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Antiallergic and antitussive drugs
F.A. Nelemans
17
Antiallergic and antitussive drugs
Several drugs used in bronchial asthma and cough are dealt with in other chapters. These include xanthine compounds (Chapter 1), the opiates and derivatives such as dextromethorphan (Chapter 8), the parasympatholytic agents (Chapter 14), the antihistamines (Chapter 16) and the corticosteroids (Chapter 41). Editorial note
DRUGS USED IN BRONCHIAL A S T H M A A N D A L L E R G Y (SED-11,
322; SEDA-12, 144; SEDA-13, 134; SEDA-14, 139; SEDA-15, 161; SEDA-16, 167," SEDA-17, 205; SED-12, 374) Terbutaline (SEDA-1L 165; SED-12, 321) Bambuterol ( SED-12, 269)
Bambuterol was tested in a randomized, crossover, and double-blind study in elderly asthmatic patients aged 64 to 82 years (n = 81). They received placebo and 5 mg, 10 mg, 20 mg tablets once daily for a week at each dose. The plasma concentration of the active metabolite, terbutaline, increased linearly with the dose of drug (P <0.001). Peak expiratory flow rate increased with dose in the morning (P < 0.001 for 10 mg and 20 mg doses) and afternoon (P <0.05 for 10 mg; P <0.001 for 20 mg) and was different from placebo for 10 mg/day and 20 mg/day regimens. The use of supplemental inhaled fl2-adrenergic agonist therapy was reduced during the night for the I0 mg (P < 0.05) and 20 mg (P < 0.01) doses in comparison to placebo. No significant effects of treatment on blood pressure and pulse were demonstrated. 9 1995 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs Annual 18 J.K. Aronson and C.J. van Boxtel, eds.
188
Tremor and palpitations were mild and related to the dose. These data suggest that treatment once daily with bambuterol hydrochloride in a dose of 10 or 20 mg improves pulmonary function and is well tolerated as brochodilator therapy in elderly patients with asthma (lC). In an other study bambuterol was compared with placebo in 28 patients with nocturnal asthma in a randomized, double-blind crossover study. All patients were symptomatic despite taking inhaled fl2-agonists, inhaled corticosteroids (in 26 patients the median daily dose was 1500 ag) and oral corticosteroids (in eight patients the median daily dose was 10 mg). Patients demonstrated - 2 0 % overnight fall in peak expiratory flow (PEF) for at least half of the 14-day run-in period. They then entered two treatment periods lasting 14 days when bambuterol 20 mg nocte and placebo were given in random order. Compared to placebo, bambuterol produced a 16% improvement in mean PEF on walking (271 l/min vs. 239 1/min P = 0.0002) and a 10% improvement in evening PEF measured 24 h after drug intake (318 l/rain vs. 296 1/min P = 0.01). Bambuterol significantly reduced frequency of nocturnal awakening from 1.1 to 0.7 per night (P = 0.01) and nocturnal flz-agonist use from 2.7 to 2.1 puffs (P = 0.0004). Other nocturnal symptoms: cough, wheeze and dyspnea were also significantly reduced during bambuterol treatment and patients' quality of sleep was improved. The results indicate bambuterol (20 mg nocte) provides effective nocturnal bronchodilation with sustained effect for 24 h and may have a useful therapeutic role in the control of symptomatic nocturnal asthma. Patients with asthma often experience worsening of their symptoms and reduction in airway function in the early hours of the morning (1, 2), with 75% of asthmatics suffering from sleep disturbance from time to time. Additionally, asthmatic deaths and respiratory arrests occur more frequently during the night. The precise
Antiallergic and antitussive drugs Chapter 17
189
mechanism of this is unknown but is likely to be multifactorial (3 c, 4R). Nocturnal symptoms may remain troublesome and interfere with quality of sleep despite the use of inhaled fl-agonist and inhaled corticosteroids (2c). Bambuterol is the first long-acting oral fl2agonist with a 24 h effective duration. In order to investigate the possibility of replacing established treatment modalities with bambuterol once daily, the bronchodilating and tremorogenic effects of bambuterol, 10 mg once daily, and terbutaline, 5 mg controlled-release (CR) tablets twice daily, was compared. The study was of a double-blind, double-dummy, randomized, cross-over design and involved two, two week treatment periods, separated by one week wash-out period. PEF recorded in patients' diaries was the primary efficacy variable. Seventy adult, asthmatic out-patients with mild to moderate asthma were included (forced expiratory volume in one second (FEV 1) -> 50% predicted). After treatment with bambuterol, mean morning and evening PEF (S.D.) were 347 (122) and 365 (121) l/min, respectively and 346 (121) and 365 l/min, respectively, after treatment with terbutaline. FEV 1 (S.D.) was 2.21 (0.91) 1 and 2.27 (0.93) 1 after bambuterol and terbutaline treatments, respectively. Tremor scores tended to be lower during treatment with bambuterol, although not significantly so. Tremor scores were low, in general. In conclusion, no difference in the bronchoditating effect was demonstrated between bambuterol, 10 mg once daily, and controlled release terbutaline, 5 mg twice daily. A tendency towards less tremor was seen with bambuterol (5c). Isoprenaline (SEDA-17, 163; SED-12, 312;
see
also Chapter 14) Isoprenaline was revisited by several authors. They concluded that it is a matter of concern that regular, excessive use of contemporary sympathomimetics has been associated with morbidity and mortality from asthma. As a consequence, restrictions on sympathomimetic usage have recently been advocated in asthma management guidelines. The association between excessive use of inhaled isoprenaline and an epidemic of asthma deaths in the 1960s provides a precedent; hence the numerous clinical and experimental reports concern-
ing isoprenaline were reviewed to provide insight into the present controversy (3c). A number of new medications for treatment of asthma and chronic obstructive pulmonary disease have been developed in recent years. However, serious issues persist in the management of these illnesses. Prevalence, morbidity, and mortality of asthma are increasing despite the introduction of these new agents. Airflow obstruction is only partially reversible in chronic obstructive pulmonary disease, and drug treatment can only partially mitigate disability. Drug toxicity is also an important concern. The five classes of agents (fl-adrenergic agonists, anticholinergic agents, theophylline, cromolyn, and corticosteroids) available for treatment were examined, emphasizing efficacy and toxicity. Less commonly used agents and newly developed compounds that are still under investigation are also discussed (4R). Determinants of acute severe asthma
A short attack duration is associated with an increased risk of near fatality in acute severe asthma. This is particularly evident in hyperacute attacks. Hyperacute attacks resolve rapidly once bronchodilator therapy has been instituted, suggesting that smooth muscle spasm is the predominant pathogenetic mechanism. The importance of routine anti-inflammatory therapy in mild to moderate asthma requires re-emphasis but, in addition, all patients should be provided with, and educated in the use of, broncholilator rescue therapy, which should be available at all times. Despite current trends the use of regular, prophylactic bronchodilator therapy in strict conjunction with anti-inflammatory agents may still be indicated. There is little evidence in the present data obtained from near-fatal cases to support the concept that cardiotoxicity related to bronchodilators contributes significantly to mortality from asthma (6c). Salmeterol (SEDA-17, 165)
Salmeterol (Serevent) is an inhaled fl2-receptor agonist with more than twelve hours' effect duration compared with 4-6 hours for the short-acting substances like salbutamol, and terbutaline. Salmeterol has been studied in several large-scale double-blind multicenter
190 studies with up to one year's duration. More than 6000 asthmatics have been treated with salmeterol during these controlled studies. All studies show salmeterol to have a significantly better and well-maintained bronchodilating effect with better asthma control, fewer asthma exacerbations, and a decreased need for rescue albuterol inhalations used on demand compared to treatments in the control groups ( 2 0 0 4 0 0 / t g albuterol q.i.d., inhaled albuterol given only p.r.n., terbutaline given regularly, or individually titrated slow-release theophylline). Salmeterol should be given b.i.d, and in combination with inhaled corticosteroids (7c). In another study a low prevalence of mild side effects was observed in subjects treated with 100 ~tg, but not with 50 p g b.i.d., of inhaled salmeterol. Thus, salmeterol, taken twice daily, can control asthma and prevent exacerbations, reducing morbidity and improving the quality of life; the long duration of action of salmeterol can allow the change from symptomatic to prophylactic use of the new fl2-agonist; however, the exact role of this drug in the strategies of asthma treatment needs to be better clarified, in particular the interaction with inhaled anti-inflammatory drugs (8c). Cortieosteroids (SED-12, 379)
Ever since cortisone was first tried as a novel treatment for asthma over forty years ago, glucocorticoids have been recognized to be among the most effective medications for controlling asthma. Glucocorticoids do not cure asthma; they merely suppress the inflammation and the disease flares when drug administration is stopped. They do not relieve symptoms promptly; they take hours to days to be effective and they do not completely abolish airway hyper-responsiveness, although they reduce it. And most importantly, they cause unwanted adverse effects in other organs that require a careful assessment of the risk-benefit ratio. Nevertheless, they are invaluable for patients whose asthma is severe or persistent enough to interfere with ordinary activities. Preparations for aerosol administration have led to a considerable improvement in the risk-benefit ratio for chronic administration, to the extent that there now is a general consensus that they are underprescribed (9~). The influence of immunosuppressive drugs
Chapter 17 EA. Nelemans
was investigated in 11 neonates delivered from mothers after renal transplantation. There were two infants with a single, transient episodes of lymphopenia, but all were found to have normal red blood cell and platelet counts, as well as normal OKT subsets and serum IgG, IgM and IgA. There were no clinical infections. Blood cortisol levels of 6 infants measured were within normal ranges, and only one out of 8 infants measured had a low blood ACTH. Urine analysis revealed one out of 8 infants with 17-OHCS and one of 7 with 17-KS of high levels, but there were no abnormal findings (10c). Despite their diabetogenic properties, little attention has been paid to the effect of glucocorticosteroid hormones on maternal glucose tolerance during pregnancy. In healthy nonpregnant volunteers, ritodrine caused mild hyperglycemia in the range of 150 mg/dl. However, the mean glucose concentration was 200 mg/dl after simultaneous administration of 10 mg dexamethasone. A reduction in the frequency of fetal movements, suggesting fetal compromise, followed the administration of 6 mg betamethasone after the 25th week of pregnancy. This reduction was most pronounced between the 29th and the 34th gestational weeks. Later reduced activity and variability of the fetal heart rate (FHR) were also noted. However, the biophysical profile and the umbilical blood flow velocity findings remained unimpaired. The authors commented as follows: 'Perplexingly, no literature could be found on the effects of steroids on fetal behaviour' (11% Corticosteroid therapy generally is the first choice for treatment of various inflammatory disorders including polymyositis and dermatomyositis. This therapy, however, occasionally induces steroid myopathy, the clinical symptoms of which are similar to those of polymyositis and dermatomyositis. Because the dose of corticosteroid administered must be decreased as soon as possible in steroid myopathy, diagnosis of steroid myopathy early in the clinical course is crucial. The correlation between the development of steroid myopathy and the elevation of serum lactic dehydrogenase (LDH) 1, 2, and 3 isoenzymes was described (12r The changing emphasis to the earlier use of preventative anti-inflammatory therapy has resuited in a trend towards the use of increasingly
Antiallergic and antitussive drugs Chapter17 higher doses of inhaled steroids to completely suppress symptoms. Guidelines such as those issued by the British Thoracic Society suggest that in addition to stepwise increments of inhaled steroid titrated against parameters of disease activity, once adequate control has been obtained, the dose should gradually be lowered to achieve an individualized maintenance dose. Large multicenter studies are now indicated to evaluate whether the long-term use of intermediate doses (800-1600/2g daily) of inhaled corticosteroid produce significant bone loss, in particular in post-menopausal women. It might be worth exploring whether the adjunctive use of high-dose inhaled corticosteroids in addition to systemic corticosteroids, in acute asthma might allow a lower dose of the latter to be used, which may be relevant in the light of recent findings that even a short course of systemic corticosteroid produces significant effects on bone turnover. The next decade of research into the use of inhaled corticosteroids in asthma is, therefore, awaited with keen interest and hopefully may answer some important unresolved questions (13R).
Beclomethasone dipropionate ( SED-12, 379) In patients stressed by uncontrolled asthma, the antiasthmatic effect of high dose beclomethasone dipropionate and budesonide was accompanied by a significant initial decrease in insulin resistance with a parallel improvement in glucose tolerance. During prolonged treatment a small increase in insulin sensitivity was found. The overall effect of beclomethasone dipropionate and budesonide inhalations on carbohydrate metabolism may be beneficial in patients with uncontrolled asthma (14c).
Dexamethasone (SED-12, 981; SEDA-17, 445) Knemometry has been used to measure lower leg growth during 32 nine day courses of deaxamethasone in 26 babies with gestational age ranging from 24 to 32 weeks. Mean leg length velocity was 0.37 mm/day in the 10 days before steroids. Administration of dexamethasone was associated with a decrease in velocity in all babies, and in 15 leg shortening was documented. Mean leg length velocity during steroid treatment was ~0.003 mm/day (15c).
19t
Fluticasone propionate Two hundred and fifty-one patients, aged 16 years and over, with perennial rhinitis were recruited to this multicenter, randomized, double-blind, parallel group study. One hundred and fifty-nine patients received fluticasone propionate (200 g) aqueous nasal spray (FPANS) twice daily, and 83 patients received beclomethasone dipropionate 200 pg) aqueous nasal spray (BDPANS) twice daily. After 1 year of treatment, nasal blockage (P = 0.002), nasal discharge (P = 0.002) and eye watering/irritation (P = 0.048) were significantly improved in patients treated with FPANS twice daily, compared to patients treated with BDPANS twice daily. The symptom grades for nasal itching (P = 0.052) were improved in the FPANS group, but just failed to attain statistical significance at the 5% level. The symptom grades for sneezing tended to be better for the FPANS group, but the difference was not statistically significant. Assessments of changes in the findings during nasal examination (rhinoscopy) and in hematological, biochemical and urinary parameters, and measurements of plasma cortisol levels during the one year of treatment with the study drugs, showed that there were no clinically significant differences between the two treatment groups and that the study drugs were equally well tolerated. This study indicates that long-term use of FPANS provides better relief than BDPANS for most of the symptoms of perennial rhinitis (16c). In an other study the treatment comparison of beclomethasone with fluticasone showed a significant difference (P = 0.045) in favor of beclomethasone but both means were within the normal range. This treatment difference was judged not to be of clinical importance. There were no consistent changes in biochemical or hematological parameters on either treatment. During the long-term part of this study there were 431 and 229 adverse events during treatment with fluticasone propionate and beclomethasone dipropionate in 59 and 63% of patients respectively. These included serious adverse events in 14 and 15% for fluticasone propionate and beclomethasone dipropionate respectively, leading to 11% of patients withdrawing in both groups. The investigators judged that 12 and 11% of the reports in the fluticasone propionate and be-
192 clomethasone dipropionate groups, respectively, were drug-related. No clinically relevant changes in weight, pulse rate or systolic or diastolic blood pressure were detected. The results of the short-term phase of the study demonstrated that fluticasone propionate 500 Bg/day administered as a dry powder formulation via Diskhaler or via pressurized inhaler was equal in terms of therapeutic effect to 1000 /.tg/day beclomethasone dipropionate administered as a pressurized inhaler in the treatment of moderate asthma (17c).
Chapter 17 EA. Nelemans
differences in other side effects (medication run-off, BDAS > TAA and medication induced sneezing, TAA >BDAS). Both once daily TAA and twice daily BDAS were found to be effective therapies for allergic rhinitis, but TAA provided somewhat greater relief as evidenced by significantly higher patients' global evaluation scores along with a numeric trend towards greater improvements in physicians' global evaluations and primary nasal symptoms. The treatments had equally favorable irritation profiles and other side effects were generally minor (19c).
Hydrocortisone sodium hemisuccinate Prednisoione
A 32-year-old male with aspirin sensitivity was treated for moderate wheezing with 200 mg Solu-Cortef given intravenously. After this treatment, his condition deteriorated acutely and he was admitted to hospital. Intradermal skin tests revealed positive immediate reactions to Solu-Coretef, Saxizon, Solu-Medrol and Predonine. Challenge tests with 100 mg SoluCortef and Saxizon injection showed 34% and 27% decrease, respectively in FEV 1 15 min after injection. These results suggest that succinylation of steroids resulted in allergic reaction to steroids in this patient (18c). Triamcinolone acetonide
In a randomized, single-blind study, two intranasal corticoid preparations were compared for efficacy and specific side effects in the treatment of perennial allergic rhinitis. One hundred and sixty-nine patients received either once daily triamcinolone acetonide aerosol (TAA, Nasacort | at 220 Bg/day or twice daily beclomethasone dipropionate monohydrate aqueous spray (BDAS, Beconase AQ | at 168 ~tg/day in parallel fashion for four weeks. Efficacy was assessed by patients' and physicians' overall ratings, along with daily ratings of rhinitis symptoms. Specific side effect items indicative of nasal irritation (4 items), other nasopharyngeal effects (3 items), and other medication effects (3 items) were rated daily. Once daily TAA produced greater improvements in symptoms (NS), physicians' global evaluations (NS), and patients' global evaluations (P<0.05) compared to twice daily BDAS. There were no differences in nasal irritation side effects, but there were significant
A patient with spinal cord compression due to corticosteroid-induced epidural lipomatosis was reported. His predisolone treatment was replaced by hydrocortisone (20 mg/day), and betamethasone enemas were given at wider intervals (2 to 3/week). The patient was put on a low-calorie, low-simple carbohydrate, highprotein diet. Six weeks later he had lost 13 kg and was able to walk unassisted. Cushing syndrome-like features were noticeably improved, and muscle strength was rated 4+. The accumulation of epidural fat behind the spinal cord was still visible on sagittal magnetic resonance imaging sections obtained after three months, but on axial sections flatting of the cord was less marked and the anterior contour of the fat deposit was concave instead of convex. The follow-up CT scan showed a marked reduction in mediastinal fat. One year after the beginning of treatment, spinal cord imaging yielded normal findings (22c). A 40-year-old female presented with diplopia retrobulbar pain and blepharoptosis in her left eye. Examinations showed ipsilateral palsies of oculomotor, trochlear and abducens nerves. She was diagnosed as having TolosaHunt syndrome. The clinical symptoms disappeared after diagnostic-therapeutic systemic prednisolone but ophthalmoplegia recurred after tapering of medication. After reinstitution of prednisolone therapy at a higher dose, she developed fever and severe headache. Bacterial meningitis was diagnosed after lumbar puncture. Only slight abducens palsy remained after 1 month of systemic antibiotics, but with computed tomography a brain abscess in the occipital lobe was shown. Aspiration of the pus
Antiallergic and antitussive drugs Chapter 17 was performed. She was cured leaving right homonymous hemianopia. The possibility of infection has to be borne in mind when attempting systemic corticosteroid therapy for Tolosa-Hunt syndrome (20c). Bone mineral density (BMD) of the lumbar spine (L2-L4) was measured using dual-energy X-ray absorptiometry (DEXA), and its relationship to total dose of prednisolone and duration of prednisolone therapy was studied in 57 patients with bronchial asthma. There was a significant negative correlation between BMD and total dose of prednisolone (r = -0.463, P <0.001) and beween BMD and duration of prednisolone treatment (r = -0.30, P < 0.05). The half-yearly percent decrease of BMD measured in 17 asthmatic patients was 0.83% (P <0.01) after correction for ageassociated decline. These findings suggest that the reduction of BMD was related to the total dose of prednisolone and the duration of therapy in asthmatics (21c).
Immunotherapy Sixty patients with rhinitis and/or asthma, who had shown symptoms at least during the last two grass pollen seasons were selected. All patients showed positive skin and conjunctival tests to Phleum pratense and IgE against this pollen. Immunotherapy was carried out with a biologically standardized extract of P pratense absorbed on aluminum hydroxide gel (Pangramin Depot-B.U.). Forty-four of the treated patients finished the study: 26 in the perennial group and 18 in the seasonal group. In the first group, dropouts were due to a new sensitization (Alternaria) in 1 case, 1 patient changed residence and the remaining 3 patients withdrew from the study for no apparent reason. In the seasonal group, dropouts were due to pregnancy in 2 cases, 1 case of new sensitization (mites) 1 patient changed residence, 1 reported non-specific symptoms on immunotherapy and another withdrew due to lack of efficacy of treatment. The remaining 6 cases withdrew from the study for no apparent reason. None of the patients included in the control group withdrew from the study. The groups were homogeneous regarding age, sex, diagnosis and duration of disease (23c).
193 EXPECTORANT DRUGS
AND MUCOLYTIC
MISCELLANEOUS
Ambroxol (SEDA-13, 136; SEDA 16, 170) Of 48 patients from 8 institutions treated with ambroxol, 47 were subjected to analysis in accordance with selective criteria. Especially, for 'clearing the throat of phlegm', considered to be one of the most important subjective symptoms, 74.5% of the patients showed over one-step improvement compared with the control period. All patients considered the capsule to be 'good' mainly because it was 'easily swallowable', 'convenient', and 'sanitary'. With regard to the taste of the solution, 34.0% of the patients responded 'it can be swallowed as a medicine' and 6.4% responded 'it is extremely difficult to swallow'. Therefore further improvement of the solution is required. In all, 91.5% found the odor to be 'palatable' or 'good'. Only one patient suffered epigastric distress as a side effect. However, reduction of the dose enabled continuation of the medication in this case. No abnormal laboratory findings that could be ascribed to the drug were noted. The results suggest that the ambroxol solution capsule is safe and is a useful expectorant for patients with chronic respiratory diseases, and that its capsule form contributes to the maintenance of the dosage schedule (24c). Surfactants (SEDA-17, 211) The results of the Treatment Investigational New Drug (TIND) protocol revealed no new safety concerns associated with the widespread use of Survanta and confirmed the safety profile established in earlier controlled trials. Overall and within both prevention and rescue strategies, the percent of neonates surviving was the same as in the controlled clinical trials. Overall survival was 84.4%, compared with 84.0% for Survanta-treated neonates in the controlled trials. As expected, survival decreased with decreasing birth weight. With the large number of study centers involved, the overall incidence of concurrent diagnosis probably represents an accurate clinical picture of
194 current n e o n a t a l practice. P a t e n t ductus arteriosus, p u l m o n a r y h e m o r r h a g e , a n d p u l m o n a r y air leaks were less frequent overall in the T I N D program. T h e incidence of a n y I C H (intracranial h e m o r r h a g e ) was substantially lower in the T I N D p r o g r a m (28.9%) t h a n in the controlled trials (45.4%), as was severe I C H (13.3% vs. 22.5%). By weight group, n e o n a t e s in the T I N D p r o g r a m consistently h a d lower rates of I C H t h a n n e o n a t e s in the controlled trials. B r o n c h o p u l m o n a r y dysplasia ( B D P ) was also
Chapter 17 EA. Nelemans lower in the T I N D program, as was a combined measure o f either d e a t h or B D P at 28 days. Also lower were PIE a n d b o t h p r e t r e a t m e n t a n d p o s t t r e a t m e n t sepsis, with a p o s t t r e a t m e n t sepsis incidence of only 14.8%. According to the F o o d a n d D r u g A d m i n i s t r a t i o n ( F D A ) more t h a n 8000 n e o n a t e s were treated with S u r v a n t a u n d e r the T I N D p r o g r a m (25c). F o r cross reference to respiratory stimulants a n d a report o n theophylline, see C h a p t e r 1.
REFERENCES 1. Sitar DS, Aoki FY, Warren CP, Knight A (1993) A placebo-controlled dose-finding study with bambuterol in elderly patients with asthma. Chest, 103, 711-776. 2. Petrie GR, Chookang JY, Hassan WU (1993) Bambuterol: Effective in nocturnal asthma. Respir. Med., 87, 581 585. 3. Hansel TT, Schwartz F, Villiger B, Morley J (1993) Isoprenaline revised: Adverse effects of sympathomimetics in asthma. Agents Actions, 43 (Suppl.), 271-280. 4. Skorodin MS (1993) Pharmacotherapy for asthma and chronic obstructive pulmonary disease: Current thinking, practices, and controversies. Arch. Intern. Meal, 153, 814-828. 5. Flugleholm AM, Ibsen TB, Laxmyr L, Svendsen U (1993) Therapeutic equivalence between bambuterol, 10 mg once daily, and terbutaline controlled release, 5 mg twice daily, in mild to moderate asthma. Eur Resp. J., 6, 1474-1478. 6. Kallenbach JM, Frankel AH, Lapinsky SE (1993) Determinants of near fatality in acute severe asthma. Am. J. Med., 95, 265-272. 7. L6tvall J, Svedmyr N (1993) Salmeterol: An inhaled fl2-agonist with prolonged duration of action. Lung, 171, 249 264. 8. Paggiaro PL, Giannini D, Bacci E, Vagaggini B (1993) Clinical effects of salmeterol: A new longacting fl2-agonist. Eur Resp. Rev., 3, 319395. 9. Reed CE (1993) Glucocorticoids in asthma. Immunol. Allergy Clin. North Am., 13, 903-915. 10. Nishimura A, Matsuo Y, Tsujii H, Hasegawa K (1993) Neonates delivered from mothers who received treatment with immunosuppressive drugs after renal transplantation. Acta Neonatol. Jpn., 29, 371 375. I I. Iffy L, Evans H, Zentay Z, Ganesh V, Ayala I (1993) Fetal effect of corticosteroid-induced maternal hyperglycemia. Isr J. Med. Sci., 29, 650 653. 12. Kaneko K, Yamazaki O, Miyatake T (1993)
Correlation beween steroid myopathy and the elevated serum lactic dehydrogenase (LDH) l, 2, and 3 isoenzymes. Muscle Nerv., 16, 1135 1136. 13. Lipworth BJ (1993) Clinical pharmacology of corticosteroids in bronchial asthma. Pharmacol. Ther, 58, 173-209. 14. Kiviranta K, Turpeinen M (1993) Effect of eight months of inhaled beclomethasone dipropionate and budesonide on carbohydrate metabolism in adults with asthma. Thorax, 48, 974-978. 15. Gibson AT, Pearse RG, Wales JKH (1993) Growth retardation after dexamethasone administration: assessment by knemometry. Arch. Dis. Child., 69, 505-509. 16. Haye R, Gomez EG (1993) A multicentre study to assess long-term use of fluticasone propionate aqueous nasal spray in comparison with beclomethasone dipropionate aqueous nasal spray in the treatment of perennial rhinitis. Rhinology, 31, 169174. 17. Lundback B, Alexander M, Day J, Hebert J (1993) Evaluation of fluticasone propionate (500/lg day --~) administered either as dry powder via a Diskhaler| inhaler or pressurized inhaler and compared with beclomethasone dipropionate (1000 ~tg day--I). Respir. Med. 87, 609-620. 18. Yoshikawa T, Iida Y, Horiuchi I, Inaha S, Terai T (1993) Bronchospasms caused by intravenous hydrocortisone sodium hemisuccinate (Solucortef) in an apirin-sensitive astmatic patient. Jpn. J. Thorac. Dis., 31, 1024-1028. 19. Winder J, Bell T, Brodsky L, English G (1993) A comparative study of intranasal triamcinolone acetonide aerosol and intranasal beclomethasone dipropionate aqueous spray in perennial allergic rhinitis. Immunol. Allergy Pract., 15, 203-209. 20. Zakou M, Arai M, Kubo R, Ohzuno I (1993) Brain abscess developed following systemic corticosteroid therapy in a case of Tolosa Hunt syndrome. Jpn. J. Clin. Ophthalmol., 47, 1657 1661. 21. Doi Y, Suzuki K, Tanaka M, Fujieda K, Ito T (1993) Measurement of bone mineral density
Antiallergic and antitussive drugs
Chapter 17
using dual energy X ray absorptiometry in asthmatic patients receiving prednisolone. Jpn. J. Thorac Dis., 31, 1385 1389. 22. Laroche F, Chemouilli P, Carlier R, Lebras P (1993) Efficacy of conservative treatment in a patient with spinal cord compression due to corticosteroid-induced epidural lipomatosis. Rev. Rhurn. Engl. Ed., 60, 729-731. 23. Munoz-Lejarazu D, Bernaola G, Fernandez E (1993) Seasonal versus perennial immunotherapy:
195 evaluation after three years of treatment. J. Invest. Allergol. Clin. Immunol., 3, 210~216. 24. Okubo T (1993) Clinical evaluation of ambroxol hydrochloride solution capsule for expectoration of sputum in patients with chronic respiratory disease. Ther. Res., 14, 319-344. 25. Zola EM, Overbach AM, Gunkel JH, Mitchell B (1993) Treatment investigational new drug experience with Survanta (beractant). Pediatrics, 91, 54(~ 551.
17
Antiallergic and antitussive drugs
Several drugs used in bronchial asthma and cough are dealt with in other chapters. These include xanthine compounds (Chapter 1), the opiates and derivatives such as dextromethorphan (Chapter 8), the parasympatholytic agents (Chapter 14), the antihistamines (Chapter 16) and the corticosteroids (Chapter 41). Editorial note
DRUGS USED IN BRONCHIAL A S T H M A A N D A L L E R G Y (SED-11,
322; SEDA-12, 144; SEDA-13, 134; SEDA-14, 139; SEDA-15, 161; SEDA-16, 167," SEDA-17, 205; SED-12, 374) Terbutaline (SEDA-1L 165; SED-12, 321) Bambuterol ( SED-12, 269)
Bambuterol was tested in a randomized, crossover, and double-blind study in elderly asthmatic patients aged 64 to 82 years (n = 81). They received placebo and 5 mg, 10 mg, 20 mg tablets once daily for a week at each dose. The plasma concentration of the active metabolite, terbutaline, increased linearly with the dose of drug (P <0.001). Peak expiratory flow rate increased with dose in the morning (P < 0.001 for 10 mg and 20 mg doses) and afternoon (P <0.05 for 10 mg; P <0.001 for 20 mg) and was different from placebo for 10 mg/day and 20 mg/day regimens. The use of supplemental inhaled fl2-adrenergic agonist therapy was reduced during the night for the I0 mg (P < 0.05) and 20 mg (P < 0.01) doses in comparison to placebo. No significant effects of treatment on blood pressure and pulse were demonstrated. 9 1995 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs Annual 18 J.K. Aronson and C.J. van Boxtel, eds.
188
Tremor and palpitations were mild and related to the dose. These data suggest that treatment once daily with bambuterol hydrochloride in a dose of 10 or 20 mg improves pulmonary function and is well tolerated as brochodilator therapy in elderly patients with asthma (lC). In an other study bambuterol was compared with placebo in 28 patients with nocturnal asthma in a randomized, double-blind crossover study. All patients were symptomatic despite taking inhaled fl2-agonists, inhaled corticosteroids (in 26 patients the median daily dose was 1500 ag) and oral corticosteroids (in eight patients the median daily dose was 10 mg). Patients demonstrated - 2 0 % overnight fall in peak expiratory flow (PEF) for at least half of the 14-day run-in period. They then entered two treatment periods lasting 14 days when bambuterol 20 mg nocte and placebo were given in random order. Compared to placebo, bambuterol produced a 16% improvement in mean PEF on walking (271 l/min vs. 239 1/min P = 0.0002) and a 10% improvement in evening PEF measured 24 h after drug intake (318 l/rain vs. 296 1/min P = 0.01). Bambuterol significantly reduced frequency of nocturnal awakening from 1.1 to 0.7 per night (P = 0.01) and nocturnal flz-agonist use from 2.7 to 2.1 puffs (P = 0.0004). Other nocturnal symptoms: cough, wheeze and dyspnea were also significantly reduced during bambuterol treatment and patients' quality of sleep was improved. The results indicate bambuterol (20 mg nocte) provides effective nocturnal bronchodilation with sustained effect for 24 h and may have a useful therapeutic role in the control of symptomatic nocturnal asthma. Patients with asthma often experience worsening of their symptoms and reduction in airway function in the early hours of the morning (1, 2), with 75% of asthmatics suffering from sleep disturbance from time to time. Additionally, asthmatic deaths and respiratory arrests occur more frequently during the night. The precise
Antiallergic and antitussive drugs Chapter 17
189
mechanism of this is unknown but is likely to be multifactorial (3 c, 4R). Nocturnal symptoms may remain troublesome and interfere with quality of sleep despite the use of inhaled fl-agonist and inhaled corticosteroids (2c). Bambuterol is the first long-acting oral fl2agonist with a 24 h effective duration. In order to investigate the possibility of replacing established treatment modalities with bambuterol once daily, the bronchodilating and tremorogenic effects of bambuterol, 10 mg once daily, and terbutaline, 5 mg controlled-release (CR) tablets twice daily, was compared. The study was of a double-blind, double-dummy, randomized, cross-over design and involved two, two week treatment periods, separated by one week wash-out period. PEF recorded in patients' diaries was the primary efficacy variable. Seventy adult, asthmatic out-patients with mild to moderate asthma were included (forced expiratory volume in one second (FEV 1) -> 50% predicted). After treatment with bambuterol, mean morning and evening PEF (S.D.) were 347 (122) and 365 (121) l/min, respectively and 346 (121) and 365 l/min, respectively, after treatment with terbutaline. FEV 1 (S.D.) was 2.21 (0.91) 1 and 2.27 (0.93) 1 after bambuterol and terbutaline treatments, respectively. Tremor scores tended to be lower during treatment with bambuterol, although not significantly so. Tremor scores were low, in general. In conclusion, no difference in the bronchoditating effect was demonstrated between bambuterol, 10 mg once daily, and controlled release terbutaline, 5 mg twice daily. A tendency towards less tremor was seen with bambuterol (5c). Isoprenaline (SEDA-17, 163; SED-12, 312;
see
also Chapter 14) Isoprenaline was revisited by several authors. They concluded that it is a matter of concern that regular, excessive use of contemporary sympathomimetics has been associated with morbidity and mortality from asthma. As a consequence, restrictions on sympathomimetic usage have recently been advocated in asthma management guidelines. The association between excessive use of inhaled isoprenaline and an epidemic of asthma deaths in the 1960s provides a precedent; hence the numerous clinical and experimental reports concern-
ing isoprenaline were reviewed to provide insight into the present controversy (3c). A number of new medications for treatment of asthma and chronic obstructive pulmonary disease have been developed in recent years. However, serious issues persist in the management of these illnesses. Prevalence, morbidity, and mortality of asthma are increasing despite the introduction of these new agents. Airflow obstruction is only partially reversible in chronic obstructive pulmonary disease, and drug treatment can only partially mitigate disability. Drug toxicity is also an important concern. The five classes of agents (fl-adrenergic agonists, anticholinergic agents, theophylline, cromolyn, and corticosteroids) available for treatment were examined, emphasizing efficacy and toxicity. Less commonly used agents and newly developed compounds that are still under investigation are also discussed (4R). Determinants of acute severe asthma
A short attack duration is associated with an increased risk of near fatality in acute severe asthma. This is particularly evident in hyperacute attacks. Hyperacute attacks resolve rapidly once bronchodilator therapy has been instituted, suggesting that smooth muscle spasm is the predominant pathogenetic mechanism. The importance of routine anti-inflammatory therapy in mild to moderate asthma requires re-emphasis but, in addition, all patients should be provided with, and educated in the use of, broncholilator rescue therapy, which should be available at all times. Despite current trends the use of regular, prophylactic bronchodilator therapy in strict conjunction with anti-inflammatory agents may still be indicated. There is little evidence in the present data obtained from near-fatal cases to support the concept that cardiotoxicity related to bronchodilators contributes significantly to mortality from asthma (6c). Salmeterol (SEDA-17, 165)
Salmeterol (Serevent) is an inhaled fl2-receptor agonist with more than twelve hours' effect duration compared with 4-6 hours for the short-acting substances like salbutamol, and terbutaline. Salmeterol has been studied in several large-scale double-blind multicenter
190 studies with up to one year's duration. More than 6000 asthmatics have been treated with salmeterol during these controlled studies. All studies show salmeterol to have a significantly better and well-maintained bronchodilating effect with better asthma control, fewer asthma exacerbations, and a decreased need for rescue albuterol inhalations used on demand compared to treatments in the control groups ( 2 0 0 4 0 0 / t g albuterol q.i.d., inhaled albuterol given only p.r.n., terbutaline given regularly, or individually titrated slow-release theophylline). Salmeterol should be given b.i.d, and in combination with inhaled corticosteroids (7c). In another study a low prevalence of mild side effects was observed in subjects treated with 100 ~tg, but not with 50 p g b.i.d., of inhaled salmeterol. Thus, salmeterol, taken twice daily, can control asthma and prevent exacerbations, reducing morbidity and improving the quality of life; the long duration of action of salmeterol can allow the change from symptomatic to prophylactic use of the new fl2-agonist; however, the exact role of this drug in the strategies of asthma treatment needs to be better clarified, in particular the interaction with inhaled anti-inflammatory drugs (8c). Cortieosteroids (SED-12, 379)
Ever since cortisone was first tried as a novel treatment for asthma over forty years ago, glucocorticoids have been recognized to be among the most effective medications for controlling asthma. Glucocorticoids do not cure asthma; they merely suppress the inflammation and the disease flares when drug administration is stopped. They do not relieve symptoms promptly; they take hours to days to be effective and they do not completely abolish airway hyper-responsiveness, although they reduce it. And most importantly, they cause unwanted adverse effects in other organs that require a careful assessment of the risk-benefit ratio. Nevertheless, they are invaluable for patients whose asthma is severe or persistent enough to interfere with ordinary activities. Preparations for aerosol administration have led to a considerable improvement in the risk-benefit ratio for chronic administration, to the extent that there now is a general consensus that they are underprescribed (9~). The influence of immunosuppressive drugs
Chapter 17 EA. Nelemans
was investigated in 11 neonates delivered from mothers after renal transplantation. There were two infants with a single, transient episodes of lymphopenia, but all were found to have normal red blood cell and platelet counts, as well as normal OKT subsets and serum IgG, IgM and IgA. There were no clinical infections. Blood cortisol levels of 6 infants measured were within normal ranges, and only one out of 8 infants measured had a low blood ACTH. Urine analysis revealed one out of 8 infants with 17-OHCS and one of 7 with 17-KS of high levels, but there were no abnormal findings (10c). Despite their diabetogenic properties, little attention has been paid to the effect of glucocorticosteroid hormones on maternal glucose tolerance during pregnancy. In healthy nonpregnant volunteers, ritodrine caused mild hyperglycemia in the range of 150 mg/dl. However, the mean glucose concentration was 200 mg/dl after simultaneous administration of 10 mg dexamethasone. A reduction in the frequency of fetal movements, suggesting fetal compromise, followed the administration of 6 mg betamethasone after the 25th week of pregnancy. This reduction was most pronounced between the 29th and the 34th gestational weeks. Later reduced activity and variability of the fetal heart rate (FHR) were also noted. However, the biophysical profile and the umbilical blood flow velocity findings remained unimpaired. The authors commented as follows: 'Perplexingly, no literature could be found on the effects of steroids on fetal behaviour' (11% Corticosteroid therapy generally is the first choice for treatment of various inflammatory disorders including polymyositis and dermatomyositis. This therapy, however, occasionally induces steroid myopathy, the clinical symptoms of which are similar to those of polymyositis and dermatomyositis. Because the dose of corticosteroid administered must be decreased as soon as possible in steroid myopathy, diagnosis of steroid myopathy early in the clinical course is crucial. The correlation between the development of steroid myopathy and the elevation of serum lactic dehydrogenase (LDH) 1, 2, and 3 isoenzymes was described (12r The changing emphasis to the earlier use of preventative anti-inflammatory therapy has resuited in a trend towards the use of increasingly
Antiallergic and antitussive drugs Chapter17 higher doses of inhaled steroids to completely suppress symptoms. Guidelines such as those issued by the British Thoracic Society suggest that in addition to stepwise increments of inhaled steroid titrated against parameters of disease activity, once adequate control has been obtained, the dose should gradually be lowered to achieve an individualized maintenance dose. Large multicenter studies are now indicated to evaluate whether the long-term use of intermediate doses (800-1600/2g daily) of inhaled corticosteroid produce significant bone loss, in particular in post-menopausal women. It might be worth exploring whether the adjunctive use of high-dose inhaled corticosteroids in addition to systemic corticosteroids, in acute asthma might allow a lower dose of the latter to be used, which may be relevant in the light of recent findings that even a short course of systemic corticosteroid produces significant effects on bone turnover. The next decade of research into the use of inhaled corticosteroids in asthma is, therefore, awaited with keen interest and hopefully may answer some important unresolved questions (13R).
Beclomethasone dipropionate ( SED-12, 379) In patients stressed by uncontrolled asthma, the antiasthmatic effect of high dose beclomethasone dipropionate and budesonide was accompanied by a significant initial decrease in insulin resistance with a parallel improvement in glucose tolerance. During prolonged treatment a small increase in insulin sensitivity was found. The overall effect of beclomethasone dipropionate and budesonide inhalations on carbohydrate metabolism may be beneficial in patients with uncontrolled asthma (14c).
Dexamethasone (SED-12, 981; SEDA-17, 445) Knemometry has been used to measure lower leg growth during 32 nine day courses of deaxamethasone in 26 babies with gestational age ranging from 24 to 32 weeks. Mean leg length velocity was 0.37 mm/day in the 10 days before steroids. Administration of dexamethasone was associated with a decrease in velocity in all babies, and in 15 leg shortening was documented. Mean leg length velocity during steroid treatment was ~0.003 mm/day (15c).
19t
Fluticasone propionate Two hundred and fifty-one patients, aged 16 years and over, with perennial rhinitis were recruited to this multicenter, randomized, double-blind, parallel group study. One hundred and fifty-nine patients received fluticasone propionate (200 g) aqueous nasal spray (FPANS) twice daily, and 83 patients received beclomethasone dipropionate 200 pg) aqueous nasal spray (BDPANS) twice daily. After 1 year of treatment, nasal blockage (P = 0.002), nasal discharge (P = 0.002) and eye watering/irritation (P = 0.048) were significantly improved in patients treated with FPANS twice daily, compared to patients treated with BDPANS twice daily. The symptom grades for nasal itching (P = 0.052) were improved in the FPANS group, but just failed to attain statistical significance at the 5% level. The symptom grades for sneezing tended to be better for the FPANS group, but the difference was not statistically significant. Assessments of changes in the findings during nasal examination (rhinoscopy) and in hematological, biochemical and urinary parameters, and measurements of plasma cortisol levels during the one year of treatment with the study drugs, showed that there were no clinically significant differences between the two treatment groups and that the study drugs were equally well tolerated. This study indicates that long-term use of FPANS provides better relief than BDPANS for most of the symptoms of perennial rhinitis (16c). In an other study the treatment comparison of beclomethasone with fluticasone showed a significant difference (P = 0.045) in favor of beclomethasone but both means were within the normal range. This treatment difference was judged not to be of clinical importance. There were no consistent changes in biochemical or hematological parameters on either treatment. During the long-term part of this study there were 431 and 229 adverse events during treatment with fluticasone propionate and beclomethasone dipropionate in 59 and 63% of patients respectively. These included serious adverse events in 14 and 15% for fluticasone propionate and beclomethasone dipropionate respectively, leading to 11% of patients withdrawing in both groups. The investigators judged that 12 and 11% of the reports in the fluticasone propionate and be-
192 clomethasone dipropionate groups, respectively, were drug-related. No clinically relevant changes in weight, pulse rate or systolic or diastolic blood pressure were detected. The results of the short-term phase of the study demonstrated that fluticasone propionate 500 Bg/day administered as a dry powder formulation via Diskhaler or via pressurized inhaler was equal in terms of therapeutic effect to 1000 /.tg/day beclomethasone dipropionate administered as a pressurized inhaler in the treatment of moderate asthma (17c).
Chapter 17 EA. Nelemans
differences in other side effects (medication run-off, BDAS > TAA and medication induced sneezing, TAA >BDAS). Both once daily TAA and twice daily BDAS were found to be effective therapies for allergic rhinitis, but TAA provided somewhat greater relief as evidenced by significantly higher patients' global evaluation scores along with a numeric trend towards greater improvements in physicians' global evaluations and primary nasal symptoms. The treatments had equally favorable irritation profiles and other side effects were generally minor (19c).
Hydrocortisone sodium hemisuccinate Prednisoione
A 32-year-old male with aspirin sensitivity was treated for moderate wheezing with 200 mg Solu-Cortef given intravenously. After this treatment, his condition deteriorated acutely and he was admitted to hospital. Intradermal skin tests revealed positive immediate reactions to Solu-Coretef, Saxizon, Solu-Medrol and Predonine. Challenge tests with 100 mg SoluCortef and Saxizon injection showed 34% and 27% decrease, respectively in FEV 1 15 min after injection. These results suggest that succinylation of steroids resulted in allergic reaction to steroids in this patient (18c). Triamcinolone acetonide
In a randomized, single-blind study, two intranasal corticoid preparations were compared for efficacy and specific side effects in the treatment of perennial allergic rhinitis. One hundred and sixty-nine patients received either once daily triamcinolone acetonide aerosol (TAA, Nasacort | at 220 Bg/day or twice daily beclomethasone dipropionate monohydrate aqueous spray (BDAS, Beconase AQ | at 168 ~tg/day in parallel fashion for four weeks. Efficacy was assessed by patients' and physicians' overall ratings, along with daily ratings of rhinitis symptoms. Specific side effect items indicative of nasal irritation (4 items), other nasopharyngeal effects (3 items), and other medication effects (3 items) were rated daily. Once daily TAA produced greater improvements in symptoms (NS), physicians' global evaluations (NS), and patients' global evaluations (P<0.05) compared to twice daily BDAS. There were no differences in nasal irritation side effects, but there were significant
A patient with spinal cord compression due to corticosteroid-induced epidural lipomatosis was reported. His predisolone treatment was replaced by hydrocortisone (20 mg/day), and betamethasone enemas were given at wider intervals (2 to 3/week). The patient was put on a low-calorie, low-simple carbohydrate, highprotein diet. Six weeks later he had lost 13 kg and was able to walk unassisted. Cushing syndrome-like features were noticeably improved, and muscle strength was rated 4+. The accumulation of epidural fat behind the spinal cord was still visible on sagittal magnetic resonance imaging sections obtained after three months, but on axial sections flatting of the cord was less marked and the anterior contour of the fat deposit was concave instead of convex. The follow-up CT scan showed a marked reduction in mediastinal fat. One year after the beginning of treatment, spinal cord imaging yielded normal findings (22c). A 40-year-old female presented with diplopia retrobulbar pain and blepharoptosis in her left eye. Examinations showed ipsilateral palsies of oculomotor, trochlear and abducens nerves. She was diagnosed as having TolosaHunt syndrome. The clinical symptoms disappeared after diagnostic-therapeutic systemic prednisolone but ophthalmoplegia recurred after tapering of medication. After reinstitution of prednisolone therapy at a higher dose, she developed fever and severe headache. Bacterial meningitis was diagnosed after lumbar puncture. Only slight abducens palsy remained after 1 month of systemic antibiotics, but with computed tomography a brain abscess in the occipital lobe was shown. Aspiration of the pus
Antiallergic and antitussive drugs Chapter 17 was performed. She was cured leaving right homonymous hemianopia. The possibility of infection has to be borne in mind when attempting systemic corticosteroid therapy for Tolosa-Hunt syndrome (20c). Bone mineral density (BMD) of the lumbar spine (L2-L4) was measured using dual-energy X-ray absorptiometry (DEXA), and its relationship to total dose of prednisolone and duration of prednisolone therapy was studied in 57 patients with bronchial asthma. There was a significant negative correlation between BMD and total dose of prednisolone (r = -0.463, P <0.001) and beween BMD and duration of prednisolone treatment (r = -0.30, P < 0.05). The half-yearly percent decrease of BMD measured in 17 asthmatic patients was 0.83% (P <0.01) after correction for ageassociated decline. These findings suggest that the reduction of BMD was related to the total dose of prednisolone and the duration of therapy in asthmatics (21c).
Immunotherapy Sixty patients with rhinitis and/or asthma, who had shown symptoms at least during the last two grass pollen seasons were selected. All patients showed positive skin and conjunctival tests to Phleum pratense and IgE against this pollen. Immunotherapy was carried out with a biologically standardized extract of P pratense absorbed on aluminum hydroxide gel (Pangramin Depot-B.U.). Forty-four of the treated patients finished the study: 26 in the perennial group and 18 in the seasonal group. In the first group, dropouts were due to a new sensitization (Alternaria) in 1 case, 1 patient changed residence and the remaining 3 patients withdrew from the study for no apparent reason. In the seasonal group, dropouts were due to pregnancy in 2 cases, 1 case of new sensitization (mites) 1 patient changed residence, 1 reported non-specific symptoms on immunotherapy and another withdrew due to lack of efficacy of treatment. The remaining 6 cases withdrew from the study for no apparent reason. None of the patients included in the control group withdrew from the study. The groups were homogeneous regarding age, sex, diagnosis and duration of disease (23c).
193 EXPECTORANT DRUGS
AND MUCOLYTIC
MISCELLANEOUS
Ambroxol (SEDA-13, 136; SEDA 16, 170) Of 48 patients from 8 institutions treated with ambroxol, 47 were subjected to analysis in accordance with selective criteria. Especially, for 'clearing the throat of phlegm', considered to be one of the most important subjective symptoms, 74.5% of the patients showed over one-step improvement compared with the control period. All patients considered the capsule to be 'good' mainly because it was 'easily swallowable', 'convenient', and 'sanitary'. With regard to the taste of the solution, 34.0% of the patients responded 'it can be swallowed as a medicine' and 6.4% responded 'it is extremely difficult to swallow'. Therefore further improvement of the solution is required. In all, 91.5% found the odor to be 'palatable' or 'good'. Only one patient suffered epigastric distress as a side effect. However, reduction of the dose enabled continuation of the medication in this case. No abnormal laboratory findings that could be ascribed to the drug were noted. The results suggest that the ambroxol solution capsule is safe and is a useful expectorant for patients with chronic respiratory diseases, and that its capsule form contributes to the maintenance of the dosage schedule (24c). Surfactants (SEDA-17, 211) The results of the Treatment Investigational New Drug (TIND) protocol revealed no new safety concerns associated with the widespread use of Survanta and confirmed the safety profile established in earlier controlled trials. Overall and within both prevention and rescue strategies, the percent of neonates surviving was the same as in the controlled clinical trials. Overall survival was 84.4%, compared with 84.0% for Survanta-treated neonates in the controlled trials. As expected, survival decreased with decreasing birth weight. With the large number of study centers involved, the overall incidence of concurrent diagnosis probably represents an accurate clinical picture of
194 current n e o n a t a l practice. P a t e n t ductus arteriosus, p u l m o n a r y h e m o r r h a g e , a n d p u l m o n a r y air leaks were less frequent overall in the T I N D program. T h e incidence of a n y I C H (intracranial h e m o r r h a g e ) was substantially lower in the T I N D p r o g r a m (28.9%) t h a n in the controlled trials (45.4%), as was severe I C H (13.3% vs. 22.5%). By weight group, n e o n a t e s in the T I N D p r o g r a m consistently h a d lower rates of I C H t h a n n e o n a t e s in the controlled trials. B r o n c h o p u l m o n a r y dysplasia ( B D P ) was also
Chapter 17 EA. Nelemans lower in the T I N D program, as was a combined measure o f either d e a t h or B D P at 28 days. Also lower were PIE a n d b o t h p r e t r e a t m e n t a n d p o s t t r e a t m e n t sepsis, with a p o s t t r e a t m e n t sepsis incidence of only 14.8%. According to the F o o d a n d D r u g A d m i n i s t r a t i o n ( F D A ) more t h a n 8000 n e o n a t e s were treated with S u r v a n t a u n d e r the T I N D p r o g r a m (25c). F o r cross reference to respiratory stimulants a n d a report o n theophylline, see C h a p t e r 1.
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Correlation beween steroid myopathy and the elevated serum lactic dehydrogenase (LDH) l, 2, and 3 isoenzymes. Muscle Nerv., 16, 1135 1136. 13. Lipworth BJ (1993) Clinical pharmacology of corticosteroids in bronchial asthma. Pharmacol. Ther, 58, 173-209. 14. Kiviranta K, Turpeinen M (1993) Effect of eight months of inhaled beclomethasone dipropionate and budesonide on carbohydrate metabolism in adults with asthma. Thorax, 48, 974-978. 15. Gibson AT, Pearse RG, Wales JKH (1993) Growth retardation after dexamethasone administration: assessment by knemometry. Arch. Dis. Child., 69, 505-509. 16. Haye R, Gomez EG (1993) A multicentre study to assess long-term use of fluticasone propionate aqueous nasal spray in comparison with beclomethasone dipropionate aqueous nasal spray in the treatment of perennial rhinitis. Rhinology, 31, 169174. 17. Lundback B, Alexander M, Day J, Hebert J (1993) Evaluation of fluticasone propionate (500/lg day --~) administered either as dry powder via a Diskhaler| inhaler or pressurized inhaler and compared with beclomethasone dipropionate (1000 ~tg day--I). Respir. Med. 87, 609-620. 18. Yoshikawa T, Iida Y, Horiuchi I, Inaha S, Terai T (1993) Bronchospasms caused by intravenous hydrocortisone sodium hemisuccinate (Solucortef) in an apirin-sensitive astmatic patient. Jpn. J. Thorac. Dis., 31, 1024-1028. 19. Winder J, Bell T, Brodsky L, English G (1993) A comparative study of intranasal triamcinolone acetonide aerosol and intranasal beclomethasone dipropionate aqueous spray in perennial allergic rhinitis. Immunol. Allergy Pract., 15, 203-209. 20. Zakou M, Arai M, Kubo R, Ohzuno I (1993) Brain abscess developed following systemic corticosteroid therapy in a case of Tolosa Hunt syndrome. Jpn. J. Clin. Ophthalmol., 47, 1657 1661. 21. Doi Y, Suzuki K, Tanaka M, Fujieda K, Ito T (1993) Measurement of bone mineral density
Antiallergic and antitussive drugs
Chapter 17
using dual energy X ray absorptiometry in asthmatic patients receiving prednisolone. Jpn. J. Thorac Dis., 31, 1385 1389. 22. Laroche F, Chemouilli P, Carlier R, Lebras P (1993) Efficacy of conservative treatment in a patient with spinal cord compression due to corticosteroid-induced epidural lipomatosis. Rev. Rhurn. Engl. Ed., 60, 729-731. 23. Munoz-Lejarazu D, Bernaola G, Fernandez E (1993) Seasonal versus perennial immunotherapy:
195 evaluation after three years of treatment. J. Invest. Allergol. Clin. Immunol., 3, 210~216. 24. Okubo T (1993) Clinical evaluation of ambroxol hydrochloride solution capsule for expectoration of sputum in patients with chronic respiratory disease. Ther. Res., 14, 319-344. 25. Zola EM, Overbach AM, Gunkel JH, Mitchell B (1993) Treatment investigational new drug experience with Survanta (beractant). Pediatrics, 91, 54(~ 551.