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Buteyko Breathing for Bronchial Asthma

Lung disease is any pathology that occurs in the lung components and causes the lungs not to function properly and this may lead to serious problems that may cause death. They are considered the third killing factor worldwide. Lung diseases include emphysema , bronchitis, bronchial asthma, pulmonary failure, pneumonia, tuberculosis and pulmonary embolism. These diseases have the following signs and symptoms which are coughing, dyspnea, short breaths, noisy breath sound, fever, chest pain , and using accessory muscle of the neck which include scalene, upper trapezium and sternocleidmastoid muscles. The common causes of these lung diseases are smoking, infections, and genetics factors (Simon, 2000). Treatment of lung disease includes medications like corticosteroid, bronchodilators, antibiotics, and physical therapy that will give patients breathing exercises. One of the most common chronic obstructive disease, is bronchial asthma. Bronchial asthma is the fifth reason for hospitalized worldwide. Physiotherapists used to treat bronchial asthma patients who have hyperventilation symptoms using breathing exercises known as buteyko breathing technique (BBT) in additional to bronchial asthma therapy. (Bishop, 2007)
Background Professor Konstantin Buteyko was a Russian physiologist (1932-2003) , who gave his name to a treatment for bronchial asthma patients. The whole idea started in 1960s when he came with the idea that shallow breathing is going to help patients who suffer from hyperventilation like bronchial asthma and stenocardia. He suggested that hyperventilation lead to decrease the amount of blood that is going to alveoli and low- level of CO2 lead to bronchoconstriction which increase hyperventilation. (Bishop, 2007)
Literature Review Robert L. and other on 2007 tried to evaluate the efficiency of a non —pharmacological intervention Buteyko Breathing Technique (BBT) in patients with asthma with their corticosteroid medication consumption. The design of the study was a randomized control trail of buteyko technique involving 182 subject divided into group of adult with asthma their age ranged from 18-50 years old. While the control group was trained by physiotherapy for relaxation breathing technique. The main results measures by level of asthma control, defined by composite score based on Canadian asthma consensus reported 6 months after completion of intervention. The consequences show that both groups had related enhancement and a high amount with asthma control six months after accomplishment of the intervention. In the Buteyko group the degree with asthma control increased from 40% to 79% percent and in the control group from 44% to 72%. The main conclusion that six month after completion of the intervention, a large majority of subject in each group shown control of their asthma with the additional benefits of lessening in inhaled corticosteroid use in buteyko group.(Robert, 2007)
McHugh on 2003 made a study to evaluate the impact of buteyko breathing technique (BBT) on medication consumption in asthma patients. The method used is a blinded randomized control trail comparing BBT with medication control . It was directed over 38 people with asthma aged between 18-70 years. Members were followed for six months. Medication use and tempts of ventilator function were recorded. The results exhibited that BBT group shown a lessening in inhaled steroid use of 50% only and beta-agonist use 85% after six month from intervention. In the control group there was no significant outcomes. The main conclusion that BBT is a safe and effective for asthma controlling for it is sign and symptoms. BBT has clinical and potential pharm-economics benefits that must have advance studies.(McHugh, 2003)
Cooper and his colleges in 2003 completed a study to compare the effect of two breathing exercises which they are buteyko and pranayma which is a yoga breathing method for bronchial asthma patients. This study involve 90 grown-ups who complain of asthma and control it by using medications. They were divided into three groups First group follow buteyko breathing technique ,the second group use a pranayma which is a yoga technique and the last group were the placebo group. Result measure used are symptoms score level , bronchial hyper reaction, medication used, forced expiratory volume before and after buteyko technique. The results showed that ( p=0.003) were the mean for buteyko group and bronchodilator uses have been lessened by two puffs/day after 6 month of practicing buteyko technique while there was no change in the mean in the other two groups. There wasn’t difference in the forced expiratory volume or even volume to reduce inhaled corticosteroids. The main conclusion that BBT can recover symptoms and lessen bronchodilator use but doesn’t seem to change bronchial responsiveness or lung function in patients with asthma.(Cooper, 2003)
Anatomy of Respiratory System When we breathe air it go through nose to the lower respiratory tract. The advantage of nose breathing is that when air passes through the nose it will be moisturizer, heated and cleaned from any dust. After that air moves to larynx to go into trachea. Trachea is a sensitive structure because if any cold or dry air go into it , this will cause coughing and wheezing as normal interaction to these irritation .After that air moves from the trachea to the lung through the bronchi which are entered in each lung (Figure 1). The lungs are the most important part of human respiratory system. The right lung is divided into three lobes m while the left lung is divided into two lobes. Both lungs are protected by the chest wall. In the lung small air sacs known as alveoli . Then the gases exchanged from the alveoli to the blood stream through small blood vessels known as capillaries. On the other hand , the body waste CO2 returns to the capillaries to be exhaled during breathing. Healthy bronchial tubes make rapid gases exchange to maintain unchanged level of O2 and CO2 in the blood stream. The outer surface of bronchi is surrounded with smooth muscles that contract , relax in smooth rapid way in each breath. This process will maintain the required amount of air that is needed to go into lung tissues for normal gases exchange. This process of contraction and relaxation of muscles in controlled by sympathetic and parasympathetic of nerves system.(Gerard J,2005)
What is Bronchial Asthma? One of the most common chronic obstructive pulmonary diseases (COPD) is bronchial asthma. Bronchial asthma is a chronic inflammation of lung airways that leads to swelling and narrowing of them. The results of this narrowing is difficulty in breathing. The narrowing of airways may be total or partial and can be reversed with treatments. Bronchial asthma is one of the most common diseases , it affect one in every 15 adults in United states of America. It is known to cause physiologically reversible or total obstruction or narrowing to air . Pathologically this will increase thickening of airways because of inflammation and bronchoconstriction. Also narrowing of airways maybe due to swelling which is caused by immune response to allergic materials. (Gerard J,2005)
Causes of Bronchial Asthma
The main cause of bronchial asthma is inflammation of lung airways that is increased by the increase of irritable stimulations such as dust, vapor, humid weather, cold air, smoke , air pollutions, and fumes.(Gerard J, 2005)
Signs and Symptoms of Bronchial Asthma
Bronchial asthma have major sign and symptoms that are diverse depending on the severity of the disease. These signs and symptoms include wheezing that is defined as a whistling , hissing sound when exhaling air. Prolonged Coughing, that is usually at night not as good as at early morning, and may occur after workout or when unprotected against cold or dry air. Fast breathing is another symptom of bronchial asthma because fewer air reaches the lungs which is the reasons fast breathing to make up the insufficiency. Another symptoms is the usage of accessory muscle of neck and upper shoulder. Palpitation is another symptoms which is caused by as an asthma attack become worse the airways forceful air through the narrow airways become harder. Muscles of your trunk start to help. This is seen in motion (Figure 3) of the esophagus (2), and sucking in of the abdominal just under the breast bone (5) and among the ribs (4) with each breath leading to heart palpitation. As a response to less air passing through inflamed airways that will cause body to do more strength to move air and due to that heart starts to contract faster (3).( Gerard , 2005)
Prevention of Bronchial Asthma
Bronchial asthma can be prevented by following these strategies:
Always check with medical physician for treatment plan to mange signs and symptoms for bronchial asthma .
Know the trigger of asthma to be avoided such as pollen air and cold air .
Always monitor their breathing type so that they can recognize early symptoms of asthma attack that include coughing, wheezing or shortness of breath.
Quickly treat of bronchial asthma attack with immediate taking of medications prescribed and stopping the activity that may be the cause to trigger the attack. (Sue, 2002)
Treatment of Bronchial Asthma
Bronchial asthma can be treated by different types of medications like corticosteroids, bronchodilators, antibiotics, and by physical therapy. One of the important technique that help patients to control signs and symptoms of bronchial asthma is the Buteyko Breathing Technique (BBT). (Sue, 2002)
What is Buteyko Breathing Technique? Buteyko technique is a breathing regulator technique to reduce minute ventilation besides inhibit hyperventilation to treat bronchial asthma as an alternative approach ,besides to the drugs used. Buteyko technique needs that breathing originates from diaphragm not mouth. The main purpose while practicing buteyko breathing style is to breath in a very controlled and shallow manner without holding in the air like your last breath, it should be a gentle rhythm of breathing in and out.(Bruton,2003)
Preparation For Buteyko Breathing Technique?
Before starting the Buteyko Breathing technique session the physiotherapist should first takes patient pulse per minute and ability to exhale through Forced Expiratory Spiro-meter and measure the blood pressure and check if the patient have any health problems that may be contraindicated to buteyko breathing technique. Also it is important to take full medical history of management of patient bronchial asthma that usually includes hospital admission , consultant referrals and type of medication taken and their dosage. Also check if patient take other medication for other medical conditions. Physiotherapist should also check main signs and symptoms that affecting the patients daily work as if climbing stairs that increase shortness of breath to the patient. After that physiotherapist should inform bronchial asthma patient that buteyko session can be practiced three to five times a day . Before starting buteyko breathing technique session the physiotherapist should educate patient that this technique focus on breathing from the nose, so that nose clearness exercises should be given before starting session (Figure 5). The nose clearance exercises include pinching the nose gently and then move head forward and backward. Usually starting position will be sitting on chair without armrest after that progress to lying supine and finally to make patient adapt to this technique to be practiced in all active daily living of patients life, like climbing stairs. (kellet,2005)
Steps of Buteyko Breathing Technique
The Procedure of Buteyko Breathing Techniques is characterized by the following steps:
Step 1: Close your mouth and breathe from the nose to get all the advantages mention before of nose breathing. (Figure 6).This step may be hard to be followed in the beginning but with practice it became easier with training.
Step 2 : Use diaphragm to during breathing in and out , when patients practice breathing using diaphragm they should take in consideration to eliminate using of accessory muscle of neck and upper chest . (Figure 7).
Step 3: Measure control pause for bronchial asthma patient , which is the time that patient able to grasp the nose and avoid air entry until the first feel of needing to re-breath again in the same way and pattern .ÂÂ ( Figure8) can be measure using stop watch.
Step 4: Sit in an upright position and reduce breath for around 2 — 3 minutes, after that bronchial asthma patient will take short rest for 20-30 second and followed by another reduce breathing period for 3 minute followed by short rest again.
Step 5: After the last short rest ,the physiotherapists check the final control pause again to check progress in amount of time patient able to hold breath. Usually in first session patient will able to increase time of control pause 2-3 seconds.(Oliver, 2009)
Physiological Effects of Buteyko Breathing Technique
During an asthma attack people start to panic and breath faster more than body demands. They actually over breathe because they are breathing so rapidly that causes the amount of carbon dioxide in the blood to fall too low. The body responds to that by causing the airways of the lungs to become tighter which leads to decrease inhaled air in each breathe which is shown when bronchial asthma patients trying to breathe harder. This technique will help to break this negative feedback cycle by educating bronchial asthma patients to breath in a shallow way and this will lead to decrease the amount of air that reach lung during breathing. Another benefit is increasing tolerance of body for higher levels of carbon dioxide in your blood.(Oliver,2009)
Who will benefit from Buteyko Breathing Technique?
Buteyko breathing technique is suitable for bronchial asthma patients and some other conditions that lead to hyperventilation such as hay fever , which is allergic and inflammation due to dust , rhinitis which is also known as stuffy nose that happen due to inflammation of inner nose parts. Buteyko breathing technique can be included also for nose congestion, panic attack, resent heart, persistent cough, bronchitis, snoring and last for COPD patients .(Oliver,2009)
Contraindications for Buteyko Breathing Technique
Patients with these conditions will not be able to practice BBT even if they have bronchial asthma or any other condition that lead to hyperventilation . These conditions include kidney failure specially if patient on dialysis, current organ transplant, previous brain hemorrhage, recent heart attack or stroke, cardiac peacemaker device, active stomach ulcer, pregnancy, schizophrenia, uncontrolled high blood pressure, any current cancer treatment, sickle- cell anemia and sever emphysema with heart failure. (Oliver,2009)
Conclusions Asthma is a common lung disease around the world and usually patients suffer from a lot of sign and symptoms like attacks of shortness of breath, chest tightness, and coughing that may affect their quality of life so that it need pharmacological agents to control it beside non-pharmacological techniques of pulmonary rehab such as buteyko technique. Buteyko breathing technique is a complementary method that proven it is effectiveness to control breathing in hyperventilation cases such as asthma and improve their quality of life, level of exercises, and forced respiratory volume. There are five core components of the buteyko breathing technique that they are the nose breathin , relax upper muscles, use diaphragm breathing, small gentle breaths and maintain good posture. The buteyko exercises can be done 3-5 times a day and it need committed for these exercises and make lifestyle changes, to be able to use fewer medication.

Non Steroidal Anti Inflammatory Drugs (NSAID): Effects

Non steroidal anti inflammatory drugs or NSAIDs are inhibitors of prostaglandin, they have several key therapeutic effects, anti-inflammatory, antipyretic (reduces fevers) and analgesic. NSAIDs prevent the synthesis of prostaglandins; theses are made from the enzyme cyclo-oxygenase (COX) which supports inflammation, pain and fever, there are two cyclo-oxgenase COX-1 and COX-2. NSAIDs block the enzyme COX thus reducing the amount of prostaglandins and therefore reducing inflammation, pain and fevers.
The main mechanism of action of NSAIDs is the inhibition of enzyme cyclo-oxygenase (COX). COX converts the fatty acid arachidonic acid into endoperoxide, prostaglandins and thromoxanes. The prostanoids have many physiological functions such as protecting the gastrointestinal tract, renal, homeostasis responses, platelet aggregation, contraction of uterine smooth muscle etc. There are two isoforms of COX, COX-1 and COX-2. COX-1 produces prostaglandin that support platelets and protect the stomach therefore has the most adverse side effects. COX-2 is inducible and found is inflammatory conditions and some types of carcinoma. Some drugs only inhibit COX-2 which reduces adverse effects that are associated with COX-1, such as the irritation of the stomach lining. Prostaglandins have numerous tasks to play as mediators of inflammation. They enhance the action of histamine and other natural compounds causing vasodilatation and increasing vascular permeability to fluids. These two factors result in the symptoms of inflammation. As well prostaglandins they relay pain messages to the brain.
This journal article supports my essay on NSAIDs [i] “Salicylic acid and salicylates, obtained from natural sources, have long been used as medicaments. Salicylic acid was chemically synthesized in 1860 and was used as an antiseptic, an antipyretic, and an antirheumatic. Twenty-five years ago, it was proposed that the mechanism of action of NSAIDs was through their inhibition of prostaglandin biosynthesis. Since then, there has been general acceptance of the concept that these drugs work by inhibition of the enzyme cyclo-oxygenase (COX), which we now know to have at least two distinct isoforms: the constitutive isoform, COX-1, and the inducible isoform, COX-2. COX-1 has clear physiologic functions.
Its activation leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic and when released by the gastric mucosa is cytoprotective. COX-2, discovered 6 years ago, is induced by inflammatory stimuli and cytokines in migratory and other cells. It is therefore attractive to suggest that the anti-inflammatory actions of NSAIDs are due to inhibition of COX-2, whereas the unwanted side-effects, such as irritation of the stomach lining, are due to inhibition of COX-1. Drugs that have the highest COX-2 activity and a more favourable COX-2: COX-1 activity ratio will have a potent anti-inflammatory activity with fewer side-effects than drugs with a less favourable COX-2: COX-1 activity ratio. The identification of selective inhibitors of COX-2 will therefore lead to advances in therapy.”
NSAIDs are highly lipophilic substances, adsorption occurs through the gastrointestinal tract, as NSAIDs are weak acids they are less ionised in the gastric juices and therefore are absorbed by the mechanism of ionic or diffusion tapping. Most NSAIDs are given as oral tablets or capsules; others are given by injection to avoid gastric irritation.
The main use of anti-inflammatory drugs is in the treatment of pain resulting from rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is an inflammatory condition of connective tissue especially within the joint capsule; it may be described as an autoimmune disease, whereby the body’s own immune system starts to destroy the synovial membrane. This may lead a complete destruction of the joint. Osteoarthritis is due to a mechanical damage to the joint which leads to degeneration of the articular cartilage the hip joint is commonly affected. Prostaglandins are found in the hypothalamus are involved in raising the temperature of the body during infection, therefore NSAIDs are useful in inhibiting prostaglandins and reducing body temperature, this is called antipyretic . Most prostaglandin inhibitors are acidic drugs that can directly irritate the gastric mucosa. Prostaglandins in the stomach lead to a decrease in gastric secretions; therefore, inhibiting the synthesis of prostaglandins leads to an increase in sections which may lead to ulcers.
Aspirin is an irreversible inhibitor of COX-1 but has adverse side an effect, most side effects of NSAIDs is related to their action on the gastrointestinal tract. In the stomach prostaglandins are normally involved in the protection of the gastric mucosa (lining of the stomach) against the corrosive actions of the gastric acid; prevention of prostaglandin synthesis by NSAIDs therefore remove this protection and make the stomach open to irritation and ulceration. NSAIDs themselves are irritant chemicals which have a direct effect on the gastric mucosa. Other Problems of NSAIDs such as aspirin have an effect the kidneys, because the role of prostaglandins in the maintenance of blood flow to the kidneys, NSAIDs often cause kidney damage and disorders of salt and fluid balance.
This article shows the adverse effects and mechanism of NSAIDs on the gastrointestinal tract.
Mechanisms of gastrointestinal (GI) injury
NSAIDs injure the gut by causing topical injury to the mucosa and systemic effects associated with mucosal prostaglandin depletion derived from COX-1. The systemic effects of NSAIDs appear to have the predominant role. Because of that the use of enteric-coated aspirin preparations and parenteral or rectal administration of NSAIDs in order to prevent topical mucosal injury has failed to prevent the development of ulcers.
Topical injury
The acidic properties of most NSAIDs (included ASA) initiate mucosal damage. These weak acids remain in their non ionised lipophilic form in the highly acidic gastric environment. These conditions favour migration into surface epithelial cell, where NSAIDs are dissociated into the ionised form that traps hydrogen ions, inducing mucosal injury.
Systemic effects NSAIDs inhibit cyclooxygenase (COX), a key in the biosynthesis of prostaglandins. There are two isoforms, COX 1 and COX 2. Traditional NSAIDs (tNSAIDs) and ASA inhibit both isoforms. Selective NSAIDs (COXIBs) spare COX 1 and primarily inhibit COX 2. COX 1 isoform is expressed in most tissues, producing prostaglandins that play an important protective role in the gut by stimulating the synthesis and secretion of mucus and bicarbonate, increasing mucosal blood flow and promoting epithelial proliferation. When NSAIDs inhibit this enzyme create a gastric environment that is more susceptible to topical attack by endogenous and exogenous factors. Besides, the inhibition of the COX 1 blocks platelet production of thromboxane, which increases bleeding when an active GI bleeding site is present .On the other hand, COX2 isoform is induced inmost tissues in response to inflammatory stimuli. Prostaglandins derived from COX-2 can be generated at the ulcer margin and appear to play an important role in ulcer healing through triggering the cell proliferation, promotion of angiogenesis and restoration of mucosal integrity .This isoform is the primary target for anti-inflammatory drugs. Therefore selective COX-2 NSAIDs while having little to no effect on COX-1 should result in effective pain relief with reduced adverse GI effects. This ‘COX2 hypothesis’ has been challenged by data from animal studies. Wallace et al reported that inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.”
Aspirin (acetylsalicylic acid) was first isolated in 1829 by Leroux from willow bark. It can cause irreversible inactivation of cyclo-oxygenase, acting on both COX-1 and COX-2. Aspirin has many pharmacologic effects for example it has antipyretic action it reduces fevers and is rapidly effective in febrile patients, yet has little effect on normal body temperature. It has many effects on the body; prostaglandin PGE2 is produced in the brain and causes the temperature regulatory centre in the hypothalamus to raise the body temperature, Aspirin inhibits PGE2 production so body temperature falls.
Aspirin also has anti-inflammatory action, during inflammation, prostaglandin and other arachidonic acid are produced and contribute to the pain, swelling and tissue damage, and aspirin inhibits the production of arachidonic acid thus reducing inflammation. It is a very good anti-inflammatory effects it helps in condition for example the treatment of musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.
The ability of aspirin to control pain occurs both through a peripheral and central action when aspirin inhibits the synthesis of prostaglandins in inflamed tissue, and it prevents the prostaglandin from sensitising the nociceptors, by inhibiting prostaglandin synthesis in the brain. Aspirin is also thought to also modify transmissions in the pain conducting pathways. Aspirin has other analgesic effects which is usually effective for low- to moderate-intensity pain. Integument pain is relieved better than the pain from hollow visceral areas. Relief of pain occurs through both peripheral and central mechanisms. In the peripherally, it inhibits the synthesis of PGs in inflamed tissues, thus preventing the sensitisation of pain receptors to both mechanical and chemical stimuli. Also in the centrally, the analgesic site exists in close proximity to the antipyretic region in the hypothalamus. Its analgesia action is not associated with mental alterations, such as hypnosis or changes in sensation other than pain.
EFFECTS OF ASPIRIN ON PROSTAGLANDIN SYNTHESIS Both COX-1 and COX-2 enzymes are inhibited by aspirin, but not by opioids, acetaminophen, or tramadol. The active site of both enzymes appears to be at the end of a long, tubular channel in the molecule. Aspirin block arachidonate’s entrance to this channel (as seen in picture below). Aspirin does this by irreversibly acetylating a specific serine molecule (serine 530 for COX-1 and serine 516 for COX-2) When blocked by aspirin, COX-1 becomes completely inactive. COX-2, on the other hand, converts arachidonate to 15-R-hydroxyeicosatetraenoic acid (15-R-HETE). Neither enzyme is capable of producing prostaglandin H2, the necessary precursor of prostaglandin and thromboxane synthesis.
Aspirin causes damage to the gastric mucosa partly by inhibiting the formulation of prostaglandins that protect stomach wall from gastric acids. Aspirin in addition has Gastrointestinal effects such as It can cause epigastric distress, nausea, and vomiting by irritating the gastric mucosal lining and stimulating the chemoreceptor trigger zone in the CNS. It may cause a dose-related gastric ulceration, bleeding, and erosive gastritis because of inhibiting the formation of PGE2, which inhibits gastric acid secretion and has a cytoprotective effect. Salicylates-induced gastric bleeding is painless and may lead to an iron deficiency anemia. Aspirin is used in restricted situation for the symptomatic relief of fever. Because of an increased incidence of Reye’s syndrome in children who previously were given aspirin for the relief of viral fevers, it is now recommended that a child with any fever be given paracetamol instead, if medication is required. It is useful as analgesics for certain categories of pain, such as headache, arthritis, and dysmenorrhea. It remains the standard, first-line drug in the therapy of rheumatoid arthritis, and can provide relief of symptoms in acute rheumatic fever. Some clinicians recommend small daily doses of aspirin for prophylaxis of thromboembolism, stroke, or myocardial infarction because of its antiplatelet activity.
Some adverse effects of aspirin when uses in large repeated dosages are headache, mental confusion, lassitude, and drowsiness, tinnitus and difficulty in hearing, hyperthermia, sweating, thirst, hyperventilation, vomiting, and diarrhea.
Contraindications Aspirin, non-steroidal anti-inflammatory drugs and anticoagulants should be avoided in all patients with liver disease because of the risk of altering platelet function, causing gastric ulceration and bleeding. NSAIDs have also been implicated in precipitating renal dysfunction and vericeal bleeding in patients with end-stage liver disease. Although COX-2 inhibitors may cause a lower incidence of bleeding complication, currently they are avoided in patients with liver disease as their still pose a risk.
Paracetamol is an analgesic agent. It does not have ant-inflammatory or anti-platelet activities, but it is a useful analgesic in febrile illnesses such as influenza. As paracetamol has no anti-inflammatory properties it does not inhibit prostaglandin thus have no affect on the gastric mucosa. As an analgesic, paracetamol is best taken on an empty stomach for fast action, as it gets absorbed faster. As it is not associated with Reyes’s syndrome, it is the preferred analgesic in the symptomatic treatment of children with viral infections.
The mechanism of action of paracetamol is now thought to be via COX-3 inhibition. This enzyme is present in the brain and spinal cord and is selectively inhibited by paracetamol. Paracetamol has no action on COX-1 and COX-2, thus does not have any gastric side effects. The central action of paracetamol explains it antipyretic effects and its lack of other peripheral adverse effects associated with NSAIDs. Paracetamol has few adverse side effects as it is tolerated by the stomach because inhibition of prostaglandin in the periphery is weak; allergic reactions and skin rash sometimes occur. Heavy, long term daily use may predispose chronic renal disease.

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