Speciality
Spotlight

 




           

Clinical Pharmacology

       

     





Asthma

   

  • Johannes.H.
    Wildhaber, Grant W Waterer, et al, (Department
    of Respiratory Medicine, Univ. Children’s Hospital,
    Switzerland and Royal Perth Hospital, Western
    Australia
    )

    Reducing
    electrostatic charge on spacer devices and
    bronchodilator response.

    Br.J.Cl. Pharmacol; Sept.2000: 50(3), 277-280.

      

    Summary
    : Plastic spacers are widely used with pressurised
    metered dose inhalers (pMdi).
    Reducing electrostatic charge by washing
    spacers with detergent has been shown to greatly
    improve drug delivery.
    The authors have assessed whether this
    finding is associated with an improved
    bronchodilator response in adult asthmatics.
    They have shown an improvement in
    bronchodilator response, in adult asthmatics, after
    reducing the electrostatic charge in a spacer device
    by washing it with ordinary household detergent.

       

  • J
    Tamaoki, M Kondo, et al (First Department of
    Medicine, Tokyo Women’s Medical University School of
    Medicine, Tokyo)

    Effect
    of Suplatast tosilate,
    a Th2 cytokine
    i
    nhibitor, on steroid-dependent asthma:
    a double blind randomised
    study.

    Lancet,
    vol. 356, July 22, 2000, p. 273-278.

      

    Th2
    cytokines play an important part in pathogenesis of
    asthma. Authors
    have studied the effect of suplatast tosilate, a
    selective Th2 cytokine inhibitor, on asthma control
    and asthma exacerbations during reduction of inhaled
    corticosteroid dose in patients with steroid
    dependent asthma. In
    an uncontrolled trial, 6 week treatment with
    suplatast tosilate, reduced airway hyper
    responsiveness and eosinophilic airway inflammation
    in mild asthma.

     

    This
    study has looked at the possible steroid -sparing
    effect of suplatast tosilate in treatment of
    patients with moderate to severe persistent asthma
    who required high-dose inhaled beclomethasone
    dipropionate to control their symptoms in a
    double-blind, randomised, parallel group,
    multicentric trial.

      

    Treatment with this Th2 cytokine inhibitor in
    steroid-dependent asthma improves pulmonary function
    and symptom control and allows a decrease in dose of
    inhaled corticosteroid without significant
    side-effects.

       

  • Martin
    H Brutsche, I C Brutsche, et al

    Comparison
    of pharmacokinetics and systemic effects of inhaled
    fluticasone propionate in patients with asthma and
    healthy volunteers: a randomized crossover study.

    The
    Lancet, vol. 356, August 12, 2000, pg. 556-561.

     

    In
    this study, pharmacokinetics of fluticasone
    propionate was studied in patients with asthma
    receiving appropriate doses for severity.
    It was a double-blind, randomised, cross-over
    study in 11 patients with asthma and 13 matched
    healthy controls. 
    Patients received 1000 mciro-gm of
    Fluticasone propionate as a single IV dose or 1000
    micro-gm per day for 7 days by inhalation (via
    spacer device). In
    the 12h, after dosing, plasma fluticasone propionate
    and cortisol concentrations were assayed.

      

    Authors
    interpretation was that systemic availability of
    fluticasone propionate is substantially less in
    patients with moderate to severe asthma than in
    healthy controls. Inhaled
    corticosteroids that are absorbed through the lungs,
    need to be assessed in patients who are receiving
    doses appropriate for disease severity, and not in
    normal volunteers.

        

  • Introduction:

      

    Asthma is a serious chronic disease that causes a
    substantial morbidity and mortality in more than 17
    million people in the United States.
    It is a leading chronic illness in children
    and forms the fourth leading cause of disability in
    them. Since
    1980, the prevalence of asthma has increased by 61%
    and the mortality rate due to asthma has jumped from
    0.9 per every hundred
    thousand, 20 years back to 1.5 per every hundred
    thousand uptil 1995. Coming to an alarming 67% increase, the
    annual healthcare costs resulting from asthma
    estimated to be 12.6 billion dollars and asthma
    leads to 10 million lost school days and 3 million
    lost work days.

      

    Development of Asthma

        

    RT
    Stein, CJ Holberg, D Sherrill, et al (Pontificia
    Universidade Catolica RS, Porto Alegre, Brazil; Univ
    of Arizna Tucson; Natl Jewish Med and Research Ctr,
    Denver)

    Influence of Parental Smoking on Respiratory
    Symptoms during the First Decade of Life: The Tucson
    Children’s Respiratory Study


    Am J Epidemiol 149: 1030-1037, 1999

       

    The exact effect of parental smoking on childhood
    respiratory illness has been difficult to point out.
    However, Sten and colleagues in the largest Tucson
    Children’s Respiratory Study, evaluated the link
    between prenatal and postnatal maternal smoking
    based upon a careful longitudinal study. They have
    found that maternal prenatal smoking is associated
    to wheezing below 3 years of age and interestingly
    this effect was found to be more pronounced in girls
    rather than in boys. It is likely that this prenatal
    smoking results in smaller airways due to the
    reduced lung development, resulting into wheezing.
    Postnatal smoking, however, is likely to be related
    to recurrent upper respiratory tract infections.
    Hence our aim to prevent smoking induced lung
    disease should be aimed at the potential mother.

        

  • C
    Bodner, for the Aberdeen WHEASE Group (Univ of
    Aberdeen, Scotland)

    Family size, childhood infection and Atopic
    disease

    Thorax, 53: 28-32, 1998

       

    The prevalance of asthma and other allergic disease
    among children in the developed countries has
    increased in the past 3 decades.

        

    Bodner and Aberdeen have in this group reported on
    cross-sectional survey of 2111 subjects analysed for
    the determinants of asthma and atopy. They found
    that hay-fever and eczema were inversely related to
    family size but asthma less so. They also found a
    small increased risk for asthma with increasing
    number of childhood infection. Measles, however,
    demonstrated a small protective effect for asthma.
    The effect of childhood infections on this
    immunoligic perturbation is unknown but is likely
    specific to the class or type of infection.

       

  • M.
    Kraft, RJ Martin, S Wilson, et al (Unvi of Colorado,
    Denver; Univ of Southampton, England)

    Lymphocyte and Eosinophilia influx into Aleovular
    Tissue in Nocturnal Asthma

    Am. J  Resp. Crit Care Med 159: 228-234,
    1999

        

    Inflammatory cytokines which are produced bu T
    lymphocytes help the promotion of eosinophil
    migration from blood through the vascular
    endothelium and the key source for these cytokines
    probably is the CD4+ lymphocytes, which may also
    produce chemokines involved in eosinophil
    chemotaxies, survival, maturation as well as their
    activation.

        

    The study has been performed into two separate
    groups. The patient were subjected to bronchoscopies
    followed by endobronchial and transbronchial biospy
    specimens. Amongst patients suffering from nocturnal
    asthma and those without suffering from nocturnal
    asthma i.e. nonnocturnal asthma group.
    Bronchoscopies were performed in a random order, a
    week apart at 1 at 4 pm and the other at 4 am. The
    numbers of CD3+, CD4+. CD8+ cells and EG2+
    esosinohils were measured in the epthelium, lamina
    propria and the alveolar tissues.

       

    These studies from kraft and her colleagues at
    National Jewish have enlightened us with a role of
    alveolar tissue inflammation in asthma. The
    study  demonstrates that there are an increased
    number of CD4+ lymphocytes in alveoli in patients
    with nocturnal asthma and with those
    correlated  inversely with nighttime lung
    function. Whether this was causally related is
    unknown. More information is needed regarding the
    circulation of CD4 lymphocytes in the lungs and
    their release of potential mediators of asthama
    symptoms. These cells may be either innocents
    bystanders or be the result in the alveoli from the
    spilling over from the increased numbers in the
    airways. Further studies of optimal timing of
    anti-inflammatory mediators in patients with
    nocturnal asthma are needed.

        

  • BH
    Rowe, GW Bota, et al (Univ of Alberta, Edmonton,
    Canada; Sudbury Regional Hosp, Ont, Canada; univ of
    British Columbia, Vancouver Canada, Et al)

    Inhaled Budesonide in Addition to Oral
    corticosteroids to prevent asthma relapse following
    discharge from the Emergency Dept. – A Randomized
    Control Trial.

    Jama 281: 2119-2126, 1999

        

    Systemic corticosteriod treatment can decrease acute
    asthma relapses after discharge from the emergency
    department. This study undertook to decide whether
    inhaled corticosteroids provide any additional
    benefits.

        

    The study is double-blind palcebo-controlled
    randomized clinical trials which was conducted over
    a period of 2 yrs on patient between ages from 16 to
    60. 188 patients were included in this study and on
    discharge they were given non-tapering course of
    oral prednisolone which is 50mg/days for 7 days
    along with 1600
    mg
    inhaled budesonide or a placebo. These patients were
    followed up for a period of 21 days.

        

    This well performed study demonstrates a beneficial
    effect from the addition of inhaled corticosteroids
    for asthma patients at discharge. Few of them being
    cost. lack of long term of fellow up with the
    patient, interference with primary care physician’s
    role inadequate time to provide a metered dose
    inhaler technique information.

       

    However, this study argues whether we should be
    changing our emergency department practice to
    include inhaled corticosteroids for a minimum of 3
    weeks period probably even longer and to prove our
    point we need further studies to determine the
    optimal dosages and the length of treatment
    required.

        

  • SF
    Lanes, JE Garrett, et al (Epidemiology Resources
    Inc, Newton Lower Falls, Mass; Green Lane Hosp,
    Auckland, New Zealand, Vancouver Gen Hosp, BC,
    Canada; et al )

    The effect of adding atropine bromide and
    salbutamol in the treatment of acute asthma. This is
    a pooled analysis of 3 trials.

    Chest 114: 365-373, 1998

        

    For patients with acute asthma, it is not clear
    whether an addition of ipratropium bromide would
    result in bronchodilatation rather than just
    b2
    against therapy. Three major randomized trials which
    have been performed were pulled into the study. An
    American study found no difference, whereas study
    from New Zealand showed significant advantage with
    the combination therapy and a been pooled to
    estimate the effects of ipratropium bromide +
    salbutamol in patients with acute asthma.

         

    Several studies have demonstrated that ipratropium
    bromide should be added to acute treatment for
    patients with asthma both in adult as well as in
    children. Zorc et al found a significant reduction
    in length of stay in emergency department and use of
    additional doses of albuterol. A reduction of lenght
    of stay is found in any busy urban emergency
    department. It is important to keep in mind that the
    effectiveness of ipratropium is primarily in acute
    treatment in the emergency dept and it should not be
    continued in hospital setting for more than 36
    hours. Thus it can be probably concluded that the
    additional use of ipratropium is not useful and will
    diminish any potential cost savings from the acute
    use of ipratropium.

        

    It is best to say the use of ipratropium bromide
    should be restricted to emergency  dept. for a
    maximum period of upto 36 hours in case of acute
    asthmatic attack.

        

  • D
    Vervloet, T Ekstrom, et al (Hospital Sainte
    Marguerite, Marseilles, France; Univ Hosp, Sweden,
    Ospedale Civile, Osimo, Italy, et al)

    A 6-month Comparison Between Formeterol and
    Salmerterol in Patients with Reversible Obstructive
    Airways Disease

    Respir Med 92: 836-842. 1998

        

    The newer long acting B2 – agonists
    including formoterol and salmeterol, can be
    prescribed for regular use by patients with asthma.
    The long-term treatment with these agents has
    important benefits including reduced symptomatology
    and improved lung function. Formoterol as well
    as salmeterol have not been directly compared for
    safety and effficacy. The efficacy and safety of 6
    months of treatment have been compared in multi-randomised
    open trials. In-vitro studies have shown that mast
    cells following treatment with formoterol have
    significantly decreased in numbers a finding, which
    is not supported by studies with salmeterol.
    However, studies by Vervlot et al argues that
    in-vivo or in real life these differences may not be
    important. Further larger double-blind randomized
    controlled trial studies with formoterol when
    compared its efficacy with salmeterol are required
    to make this decision.

        

    The study by Palmquist et al argues that formeterol
    is more protective against methacholine induced
    bronchoconstriction than salmeterol. However the
    doses to achieve this protection which they have
    implemented are much higher than the currently
    recommended one for the use of either drug in
    clinical prectise. The effect of Formeterol on the
    bronchodilating ability of short acting B-agonist
    such as albuterol over a period of time needs to be
    investigated.

        

  • F
    Pierart, JH Wildhaber, I Vranchen, et al (Princess
    Margaret Hosp for Children, Perth, Western
    Australia)

    Washing plastic spacers in household detergent
    reduces electrostatic charge and greatly improves
    delivery

    Eur. Res. Jr. 1999

         

    Plastic spacres have been widely used along with
    pressurized metered dose inhalers. However the
    electrostatic charge that accumulates on this
    devices has been shown to have significant impact on
    drug delivery. In-vitro studies suggested that the
    spacers coated with ionic detergent have reduced
    static and improved drug delivery and hence a study
    was undertaken to study the effects of these
    household detergents on the electrostatic charges on
    plastic spacers.

         

    In the vitro studies all detergent increased the
    mean small particles Salbutamol output by almost by
    50%. This increase in output was noted even for
    spacers coated with very dilute detergent in
    constitution as low as 1: 10,000. Spacers developed
    an electrostatic charge within one week after
    coating. The charged remained low for at least 4
    weeks. This is surprising finding that the use of
    household detergent to clean and keep dry on a
    spacer can improve drug delivery 3-folds. This
    simple technique is not well-known and nor it is
    found in current asthma management guideline.

        

    The study by Pierart et al demonstrated that any
    household detergent when diluted will decrease the
    electrostatic charge for up to almost 4 weeks. This
    interesting findings requires further studies to be
    performed along with other medications and other
    medications and other chlorofluorocarbon-free
    propellants to confirm the results. It is also
    important that we start educating our patients on
    the proper care of spacers so as to optimize drug
    delivery.

         

  • Chronic
    Obstructive Pulmonary Disease

    PM Dorinsky, C Reisner, GT Ferguson, et al (Boehringer
    Ingelheim Pharmaceuticals Inc, Ridgefiled, Conn;
    Wayne State Univ, Detroit)

    The combination of Ipratropium and Albuterol
    optimises pulmonary funciotn reversibility testings
    in patients with COPD.

    Chest 115: 966-971, 1999

        

    Taking into consideration the fact that long-term
    use of a combination of ipratropium and albuterol
    have been recommended doses rather than a single
    agent alone in patient with COPD. A large recently
    concluded 3 month randomized double-blind parallel
    multicentre phase III trial study has been reported
    here. Where 1067 patients with stable COPD were
    randomized to treatment with ipratropium bromide and
    albuterol or an equivalent combination of
    ipratropium bromide and albuterol sulphate.

       

    The equivalent combination of ipratropium bromide
    and albuterol sulpahte were superior to individual
    drugs. A 15% or greater increase in FEVI was
    observed in 80% of the patients who received the
    combination. Thus this outcome suggest that
    combionation of ipratropium bromide and albuterol
    sulpahte was superior to the individual drugs in
    identifying PFT reversibility in patients with
    stable COPD.            

                                                                           

  • Istvan Zelenyi and Kay Brune         

    Unconventinal Therapies in Asthma          

    Drugs of Today, 37 (10): 651-664         

                                    

    Complementary/alternative medicine (CAM) is more popular than ever before. Patients with allergic diseases often seek so-called alternative treatment as supplementation but seldom as a real alternative to classical medicine.   

                                    

    Despite the demand for CAM, there is a paucity of well-founded evidence about its effectiveness. There are few good studies and those that exist are often inconclusive. CAM should be approached in the same way as some of orthodox medicine is evaluated now and how most, if not all, will be assessed in the future. Remedies, if shown to be effective and safe, should be part of the interventions made available to patients.                

                           

    Homeopathy – There is not enough evidence to reliably assess the possible role of homeopathy in asthma. Well-controlled, randomized, double-blind trials are urgently needed.           

                                         

    Another approach involves isopathy. In this case hay fever is treated with homeopathic dilutions of corresponding pollens, also called homeopathic immunotherapy. Based on the evidence in rhinitis, the isopathic approach might have real validity in the treatment of asthma. Unfortunately, rigorously controlled and carefully performed double-blind studies are still missing. From the theoretical point of view and preliminary evidence, this suggests that isopathy could help allergic patients.

                                                  

    Mind-body therapies (Yoga and Hypnosis)-The use of yoga in asthma has been widely investigated.

    There was tendency toward lesser usage of
    b2-adrenoceptor agonists. In general, it is likely that specific, and for the patient, more advantageous, breathing techniques utilized are responsible for the beneficial effects in asthma, not the yoga postures or meditation. However, there is basically only one correctly performed, double-blind, placebo-controlled study with positive results. All other studies have several basic weaknesses, mostly few patients and not placebo controlled. Therefore there is an urgent need to perform randomized, placebo-controlled, double-blind studies.           

                                                          

    Asthma never was a psychosomatic disorder. Asthma can be triggered by emotional stress. It may be superimposed by psychic components (anxiety, depression) but the basic disease is always of organic nature. Respiratory physiotherapy seems beneficial as an adjunct to medical management of asthma. In conclusion, it remains unclear whether mind-body therapies produce a real improvement in airway inflammation.                           

                                              

    Almost all of the appropriately and carefully performed clinical studies could not show convincing positive results. Acupuncture can be useful in some patients in improving quality of life and reducing the need for using bronchodilators. In another randomized, controlled study, the results imply that asthma patients benefit from acupuncture treatment given in addition to conventional therapy. It is important to mention that in traditional Chinese medicine, acupuncture is usually used in combination with herbal drugs.                           

                                

    In conclusion, acupuncture may improve acute airway obstruction but its efficacy in long-term use has yet to be established.

                   

    Pneumothorax is the most common mechanical organ injury. In general, serious adverse effects are rare and acupuncture can generally be considered a safe treatment.                   

                                 

    Aromatherapy – Their value in asthma therapy is more than questionable.          

                  

    Naturopathy – The most important nutritional supplements seem to be vitamin C, magnesium and fish oils such as omega-3 fatty acids. It is possible that some foods (garlic, onion, essential oils, etc.) are of value in helping to improve natural defenses. However, it should also be mentioned that garlic or onion can induce asthma as well.    

                        

    In general, dietary adjustment and nutritional supplementation may benefit a small percentage of patients with asthma but extreme measures are very rarely indicated. The studies performed to date, whether showing positive or negative effects, utilized short-term supplementation. Long-term studies should be conducted to further elucidate the real role of nutrition in asthma treatment.          

                     

    Herbal medicine : Several asthma drugs had their origin in folk remedies discovered by our ancestors. Asthmatic patients were treated by stramonium cigarettes that were originally developed in India. Ephedrine, the first strong bronchodilator compound, was developed from
    ma huang, a favorite Chinese herbal remedy in use for thousands of years. Asia also provided other drugs, i.e. theophylline, which is found in tea leaves. Cromoglycate is a derivative of the chromones found in the bronchodilator
    khella in the Middle East. Bromhexine, a known mucolytic drug, is derived from the Malabar nut. Coleus forksholii is ued in Ayurvedic medicine and contains forskolin, which activates adenylate cyclase, resulting in increased cyclic adenosine monophosphate production and consequently in bronchodilation. In contrast to Asia, no major drugs have been derived from European herbal remedies. Respiratory herbs indigenous to Europe predominantly contain mucoregulatory compounds (e.g. mustard, horseradish, menthol, fennel, etc.)             

                          

    Traditional Chinese medicines are decoctions of mixtures of up to 20 herbs that are customized for each individual patient. Of them, the only herb with proven pharmacodynamic effect is
    ma huang, a source of ephedrine. Ginkgo biloba is also used as an asthma remedy, although its clinical value appears to be negligible. Wu-Hu-Tang, a Chinese formulation, which consists of seven crude drugs, has been used for the treatment of asthma for hundreds of years. Recently, it has been demonstrated in animal studies that the aqueous extract of
    Wu-Hu-Tang  may have inhibitory effects on mediators of immediate hypersensitivity. Many of the herbs used by Chinese physicians have been carefully reviewed by Bielory and Lupoli but their clinical value remains uncertain.                 

                                   

    Based on experimental data, saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma. Other herbal formulations have also suppressed either nasal allergy or asthmatic reactions in actively sensitized animals.

                                  

    Some Ayurvedic drugs of interest for consideration in asthma include Datura plants, the historical source of atropine. Of the Indian plants,
    Tylophora asthmatica (also known as Tylophora indica 
    or Indian ipecac; the primary ingredient is the alkaloid tylophorine) is often used in treating asthma. Another interesting herbal medicine is the gum resin of Boswellia serrata. Boswellia not only inhibited leukotriene formation but also prevented development of inflammation in rats.           

                                      

    Recent clinical results show a certain potential role of this herb. Extended controlled clinical trials are required to identify the place for this plant in asthma therapy.                

                                    

    Furthermore, steroids are widely used in several so-called herbal preparations.                

                                                   

    Fugh-Berman published a very important summary of interactions between herbal and pharmaceutical drugs. It has been pointed out by the author that all persons involved in health care should caution patients against mixing herbs and synthetic drugs.                     

                                 

    Marine products:                     

    Perilla seed oil-rich supplementation (omega-3 fatty acids) is, in contrast to corn oil (omega-6 fatty acids), useful for asthma treatment in terms of improvement of pulmonary function and reduction of leukotriene production. 

                        

    The long-time native Maori people of New Zealand have included the New Zealand green-lipped mussel (Perna canaliculus) as a staple in their diet. In the last 20 years, polyunsaturated fatty acids have had a major impact on the thinking in medicine. It has recently been discovered that the green-lipped mussel, rich in omega-3 fatty acids, inhibits
    LTB4 production by human monocytes and likely has a certain steroid-sparing effect. Although omega-3 fatty acid may reduce bronchial hyperresponsiveness, there is little evidence to recommend that asthmatics supplement or modify their dietary intake of n-3 fatty acids (fish oil) in order to improve their asthma control.             

                                                         

    A new steroid compound has recently been isolated from a sea sponge (Petrosia contignata) collected in Papua New Guinea. The steroid, called 
    “contignasterol”, has anti-inflammatory and antiasthmatic properties in animal experiments. First clinical studies are now ongoing. Two interesting steroids, halicostanone and halistanol were isolated from a
    Haliclona sp. marine sponge with a similar structure to that of contignasterol. Data as to antiallergic activity are not available at present.   

                                                    

    Since several methods of CAM are being used more and more in routine healthcare, the question as to its efficacy is certainly justified. Although some studies have shown promising results, the efficacy of CAM has not been proven beyond reasonable doubt. In general, the research on alternative medicine is of poor quality. For these reasons, it is absolutely essential to perform well-planned, placebo-controlled, double-blind clinical trials as soon as possible. Additionally, a sufficiently large number of patients should be involved in these studies.                

                                                           

    Last but not the least: in the past few years, health information and therapy recommendation have become readily available through the internet. Profit-based companies often advertise a product claimed to be effective for asthmatic disorders without any scientific evidence. There is a future requirement for all of us: we have to critically evaluate the contents of the Website and should inform our patients about all false information.           

        



  
 



 

     

Speciality Spotlight

 

           
Clinical Pharmacology
       

     

Asthma
   

  • Johannes.H. Wildhaber, Grant W Waterer, et al, (Department of Respiratory Medicine, Univ. Children’s Hospital, Switzerland and Royal Perth Hospital, Western Australia)
    Reducing electrostatic charge on spacer devices and bronchodilator response.
    Br.J.Cl. Pharmacol; Sept.2000: 50(3), 277-280.
      
    Summary : Plastic spacers are widely used with pressurised metered dose inhalers (pMdi). Reducing electrostatic charge by washing spacers with detergent has been shown to greatly improve drug delivery. The authors have assessed whether this finding is associated with an improved bronchodilator response in adult asthmatics. They have shown an improvement in bronchodilator response, in adult asthmatics, after reducing the electrostatic charge in a spacer device by washing it with ordinary household detergent.
       

  • J Tamaoki, M Kondo, et al (First Department of Medicine, Tokyo Women’s Medical University School of Medicine, Tokyo)
    Effect of Suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double blind randomised study.
    Lancet, vol. 356, July 22, 2000, p. 273-278.
      
    Th2 cytokines play an important part in pathogenesis of asthma. Authors have studied the effect of suplatast tosilate, a selective Th2 cytokine inhibitor, on asthma control and asthma exacerbations during reduction of inhaled corticosteroid dose in patients with steroid dependent asthma. In an uncontrolled trial, 6 week treatment with suplatast tosilate, reduced airway hyper responsiveness and eosinophilic airway inflammation in mild asthma.
     
    This study has looked at the possible steroid -sparing effect of suplatast tosilate in treatment of patients with moderate to severe persistent asthma who required high-dose inhaled beclomethasone dipropionate to control their symptoms in a double-blind, randomised, parallel group, multicentric trial.
      
    Treatment with this Th2 cytokine inhibitor in steroid-dependent asthma improves pulmonary function and symptom control and allows a decrease in dose of inhaled corticosteroid without significant side-effects.
       

  • Martin H Brutsche, I C Brutsche, et al
    Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomized crossover study.
    The Lancet, vol. 356, August 12, 2000, pg. 556-561.
     
    In this study, pharmacokinetics of fluticasone propionate was studied in patients with asthma receiving appropriate doses for severity. It was a double-blind, randomised, cross-over study in 11 patients with asthma and 13 matched healthy controls.  Patients received 1000 mciro-gm of Fluticasone propionate as a single IV dose or 1000 micro-gm per day for 7 days by inhalation (via spacer device). In the 12h, after dosing, plasma fluticasone propionate and cortisol concentrations were assayed.
      
    Authors interpretation was that systemic availability of fluticasone propionate is substantially less in patients with moderate to severe asthma than in healthy controls. Inhaled corticosteroids that are absorbed through the lungs, need to be assessed in patients who are receiving doses appropriate for disease severity, and not in normal volunteers.
        

  • Introduction:
      
    Asthma is a serious chronic disease that causes a substantial morbidity and mortality in more than 17 million people in the United States. It is a leading chronic illness in children and forms the fourth leading cause of disability in them. Since 1980, the prevalence of asthma has increased by 61% and the mortality rate due to asthma has jumped from 0.9 per every hundred thousand, 20 years back to 1.5 per every hundred thousand uptil 1995. Coming to an alarming 67% increase, the annual healthcare costs resulting from asthma estimated to be 12.6 billion dollars and asthma leads to 10 million lost school days and 3 million lost work days.
      
    Development of Asthma
        
    RT Stein, CJ Holberg, D Sherrill, et al (Pontificia Universidade Catolica RS, Porto Alegre, Brazil; Univ of Arizna Tucson; Natl Jewish Med and Research Ctr, Denver)
    Influence of Parental Smoking on Respiratory Symptoms during the First Decade of Life: The Tucson Children’s Respiratory Study
    Am J Epidemiol 149: 1030-1037, 1999
       
    The exact effect of parental smoking on childhood respiratory illness has been difficult to point out. However, Sten and colleagues in the largest Tucson Children’s Respiratory Study, evaluated the link between prenatal and postnatal maternal smoking based upon a careful longitudinal study. They have found that maternal prenatal smoking is associated to wheezing below 3 years of age and interestingly this effect was found to be more pronounced in girls rather than in boys. It is likely that this prenatal smoking results in smaller airways due to the reduced lung development, resulting into wheezing. Postnatal smoking, however, is likely to be related to recurrent upper respiratory tract infections. Hence our aim to prevent smoking induced lung disease should be aimed at the potential mother.
        

  • C Bodner, for the Aberdeen WHEASE Group (Univ of Aberdeen, Scotland)
    Family size, childhood infection and Atopic disease
    Thorax, 53: 28-32, 1998
       
    The prevalance of asthma and other allergic disease among children in the developed countries has increased in the past 3 decades.
        
    Bodner and Aberdeen have in this group reported on cross-sectional survey of 2111 subjects analysed for the determinants of asthma and atopy. They found that hay-fever and eczema were inversely related to family size but asthma less so. They also found a small increased risk for asthma with increasing number of childhood infection. Measles, however, demonstrated a small protective effect for asthma. The effect of childhood infections on this immunoligic perturbation is unknown but is likely specific to the class or type of infection.
       

  • M. Kraft, RJ Martin, S Wilson, et al (Unvi of Colorado, Denver; Univ of Southampton, England)
    Lymphocyte and Eosinophilia influx into Aleovular Tissue in Nocturnal Asthma
    Am. J  Resp. Crit Care Med 159: 228-234, 1999
        
    Inflammatory cytokines which are produced bu T lymphocytes help the promotion of eosinophil migration from blood through the vascular endothelium and the key source for these cytokines probably is the CD4+ lymphocytes, which may also produce chemokines involved in eosinophil chemotaxies, survival, maturation as well as their activation.
        
    The study has been performed into two separate groups. The patient were subjected to bronchoscopies followed by endobronchial and transbronchial biospy specimens. Amongst patients suffering from nocturnal asthma and those without suffering from nocturnal asthma i.e. nonnocturnal asthma group. Bronchoscopies were performed in a random order, a week apart at 1 at 4 pm and the other at 4 am. The numbers of CD3+, CD4+. CD8+ cells and EG2+ esosinohils were measured in the epthelium, lamina propria and the alveolar tissues.
       
    These studies from kraft and her colleagues at National Jewish have enlightened us with a role of alveolar tissue inflammation in asthma. The study  demonstrates that there are an increased number of CD4+ lymphocytes in alveoli in patients with nocturnal asthma and with those correlated  inversely with nighttime lung function. Whether this was causally related is unknown. More information is needed regarding the circulation of CD4 lymphocytes in the lungs and their release of potential mediators of asthama symptoms. These cells may be either innocents bystanders or be the result in the alveoli from the spilling over from the increased numbers in the airways. Further studies of optimal timing of anti-inflammatory mediators in patients with nocturnal asthma are needed.
        

  • BH Rowe, GW Bota, et al (Univ of Alberta, Edmonton, Canada; Sudbury Regional Hosp, Ont, Canada; univ of British Columbia, Vancouver Canada, Et al)
    Inhaled Budesonide in Addition to Oral corticosteroids to prevent asthma relapse following discharge from the Emergency Dept. – A Randomized Control Trial.
    Jama 281: 2119-2126, 1999
        
    Systemic corticosteriod treatment can decrease acute asthma relapses after discharge from the emergency department. This study undertook to decide whether inhaled corticosteroids provide any additional benefits.
        
    The study is double-blind palcebo-controlled randomized clinical trials which was conducted over a period of 2 yrs on patient between ages from 16 to 60. 188 patients were included in this study and on discharge they were given non-tapering course of oral prednisolone which is 50mg/days for 7 days along with 1600
    mg inhaled budesonide or a placebo. These patients were followed up for a period of 21 days.
        
    This well performed study demonstrates a beneficial effect from the addition of inhaled corticosteroids for asthma patients at discharge. Few of them being cost. lack of long term of fellow up with the patient, interference with primary care physician’s role inadequate time to provide a metered dose inhaler technique information.
       
    However, this study argues whether we should be changing our emergency department practice to include inhaled corticosteroids for a minimum of 3 weeks period probably even longer and to prove our point we need further studies to determine the optimal dosages and the length of treatment required.
        

  • SF Lanes, JE Garrett, et al (Epidemiology Resources Inc, Newton Lower Falls, Mass; Green Lane Hosp, Auckland, New Zealand, Vancouver Gen Hosp, BC, Canada; et al )
    The effect of adding atropine bromide and salbutamol in the treatment of acute asthma. This is a pooled analysis of 3 trials.
    Chest 114: 365-373, 1998
        
    For patients with acute asthma, it is not clear whether an addition of ipratropium bromide would result in bronchodilatation rather than just
    b2 against therapy. Three major randomized trials which have been performed were pulled into the study. An American study found no difference, whereas study from New Zealand showed significant advantage with the combination therapy and a been pooled to estimate the effects of ipratropium bromide + salbutamol in patients with acute asthma.
         
    Several studies have demonstrated that ipratropium bromide should be added to acute treatment for patients with asthma both in adult as well as in children. Zorc et al found a significant reduction in length of stay in emergency department and use of additional doses of albuterol. A reduction of lenght of stay is found in any busy urban emergency department. It is important to keep in mind that the effectiveness of ipratropium is primarily in acute treatment in the emergency dept and it should not be continued in hospital setting for more than 36 hours. Thus it can be probably concluded that the additional use of ipratropium is not useful and will diminish any potential cost savings from the acute use of ipratropium.
        
    It is best to say the use of ipratropium bromide should be restricted to emergency  dept. for a maximum period of upto 36 hours in case of acute asthmatic attack.
        

  • D Vervloet, T Ekstrom, et al (Hospital Sainte Marguerite, Marseilles, France; Univ Hosp, Sweden, Ospedale Civile, Osimo, Italy, et al)
    A 6-month Comparison Between Formeterol and Salmerterol in Patients with Reversible Obstructive Airways Disease
    Respir Med 92: 836-842. 1998
        
    The newer long acting B2 – agonists including formoterol and salmeterol, can be prescribed for regular use by patients with asthma. The long-term treatment with these agents has important benefits including reduced symptomatology and improved lung function. Formoterol as well as salmeterol have not been directly compared for safety and effficacy. The efficacy and safety of 6 months of treatment have been compared in multi-randomised open trials. In-vitro studies have shown that mast cells following treatment with formoterol have significantly decreased in numbers a finding, which is not supported by studies with salmeterol. However, studies by Vervlot et al argues that in-vivo or in real life these differences may not be important. Further larger double-blind randomized controlled trial studies with formoterol when compared its efficacy with salmeterol are required to make this decision.
        
    The study by Palmquist et al argues that formeterol is more protective against methacholine induced bronchoconstriction than salmeterol. However the doses to achieve this protection which they have implemented are much higher than the currently recommended one for the use of either drug in clinical prectise. The effect of Formeterol on the bronchodilating ability of short acting B-agonist such as albuterol over a period of time needs to be investigated.
        

  • F Pierart, JH Wildhaber, I Vranchen, et al (Princess Margaret Hosp for Children, Perth, Western Australia)
    Washing plastic spacers in household detergent reduces electrostatic charge and greatly improves delivery
    Eur. Res. Jr. 1999
         
    Plastic spacres have been widely used along with pressurized metered dose inhalers. However the electrostatic charge that accumulates on this devices has been shown to have significant impact on drug delivery. In-vitro studies suggested that the spacers coated with ionic detergent have reduced static and improved drug delivery and hence a study was undertaken to study the effects of these household detergents on the electrostatic charges on plastic spacers.
         
    In the vitro studies all detergent increased the mean small particles Salbutamol output by almost by 50%. This increase in output was noted even for spacers coated with very dilute detergent in constitution as low as 1: 10,000. Spacers developed an electrostatic charge within one week after coating. The charged remained low for at least 4 weeks. This is surprising finding that the use of household detergent to clean and keep dry on a spacer can improve drug delivery 3-folds. This simple technique is not well-known and nor it is found in current asthma management guideline.
        
    The study by Pierart et al demonstrated that any household detergent when diluted will decrease the electrostatic charge for up to almost 4 weeks. This interesting findings requires further studies to be performed along with other medications and other medications and other chlorofluorocarbon-free propellants to confirm the results. It is also important that we start educating our patients on the proper care of spacers so as to optimize drug delivery.
         

  • Chronic Obstructive Pulmonary Disease
    PM Dorinsky, C Reisner, GT Ferguson, et al (Boehringer Ingelheim Pharmaceuticals Inc, Ridgefiled, Conn; Wayne State Univ, Detroit)
    The combination of Ipratropium and Albuterol optimises pulmonary funciotn reversibility testings in patients with COPD.
    Chest 115: 966-971, 1999
        
    Taking into consideration the fact that long-term use of a combination of ipratropium and albuterol have been recommended doses rather than a single agent alone in patient with COPD. A large recently concluded 3 month randomized double-blind parallel multicentre phase III trial study has been reported here. Where 1067 patients with stable COPD were randomized to treatment with ipratropium bromide and albuterol or an equivalent combination of ipratropium bromide and albuterol sulphate.
       
    The equivalent combination of ipratropium bromide and albuterol sulpahte were superior to individual drugs. A 15% or greater increase in FEVI was observed in 80% of the patients who received the combination. Thus this outcome suggest that combionation of ipratropium bromide and albuterol sulpahte was superior to the individual drugs in identifying PFT reversibility in patients with stable COPD.            
                                                                           

  • Istvan Zelenyi and Kay Brune         
    Unconventinal Therapies in Asthma          
    Drugs of Today, 37 (10): 651-664         
                                    
    Complementary/alternative medicine (CAM) is more popular than ever before. Patients with allergic diseases often seek so-called alternative treatment as supplementation but seldom as a real alternative to classical medicine.   
                                    
    Despite the demand for CAM, there is a paucity of well-founded evidence about its effectiveness. There are few good studies and those that exist are often inconclusive. CAM should be approached in the same way as some of orthodox medicine is evaluated now and how most, if not all, will be assessed in the future. Remedies, if shown to be effective and safe, should be part of the interventions made available to patients.                
                           
    Homeopathy – There is not enough evidence to reliably assess the possible role of homeopathy in asthma. Well-controlled, randomized, double-blind trials are urgently needed.           
                                         
    Another approach involves isopathy. In this case hay fever is treated with homeopathic dilutions of corresponding pollens, also called homeopathic immunotherapy. Based on the evidence in rhinitis, the isopathic approach might have real validity in the treatment of asthma. Unfortunately, rigorously controlled and carefully performed double-blind studies are still missing. From the theoretical point of view and preliminary evidence, this suggests that isopathy could help allergic patients.
                                                  
    Mind-body therapies (Yoga and Hypnosis)-The use of yoga in asthma has been widely investigated.
    There was tendency toward lesser usage of
    b2-adrenoceptor agonists. In general, it is likely that specific, and for the patient, more advantageous, breathing techniques utilized are responsible for the beneficial effects in asthma, not the yoga postures or meditation. However, there is basically only one correctly performed, double-blind, placebo-controlled study with positive results. All other studies have several basic weaknesses, mostly few patients and not placebo controlled. Therefore there is an urgent need to perform randomized, placebo-controlled, double-blind studies.           
                                                          
    Asthma never was a psychosomatic disorder. Asthma can be triggered by emotional stress. It may be superimposed by psychic components (anxiety, depression) but the basic disease is always of organic nature. Respiratory physiotherapy seems beneficial as an adjunct to medical management of asthma. In conclusion, it remains unclear whether mind-body therapies produce a real improvement in airway inflammation.                           
                                              
    Almost all of the appropriately and carefully performed clinical studies could not show convincing positive results. Acupuncture can be useful in some patients in improving quality of life and reducing the need for using bronchodilators. In another randomized, controlled study, the results imply that asthma patients benefit from acupuncture treatment given in addition to conventional therapy. It is important to mention that in traditional Chinese medicine, acupuncture is usually used in combination with herbal drugs.                           
                                
    In conclusion, acupuncture may improve acute airway obstruction but its efficacy in long-term use has yet to be established.
                   
    Pneumothorax is the most common mechanical organ injury. In general, serious adverse effects are rare and acupuncture can generally be considered a safe treatment.                   
                                 
    Aromatherapy – Their value in asthma therapy is more than questionable.          
                  
    Naturopathy – The most important nutritional supplements seem to be vitamin C, magnesium and fish oils such as omega-3 fatty acids. It is possible that some foods (garlic, onion, essential oils, etc.) are of value in helping to improve natural defenses. However, it should also be mentioned that garlic or onion can induce asthma as well.    
                        
    In general, dietary adjustment and nutritional supplementation may benefit a small percentage of patients with asthma but extreme measures are very rarely indicated. The studies performed to date, whether showing positive or negative effects, utilized short-term supplementation. Long-term studies should be conducted to further elucidate the real role of nutrition in asthma treatment.          
                     
    Herbal medicine : Several asthma drugs had their origin in folk remedies discovered by our ancestors. Asthmatic patients were treated by stramonium cigarettes that were originally developed in India. Ephedrine, the first strong bronchodilator compound, was developed from ma huang, a favorite Chinese herbal remedy in use for thousands of years. Asia also provided other drugs, i.e. theophylline, which is found in tea leaves. Cromoglycate is a derivative of the chromones found in the bronchodilator khella in the Middle East. Bromhexine, a known mucolytic drug, is derived from the Malabar nut. Coleus forksholii is ued in Ayurvedic medicine and contains forskolin, which activates adenylate cyclase, resulting in increased cyclic adenosine monophosphate production and consequently in bronchodilation. In contrast to Asia, no major drugs have been derived from European herbal remedies. Respiratory herbs indigenous to Europe predominantly contain mucoregulatory compounds (e.g. mustard, horseradish, menthol, fennel, etc.)             
                          
    Traditional Chinese medicines are decoctions of mixtures of up to 20 herbs that are customized for each individual patient. Of them, the only herb with proven pharmacodynamic effect is ma huang, a source of ephedrine. Ginkgo biloba is also used as an asthma remedy, although its clinical value appears to be negligible. Wu-Hu-Tang, a Chinese formulation, which consists of seven crude drugs, has been used for the treatment of asthma for hundreds of years. Recently, it has been demonstrated in animal studies that the aqueous extract of Wu-Hu-Tang  may have inhibitory effects on mediators of immediate hypersensitivity. Many of the herbs used by Chinese physicians have been carefully reviewed by Bielory and Lupoli but their clinical value remains uncertain.                 
                                   
    Based on experimental data, saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma. Other herbal formulations have also suppressed either nasal allergy or asthmatic reactions in actively sensitized animals.
                                  
    Some Ayurvedic drugs of interest for consideration in asthma include Datura plants, the historical source of atropine. Of the Indian plants, Tylophora asthmatica (also known as Tylophora indica  or Indian ipecac; the primary ingredient is the alkaloid tylophorine) is often used in treating asthma. Another interesting herbal medicine is the gum resin of Boswellia serrata. Boswellia not only inhibited leukotriene formation but also prevented development of inflammation in rats.           
                                      
    Recent clinical results show a certain potential role of this herb. Extended controlled clinical trials are required to identify the place for this plant in asthma therapy.                
                                    
    Furthermore, steroids are widely used in several so-called herbal preparations.                
                                                   
    Fugh-Berman published a very important summary of interactions between herbal and pharmaceutical drugs. It has been pointed out by the author that all persons involved in health care should caution patients against mixing herbs and synthetic drugs.                     
                                 
    Marine products:                     
    Perilla seed oil-rich supplementation (omega-3 fatty acids) is, in contrast to corn oil (omega-6 fatty acids), useful for asthma treatment in terms of improvement of pulmonary function and reduction of leukotriene production. 
                        
    The long-time native Maori people of New Zealand have included the New Zealand green-lipped mussel (Perna canaliculus) as a staple in their diet. In the last 20 years, polyunsaturated fatty acids have had a major impact on the thinking in medicine. It has recently been discovered that the green-lipped mussel, rich in omega-3 fatty acids, inhibits LTB4 production by human monocytes and likely has a certain steroid-sparing effect. Although omega-3 fatty acid may reduce bronchial hyperresponsiveness, there is little evidence to recommend that asthmatics supplement or modify their dietary intake of n-3 fatty acids (fish oil) in order to improve their asthma control.             
                                                         
    A new steroid compound has recently been isolated from a sea sponge (Petrosia contignata) collected in Papua New Guinea. The steroid, called  “contignasterol”, has anti-inflammatory and antiasthmatic properties in animal experiments. First clinical studies are now ongoing. Two interesting steroids, halicostanone and halistanol were isolated from a Haliclona sp. marine sponge with a similar structure to that of contignasterol. Data as to antiallergic activity are not available at present.   
                                                    
    Since several methods of CAM are being used more and more in routine healthcare, the question as to its efficacy is certainly justified. Although some studies have shown promising results, the efficacy of CAM has not been proven beyond reasonable doubt. In general, the research on alternative medicine is of poor quality. For these reasons, it is absolutely essential to perform well-planned, placebo-controlled, double-blind clinical trials as soon as possible. Additionally, a sufficiently large number of patients should be involved in these studies.                
                                                           
    Last but not the least: in the past few years, health information and therapy recommendation have become readily available through the internet. Profit-based companies often advertise a product claimed to be effective for asthmatic disorders without any scientific evidence. There is a future requirement for all of us: we have to critically evaluate the contents of the Website and should inform our patients about all false information.           
        

    

 

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