CORTICOTERAPIA IN NEUROLOGIE Constantin Popa

Colectia Medicala

La peste 50 de ani dupa introducerea in pratica medicala a corticoterapiei, glucocorticoizii sunt astazi indispensabili in numeroase domenii terapeutice. In domeniul neurologiei nu putem apela intotdeauna la regulile de consens, nici, din pacate, la medicina bazata pe dovezi; suntem obligati de unul sau mai multe din mecanismele bolii - cu aparitie episodica sau neasteptata - sa eliminam cat mai rapid din evolutia unei boli neurologice edemul sau inflamatia, de exemplu, cu ajutorul corticoterapiei, pe o perioada limitata de timp. Lucrarea de fata abordeaza principalele afectiuni neurologice in care se utilizeaza corticoterapia la ora actuala, atragand atentia asupra importantei din ce in ce mai mari pe care o capata utilizarea metilprednisolonului in doze mari, cel putin in scleroza in placi. CORTICOTERAPIA IN PRACTICA MEDICALA coordonator Andrei Nanu Colectia Medicala Lucrarea reprezinta o sinteza a utilizarii corticoterapiei in practica medicala, structurata pe specialitati medicale. Volumul nu are un caracter descriptiv, ci mai degraba unul ilustrativ, cu sansa ca cititorul sa acceseze cu usurinta datele actuale ale practicii medicale la nivel mondial in acest domeniu. Prezentarea pe specialitati medicale a pornit de la interesul practic pe care aceasta il implica. Utilizarea graficelor-sinteza permite orientari practice ce rezulta din continutul graficelor, nu numai din concluzii. Modul de ilustrare tehnica sugereaza elemente generale de orientare si caracterul concis al unei problematici de mare complexitate care, indiferent de specialitate, include in ea intreaga practica medicala. Contributia liderilor din domeniile medicale din Romania implicati in sistemul de invatamant si in elaborarea ghidurilor de practica a condus la realizarea acestui volum util medicului, indiferent de specialitate, acesta putandu-se orienta mai usor pe baza indexului. Cartea nu este un tratat, nu este nici o monografie, ci este o elaborare particulara a modului de aplicare a corticoterapiei in practica clinica, o sinteza care permite intelegerea integrativa a aplicarii corticoterapiei in practica medicala din orice specialitate.

Corticoterapia duntoare n traumatismele craniene? 26 Mai 2005 Rezultatele unui vast studiu randomizat, recent finalizat, demonstreaz ineficiena i chiar efectul duntor al corticoterapiei, folosit de mai mult de 30 de ani n acest context, n tratamentul traumatismelor cranio-cerebrale acute, aflm dintr-un comunicat publicat azi de The Lancet. Consecutiv studiului CRASH, incluznd 10.000 de pacieni aduli cu traumatism craniocerebral acut, s-a descoperit c mortalitatea la 2 sptmni dup accident era mai mare n grupul tratat cu steroizi dect printre cei care au primit placebo. Mortalitatea la 6 luni la fel era crescut n urma administrrii corticosteroizilor, aceste date sugernd necesitatea reformulrii ct mai urgente a strategiilor de tratament n asemenea cazuri. Corticoterapia prospectul unui medicament - exemplu BERLICORT , comprimate triamcinolonum Compoziie: 1 comprimat conine 4,0 mg triamcinolon Indicaii: n terapii sistemice cu corticosteroizi. Boli alergice ca: astm bronic, bronit cronic cu emfizem, rinit alergic sau vasomotorie n cazuri severe i dac nu se obin rezultate n tratamentul local al acestora; reacii alergice cutanate nsoite de urticarie sever dac nu sunt eficiente alte tratamente, dermatit de contact i dermatit atopic, pentru un tratament de scurt durat; alergii medicamentoase: erupii sau boala serului, n combinaie cu alte msuri terapeutice; boli reumatice ca: polimialgie reumatoid; colagenoze n faza pasiv (lupus eritematos diseminat, periarterit nodoas i alte tipuri de vasculite, polimiozite, colagenoze mixte); poliartrite cronice n faza de maxim activitate i n forme speciale (ex. manifestri viscerale); artrita juvenil (ex. uveita) alte forme ale poliartritei reumatoide cu tablou clinic sever i rezistente la ageni antireumatici nesteroidieni; dermatite alergice; fibroz pulmonar, sarcoidoz (M. Boeck) sindrom nefrotic; boli ale sistemului limfatic (leucemie limfatic, limfosarcom, limfogranulomatoz) i purpur trombopenic sau anemie hemolitic. Contraindicaii: Nu se va administra n caz de ulcer gastric i duodenal, osteoporoz, tulburri psihice chiar i n anamnez, mbolnviri cauzate de virui, varicel, amibiaz, micoze sistemice, poliomielit - cu excepia formei cu atingere bulboencefalic, cu 8 sptmni nainte i 2 sptmni dup o vaccinare, cataract. Utilizarea n cazul unei infecii grave se va face numai n combinaie cu o terapie simptomatic. Se va administra cu pruden n: ulcer gastroduodenal, diverticulit, anastomoze intestinale recente, miozit, tendin la tromboz i embolie, carcinoame cu metastaze, diabet zaharat, boli renale, glomerulonefrit acut, nefrit cronic, limfadenit consecutiv vaccinrii B.C.G. i la copii. Atenie n caz de tuberculoz n antecedente (pericol de reactivare).

Sarcin i alptare: Sarcin: nu se vor administra corticosteroizi, dect n cazul unei indicaii vitale. Alptare: dac este necesar un tratament cu o doz mai mare i pe o perioad mai lung de timp, se va ntrerupe alimentaia la sn a copilului. Efecte adverse: Administrarea sistemic de glucocorticoizi poate duce la: fa "n lun plin", adipozitate, efecte la nivelul muchilor (miopatie, atrofie), osteoporoz, scderea toleranei la glucoz, activarea sau agravarea diabetului, tulburri ale secreiei hormonilor sexuali, teleangiectazii, peteii, echimoze cutanate, acnee, pierderi de potasiu, tulburri gastrointestinale, ulcer gastroduodenal, creterea riscului la infecii, scderea capacitii de aprare a organismului, ntrzierea procesului de vindecare a rnilor sau de sudare a oaselor, tulburri de cretere la copii, necroze osoase aseptice, cefalee, hipertensiune arterial, transpiraie excesiv, ameeli, glaucom, cataract, tendin la tromboz, pancreatit, inactivarea sau atrofierea corticosuprarenalei, depresie. Interaciuni: Glicozide cardiotonice: aciunea glicozidelor este potenat prin pierderea de potasiu. Saluretice: este crescut eliminarea de potasiu. Antidiabetice: diminuarea efectului hipoglicemiant. Derivai cumarinici: diminuarea efectului anticoagulant. Rifampicina, fenitoina, barbituricele: reduc efectul corticoid. Antiinflamatoare nesteroidiene/ antireumatice: crete riscul apariiei hemoragiilor gastrointestinale. Mod de administrare: Doza iniial la aduli netratai anterior este de 24-40 mg Berlicort /zi, pentru copii sub 27 kg greutate corporal sau pentru copii ntre 9-10 ani , doza este de 4-12 mg /zi. Schem de tratament: Aduli: I i a II-a zi 24 mg a III-a zi 16 mg a IV-a i aV-a zi 8 mg Doza de ntreinere este de 2-8 mg triamcinolon /zi. Doza pentru o terapie de lung durat este de 4-12 mg la fiecare dou zile. Copii: Copiii sub 27 kg greutate corporal avnd pn la 9-10 ani primesc ntre 1/3-1/2 din doza unui adult. ntreaga doz zilnic se va administra pe ct posibil dimineaa ntre orele 6,00-8,00, cel mai bine dup micul dejun, cu o cantitate de lichid. Corticoterapia nu se va ntrerupe brusc; doza trebuie redus treptat. Form de prezentare: Cutii cu 20, 25, 50, 100 comprimate. Valabilitate: 3 ani. A.P.P.: Productor: Berlin-Chemie Menarini Group

http://ebm.bmjjournals.com/cgi/content/full/7/3/76
Leucotriene - tabel Antileukotriene (AL) agents (higher-than-licensed dose) plus inhaled corticosteroids (ICS) v ICS alone for symptomatic chronic asthma at 4 to 16 weeks* Outcome AL + ICS ICS RRR (95% CI) NNT (CI) Exacerbations 2% 7% 66% (12 to 87) 22 (12 to 125) *Abbreviations defined in glossary; RRR, NNT, and CI calculated from data in article. Leucotriene text Therapeutics Review: adding antileucotrienes to inhaled corticosteroids reduces exacerbations in symptomatic chronic asthma Ducharme F, Hicks G, Kakuma R. Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev 2002;(1):CD003133 (latest version 25 Oct 2001). QUESTION: In patients with chronic asthma, how effective and safe is daily antileucotriene (AL) treatment plus inhaled corticosteroids (ICS) compared with ICS alone? Data sources Studies were identified by searching 4 electronic databases up to September 2001; scanning the reference lists of articles and reviews; reviewing meeting abstracts (1998 to 2000); and contacting the international headquarters of AL manufacturers. Study selection Studies were selected if they were randomised controlled trials evaluating the effectiveness of AL for 1 month in patients with asthma who were 2 years of age. Data extraction Data were extracted independently by 2 reviewers on study quality, patient characteristics, intervention type and duration, and main outcome measures. Main results 13 trials (12 in adults and 1 in children) were included. Combining data from 2 of the 6 trials in symptomatic patients and after 4 to 16 weeks of treatment showed that the addition of higher-than-licensed AL doses to ICS reduced the risk for exacerbations requiring systemic corticosteroids (table). The addition of higher-than-licensed doses also led to an improvement in FEV1 (weighted mean difference [WMD] 0.10 litre, 95% CI 0.01 to 0.20), peak expiratory flow rate (WMD 27.2 l/min, CI 18.6 to 35.8), asthma symptom scores (standardised mean difference [SMD] 0.46, CI 0.25 to 0.66), and mean use of 2 agonists (SMD 0.43 puffs/d, CI 0.22 to 0.63). The groups did not

differ for any other outcomes. The addition of licensed doses led to non-statistically significant reductions in the risk for exacerbations requiring systemic steroids (relative risk reduction 39%, CI 5% to 64%). View this table: [in this window] [in a new window] Antileukotriene (AL) agents (higher-than-licensed dose) plus inhaled corticosteroids (ICS) v ICS alone for symptomatic chronic asthma at 4 to 16 weeks* 2 trials that compared ICS plus AL at higher-than-licensed doses with double dose ICS in symptomatic patients showed no differences between groups for the number of exacerbations requiring systemic steroids or for any other outcome. 4 trials that compared AL (at licensed doses) plus ICS with the same dose of ICS in well controlled patients showed no difference in reduction in ICS dose after 12 to 20 weeks and no difference in the lowest tolerated dose of ICS. Conclusions In patients with chronic asthma who are symptomatic while receiving moderate to high doses of inhaled beclomethasone, the addition of 2 to 4 times the licensed dose of antileucotriene agents reduces the rate of exacerbations that require systemic corticosteroids. Insufficient evidence exists that antileucotriene confers benefit over doubling the dose of corticosteroids or that it has an inhaled corticosteroid-sparing effect. Footnotes Source of funding: in part, Canadian Cochrane Network. For correspondence: Dr F M Ducharme, McGill University, Montreal, Quebec, Canada. Francine.ducharme@muhc.mcgill.ca.

Commentary P John Rees, MD Guy's, King's and St Thomas's School of Medicine London, UK AL agents provide the first new treatment option in asthma for some time. ALs might be helpful as alternatives to ICS in patients starting regular treatment and as an addition to ICS. The review by Ducharme et al deals with the latter, when control is inadequate with ICS or as a method of reducing the ICS dose. The reported results are disappointing. In short

term studies, exacerbations were reduced and control was slightly improved with the addition of AL, but some doses were greater than current licences allow. No difference existed between adding AL to ICS and doubling the dose of ICS, although steroids have been found to have a rather flat dose response, and the introduction of AL did not allow for a reduction in ICS dose in these studies. 2 large studies1,2 have examined the effects of adding long acting inhaled agonists (LABAs) at the same point and have shown that LABAs add to the benefits of ICS and are more effective than doubling the steroid dose. LABAs also reduce exacerbations.1 In the studies reviewed by Ducharme et al, patients were not taking LABAs. The clinical implications would seem to be that LABAs should be the first option for patients who are not well controlled with ICS or who require high doses for control. AL might be considered after assessing the response in each patient. The use of AL as a first prophylactic agent has been assessed in a Cochrane review.3 AL agents were inferior to ICS for effects on lung function, symptoms, and quality of life, although again they were not statistically different for exacerbations. New drugs for asthma must contend with the fact that ICSs are very effective in asthma and have few side effects at usual doses. AL agents, at the higher doses seen in this review, were found to affect liver function tests, but they are generally safe drugs in asthma; however, their effectiveness is limited and indications for their use have not been broadened by this review. References Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:140511.[Abstract/Free Full Text] Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:21924.[Medline] Ducharme FM, Hicks GC. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma. Cochrane Database Syst Rev 2000; (3):CD002314.

http://postamedicala.ro/content/view/228/48/
Nouti impresionante n tratamentul bolnavilor cu BPCO 05 Aprilie 2005 Bronhopneumopatia cronic obstructiv numit i plmnul fumtorilor afecteaz circa 6% din populaia Marii Britanii. Cercettori din Londra au descoperit de ce boala care constituie a 4-a cauz de deces n Anglia, cu o prevalen n cretere, este rezistent la corticoterapie. Steroizii reprezint terapia de baz n tratamentul multor boli inflamatorii cronice printre care i BPCO. ns aceti bolnavi par s fie rezisteni la

steroizi, ceea ce constituie o problem clinic major, ce duce la creterea prevalenei i la o progresie mai rapid a bolii. Inflamaia este cauzat de anumite celule productoare de mediatori chimici, prin exprimarea anumitor gene. Pentru stoparea acestui mecanism este nevoie de o enzim denumit Histon 2 Diacetilaz (HDAC2). Aa cum reiese din studiul efectuat de Prof. Peter Barnes i colab. steroizii se poart ca i o punte molecular care leag acest enzim HDAC2 de gena corespunztoare blocndu-i activitatea. n BPCO nivelul celular al acestei enzime este mult mai sczut fa de celulele normale, iar astfel steroizii nu i pot exercita efectul protector. Cercettorii englezi i pun mari sperane ntr-un medicament foarte rspndit i ieftin care n doze mici ar putea duce la creterea nivelului celular al acestei enzime, i anume Teofilina.Este n lucru un nou studiu clinic care dac va da rezultate bune va nsemna un pas important n abordarea tratamentului acestor bolnavi. HDAC2 este o enzim care poate dezactiva anumite gene prin alterarea proteinelor care conin materialul genetic din nucleul celular. HDAC2 acioneaz asupra proteinelor denumite histone prin alterarea structurii lor, materialul genetic transformndu-se n nite pachete torsionate, nclcite care nu mai pot fi accesibile, iar informaia coninut nu mai poate fi tradus n semnale (mediatori) chimice.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&list_uids=10748747&dopt=Abstr act:

Substituted benzo[b]thiophenes with anti-leukotriene activity] [Article in Czech] Nic M, Havelkova M, Terinek M, Palecek J, Svoboda J, Jandera A, Panajotova V, Kuchar M. Ustav organicke chemie Vysoke skoly chemicko-technologicke, Praha. The cyclizing reaction of cinnamic acid (Ia) with thionyl chloride was optimized and a series of 3-chloro-6-subst.benzo[b]thiophene-2-carbonyl chlorides Va-Vn was prepared. Chloride Va was transformed into a series of N-aryl-3-subst. (Cl, OCH3, OH) benzo[b]thiophene-2-carboxamides VII, IX, X. The drugs were subjected to an evaluation of selected antileucotriene activities in vitro and of the anti-inflammatory effect in vivo. In agreement with the assumed mechanism, inhibition of the ear inflammation is conditioned by the antileucotriene activity, whereas inhibition of the carrageen oedema is not due to this mechanism alone. PMID: 10748747 [PubMed - indexed for MEDLINE]

http://www.aaiba.com.ar/libro/_private/antileukotriene_drugs _in_the_man.htm
ANTILEUKOTRIENE DRUGS IN THE MANAGEMENT OF ASTHMA

Sally E. Wenzel, MD

Despite advances in the understanding and treatment of the inflammatory processes that mediate the clinical symptoms of asthma, (1) the mortality and morbidity associated with this disease have not appreciably declined, (2) It continues to be imperative to develop new approaches to asthma therapy. Antileukotriene drugs are a novel form of asthma pharmacotherapy and the first new treatment strategy for chronic asthma in 20 years. In experimental studies, cysteinyl leukotrienes (LTC4, LTD4, and LTE4, together known formerly as slow-reacting substance of anaphylaxis or SRS-A) were found to be extremely potent bronchoconstrictors and to attract inflammatory cells, increase mucous production, and alter vascular permeability (8). LTB4 was found to be a potent chemoattractant for neutrophils and eosinophils, but not to have a bronchoconstrictive effect (3). The cysteinyl leukotrienes were also shown to be produced by activated inflammatory cells (eosinophils, basophils, and mast cells) known to be present, in the airways of patients with asthma, (3) and were recovered in increased amounts at baseline, after allergen challenge, and during asthma exacerbation's from bronchoalveolar lavage fluid and urine of patients with asthma (3)(5). These observations suggested that leukotrienes could be important in the clinical symptoms and physiologic changes of asthma, but confirmation of that concept required the development of drugs that either blocked the synthesis of leukotrienes from arachidonic acid (5-lipoxygenase [5-LO] inhibitors and 5-lipoxygenase activating protein [FLAP] inhibitors) or antagonized the activity of the sisterly leukotrienes at their receptor, cys LTi (leukotriene receptor antagonists).

Four oral antileukotriene drugs are now available for the treatment of asthma: 3 leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast (not available in the United States), and a 5-LO inhibitor, zileuton. Although 5-LO inhibitors inhibit the synthesis of LTB4 as well as the cysteinyl leukotrienes, it remains to be seen whether this broader spectrum of activity produces greater efficacy in the treatment of asthma. These

antileukotriene drugs have been extensively studied in clinical trials, but long-term data on effectiveness and adverse effects are lacking.

Efficacy

Studies indicate that antileukotriene drugs directly inhibit bronchoconstriction and have anti-inflammatory effects as well, a combination of actions that has not been demonstrated as clearly in other classes of asthma drugs. Early in their development, the leukotriene receptor antagonists and FLAP inhibitors, in single doses, were found to almost completely eliminate the immediate bronchoconstricion response to allergen challenge and to reduce the later bronchoconstriction response by approximately 50%(6). Antileukotriene drugs also abolished the bronchoconstriction response that is observed after the administration of very small doses of aspirin in patients with aspirin-sensitive asthma (7). Further, they reduced exercise-induced bronchoconstriction by 40% to 60% (8), and recent evidence suggests that this protective effect has no tachyphylaxis, unlike that reported with the use of the long-acting b2-agonist salmeterol (9)(10). Studies of the anti-inflammatory effects of the antileukotriene drugs have shown significant reductions from baseline in the number and proportion of airway and circulating eosinophils in patients with asthma treated with these drugs compared with those who received placebo (11)(13).

The initial clinical trials of the antileukotriene drugs were done in patients with mild to moderate asthma who were being treated with b2-agonists alone. In a multitude of randomized studies of 12 to 24 weeks duration, patients treated with antileukotriene drugs had statistically and clinically significant improvements in lung function and asthma symptoms compared with patients who received placebo. Increases of 7% to 18% in forced expiratory volume in 1 second (FEV1), 25% to 35% improvements in daytime and nocturnal asthma symptom scores and reductions in reliever b2-agonist, use, and 30% to 60% decreases in exacerbation rates were reported in patients with asthma treated with antileukotriene drugs (11)(13)(14). The improvement in symptom scores and b2agonist use often appeared disproportionately greater than objective improvements in FEV1. Improvements in quality-of-life score were also statistically significant in patients treated with antileukotriene drugs (18). These studies demonstrated that antileukotriene drugs were efficacious, but it remained to be seen how these drugs compared with inhaled corticosteroids, the gold standard of anti-inflammatory asthma therapy.

Several randomized trials in patients with moderate persistent asthma have compared the efficacy of antileukotriene drugs with that of inhaled corticosteroids. The results of these studies are consistent and demonstrate almost a 2-fold greater increase from baseline in FEV1 in patients treated with low doses of inhaled corticosteroids than in patients treated with antileukotriene drugs, but, interestingly, smaller differences were found in outcomes such as symptom scores and b2-agonist use (15)(16).

Many questions about the use of inhaled corticosteroids vs. antileukotriene drugs remain unanswered-perhaps most critically; differences in long-term outcomes and indications for use in patients with truly mild persistent asthma. Also the results of clinical trials may not apply to real-world experience. Although inhaled corticosteroids are efficacious, patients with asthma, including those who have minimal to moderate symptoms, are often poorly adherent to inhaled therapy and have problems achieving adequate delivery (17). Further study is needed comparing the practical effectiveness of these medications.

Combination Therapy

Inhaled corticosteroids in moderate to high doses have been associated with a decreased rate of growth in children, decreased bone mineral density, (1) and the development of glaucoma (18). With only modest evidence to suggest that corticosteroids have any direct impact on leukotriene synthesis in vivo, the combination of an antileukotriene drug with an inhaled corticosteroid has a theoretical basis for additive efficacy. In a controlled trial, patients with moderate to severe persistent asthma requiring 1500 mg/d or more of inhaled beclomethasone were able to reduce their total daily beclomethasone dose by 50% when pranlukast was added, without a deterioration in lung function or evidence of increased inflammation. In contrast, patients who received placebo had significant declines in lung function and increased inflammation from baseline following the same reduction in inhaled corticosteroid dose (19). Supporting evidence suggests that antileukotriene agents in combination with inhaled beclomethasone of budesonide are likely to improve lung function and asthma symptoms more than high-dose inhaled corticosteroid therapy alone (20). Finally, the addition of zileuton to inhaled and/or oral corticosteroids for 6 weeks in patients with aspirin-sensitive asthma was associated with significant improvements in pulmonary and sinus symptoms from baseline compared with placebo. (21) The results of these studies suggest that antileukotriene drugs have a steroid-sparing effect similar to that of salmeterol and theophylline. Further, because antileukotriene drugs may have anti-inflammatory effects complementary to those of inhaled corticosteroids, they may become the additive drugs of choice to inhaled

corticosteroid therapy. Trial scampering different drugs in combination with inhaled corticosteroids are needed.

Safety

The most noteworthy adverse event associated with antileukotriene drugs has been the extremely rare development of Churg-Strauss syndrome, an eosinophilic vasculitis, usually seen when oral corticosteroids were tapered in patients with severe asthma treated with leukotriene receptor antagonists (22). It remains unclear whether the antileukotriene drugs were causative or whether the clinical syndrome was unmasked as systemic steroids were withdrawn, but patients treated with antileucotriene drugs in combination with corticosteroids should be monitored for the appearance of Churg-Strauss syndrome. Liver enzyme elevations have been observed in patients treated with zileuton and high doses (>40mgtwice a day) of zafirlukast. It is recommended that alanine aminotransferase level be monitored regularly during zileuton therapy, especially in the first 3 months of use; specific recommendations for monitoring liver enzyme levels during treatment with zafirlukast do or exist, but regular monitoring seems prudent with high doses.

Clinical Use

Based on the data available at the time, the 1997 Expert Panel Report 2 listed the antileukotriene drugs as possible alternatives to preferred therapy with inhaled corticosteroids for the treatment of adult patients with mild persistent asthma (1). Considerable new evidence is available that likely broadens the indications for their use. However, studies indicate that not all patients treated with an antileukotriene drug will have a significant clinical improvement, (16) and no factors have been identified that reliably predict the clinical response to these drugs, including age, atopic state, or urinary leukotriene excretion. It is also not known whether a particular antileukotriene drug is more efficacious than another because there have not been any head-to-head comparisons. As with any new drug treatment, it is imperative to have clinical follow-up 2 to 4 weeks after initiating antileukotriene therapy.

Although inhaled corticosteroids are the preferred therapy for chronic asthma because of the long-term experience with these drugs and their documented anti-inflammatory effects, they are not with-out safety concerns, and antileukotriene, drugs offer at least 1 distinct advantage: oral delivery. For this reason, substituting an oral antileukotriene drug when patients with mild persistent and moderate persistent asthma are poorly adherent of have a suboptimal response to inhaled corticosteroid therapy could improve clinical outcomes. In patients treated with low to moderate doses of inhaled corticosteroids who are still symptomatic, antileukotriene drugs offer an attractive option for add-on therapy. Patients with aspirin-sensitive asthma also appear to benefit from the addition of antileuckotriene drugs, (21) but whether the response to these drugs is better in this subgroup of patients than in others is not known. Finally, any patient with severe asthma requiring high doses of inhaled and/or oral corticosteroids should be given a trial of an antileukotriene drug.

Greater clinical experience with antileukotriene drugs will Iead to a better understanding of their precise place in asthma management, including their use in the treatment of acute asthma (11,28). For the present, these drugs offer a new and potentially very valuable treatment for chronic asthma, one that is considerably different from any other available option.

http://www.freenepal.com/9eng_art_premal.htm

POLYPOSIS AND ALLERGY 1. Nasosinusal polyposis and allergy must be considered as two distinct conditions. 2. POLYPOSIS: Approximately 1% of the general population has Nasosinusal polyposis, a condition strongly associated with asthma (about one-third of the patients with polyposis have asthma). Patients with Nasosinusal should undergo a complete respiratory examination in order to search for asthma or an asthma equivalent. 3. EOSINOPHILS: eosinophils play a crucial role in the inflammatory reaction, releasing almost all the known inflammatory mediators: cytokines, chemokines and growth factors. 4. EPITHELIAL CELL: The epithelial cell probably plays a very important role. 5. MEDICAL TREATMENT: Long-duration intranasal corticotherapy is the basis of drug treatment. Short courses of oral corticosteroids may be useful during acute

episodes in inflammation. The exact effect of oral corticosterid is not clearly elucidated but it is known that non-steroidal anti-inflammatory drugs (NSAID) are contraindicated in polyposis. 6. SURGICAL TREATMENT: Surgery is reserved for medical failures or for patients with a contraindication for drug therapy. Endonasal ethmoidectomy is the basis treatment. 7. PERSPECTIVES: Better understanding of the underlying pathophysiology and the probable genetic component will determine future treatments. Perspectives include anti-inflammatory drugs currently reserved for other conditions (antileucotriene, antiTNFa, IL-18) and elaboration of new anti-inflammatory drugs Laser surgery or routine surgery were followed up for 18-36 months. The postoperative recurrence rates were 40.6% (24/54) and 66.6% (32/48) respectively for the patients of the two groups. Laser surgery is the most effected in nasal polyps associated with purulent sinusitis Treatment of polypous sinusitis was not effective. Laser surgery has been proved to be ineffective in cases of bronchial asthma and aspirin sensitivity Laser surgery is marked by less bleeding no postoperative packing of the nose and lower postoperative recurrence rate, reduced post operative pain due to minimal thermal effect. increased accuracy of the surgical wound possibility of ambulatory surgery quick post op. healing and it seems to be better than routine removal in the treatment of nasal polyps. Disadvantages of Laser : a) high cost of equipment and maintenance b) special surgical skills c) increased set-up time of equipment d) need of safety eyewear e) increased care for patient safety f) explosion or fire hazard . In the selection of the patients We took in consideration the following relative contraindications : a) acute inflammation b) hypertension c) disturbances of coagulation d) diabetes Laser polypectomy. The clinical experience in cases with recurrent polyposis is presented. The

therapeutic results are evaluated. Although patients with nasal polyposis remain to be treated on an individual basis, due to the multifactorial etiopathogenesis of this disorder, the initial results with this new surgical procedure are promising. We present our concept for treating patients suffering from recurrent sinusitis with coagulating lasers The middle meatus is often narrowed by a hyperplastic middle turbinate, septum spurs and ridges, or by isolated polyps that block an ostium. We treat these patients by linear or punctate coagulation of the lateral wall of the middle turbinate, reducing the size of septum spurs, and blunting septal ridges or coagulating polyps. The outpatient procedure is performed with a laser fiberoptic system of 400 N.M. in contact mode with an energy of 3-5 watts. The amount of total energy applied to a specific tissue depends on the duration of laser contact at that point. The patient is anaesthetised superficially. The anaesthesia parameters used in all patients were for premeditation , diazepam 5mg + atropine 0,5 mg in adults and appropriate dosage in children. For local superficial anaesthesia xylocaine spray 10 % , or lindocaine + prilocaine cream , or pantocaine - cocaine solution was used. For infiltration anaesthesia xylocaine 2 % + 1: 100.000 adrenaline solution. General anaesthesia as administered by the anaesthesiologist . Patients with a high degree of nasal hyperactivity also receive antihistaminic preoperative treatment. Initial results show a significant increase of nasal flow with a decrease of sinus symptoms. Glucocorticosteroizi Adrenocorticoizi Corticosteroizi Glucocorticoizi inhalatorii: Beclometazona Budesonid Flunisolid Fluticason Triamcinolon Tablete sau sirop: hidrocortizon metilprednisolon prednisolon prednison Teofilina cu Inhalatorii: Doza initiala n functie de gravitatea astmului, apoi doza diminuata pe o perioada de 2-3 luni pna la cea mai mica doza o data ce s-a obtinut controlul Tablete sau sirop: Pentru control zilnic, se utilizeaza cea mai mica doza 5-40mg de prednison, iar n caz de crize severe, 40-60mg zilnic; priza unica la adulti, iar pentru copii 1-2 mg/kg zilnic. Inhalatorii: Riscul potential, dar nesemnificativ, de aparitie a efectelor secundare este contrabalansat de eficienta. Folosirea MDI cu spacere si clatirea gurii dupa inhalatie scad incidenta candidozei orale. Tablete sau sirop: Utilizare pe termen lung: alternarea dozajului zilnic produce mai putina toxicitate. Pe termen scurt "puseuri" de 3-10 zile sunt eficiente n obtinerea controlului prompt. Monitorizarea nivelului de

Doza initiala 10mg/kg/zi cu maxim

eliberare prelungita Teofilina Aminofilina Metilxantina

800mg Administrate n 1-2 prize

teofilina este adesea necesara. Absorbtia si metabolismul pot fi afectate de un numar de factori, inclusiv bolile febrile

Antileucotriene Montelukast (M) Pranlukast (P) Zafrilukast (Z) Zileuton (Zi

Adulti: M 10mg x 1/24h P 450mg de 2ori/zi Z 20mg de 2 ori/zi Zi 600mg 1/24h. Copii: M 5mg 1/24h (6-14 ani) M 4mg 1/24h (2-5 ani) Z 10mg de 2 ori/zi (7-11ani).

Nu s-a stabilit cu exactitate pozitia antileukotrienelor n terapia astmului. Acestea aduc o mbunatatire suplimentara ca adjuvant al glucocorticosteroizi inhalati, desi nu sunt la fel de eficiente precum 2-agonistii inhalati cu actiune de lunga durata.

http://stiri.rol.ro/stiri/2005/05/189218.htm

Astmul bronsic este in crestere la copii 6 mai 2005

Copiii cu astm bronsic - care este o boala cronica - nu se pot vindeca dar ca urmare a achizitiilor terapeutice afectiunea poate fi controlata, a declarat, joi, intr-o conferinta de presa, prof. dr. Mircea Nanulescu de la Clinica de Alergologie din Cluj-Napoca. Prof. dr. Mircea Nanulescu a spus ca astmul este cea mai frecventa boala cronica la copii iar studiile realizate in anul 1994-1995, la Cluj-Napoca, pe un esantion reprezentativ de copii, cu varste intre 13 si 14 ani, a aratat ca 43% dintre copii aveau astm bronsic. 73% sau dovedit cu astm bronsic necontrolat. Potrivit studiului realizat la Cluj-Napoca, prevalenta bolii in perioada 1994-12995 a relevat ca raspandirea astmului la copii era de 53%. Sase ani mai tarziu, studiul a fost reluat, astfel ca in 2001 s-a constatat o crestere cu 2% a numarului copiilor afectati de astm. Potrivit datelor epidemiologice, Romania are, ca frecventa, un numar mai mic de cazuri de astm decat Australia, de pilda, cu 30% sau Austria, cu 42%. Aceste diferente apar si ca

urmare a faptului ca astmul este frecvent subdiagnosticat. Astfel, unul din patru-cinci copii au simptomatologie asemanatoare astmului, dar nu sunt recunoscuti cu astm, iar un numar destul de important fac forme atipice de astm. De asemenea, prof. dr. Mircea Nanulescu s-a referit la Programul National pe care Ministerul Sanatatii il desfasoara cu privire la controlul astmului, program care contribuie la depistarea de noi cazuri si la dezvoltarea de noi centre de tratamente, care contribuie, ulterior, la pregatirea specialistilor pentru alte centre. Astmul este o boala care daca este bine tratata poate fi controlata si poate da o calitate foarte buna vietii. S-a constatat ca la unu din trei copii care au astm efortul fizic intens determina o obstructie. In general, educatia fizica si sportul sunt indicate la copii pentru ca, pe de o parte, reduc numarul crizelor si au un impact psihologic foarte important, contribuind la cresterea increderii in propria persoana, fapt care ii ajuta foarte mult pe copii. In fiecare an, la 3 mai este marcata Ziua Internationala a Astmului. Boala afecteaza populatia de pe intreg globul, a subliniat, la randul sau, prof. dr. Jeana-Rodica Radu, sefa Clinicii de Alergologie din cadrul Universitatii de Medicina si Farmacie "Carol Davila" din Bucuresti. Aceasta boala cauzeaza multe suferinte si se asociaza si cu alte boli cum ar fi de pilda rinita alergica. Studii internationale au demonstrat ca aceasta situatie este globala, afectand intre 5-50% din populatia globului. 40-50% dintre persoanele cu rinite alergice dezvolta mai tarziu astm bronsic; patru din cinci pacienti cu astm au si rinita alergica asociata. Aceasta reprezinta un factor de risc pentru astm si studiile au aratat cu rinita creste riscul de astm de trei ori. In cazul in care astmul este asociat cu rinita alergica, intensitatea crizelor astmatice creste si le face mai dese, de aceea in aceste situatii se impune prezentarea pacientului la medic. In opinia prof. dr. Dimitrie Dragomir, pacientii astmatici si asociati cu rinita alergica beneficiaza de un tratament de ultima generatie foarte eficient. Acest tratament care se face cu "Singulair" este disponibil pe baza de prescriptie medicala si are un mod de actiune diferit fata de alte antiastmatice si medicamentele pentru rinita alergica. "Singulair", este singurul medicament din aceasta clasa cu indicatia aprobata pentru tratamentul astmului si simptomelor rinitei alergice la pacientii astmatici. Astfel, s-a demonstrat ca atat astmul cat si rinita alergica sunt cauzate de inflamatiile de la nivelul cailor aeriene si acestea se dezvolta mai ales cand se schimba timpul. Simptomatologia rinitei alergice poate agrava astmul multor pacientii. Importanta tratamentului concomitent al celor doua afectiuni a fost recent sustinuta de experti din toata lumea ce au participat la intalnirea "The MetaForum: Improbing aoutcomes for asthmastic pacients with allergic rhinitis". Cu acest prilej, expertii au evidentiat imbunatatirea activitatilor terapeutice la pacientii astmatici cu rinita alergica. Astfel, pentru 40 de specialisti in astm bronsic si rinita alergica au ajuns la un consens in privinta domeniilor de actiune si a pasilor de urmat pentru imbunatatirea rezultatelor terapeutice la pacientii astmatici cu rinita alergica. Cu acest prilej s-au facut cinci recomandari majore, si anume: medicii si pacientii trebuie sa recunoasca si sa inteleaga

impactul pe care rinita alergica il are asupra simptomelor pragmatice, rezultatelor terapeutice si calitatii vietii; ghidurile ar trebui sa fie evaluate pentru a reflecta informatiile medicale de ultima ora; toti pacientii astmatici ar trebui evaluati pentru simptome de rinita alergica si invers; astmul si rinita alergica ar trebui tratate terapeutic impreuna; persoanele implicate trebuie educate in privinta abordarii terapeutice a bolilor combinate - astm si rinita alergica - a subliniat prof. dr. Dimitrie Dragomir. Tratamentul cu "Singulair" este eficient si pentru faptul ca se administreaza o singura data pe zi si se ia pe cale orala, nefiind nevoie, in special pentru copii, de pufurile cu spray-uri. "Singulair" se gaseste pentru copiii cu varsta de pana la 18 ani in tablete de cinci miligrame iar pentru adulti de 10 miligrame. De asemenea, produsul se mai prezinta si sub forma unor tablete de patru miligrame. Costul tratamentului pentru o luna la tabletele de cinci miligrame este de 1.850.000 lei; la cele de 10 miligrame si patru miligrame - 1.600.000 lei/luna. Pentru copii de pana la 18 ani, tratamentul de patru si cinci miligrame este gratuit; studentii pana in 25 de ani beneficiaza si ei de tratament gratuit; pentru adulti compensarea este de 50%. ROMPRES

Medicamentele de electie sunt antileucotrienele, de tipul montelukast-ului sodic (Singulair), care blocheaza efectul leucotrienelor la nivelul receptorilor endobronsici . Toate celelalte antiinflamatoare de tipul: Aspirina, Fenilbutazona, Indometacina, Ibuprofen, Piroxicam, Diclofenac, sunt interzise. http://www.cronicaromana.ro/primavara-alergiile-respiratorii-se-inmultesc.html La randul sau, dl. Prof. Dr. Dimitrie Dragomir considera ca la pacientii astmatici cu rinita alergica asociata, Singulair (montelukast sodium) este singura terapie cu administrare orala care trateaza eficient si in conditii de siguranta ambele afectiuni. Prin ameliorarea simptomelor rinitei alergice la pacientii astmatici, este oferita medicilor o optiune care poate simplifica terapia generala pentru cele doua afectiuni inrudite, asigurand, in acelasi timp, un beneficiu clinic general. Medicamentul este membru al unei clase terapeutice de control, care ofera o importanta alternativa la corticosteroizii inhalatori, reducand nevoia de bronhodilatatori. El reprezinta singura terapie orala ce amelioreaza efectele rinitei alergice si asigura un control eficient al astmului bronsic, fiind gratuit pentru copii pana la 18 ani si pentru studenti, pentru adulti fiind compensat 50%. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15939317&itool=iconabstr&quer y_hl=3 Pulm Pharmacol Ther. 2005;18(5):374-80. Epub 2005 Apr 26. Related Articles,Links

The effect of montelukast and different doses of budesonide on IgE serum levels and clinical parameters in children with newly diagnosed asthma. Stelmach I, Bobrowska-Korzeniowska M, Majak P, Stelmach W, Kuna P. The M Curie Hospital, Department of Pediatrics and Allergy, Zgierz, Poland. BACKGROUND: Since IgE is considered to play a crucial role in allergic immune responses, the reduction of free IgE level has been an attractive target in the treatment of allergic diseases. The present study was conducted to determine the effects of a 6-month treatment with different doses of inhaled budesonide and montelukast sodium in children with newly diagnosed atopic asthma. METHODS: In this randomized, double-blind, double-dummy trial, 51 children with newly diagnosed asthma and sensitivity to housedust mites were randomly allocated to receive budesonide (in two different doses 400 or 800mcg) or montelukast for 6 months. The primary end point was the level of serum total and specific IgE before and after treatment. The secondary end points were clinical parameters and forced expiratory volume in 1s (FEV1). RESULTS: After 6 months of treatment, a high dose of inhaled corticosteroid and montelukast, significantly decreased levels of total and specific IgE. Medium dose of inhaled corticosteroid had no effect on total and specific IgE serum level. Clinical score and FEV1 significantly improved after 6 months of treatment with medium (P=0.002) and high dose (P=0.001) of inhaled budesonide and montelukast (P=0.002). There were no differences between groups in changes of all clinical parameters after treatment. CONCLUSION: Only high doses of inhaled corticosteroids and montelukast decreased the serum IgE levels. Perhaps longterm treatment with montelukast will be beneficial to asthma patients by decreasing IgE levels. Findings of the present study suggest that montelukast possesses an anti-inflammatory effect on burn-induced damage in remote organs and protects against oxidative organ damage by a neutrophil-dependent mechanism. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15888830&itool=iconabstr&quer y_hl=2 STUDY OBJECTIVES: Salmeterol (S) and montelukast (M) individually inhibit the obstructive consequences of thermal stimuli such as exercise and hyperventilation (HV), but there is no information on whether these drugs can interact positively. CONCLUSION: These data indicate that the concurrent administration of single standard doses of S and M appears to provide greater protection against thermal stimuli than does either drug alone. Further experimentation will be required to ascertain whether the combination will provide additional clinical benefits to patients over those of the single agents

OBJECTIVE: To study the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist, in the treatment and prevention of exercise-induced bronchoconstriction (EIB) in mild asthmatic patients and patients with exercise-induced asthma (EIA). CONCLUSION: Montelukast attenuates and protects against EIB/EIA. PURPOSE: The purpose was to develop a population pharmacokinetic model for montelukast after intravenous administration. Clinical trial simulations were conducted using the model developed to identify the lowest intravenous dose in 6- to 14-year-old children that would give montelukast systemic exposures that were comparable to those found to be associated with efficacy in adults. CONCLUSIONS: The model developed can adequately describe the intravenous pharmacokinetics of montelukast and can be used as a useful tool for dose selection in pediatric subpopulations.

Montelukast, a leukotriene receptor antagonist, has demonstrated efficacy and tolerability in the treatment of asthma in patients age 6 years and older. The purpose of this open, one-period, multicenter population pharmacokinetic study was to identify a chewable tablet (CT) dose of montelukast for administration to children ages 2 to 5 years with asthma, yielding a single-dose pharmacokinetic profile (area under the plasma concentration-time curve [AUC]) comparable to that of the 10 mg film-coated tablet (FCT) dose in adults. Because patient numbers were small and the volume of blood that could be collected from individual 2- to 5-year-old patients was limited, a population pharmacokinetic approach was used to estimate population AUC (AUCpop). The 4 mg CT dose of montelukast was well tolerated and yielded an AUCpop (2721 ng.h/mL) similar to that of the adult AUCpop (2595 ng.h/mL) observed after a 10 mg FCT dose. These results support the selection of a 4 mg once-daily CT dose of montelukast for future efficacy and safety studies in children ages 2 to 5 years with asthma.