Celebrex (celecoxib) belongs to the class of nonsteroidal anti-inflammatory(NSAID) drugs which is widely employed for pain and inflammation management. Pain, fever and swelling provoked by osteoarthritis and rheumatoid arthritis is only relieved but the medicine does not avert the progress of the pathology development. The main feature which differs Celebrex from other NSAIDs (nonsteroidal anti-inflammatory ) is that doesn’t does not impede with the blood clot and has mild affect on stomach and intestine. If applied for a short time the medicine causes little or no inflammation and ulceration of the abovementioned organs. NSAIDs prevents the appearance of polyps. It’s also effective at reduction of the size of polyps and reliefs pains.
Anti-inflammatory
Inflammation is defined as a normal protective response of the body to injury caused by physical trauma or impact, chemicals or microbiological agents. Inflammation is an essential body response for survival – without it, simple or mild environmental pathogens couldeasily kill us!
There are four classic inflammatory responses, regardless of cause – warmth, pain, redness, and swelling.
Inflammation is initiated by inflammatory cells found all over the body like macrophages, dendritic cells, histiocytes, Kupffer cells. These cells release inflammatory mediators such as histamine, IFN ã, IL 8, leukotriene B4, nitric oxide, prostaglandins, TNFá and IL-1. Plasma derived mediators are also involved, like bradykinin, C3, C5a, plasmin and thrombin.
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Celebrex is a non-steroidal anti inflammatory drug (NSAIDs) belonging to the selective COX – 2 inhibitors class. Its molecular formula is C17H14F3N3O2S.
Celebrex is an anti-inflammatory, analgesic and antipyretic drug. It was approved by the US FDA since 1998 for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain and primary dysmenorrhea. Let us discuss the drug’s indications.
Analgesic
Pain is defined as an unpleasant sensory and emotional experience. It is a subjective, individual feeling that no single test can diagnose. Pain is usually associated with an actual or potential damage in the tissues. There are three classes of pain: acute pain (lasts for less than 30 days, usually self limiting), chronic pain (episodic pain that greatly affects the person’s well being) and breakthrough pain (intermittent, slowly increasing pain, with precipitating factors or causes).
Because pain is a very subjective feeling, diagnosis and assessment may be difficult. Patients may be in a very obvious distress, while some can appear to have no noticeable suffering. Patients may describe pain as something sharp, dull, burning, shock-like, tingling, shooting, radiating, or fluctuating in intensity.
The feeling of pain is mainly caused by the compound prostaglandin. Prostaglandin is liberated by substances such as bradykinin and cytokines (like TNFá, IL-1, and IL-8). Studies show that other compounds like neuropeptides [substance P and calcitonin gene-related peptide (CGRP)] are involved in pain.
Antipyretic
Fever, or pyrexia or hyperthermia, is defined as a body temperature above the normal range, which is 36.5-37.5oC (98-100oF). The hypothalamus is the part of the body responsible for temperature regulation. Our body occasionally experiences an increase in body temperature, for example, as a response to exercise or to ambient temperature. However, in fever,the temperature increase is the response of the body as a result of an infection, tissue damage, inflammation or malignancy.
Cytokines (such as IL-1â, IL-6), interferons and TNFá initiate fever. These compounds increase the synthesis of prostaglandin, especially prostaglandin E2 that increases cAMP, which in turn signals the hypothalamus to increase the temperature.
COX Inhibition
Most NSAIDs act by inhibiting prostaglandin formation. In the above conditions, prostaglandin is one of the main mediators that cause pain, inflammation and fever. NSAIDs act on prostaglandin by inhibition of enzymes necessary for its production. These enzymes are called prostaglandin G/H (PGH) synthase enzymes or otherwise they are called cyclooxygenases. The following figure shows the reaction mechanism of arachidonic acid to prostaglandin, in which PGH synthase or cyclooxygenase plays a major role.
Fig 2. Reaction mechanism: Conversion of arachidonic acid to prostaglandin.
As shown in the diagram, COX inhibition results to inhibition of prostaglandin synthesis – leading to the pharmacological effects of NSAIDs.
There are two isoenzymes of COX – COX-1 and COX-2. These two are molecularly the same, but have different functions. COX-1 is found mainly in gastric epithelial cells. Its function there is cytoprotective prostaglandin formation (Seibert et al., 1997). COX-2, on the other hand, is found in endothelial cells (Topper, 1996), and their main function is the induction of inflammation. Since most NSAIDs are both COX-1 and 2 inhibitors, prostaglandin formation in the stomach and inflammatory cells are halted. Inflammation is halted; however, the natural gastric protection is also affected. Much of the gastric adverse effects of NSAIDs (gastric pain, bleeding, and ulcers) are felt due to the inhibition of COX-1. Due to this unwanted side effects, many researchers sought of a drug that can act only on COX-2.
Selective COX II inhibitors were thus born, and Celebrex (Celecoxib) is the first ever coxib approved for use. NSAIDs use was poorly tolerated because of severe gastric adverse effects. Chronic users are almost certain to feel the adverse effect. But ever since coxibs were released, the number of people suffering from this side effect has greatly decreased. The coxibs were very acceptable for most patients, especially those suffering from gastric problems like ulcers.
Research on Cancer Treatment and Prevention
In the past decade, heavy research has been done and continuously being done regarding the chemo preventive and chemotherapeutic properties of Celebrex for cancer.
Large scale epidemiological and laboratory studies have found that long-term users of NSAIDs have relatively lower risk for cancer. Studies have shown that risks for colon cancer (Kawamori et al., 1998), breast cancer (Harris, et al., 200), colorectal cancer (Gupta & Dubois, 2001) have been reduced with use of NSAIDs. This prompted many researchers to determine how NSAIDs affect cancer.
NSAIDs are drugs that inhibit prostaglandin by cyclooxygenase inhibition. Interestingly, Kawamori and colleagues (1998) have stated that there is an abundant supply of COX in tumors. Since there is an abnormally high amount of COX, it can be considered a drug target for cancer. Gupta & Dubois (2001) have found high levels of COX in colorectal cancer, and determined that COX is responsible for tumor promotion in colorectal cancer. In another study by Hsu et al. (2001), they found that COX is also expressed in large quantities in prostate cancer cells. Koehne& Dubois (2004) even stated that COX is overly expressed in several premalignant and malignant lesions.
In a systematic review by Xu in 2002, she reported that COX-2 is inducible by various agents such as growth factors and tumor promoters, which are present in cancer. She further reported six possible effects or contributions of COX-2 to cancer:
• increased production of prostaglandins
• conversion of procarcinogens to carcinogens
• inhibition of apoptosis (natural cell death)
• promote angiogenesis (cancer initiation)
• modulation of inflammation and immune function
• increased tumor cell invasiveness
These findings were supported by another study made by Arico et al., (2002). They reported that COX may promote cancer by COX dependent (prostaglandin related) and COX independent pathways.
Several studies have proven the effectiveness of Celebrex as a chemo-preventive therapy for cancer in rats. Colon carcinogenesis was found to be prevented by Kawamori and colleagues (1998). A more detailed study on colon cancer was done by Reddy et al. in 2000. They administered Celebrex in different stages of carcinogenesis, and found that it is effective at every stage.
Celebrex was effective in preventing breast carcinogenesis in rats. This was found by Harris et al. in 2000. The group compared Celebrex with ibuprofen, a non specific COX inhibitor. Though both drugs showed significant results, Celebrex was found superior in reducing incidence (68%), multiplicity (86%) and volume of tumors (81%) as compared to ibuprofen (40%, 52% and 57%, respectively). In a review made by Arun and Goss (2004), they reported that several clinical trials have been done with Celebrex as an adjunctive therapy for breast cancer. Furthermore, they reported that the National Cancer Institute of Canada Clinical Trials Group has reached phase III clinical trials of Celebrex together with Exemestane, an aromatase inhibitor used for breast cancer.
Relatively small amounts of data are available regarding prostate cancer. Hsu et al. (2000) reported that, though most cancers in which Celebrex was effective was due to direct COX inhibition, prostate cancer prevention is based on a different mechanism. They found that the inhibition of Akt activation is the mechanism by which apoptosis was induced by Celebrex.
Cardiovascular Risk
As with all NSAIDs, Celebrex poses a risk for cardiovascular side effects such as thrombotic events, myocardial infarction and stroke. When compared to other NSAIDs, Celebrex does not have a higher risk (Dean, 2011; Johnsen, et.al., 2005). When compared to another selective COX-2 inhibitor (rofecoxib), it was found that Celebrex has a lower risk (Johnsen, et.al., 2005). Another study even suggests that Celebrex at normal doses is safer from cardiovascular side effects as compared to rofecoxib (McGettigan, 2006)
Cardiovascular risk is increased with increased duration of drug use, dose and dosage regimen, as proven by several controlled studies presented in the Cross Trial Safety Analysis (Solomon et.al., 2008).
In a study made by McAdam and colleagues in 1999, they found that selective COX-2 inhibitors inhibit PGI2 formation by endothelial cells in mice. Thromboxane inhibition is the primary cause of cardiovascular side effects of most NSAIDs, since it is involved in platelet aggregation. However, though not directly inhibiting thromboxane, PGI2 inhibition results to the similar side effect, because PGI2inhbits thromboxane.
DOSAGE:
The lowest effective dose of Celebrex should always be used. The dose depends on the condition being treated:
• Osteoarthritis: Use 200 mg once per day or 100 mg twice per day.
• Rheumatoid Arthritis: Use 100 to 200 mg twice per day.
• Juvenile Rheumatoid Arthritis (patients must be 2 years old or older): For patients weighing 10-25 kg use 50 mg twice per day in patients. For patients weighing more than 25 mg use 100 mg per day.
• Ankylosing Spondylitis: Use 200 mg once per day or 100 mg twice per day. If after 6 weeks of treatment there is still no apparent effect from the drug, you can try using 400 mg per day in single or divided doses.
• Acute Pain and Primary Dysmenorrhea: On the first day, use 400 mg – if required, this can be followed by 200 mg dose on the same day. On subsequent days, use 200 mg twice per day.
• Patients with moderate liver impairment should reduce their daily dose by 50%
• Patients known or suspected to be CYP2C9 poor metabolizers may consider reducing their daily dose by 50%.
• In case of Juvenile Rheumatoid Arthritis patients with CYP2C9 poor metabolizers, alternative treatments should be considered.
CONTRAINDICATIONS AND WARNINGS
• Do not use Celebrex if you have any known hypersensitivity reactions to celecoxib or sulphonamides.
• Do not use Celebrex if you have a history of allergic reactions to aspirin or other NSAIDs (including asthma andurticaria).
• Do not use Celebrex during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery.
• surgery
• Patients with known cardiovascular (CV) disease(s) should use with caution.
• Patients with history of gastrointestinal (GI) bleeding, ulcer disease(s), or other GI-related conditions, and especially the elderly, should use with caution.
• Avoid or use with care if you are already taking any of the drugs described in the Drug Interactions section.
• Hypertensive patients should monitor their blood pressure frequently while taking Celebrex.
• Patients with heart failure, impaired renal function, fluid retention or liver dysfunction should use with caution.
• The elderlyshould use with caution.
• Discontinue use of Celebrex with the first signs of rash or skin reactions.
SIDE EFFECTS/ADVERSE REACTIONS:
Serious cardiovascular events (including thrombosis, myocardial infarction, stroke).
Serious gastrointestinal events.
Liver events (rarely serious) including elevated liver enzymes.
Hypertension (onset or worsening of existing one).
Fluid retention that can lead tooedema.
Renal injuries such as renal papillary necrosis.
Anaphylaxis (allergic reactions).
Serious skin events.
In arthritis patients, the following were sometimes observed: rash, abdominal pain, dyspepsia, diarrhoea, flatulence, peripheral oedema, rhinitis, pharyngitis,sinusitis and upper respiratory tract infection.
DRUG INTERACTIONS:
Coadministration ofCelebrex and warfarin may result inincreased risk of bleeding complications.
Coadministration of Celebrex and lithium can increase lithium plasma levels.
Coadministrationof Celebrex and angiotensin II antagonists and ACE Inhibitors mayreduce their antihypertensive effect.
Coadministration of Celebrex and drugs known to inhibit P450 2C9 or metabolized by 2D6 can possibly lead toincreased plasma levels of Celebrex.
Bibliography
ARICO, S., PATTINGRE, S., BAUVY, C., ET AL. 2002. Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line.
ARUN, B., GOSS, P. 2004. The role of COX-2 inhibition in breast cancer treatment and prevention.
DEAN, L. 2011. Comparing NSAIDs.
GUPTA, R.A. & DUBOIS, R.N. 2001. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2.
HARRIS, R.E., ALSHAFIE, G.A., ABOU-ISSA, H. & SEIBERT, K. 2000. Chemoprevention of Breast Cancer in Rats by Celecoxib, a Cyclooxygenase 2 Inhibitor.
HSU, A., CHING, T., WANG, D., ET AL. 2000. The Cyclooxygenase-2 Inhibitor Celecoxib Induces Apoptosis by Blocking Akt Activation in Human Prostate Cancer Cells Independently of Bcl-2.
JOHNSEN, S.P., LARSSON, H., TAROME, R.E., et.al. 2005. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib and other NSAIDs: A population-based case-control study.
KAWAMORI, T., RAO, C.V., SEIBERT, K. & REDDY, B.S. 1998. Chemopreventive Activity of Celecoxib, a Specific Cyclooxygenase-2 Inhibitor, against Colon Carcinogenesis.
MCADAM, B.F., CATELLA-LAWSON, F., MARDINI, I.A., ET.AL. 1999.
Systemic biosynthesis of prostacyclin by cyclooxygenase (cox)-2: the human pharmacology of a selective inhibitor of COX-2.
MCGETTIGAN, P. 2006. Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2.
REDDY, B.S., HIROSE, Y., LUBET, R., ET AL. 2000. Chemoprevention of Colon Cancer by Specific Cyclooxygenase-2 Inhibitor, Celecoxib, Administered during Different Stages of Carcinogenesis.
TOPPER, J.N., CAI, J., FALB, D., AND GIMBRONE, M.A. 1996. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress.
SEIBERT, K., ZHANG, Y., LEAHY, K., et al. 1997. Distribution of COX-1 and COX-2 in normal and inflamed tissues.
SOLOMON, S.D., et.al. 2008. Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials: The Cross Trial Safety Analysis.
XIAO-CHUN, X. 2002.COX-2 inhibitors in cancer treatment and prevention, a recent development. Retrieved from
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Celebrex (celecoxib) belongs to the class of nonsteroidal anti-inflammatory(NSAID) drugs which is widely employed for pain and inflammation management. Pain, fever and swelling provoked by osteoarthritis and rheumatoid arthritis is only relieved but the medicine does not avert the progress of the pathology development. The main feature which differs Celebrex from other NSAIDs (nonsteroidal anti-inflammatory ) is that doesn’t does not impede with the blood clot and has mild affect on stomach and intestine. If applied for a short time the medicine causes little or no inflammation and ulceration of the abovementioned organs. NSAIDs prevents the appearance of polyps. It’s also effective at reduction of the size of polyps and reliefs pains.
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