Truths, myths and mechanism of action of NSAIDS and Selective COX-2 Inhibitors (Coxibs)

Aspirin and COX-2 selective NSAIDs:

what the evidence tells us:

It was hoped that the introduction of the coxib class of COX-2 selective NSAIDs
(rofecoxib, celecoxib, etoricoxib, valdecoxib) had at last overcome the problem of
poor gastrointestinal tolerability with NSAIDs. These new agents, by selectively
inhibiting inducible COX-2 not constitutive COX-1, should have offered a safer
treatment for arthritis. Instead, they became yet another example of misguided
optimism, as long-established and evidence-based treatments were discarded in
favour of relatively untested new drugs.

What were the concerns about non-COX selective NSAIDs?

There was no evidence of differences in efficacy among older NSAIDs so attention
naturally focused on their relative safety. Before the advent of the coxibs, the major
concern about non-aspirin NSAIDs was dose-related gastrointestinal (GI) toxicity. It
was estimated that 10 - 20 percent of patients had dyspepsia while taking an NSAID
and 5 - 15 percent discontinued treatment within 6 months primarily due to adverse
GI effects1. In 1994 the Committee on Safety of Medicines ranked the most widely
prescribed non-aspirin NSAIDs in order of the risk of upper GI toxicity: ibuprofen was
associated with least risk; diclofenac, naproxen, ketoprofen and indomethacin with
intermediate risk; and piroxicam with highest risk2. Compared with ibuprofen, these
agents were associated with a 1.6 - 4.2-fold increased risk of gastrointestinal
bleeding and peptic ulcer perforation.

Non-aspirin NSAIDs were also associated with other serious adverse effects such as
renal, hepatic, allergic and haematological reactions but these events were less
common than GI toxicity and the differences between NSAIDs were less marked.

What did COX-2 selective NSAIDs offer?

COX-2 selective NSAIDs reduced the risk of GI toxicity compared with non-selective
NSAIDs. Two large trials appeared to support this. The CLASS study compared
celecoxib, diclofenac and ibuprofen in 8059 patients with rheumatoid arthritis or
osteoarthritis. It found that celecoxib was associated with a significantly lower
incidence of upper GI bleeding, perforation or ulceration and symptomatic ulcers
(1.40 vs 2.91 percent with the other NSAIDs) after 6 months; there were no
differences in the risk of cardiovascular events. The VIGOR study compared
rofecoxib and naproxen in 8076 patients with rheumatoid arthritis. After 9 months,
rofecoxib was associated with less than half the risk of upper GI bleeding, perforation
or ulceration and symptomatic ulcers (2.1 vs. 4.5 percent).

The fall of the coxibs:

Rofecoxib was withdrawn in September 2004 when, in the APPROVe trial, it was
associated with a 2-fold increased risk of myocardial infarction and stroke (6 events
per 400 pt.yrs vs. 3 per 400 pt.yrs with placebo). This was subsequently confirmed
by a meta-analysis of clinical trials. Next, another unpublished trial linked celecoxib
with an increased risk of cardiovascular events (2.3-fold increased risk at 400 mg/day
and 3.4-fold increased risk at 800 mg/day). The European Medicines Evaluation
Agency (EMEA), Europe's drug regulatory body, then advised that valdecoxib and
parecoxib (licensed only for the treatment of pain in the UK) were contraindicated in
patients undergoing coronary artery bypass surgery because of an increased risk of
serious cardiovascular thromboembolic events. Following a review of the safety of
the coxibs by the EMEA, the UK Medicines and Healthcare Products Agency issued
advice that the coxibs should not be prescribed for patients with ischaemic heart
disease or cerebrovascular disease (formerly they could be prescribed with caution
for patients with ischaemic heart disease), or in patients with moderate to severe
heart failure; an alternative treatment (an NSAID with gastroprotection if indicated)
should be considered for all patients.

Some studies have found that the coxibs do not increase cardiovascular risk and
the most recent analyses suggest that rofecoxib is associated with a higher risk than
celecoxib. But not all safety concerns focused on cardiovascular events. The
EMEA has warned that valdecoxib and parecoxib are associated with serious skin
reactions; and a Canadian analysis showed that the advantage of the lower GI risk
associated with rofecoxib and celecoxib was outweighed by their increased use, so
that total hospital admissions for GI haemorrhage actually increased after these
agents were introduced.

What is the mechanism underlying these effects?

There seems little doubt that the increased cardiovascular risk associated with the
coxibs is a class effect, with varying degrees of expression in different drugs within
the class. The underlying mechanism is still unclear but it seems likely that selective
COX-2 inhibition destabilises the balanced cardiovascular effects of thromboxane A2
and prostacyclin I2.

Prostacyclin I2 is produced by endothelial cells by COX-2; it inhibits platelet
aggregation, causes vasodilatation and (in vitro) prevents vascular cell proliferation.
Thromboxane A2 is produced by platelets by COX1 has opposing effects, promoting
platelet aggregation, vasoconstriction and vascular proliferation. COX-2 selective
NSAIDs therefore inhibit production of prostacyclin I2 without affecting thromboxane
A2 and this results in increased blood pressure and an exaggerated thrombotic
response; animal studies also suggest it enhances atherogenesis.

What lessons can we learn?

The rise and fall of the coxibs provides a salutary reminder that drug safety cannot be
taken for granted. Premarketing clinical trials involve too few patients to provide a
reliable estimate of the possible risk of uncommon but serious adverse events -
particularly when those events are relatively frequent, as is the case with myocardial
infarction. Only long-term use can provide the necessary clinical experience in large
numbers of patients, including groups with comorbidities who are more vulnerable.
Now is the right time to reappraise the safety and efficacy of the long-established
NSAIDs for which there is reliable evidence.

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Longterm use of NSAIDS painkillers linked to Increased Risk of Heart Attack

Taking certain painkillers daily for some years carries a small increased risk of heart attack and stroke, research has suggested.

The findings relate to non-steroidal anti-inflammatory drugs like ibuprofen prescribed long-term to treat painful conditions. The report, published in the British Medical Journal, looked at more than 100,000 patients in 31 clinical trials.

A Swiss team analysed data from existing large-scale studies comparing use of non-steroidal anti-inflammatory drugs (NSAIDs) – naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib and lumiracoxib – with other drugs or placebo. One of the drugs – rofecoxib (also known by its brand name, Vioxx) was withdrawn in 2004 when other studies found a raised risk of heart attacks.

Most of the patients were elderly, with conditions like osteoarthritis, and were taking high doses of NSAIDs daily for at least a year. The researchers found the medicine increased the risk of death from stroke or heart attack by between two and four times, compared with placebo.

Peter Juni, professor of clinical epidemiology at the University of Bern, Switzerland, told: “For elderly (people) with musculoskeletal pain there must be extreme care when prescribing or taking these drugs.” But he stressed that the findings did not relate to people taking anti-inflammatories now and again for symptoms such as period pain or sports injuries.

Medical director Professor Peter Weissberg said: “This confirms what has been known for some years now – taking non-steroidal, anti-inflammatory drugs on a regular basis increases heart attack or stroke risk.

“However, some patients with debilitating joint pains may consider the small increased risk worthwhile when set against the improvement in their quality of life that these drugs bring.

Professor Maxwell said: “The advice to the public should continue to be to take this class of drugs only when they are genuinely necessary to control pain and in the lowest effective dose, not only because of any cardiovascular risk but also because of potential effects on the stomach.”

Traditional NSAIDs and the newer COX-2 inhibitors are extremely important medicines to treat arthritis and other painful conditions, and for most patients the risks of side effects are outweighed by the benefits.

COX-2 inhibitors are a new generation of NSAID drugs, which include celecoxib and rofecoxib. Far fewer GPs are now prescribing NSAIDs and COX-2 to their arthritis patients, particularly those with cardio-vascular problems, because of the potential risks, yet for many people who are not at high risk of heart attacks and strokes they remain a highly effective means of combating pain.

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ADHD Animation, Causes, Sign Symptoms And Treatment

DEFINITION:
ADHD is a problem with inattentiveness, over-activity, impulsivity, or a combination. For these problems to be diagnosed as ADHD, they must be out of the normal range for the child's age and development.

Alternative Names;
ADD; ADHD; Childhood hyperkinesis

Causes, incidence, and risk factors;
ADHD affects school performance and interpersonal relationships. Parents of children with ADHD are often exhausted and frustrated.
Neuroimaging studies suggest that the brains of children with ADHD are different from those of other children. These children handle neurotransmitters (including dopamine, serotonin, and adrenalin) differently from their peers.
ADHD is often genetic. Whatever the specific cause may be, it seems to be set in motion early in life as the brain is developing.
Depression, sleep deprivation, learning disabilities, tic disorders, and behavior problems may be confused with, or appear along with, ADHD. Every child suspected of having ADHD deserves a careful evaluation to sort out exactly what is contributing to the behaviors causing concern.
Attention Deficit Disorder (ADD) is the most commonly diagnosed behavioral disorder of childhood, affecting an estimated 3 - 5% of school aged children. It is diagnosed much more often in boys than in girls.
Most children with ADHD also have at least one other developmental or behavioral problem.

Symptoms:
The Diagnostic and Statistical Manual (DSM-IV) divides the symptoms of ADHD into those of inattentiveness and those of hyperactivity and impulsivity.
To be diagnosed with ADHD, children should have at least 6 attention symptoms or 6 activity and impulsivity symptoms -- to a degree beyond what would be expected for children their age.
The symptoms must be present for at least 6 months, observable in 2 or more settings, and not caused by another problem. The symptoms must be severe enough to cause significant difficulties. Some symptoms must be present before age 7.
Older children have ADHD in partial remission when they still have symptoms but no longer meet the full definition of the disorder.
Some children with ADHD primarily have the Inattentive Type, some the Hyperactive-Impulsive Type, and some the Combined Type. Those with the Inattentive type are less disruptive and are easier to miss being diagnosed with ADHD.

Inattention symptoms:

1. Fails to give close attention to details or makes careless mistakes in schoolwork
2. Difficulty sustaining attention in tasks or play
3. Does not seem to listen when spoken to directly
4. Does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace
5. Difficulty organizing tasks and activities
6. Avoids or dislikes tasks that require sustained mental effort (such as schoolwork)
7. Often loses toys, assignments, pencils, books, or tools needed for tasks or activities
8. Easily distracted
9. Often forgetful in daily activities

Hyperactivity symptoms:

1. Fidgets with hands or feet or squirms in seat
2. Leaves seat when remaining seated is expected
3. Runs about or climbs in inappropriate situations
4. Difficulty playing quietly
5. Often "on the go," acts as if "driven by a motor," talks excessively

Impulsivity symptoms:

1. Blurts out answers before questions have been completed
2. Difficulty awaiting turn
3. Interrupts or intrudes on others (butts into conversations or games)

Signs and tests:
Too often, difficult children are incorrectly labeled with ADHD. On the other hand, many children who do have ADHD remain undiagnosed. In either case, related learning disabilities or mood problems are often missed. The American Academy of Pediatrics (AAP) has issued guidelines to bring more clarity to this issue.
The diagnosis is based on very specific symptoms, which must be present in more than one setting. The child should have a clinical evaluation if ADHD is suspected.
Evaluation may include:

• Parent and teacher questionnaires (Connors, Burks)
• Psychological evaluation of the child AND family including IQ testing and psychological testing
• Complete developmental, mental, nutritional, physical, and psychosocial examination

Treatment:
The American Academy of Pediatrics has guidelines for treating ADHD:

• Set specific, appropriate target goals to guide therapy.
• Medication and behavior therapy should be started.
• When treatment has not met the target goals, evaluate the original diagnosis, the possible presence of other conditions, and how well the treatment plan has been implemented.
• Systematic follow-up is important to regularly reassess target goals, results, and any side effects of medications. Information should be gathered from parents, teachers, and the child.

ADHD is a frustrating problem. Alternative remedies have become quite popular, including herbs, supplements, and chiropractic manipulation. However, there is little or no solid evidence for many remedies marketed to parents.
Children who receive both behavioral treatment and medication often do the best. Medications should not be used just to make life easier for the parents or the school. There are now several different classes of ADHD medications that may be used alone or in combination. Some ADHD medicines have been linked to sudden death in children with heart problems. Talk to your doctor about which drug is best for your child.
The following may also help:

• Limit distractions in the child's environment.
• Provide one-on-one instruction with teacher.
• Make sure the child gets enough sleep.
• Make sure the child gets a healthy, varied diet, with plenty of fiber and basic nutrients.

Expectations (prognosis):
ADHD is a long-term, chronic condition. About half of the children with ADHD will continue to have troublesome symptoms of inattention or impulsivity as adults. However, adults are often more capable of controlling behavior and masking difficulties.
Statistics show that there is an increased incidence in juvenile delinquency and adult encounters with the law among individuals who had ADHD as a child.
Every effort should be made to manage symptoms and direct the child's energy to constructive and educational paths.

Complications:
Many adults with ADHD are in successful jobs. Possible complications, if ADHD is not adequately treated, could include failure in school or other similar problems.

Prevention:
While there is no proven way to prevent ADHD itself, early identification and treatment can prevent many of the problems associated with ADHD.

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Actinic Keratosis Animation, Causes, Sign Symptoms and Treatment

DEFINITION:
Actinic keratosis is a precancerous skin growth usually caused by sun exposure.

Alternative Names;
Solar keratosis; Sun-induced skin changes - keratosis; Keratosis - actinic (solar)

Causes, incidence, and risk factors:
Actinic keratosis occurs most commonly in fair skin, especially in the elderly and in young individuals with light complexions. The growths occur in sun-exposed skin areas. The growths begin as flat, scaly areas that later develop a hard wart-like surface.
They are classified as precancerous growths. If left untreated, approximately 1% of actinic keratoses develop into squamous cell carcinoma.

Symptoms:

• Rough and dry textured skin lesion
• A macule, patch, or growth on the skin
  • Limited to a discrete area (localized)
  • Located on the face, scalp, back of the hands, chest or other sun-exposed areas
  • Gray, pink, red (erythematous), or the same color as the skin
  • Initially flat and scaly on the surface, becoming slightly raised
  • Becoming hard and wart-like or gritty, rough, and "sandpapery" -- may develop a horn-like texture from overgrowth of skin keratin layer (hyperkeratosis)

Signs and tests:
The health care provider bases the diagnosis on the appearance of the skin growth. A skin biopsy could reveal signs of cancerous changes, if present.

Treatment:
Because actinic keratoses represent precancerous changes, you should have them examined promptly and follow the health care provider's advice for treatment.
Growths may be removed by cryotherapy (freezing), electrical cautery (burning), or surgery. Growths may also be treated with medications that cause skin peeling or removal. More recently, lasers and other light sources have been used to treat actinic keratoses.

Expectations (prognosis):
Actinic keratosis itself is benign, but it may develop into skin cancer. Removal of the growth is usually effective.

Complications:

• Squamous cell carcinoma
• Irritation and discomfort of the skin growth

Calling your health care provider:
Call for an appointment with your health care provider if areas of persistent roughness or scaliness develop in sun-exposed skin.

Prevention:
Reduce sun exposure and protect your skin from the sun. Wear protective clothing such as hats, long-sleeved shirts, long skirts, or pants. Ultraviolet light is most intense midday, so try to avoid sun exposure during these hours.
Use high-quality sunscreens, preferably with SPF (sun protection factor) ratings of at least 15. Pick a sunscreen that blocks both UBA and UVB light. Apply sunscreen at least 30 minutes before going out into the sun, and reapply frequently. Sunscreen should be used year-round, including in the winter.

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Acne Animation, Causes and Description, Diagnosis and Treatment

Boils and carbuncles are bacterial infections of hair follicles and surrounding skin that form pustules (small blister-like swellings containing pus) around the follicle. Boils are sometimes called furuncles. A carbuncle is formed when several furuncles merge to form a single deep abscess with several heads or drainage points.



DESCRIPTION:

Boils and carbuncles are firm reddish swellings about 0.2-0.4in (5-10 mm) across that are slightly raised above the skin surface. They are sore to the touch. A boil usually has a visible central core of pus; a carbuncle is larger and has several visible heads. Boils occur most commonly on the face, back of the neck, buttocks, upper legs and groin area, armpits, and upper torso. Carbuncles are less common than single boils; they are most likely to form at the back of the neck. Males are more likely to develop carbuncles.
Boils and carbuncles are common problems in the general population, particularly among adolescents and adults.

People who are more likely to develop these skin infections include those with:

• diabetes, especially when treated by injected insulin
• alcoholism or drug abuse
• poor personal hygiene
• crowded living arrangements
• jobs or hobbies that expose them to greasy or oily substances, especially petroleum products
• allergies or immune system disorders, including HIV infection.
• family members with recurrent skin infections

CAUSES AND SYMPTOMS:

Boils and carbuncles are caused by Staphylococcus aureus, a bacterium that causes an infection in an oil gland or hair follicle. Although the surface of human skin is usually resistant to bacterial infection, S. aureus can enter through a break in the skin surface--including breaks caused by needle punctures for insulin or drug injections. Hair follicles that are blocked by greasy creams, petroleum jelly, or similar products are more vulnerable to infection. Bacterial skin infections can be spread by shared cosmetics or washcloths, close human contact, or by contact with pus from a boil or carbuncle.
As the infection develops, an area of inflamed tissue gradually forms a pus-filled swelling or pimple that is painful to touch. As the boil matures, it forms a yellowish head or point. It may either continue to swell until the point bursts open and allows the pus to drain, or it may be gradually reabsorbed into the skin. It takes between one and two weeks for a boil to heal completely after it comes to a head and discharges pus. The bacteria that cause the boil can spread into other areas of the skin or even into the bloodstream if the skin around the boil is injured by squeezing. If the infection spreads, the patient will usually develop chills and fever, swollen lymph nodes (lymphadenitis), and red lines in the skin running outward from the boil.
Furunculosis is a word that is sometimes used to refer to recurrent boils. Many patients have repeated episodes of furunculosis that are difficult to treat because their nasal passages carry colonies of S. aureus. These bacterial colonies make it easy for the patient's skin to be reinfected. They are most likely to develop in patients with diabetes, HIV infection, or other immune system disorders.
Carbuncles are formed when the bacteria infect several hair follicles that are close together. Carbunculosis is a word that is sometimes used to refer to the development of carbuncles. The abscesses spread until they merge with each other to form a single large area of infected skin with several pus-filled heads. Patients with carbuncles may also have a low-grade fever or feel generally unwell.

DIAGNOSIS:

The diagnosis of boils and carbuncles is usually made by the patient's primary care doctor on the basis of visual examination of the skin. In some cases involving recurrent boils on the face, the doctor may need to consider acne as a possible diagnosis, but for the most part boils and carbuncles are not difficult to distinguish from other skin disorders.

TREATMENT:

Patient and Family education
Patient education is an important part of the treatment of boils and carbuncles. Patients need to be warned against picking at or squeezing boils because of the danger of spreading the infection into other parts of the skin or bloodstream. It is especially important to avoid squeezing boils around the mouth or nose because infections in these areas can be carried to the brain. Patients should also be advised about keeping the skin clean, washing their hands carefully before and after touching the boil or carbuncle, avoiding the use of greasy cosmetics or creams, and keeping their towels and washcloths separate from those of other family members. Some doctors may recommend an antiseptic soap or gel for washing the infected areas.

If the patient has had several episodes of furunculosis, the doctor may examine family members or close contacts to see if they are carriers of S. aureus. In many cases they also need treatment for boils or carbuncles. Skin infections and reinfections involving small groups or clusters of people are being reported more frequently in the United States.

MEDICATION:

Boils are usually treated with application of antibiotic creams--usually clindamycin or polymyxin--following the application of hot compresses. The compresses help the infection to come to a head and drain.

Carbuncles and furunculosis are usually treated with oral antibiotics as well as antibiotic creams or ointments. The specific medications that are given are usually dicloxacillin (Dynapen) or cephalexin (Keflex). Erythromycin may be given to patients who are allergic to penicillin. The usual course of oral antibiotics is 5-10 days; however, patients with recurrent furunculosis may be given oral antibiotics for longer periods. Furunculosis is treated with a combination of dicloxacillin and rifampin (Rifadin).

Patients with bacterial colonies in their nasal passages are often given mupirocin (Bactroban) to apply directly to the lining of the nose.

SURGICAL TREATMENT:

Boils and carbuncles that are very large, or that are not draining, may be opened with a sterile needle or surgical knife to allow the pus to drain. The doctor will usually give the patient a local anesthetic if a knife is used; surgical treatment of boils is painful and usually leaves noticeable scars.

ALTERNATIVE TREATMENT:

Naturopathic therapy
Naturopathic practitioners usually recommend changes in the patient's diet as well as applying herbal poultices to the infected area. The addition of zinc supplements and vitamin A to the diet is reported to be effective in treating boils. The application of a paste or poultice containing goldenseal (Hydrastis canadensis) root is recommended by naturopaths on the grounds that goldenseal helps to kill bacteria and reduce inflammation.

Homeopathy
Homeopaths maintain that taking the proper homeopathic medication in the first stages of a boil or carbuncle will bring about early resolution of the infection and prevent pus formation. The most likely choices are Belladonna or Hepar sulphuris. If the boil has already formed, Mercurius vivus or Silica may be recommended to bring the pus to a head.

Western herbal therapies
A variety of herbal remedies can be applied topically to boils to fight infection. These include essential oils of bergamot (Citrus bergamia), chamomile (Matricaria recutita), lavender (Lavandula officinalis), and sage (Salvia officinalis), as well as tea tree oil (Melaleuca spp.). Herbalists also recommend washing the skin with a mixture of goldenseal and witch hazel. To fight the inflammation associated with boils, herbalists suggest marsh mallow (Althaea officinalis) ointment, tinctures (herbal solutions made with alcohol) of blue flag (Iris versicolor) or myrrh (Commiphora molmol), and slippery elm (Ulmus fulva) made into a poultice.

Prognosis
The prognosis for most boils is excellent. Some patients, however, suffer from recurrent carbuncles or furunculosis. In addition, although the spread of infection from boils is relatively unusual, there have been deaths reported from brain infections caused by squeezing boils on the upper lip or in the tissue folds at the base of the nose.

Prevention

• There are some precautions that people can take to minimize the risk of developing bacterial skin infections:
• cleanse skin properly with soap and water, and take showers rather than tub baths
• do not share washcloths, towels, or facial cosmetics with others
• cut down on greasy or fatty foods and snacks
• always wash hands before touching the face
• consider using antiseptic soaps and shower gels
• consult a doctor if furunculosis is a persistent problem--it may indicate an underlying disease such as diabetes

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