID toxicity would be avoiding their usage altogether and choosing alternative means for treatment of inflammation and pain (For more information, see Life Extension’s Chronic Inflammation and Chronic Pain protocols). However, because of their efficacy at reducing fever, treating inflammation, and minimizing thrombotic and cancer risk (Mills 2012), a complete cessation of NSAIDs, aspirin, or acetaminophen usage may not be suitable for everyone.

Any time acetaminophen is taken, at least 600 mg of N-acetyl cysteine should be taken along with it to help protect against liver toxicity.

Chronic users of acetaminophen or NSAIDs should have regular blood tests to monitor the health of their liver and kidneys. A simple chemistry panel can help assess both liver and kidney function, and a cystatin-C blood test helps evaluate kidney health.

If an acetaminophen overdose is suspected, call 911 or the National Poison Control Center (1-800-222-1222) immediately (NIH MedlinePlus 2012A)

9 Nutritional Support

People who take acetaminophen and NSAIDs regularly should be aware that these drugs can cause liver and kidney toxicity. When taking these medications, it is a good idea to provide antioxidant support to protect these organs.

Much of the data below is derived from animal models in which nutritional interventions garnered protection against acetaminophen and NSAID toxicity. The specific dosages studied in many of these animal models are very high when extrapolated to human equivalent doses; but lower dosages, such as those available in nutritional products, may offer antioxidant protection when used regularly in conjunction with typical doses of acetaminophen and NSAIDs in humans (Firdous 2011; Reagan-Shaw 2007).

Sulfur containing amino acids

Sulfur containing amino acids support liver health following exposure to acetaminophen. For those on a regimen of chronic acetaminophen or NSAID use, supplementing daily with sulfur containing amino acids and other compounds to support glutathione levels may protect against drug-induced toxicity.

  • N-acetyl cysteine (NAC). High dose NAC is a conventional treatment for acetaminophen overdose. It is an effective treatment for acute liver failure due to non-acetaminophen drug toxicity as well (Ghabril 2010). Any time acetaminophen is taken, at least 600 mg of N-acetyl cysteine should be taken along with it to help protect against liver toxicity.
  • Methionine. Methionine is the essential amino acid precursor to several sulfur-containing antioxidants (including cysteine and glutathione), and sufficient dietary methionine is necessary for maintaining glutathione levels. Methionine is used as an alternate conventional antidote for acetaminophen overdose; although a lack of comparative controlled trials make it difficult to determine its relative efficacy to NAC in humans (Buckley 2007). In some parts of the world, methionine (10%) is included in acetaminophen products to protect against accidental intoxication; a study in rats of a single-tablet combination demonstrated that including methionine could minimize liver toxicity (measured by serum ALT and AST) at therapeutic (100 mg/kg) and highly toxic (1000 mg/kg) acetaminophen doses (Iyanda 2010).
  • S-adenosyl methionine (SAMe). SAMe, a methionine derivative, is critical for the synthesis of nucleic acids, proteins, and phospholipids (compounds necessary for recovery after an acetaminophen overdose). Acetaminophen decreases SAMe levels in the nuclei and mitochondria of liver cells (Brown 2010). In one study, the efficacy (as an antidote) of SAMe and NAC were comparable when given to mice within one hour of acetaminophen overdose (Terneus 2008).

Selenium. Selenium is a cofactor for enzymes that synthesize glutathione and detoxify acetaminophen. In an experimental mouse model, selenium deficiency significantly reduced the size of a lethal acetaminophen dose (Peterson 1992). Injecting rats with selenium 24 hours prior to acetaminophen overdose provided significant protection against hepatotoxicity, lowered levels of ALT and AST (markers of liver damage), and increased liver glutathione levels (Schnell 1988). Oral selenium (0.5 mg/kg body weight) combined with NAC (500 mg/kg body weight) demonstrated a greater protective effect than NAC alone when administered to rats within 1 hour of acetaminophen overdose (Yalçin 2008).

Carotenoids. Several carotenoids have been examined for protection against acetaminophen overdose in rat models. Lutein (50-250 mg/kg/day) administered 7 days before overdose preserved glutathione levels and reduced elevations of ALT and AST in response to acetaminophen (Sindhu 2010). Lycopene-rich tomato extract (5 mg/kg/day) given for 7 consecutive days after overdose had a similar protective effect (Jamshidzadeh 2008). Single doses of beta-carotene (30 mg/kg) or mesozeaxanthin (50-250 mg/kg) given concurrently with a toxic acetaminophen dose reduced serum liver enzymes and in the case of mesozeaxanthin, microscopic evidence of liver tissue damage (Zahra 2010; Firdous 2011).

Silymarin. Silymarin, a mixture of several related polyphenolic compounds from milk thistle (Abenavoli 2010), promotes detoxification by several complementary mechanisms. The antioxidant capacity of silymarin can lower oxidative stress (in the liver) associated with acetaminophen metabolism in rats, which has the effect of conserving cellular glutathione levels (Campos 1989). Like NAC, silymarin can protect against acetaminophen toxicity. Furthermore, an animal study suggests it may be more effective than NAC for acetaminophen toxicity if the treatment is delayed (in a mouse model, it was effective when administered up to 24 hours after overdose) (Hau 2010).

Curcumin. When administered to rats within 30 minutes of experimental acetaminophen intoxication, 200 mg/kg of curcumin prevented the microscopic appearance of kidney damage, prevented elevations in renal lipid peroxidation, and maintained glutathione levels compared to control rats (Cekmen 2009). Oral preconditioning of rats with 50 or 100 mg/kg/day for 7 days significantly reduced markers of liver damage (ALT, AST, and lipid peroxidation) following experimental acetaminophen overdose (Girish 2009). Curcumin may also increase the efficacy of NAC as an acetaminophen antidote; the addition of 25 mg/kg curcumin to 200 mg/kg NAC protected rat liver and kidney from acetaminophen toxicity with an efficacy equivalent to 800mg/kg of NAC (Kheradpezhouh 2010).

Polyphenols. Polyphenolic antioxidants have been tested for their ability to mitigate liver damage in mouse models of acetaminophen overdose. Pretreatment of mice with either grape seed extract (100 mg/kg/day for 7 days) or green tea extract (0.25% - 1% of diet for 5 days) protected livers from acetaminophen-mediated damage, as determined by serum levels of ALT and microscopic examination (Bagchi 2002; Ray 1999; Oz 2008; Oz 2004). Resveratrol (75 mg/kg) injected into mice 1 or 6 hours after acetaminophen intoxication significantly reduced ALT levels compared to control animals (Masubuchi 2009). In addition, an injection of resveratrol (30 mg/kg) following acetaminophen-induced intoxication in mice resulted in reduced markers of hepatotoxicity (Sener 2006b).

Coenzyme Q10 (CoQ10). Treating rats by injection with CoQ10 either before or after acetaminophen overdose conferred protection from liver damage. Pretreatment with intravenous CoQ10 (5 mg/kg) reduced serum ALT and markers of oxidative stress, but had no effect on liver glutathione levels (Amimoto 1995). Two injections of CoQ10 (10 mg/kg each) given 1 and 12 hours after acetaminophen intoxication significantly reduced levels of ALT, AST, and inflammatory cytokines, suppressed lipid peroxidation, preserved glutathione, and reduced tissue death (Fouad 2012).

Vitamin C. High doses of ascorbyl palmitate (equivalent to 600 mg/kg of free vitamin C) given concurrently with acetaminophen prevented the elevation of serum liver enzymes in mice and reduced acetaminophen-mediated mortality (Jonker 1988). Free vitamin C (ascorbic acid) did not protect against liver or kidney damage in mouse models (Jonker 1988; Abraham 2005).

Botanicals. Several botanicals have been examined for protection against acetaminophen overdose in animal models. Rats pretreated with the traditional liver tonics Andrographis paniculata (100-200 mg/kg/day) and Picrorhiza kurroa (50-100 mg/kg/day) had lower markers of liver damage (ALT, AST, lipid peroxidation) after acetaminophen intoxication (Nagalekshmi 2011; Girish 2009). When given at 6 mg/kg, andrographolides, the principle bioactive compounds from andrographis, demonstrated nearly 100% survival of liver cells following acetaminophen overdose (Visen 1993). A rescue injection of Gingko biloba following acetaminophen overdose reversed the increases in serum liver enzymes, lipid oxidation, and inflammatory cytokines due to acetaminophen intoxication (Sener 2006a). Several compounds from garlic, including ajoene (Hattori 2001), diallyl disulfide (Zhao 1998), S-allylmercaptocysteine (Sumioka 2001), and fresh garlic homogenates (Wang 1996) have been shown to preserve liver glutathione levels as well as reduce serum markers of liver damage, liver tissue death, and animal mortality in rodent models of acetaminophen overdose when supplied in sufficient quantities (up to 5 g/kg for fresh garlic homogenates).

Melatonin. Treatment of mice with oral melatonin (50 or 100 mg/kg) 4 or 8 hours before acetaminophen overdose suppressed the increase in serum ALT and AST activities in a dose- and a time-dependent manner, but had no effect on liver glutathione levels. When given 4 hours before overdose, marked inhibition of liver necrosis was observed (Matsura 2006). Melatonin injections (10 mg/kg) prior to acetaminophen overdose may be more effective than “rescue” doses for reducing liver toxicity (Kanno 2006), although rescue treatments at this same dose have been shown to effectively protect kidney tissue from cell death (Ilbey 2009).

Gastrointestinal Support

Some gastrointestinal side effects of NSAIDs may be addressed using gastroprotective nutrients (For more information, see Life Extension’s Gastroesophageal Reflux Disease protocol). Gastroprotective nutrients include:

Zinc-Carnosine. Zinc-carnosine (i.e., the carnosine chelate of zinc) is a gastroprotective agent that can reduce NSAID-induced gastrointestinal epithelial cell death, possibly by quenching reactive oxygen species (Omatsu 2010). Zinc-carnosine is a prescription anti-ulcer drug in Japan, where it has been studied for over a decade (Matsukura 2000; Cho 1991). Using tracer compounds to monitor the course of the preparation in animal stomachs, researchers observed the combination adhering to the stomach wall more efficiently than either zinc or carnosine alone, allowing the beneficial effects of both components to be delivered to the site where protection is needed (Furuta 1995). A protective effect was observed in a 2007 human trial; ten healthy volunteers taking zinc-carnosine (37.5 mg twice daily) were protected against the threefold increase in gastrointestinal permeability caused by indomethacin treatment (Mahmood 2007).

Licorice. Licorice has been used historically in Europe as a gastroprotective/ulcer-healing agent (Wittschier 2009; Aly 2005). The over-the-counter ulcer treatment carbenoxolone is a derivative of a naturally occurring compound in licorice. A licorice decoction (given at 2.5 g/kg body weight) healed aspirin-induced ulcers in the stomachs of rats. The healing effect was similar to two prescription treatments (the proton-pump inhibitor omeprazole and synthetic prostaglandin misoprostol), but was not effective prophylactically (before ulceration had occurred) (Sancar 2009). In another animal study, deglycyrrhizinated licorice (DGL) in combination with the reflux drug cimetidine provided greater protection against aspirin induced mucosal damage than either substance alone (Bennett 1980). Unlike whole licorice, DGL extracts provide gastroprotective effects without glycyrrhizin (a component of whole licorice that has been shown to cause side effects such as high blood pressure) (Das 1989; Bennett 1980).

Boswellia serrata. Boswellic acids, extracted from Boswellia serrata, are anti-inflammatory compounds in their own right; they inhibit the activity of the pro-inflammatory enzyme 5-lipoxygenase and have demonstrated improvements in animal and human models of inflammatory diseases (including asthma, osteoarthritis, and Crohn’s disease) (Anonymous 2008). Boswellic acids may also protect against NSAID-induced gastric ulceration; in one study, rats pretreated with oral boswellia extract (250 mg/kg) demonstrated significantly less aspirin- or indomethacin-induced gastric ulceration (as determined by qualitative determination) than control animals (Singh 2008).

Antioxidants: Targeting Mitochondrial Health and Oxidative Stress to Reduce NSAID Toxicity

NSAIDs are known to damage the gastric mucosa and contribute to conditions such as ulcers. When examining the mechanisms driving this and other NSAID-related toxicities, much of the scientific community focuses on factors closely related to COX-1 and COX-2 inhibition. However, mitochondrial dysfunction function and oxidative stress appears to be important aspects of this equation as well (see above).

Several studies have shown that nutrients with antioxidant capacity may be able to mitigate NSAID toxicity. For example, melatonin, quercetin, and curcumin have been shown to ease gastric toxicity of NSAIDs by ameliorating oxidative stress (Maity 2009; Sandoval-Acuna 2012; Sivalingam 2008).

In addition, nutrients that support mitochondrial function such as coenzyme Q10 and pyrroloquinoline quinone (PQQ) may be able to blunt some of the mitochondrial toxicity caused by NSAIDs; although this hypothesis has yet to be confirmed in clinical trials.

Abenavoli L, Capasso R, Milic N, et al. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24(10):1423–32.

Abraham P. Mega dose of vitamin C augments the nephrotoxicity of paracetamol. Nephrology (Carlton). 2005;10(6):623–4.

Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. 2012 May;13(5):518-27.

AlyAM, Al-Alousi L, Salem HA. Licorice: a possible anti-inflammatory and anti-ulcer drug. AAPS PharmSciTech. 2005;6(1):E74–82.

Amar PJ and Schiff ER. Acetaminophen safety and hepatotoxicity--where do we go from here? Expert Opin Drug Saf. 2007;6(4):341–55.

Amimoto T, Matsura T, Koyama SY, et al. Acetaminophen-induced hepatic injury in mice: the role of lipid peroxidation and effects of pretreatment with coenzyme Q10 and alpha-tocopherol. Free RadicBiol Med. 1995;19(2):169–76.

Anonymous.Boswelliaserrata.Monograph.Altern Med Rev. 2008;13(2):165–7

Back M, Yin L, Ingelsson E. Cyclooxygenase-2 inhibitors and cardiovascular risk in a nation-wide cohort study after the withdrawal of rofecoxib. 2011 Nov 21. [Epub ahead of print]

Bagchi D, Ray SD, Bagchi M, et al. Mechanistic pathways of antioxidant cytoprotection by a novel IH636 grape seed proanthocyanidin extract. Indian J Exp Biol. 2002;40(6):717–26.

Bartolucci AA, Tendera M, Howard G. et al. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. 2011 Jun 15;107(12):1796-801.

Bennett A, Clark-Wibberley T, Stamford IF, Wright JE. Aspirin-induced gastric mucosal damage in rats: cimetidine and deglycyrrhizinatedliquorice together give greater protection than low doses of either drug alone. 1980 Feb;32(2):151.

Bessems JG and Vermeulen NP.Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol. 2001;31(1):55–138.

Brown JM, Ball JG, Hogsett A, et al. Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity. ToxicolApplPharmacol. 2010;247(1):1–9.

Buckley N and Eddleston M. Paracetamol (acetaminophen) poisoning. ClinEvid (Online).2007;(14):1738–44.

Campos R, Garrido A, Guerra R, et al. Silybindihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med. 1989;55(5):417–9.

Cekmen M, Ilbey YO, Ozbek E, et al. Curcumin prevents oxidative renal damage induced by acetaminophen in rats. Food ChemToxicol. 2009;47(7):1480–4.

Chen JT, Pucino F, Resman-Targoff BH. Celecoxib versus a Non-Selective NSAID Plus Proton-Pump Inhibitor: What Are the Considerations? J Pain Palliat Care Pharmacother. 2006;20(4):11-32.

Cho CH, Luk CT, Ogle CW. The membrane-stabilizing action of zinc carnosine (Z-103) in stress-induced gastric ulceration in rats. Life Sci. 1991;49(23):L189-94.

Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012;32(6):1491–502.

Craig DGN, Ford AC, Hayes PC, et al. Systematic review: prognostic tests of paracetamol-induced acute liver failure. Aliment PharmacolTher. 2010;31(10):1064–76.

Dal Pan GJ. Acetaminophen: Background and Overview. 6/2009. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM175767.pdf Accessed 7/18/2012.

Das SK, Das V, Gulati AK, Singh VP.Deglycyrrhizinatedliquorice in aphthous ulcers. 1989 Oct;37(10):647.

De Berardis G, Lucisano G, D'Ettorre A, et al. Association of aspirin use with major bleeding in patients with and without diabetes. 2012 Jun 6;307(21):2286-94.

Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. 2000 Nov 11;321(7270):1183-7.

Doi H and Horie T. Salicylic acid-induced hepatotoxicity triggered by oxidative stress. 2010 Feb 12;183(3):363-8.

Dolcet X, Llobet D, Pallares J, et al. NF-kB in development and progression of human cancer. 2005 May;446(5):475-82.

Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney.J Assoc Physicians India. 2004 Aug;52:632-40.

Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning.BMJ. 2011;342:d2218.

Firdous AP, Sindhu ER, Kuttan R. Hepato-protective potential of carotenoid meso-zeaxanthin against paracetamol, CCl4 and ethanol induced toxicity. Indian J Exp Biol. 2011;49(1):44–9.

Fitzgerald GA and Patrono C.The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345(6):433–42.

Fouad AA and Jresat I. Hepatoprotective effect of coenzyme Q10 in rats with acetaminophen toxicity. Environ. ToxicolPharmacol. 2012;33(2):158–67.

Furuta S, Toyama S, Miwa M, et al. Residence time of polaprezinc (zinc L-carnosine complex) in the rat stomach and adhesiveness to ulcerous sites. 1995 Apr;67(4):271-8.

García Rodríguez LA, Hernández-Díaz S, and de Abajo FJ. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. 2001 Nov;52(5):563-71.

Ghabril M, Chalasani N, Björnsson E. Drug-induced liver injury: a clinical update. CurrOpinGastroenterol. 2010;26(3):222–6.

Girish C, Koner BC, Jayanthi S, et al. Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice. FundamClinPharmacol. 2009;23(6):735–45.

Goldman L. Goldman's Cecil Medicine, 24th ed. Copyright © 2011 Saunders, An Imprint of Elsevier. Available at: http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-1604-7..C2009-0-42832-0&isbn=978-1-4377-1604-7&uniqId=345936036-9#4-u1.0-B978-1-4377-1604-7..C2009-0-42832-0--TOP Accessed 7/17/2012.

Goldstein JL, Howard KB, Walton SM, et al. Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastroduodenal ulcer complications. ClinGastroenterolHepatol. 2006;4(11):1337–45.

Gooch K, Culleton BF, Manns BJ, et al. NSAID use and progression of chronic kidney disease. 2007 Mar;120(3):280.e1-7.

Harper JM, Salmon AB, Chang Y, et al. Stress resistance and aging: influence of genes and nutrition. Mech Ageing Dev. 2006;127(8):687–94.

Harvard Medical School. 12 things you should know about pain relievers. 2006. Available at: http://www.health.harvard.edu/fhg/updates/12-things-you-should-know-about-pain-relievers.shtml. Accessed 7/17/2012.

Hattori A, Yamada N, Nishikawa T, et al. Protective effect of ajoene on acetaminophen-induced hepatic injury in mice. BiosciBiotechnolBiochem. 2001;65(11):2555–7.

Hau DKP, Wong RSM, Cheng GYM, et al. Novel use of silymarin as delayed therapy for acetaminophen-induced acute hepatic injury.ForschKomplementmed. 2010;17(4):209–13.

Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis.HandbExpPharmacol. 2010;(196):369–405.

Hwang J. Diets with corn oil and/or low protein increase acute acetaminophen hepatotoxicity compared to diets with beef tallow in a rat model. Nutr Res Pract. 2009;3(2):95–101.

Ilbey YO, Ozbek E, Cekmen M, et al. Melatonin prevents acetaminophen-induced nephrotoxicity in rats. IntUrolNephrol. 2009;41(3):695–702.

Iyanda A, Anetor J, Adeniyi F, et al. Effect of methionine on hepatic indices in male Wistar rat dosed to acetaminophen formulation. African Journal of Pharmacy and Pharmacology. 2010;4(9):653–7.

James LP, Mayeux PR. Hinson JA. Acetaminophen-induced hepatotoxicity. 2003 Dec;31(12):1499-506.

Jamshidzadeh A, Baghban M, Azarpira N, et al. Effects of tomato extract on oxidative stress induced toxicity in different organs of rats. Food ChemToxicol. 2008;46(12):3612–5.

Jeng KC, et al. Collagen induces cytokine production by synovial fluid mononuclear cells in rheumatoid arthritis. ImmunolLett 1995 Feb;45(1-2):13-7.

Johnson JB, John S, Laub DR. Pretreatment with alternate day modified fast will permit higher dose and frequency of cancer chemotherapy and better cure rates. Med Hypotheses. 2009;72(4):381–2.

Jonker D, Lee VS, Hargreaves RJ, et al. Comparison of the effects of ascorbylpalmitate and L-ascorbic acid on paracetamol-induced hepatotoxicity in the mouse.Toxicology. 1988;52(3):287–95.

Kanno SI, Tomizawa A, Hiura T, et al. Melatonin protects on toxicity by acetaminophen but not on pharmacological effects in mice. Biol Pharm Bull. 2006;29(3):472–6.

Kheradpezhouh E, Panjehshahin MR, Miri R, et al. Curcumin protects rats against acetaminophen-induced hepatorenal damages and shows synergistic activity with N-acetyl cysteine. European Journal of Pharmacology. 2010;628(1-3):274–81.

Kobrinsky NL, Hartfield D, Horner H, et al. Treatment of advanced malignancies with high-dose acetaminophen and N-acetylcysteine rescue. Cancer Invest. 1996;14(3):202–10.

Kristensen DM, Lesné L, Le Fol V, et al. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis. Int J Androl. 2012;35(3):377–84.

Kristensen, DM, Hass, U, Lesné, L, et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum. Reprod. 2011;26(1):235–44

Laine L, Kivitz AJ, Bello AE, et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers.Am J Gastroenterol. 2012;107(3):379–86.

Lanas A. Gastrointestinal bleeding associated with low-dose aspirin use: relevance and management in clinical practice. 2011 Jan;10(1):45-54.

Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364–72.

Li H, Hortmann M, Daiber A, et al. Cyclooxygenase 2-selective and nonselective nonsteroidal anti-inflammatory drugs induce oxidative stress by up-regulating vascular NADPH oxidases. 2008 Sep;326(3):745-53.

Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. 2007;56(2):168–75.

Maity P, Bindu S, Dey S, et al. Melatonin reduces indomethacin-induced gastric mucosal cell apoptosis by preventing mitochondrial oxidative stress and the activation of mitochondrial pathway of apoptosis. 2009 Apr;46(3):314-23.

Masubuchi Y, Sugiyama S, Horie T. Th1/Th2 cytokine balance as a determinant of acetaminophen-induced liver injury. ChemBiol Interact. 2009;179(2-3):273–9.

Matsukura T, Tanaka H. Applicability of zinc complex of L-carnosine for medical use. 2000 Jul;65(7):817-23.

Matsura T, Nishida T, Togawa A, et al. Mechanisms of protection by melatonin against acetaminophen-induced liver injury in mice. J Pineal Res. 2006;41(3):211–9.

Mayo Clinic.Arthritis. Updated 1/22/2011. Available at: http://www.mayoclinic.com/health/arthritis/DS01122/DSECTION=treatments-and-drugs Accessed 7/17/2012.

Mills EJ, Wu P, Alberton M, et al. Low-dose Aspirin and Cancer Mortality: A Meta-analysis of Randomized Trials. Am J Med. 2012;125(6):560–7.

Moodley I. Review of the cardiovascular safety of COXIBs compared to NSAIDS. 2008 Mar-Apr;19(2):102-7.

Moyer AM, Fridley BL, Jenkins GD, et al. Acetaminophen-NAPQI Hepatotoxicity: A Cell Line Model System Genome-Wide Association Study. Toxicol Sci. 2011;120(1):33–41.

Nagalekshmi R, Menon A, Chandrasekharan DK, et al. Hepatoprotective activity of Andrographispaniculata and Swertiachirayita. Food ChemToxicol. 2011;49(12):3367–73.

NIH MedlinePlus. Aspirin overdose. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/002542.htm Accessed 7/20/2012A.

O’Connor N, Dargan PI, and Jones AL. Hepatocellular damage from non-steroidal anti-inflammatory drugs. 2003 Nov;96(11):787-91.

Omatsu T, Naito Y, Handa O, et al. Reactive oxygen species-quenching and anti-apoptotic effect of polaprezinc on indomethacin-induced small intestinal epithelial cell injury. J Gastroenterol. 2010;45(7):692–702.

Oz HS and Chen TS.Green-tea polyphenols downregulate cyclooxygenase and Bcl-2 activity in acetaminophen-induced hepatotoxicity. Dig Dis Sci. 2008;53(11):2980–8.

Oz HS, McClain CJ, Nagasawa HT, et al. Diverse antioxidants protect against acetaminophen hepatotoxicity. J BiochemMolToxicol. 2004;18(6):361–8.

Ozkaya O, Genc G, Bek K, and Sullu Y.A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature.Ren Fail. 2010;32(9):1125–7

Patel V, Fisher M, Voelker M, et al. Gastrointestinal effects of the addition of ascorbic Acid to aspirin. 2012 Jul;12(6):476-84.

Peterson FJ, Lindemann NJ, Duquette PH, et al. Potentiation of acute acetaminophen lethality by selenium and vitamin E deficiency in mice. J Nutr. 1992;122(1):74–81.

Peterson K, McDonagh M, Thakurta S, et al. Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report. National Institute of Health (NIH) PubMed Health. Bethesda (MD): National Library of Medicine (US). Nov. 2010.

Peura DA. Gastrointestinal safety and tolerability of nonselective nonsteroidal anti-inflammatory agents and cyclooxygenase-2-selective inhibitors. Cleve Clin J Med. 2002;69Suppl 1:SI31–9.

Ray SD, Kumar MA, Bagchi D. A novel proanthocyanidin IH636 grape seed extract increases in vivo Bcl-XL expression and prevents acetaminophen-induced programmed and unprogrammed cell death in mouse liver. Arch. BiochemBiophys. 1999;369(1):42–58.

Reagan-Shaw S, Nihal M, and Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2007;22(3):659–61

Reiss AB, Anwar F, Chan ES, et al. Disruption of cholesterol efflux by coxib medications and inflammatory processes: link to increased cardiovascular risk. 2009 Aug;57(6):695-702.

Roth SH. Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety. ClinInterv Aging. 2011;6:125–31.

Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011 Jan 1;377(9759):31-41.

Sancar M, Hantash T, Okuyan B, et al. Comparative effectiveness of Glycyrrhizaglabra vs. omeprazole and misoprostol for the treatment of aspirin-induced gastric ulcers. African Journal of Pharmacy and Pharmacology. 2009;3(12):615–20.

Sandoval-Acuña C, Lopez-Alarcón C, Aliaga ME, et al. Inhibition of mitochondrial complex I by various non-steroidal anti-inflammatory drugs and its protection by quercetin via a coenzyme Q-like action. 2012 Jul 30;199(1):18-28.

Schnell RC, Park KS, Davies MH, et al. Protective effects of selenium on acetaminophen-induced hepatotoxicity in the rat.ToxicolApplPharmacol. 1988;95(1):1–11.

Schrör K. Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs incolorectal cancer. 2011 Aug;25(4-5):473-84.

Sener G, Omurtag GZ, Sehirli O, et al. Protective effects of ginkgo biloba against acetaminophen-induced toxicity in mice.Mol Cell Biochem. 2006a;283(1-2):39–45.

Sener G, Toklu HZ, Sehirli AO, et al. Protective effects of resveratrol against acetaminophen-induced toxicity in mice.Hepatol Res. 2006b;35(1):62–8.

Sharma M. Chronic Acetaminophen Toxicity. 10/26/2009. Available at: http://lib.sh.lsuhsc.edu/am_rpt/media/files/10232009.pdf Accessed 7/18/2011.

Sindhu ER, Firdous AP, Preethi KC, et al. Carotenoid lutein protects rats from paracetamol-, carbon tetrachloride- and ethanol-induced hepatic damage. J Pharm Pharmacol. 2010;62(8):1054–60.

Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am. J. Med. 1998;105(1B):31S–38S

Singh S, Khajuria A, Taneja, SC, et al. The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswelliaserrata, in rats.Phytomedicine. 2008;15(6-7):408–15

Sivalingam N, Basivireddy J, Balasubramanian KA, et al. Curcumin attenuates indomethacin-induced oxidative stress and mitochondrial dysfunction. 2008 Jul;82(7):471-81.

Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557–62.

Stark LA, Reid K, Sansom OJ, et al. Aspirin activates the NF-kappaBsignalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. 2007 May;28(5):968-76. Epub 2006 Nov 28.

Sumioka I, Matsura T, Yamada K. Therapeutic effect of S-allylmercaptocysteine on acetaminophen-induced liver injury in mice.European Journal of Pharmacology. 2001;433(2-3):177–85.

Takahashi T, Takahashi T, et al. Proinflammatory cytokines detectable in synovial fluids from patients with temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 1998 Feb;85(2):135-41.

Terneus MV, Brown JM, Carpenter AB, et al. Comparison of S-adenosyl-L-methionine (SAMe) and N-acetylcysteine (NAC) protective effects on hepatic damage when administered after acetaminophen overdose. Toxicology. 2008;244(1):25–34.

Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. 2002 Feb 20;94(4):252-66.

Toussaint K, Yang XC, Zielinski MA, et al. What do we (not) know about how paracetamol (acetaminophen) works? J Clin Pharm Ther. 2010;35(6):617–38.

Trelle S, Reichenbach S, Wandal S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.

van Leeuwen JS, Unlü B, Vermeulen NP, et al. Differential involvement of mitochondrial dysfunction, cytochrome P450 activity, and active transport in the toxicity of structurally related NSAIDs. 2012 Mar;26(2):197-205. Epub 2011 Nov 26.

Van Mil AH, and Janssens AR. [Acetaminophen use by chronic alcohol abusers: a therapeutic dose may be too much for the liver]. 2001 Sep 29;145(39):1873-6.

Vestergaard P, Hermann P, Jensen JEB, et al. Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporos Int. 2012;23(4):1255–65.

Visen PK, Shukla B, Patnaik GK, et al. Andrographolide protects rat hepatocytes against paracetamol-induced damage. J Ethnopharmacol. 1993;40(2):131–6.

Vonkeman HE and van de Laar MAFJ.Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum. 2010;39(4):294–312.

Wang EJ, Li Y, Lin M, et al. Protective effects of garlic and related organosulfur compounds on acetaminophen-induced hepatotoxicity in mice. ToxicolApplPharmacol. 1996;136(1):146–54.

Watanabe T, Tanigawa T, Nadatani Y, et al. Mitochondrial disorders in NSAIDs-induced small bowel injury. 2011 Mar;48(2):117-21. Epub 2011 Feb 26.

Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87–93.

Weir MR. Renal effects of nonselective NSAIDs and coxibs. Cleve Clin J Med. 2002;69Suppl 1:SI53-8.

Wittschier N, Faller G, Hensel A. Aqueous extracts and polysaccharides from liquorice roots (Glycyrrhizaglabra L.) inhibit adhesion of Helicobacter pylori to human gastric mucosa. J Ethnopharmacol. 2009 Sep 7;125(2):218-23. Epub 2009 Jul 14.

Wolf MS, King J, Jacobson K, et al. Risk of Unintentional Overdose with Non-Prescription Acetaminophen Products. J Gen Intern Med. 2012 May 26. [Epub ahead of print]

Yalçin S, Bilgili A, Onbasilar I, et al. Synergistic action of sodium selenite and N-acetylcysteine in acetaminophen-induced liver damage. Hum ExpToxicol. 2008;27(5):425–9.

Zahra T, Butt SA, Arshad, M. Effects of Beta Carotene on Liver Enzymes in Acetaminophen Treated Rats. Journal of Rawalpindi Medical College (JRMC). 2010;14(1):7–10.

Zhao C and Shichi H. Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine.J OculPharmacolTher. 1998;14(4):345–55.

Zhao L and Pickering G. Paracetamol metabolism and related genetic differences. Drug Metab Rev. 2011;43(1):41–52.