Efficacy of fluticasone on cough: a randomised controlled trial.

Cough may be the consequence of bronchial hyperresponsiveness (BHR) and inflammation. This study was designed to investigate the short-term effects of an inhaled steroid (fluticasone propionate (FP)) on cough, and to determine the effects of smoking, BHR, allergy and forced expiratory volume in one second (FEV1) on the efficacy of FP. In a community-based primary healthcare centre, 135 previously healthy adults suffering from cough for > or =2 weeks were enrolled in a randomised, double-blind, placebo-controlled trial of inhaled FP 500 microg b.i.d. for 2 weeks. Participants completed daily diary cards of lower respiratory tract symptoms. The primary outcome measure was the decrease in mean total daily cough score (0-6) during the second week of treatment. In the FP group, the cough score decreased from 3.8 at baseline to mean+/-SEM 1.4+/-0.2 during the second week. In the placebo group, this decrease was from 3.8 to 1.9+/-0.1 and was statistically significantly less. A favourable effect of FP was only detectable in nonsmokers, in whom the score was 0.9 points lower compared with placebo. The clinical relevance of this finding has to be established further. Allergy, FEV1 and BHR at baseline did not affect the efficacy of FP. In conclusion, anti-inflammatory treatment with the inhaled steroid fluticasone propionate reduces cough in otherwise healthy adults who do not smoke.

Children with mild asthma: do they benefit from inhaled corticosteroids?

In children with mild asthma, who show hardly any abnormalities in pulmonary function, objective measurement of the effect of inhaled corticosteroids is difficult. The short term effect of fluticasone propionate (FP) in these children was evaluated, using both subjective and objective parameters. A total of 68 children (5-10 yrs old) were randomly assigned to either FP 250 microg or placebo twice daily as metered-dose inhaler via spacer during 12 weeks. Symptom scores, use of rescue medication, wheezing, parent global evaluation and pulmonary function tests including forced expiratory volume in one second (FEV1), peak expiratory flow (PEF) and bronchial responsiveness (provocation dose of methacholine causing a 20% fall in FEV1 (PD20)) were evaluated. FP-treated versus placebo-treated children showed significant changes in percentage symptom-free days, use of beta2-mimetics, morning and evening PEF, FEV1 % pred and wheezing. No significant improvements were found in parent global evaluation, absolute values of FEV1 nor PD20. These findings show that inhaled corticosteroids are effective in children with mild asthma. This effect can be assessed by both objective and subjective parameters. Early start of inhaled corticosteroids should be considered even when pulmonary function is normal.

Peak inspiratory flow rate and slope of the inhalation profiles in dry powder inhalers.

Aerosol delivery depends on device design and inhalation technique. In vitro device evaluations have shown that the emitted dose and fine particle mass of dry powder inhalers (DPIs) increase at high peak inspiratory flow rates (PIFR). Since the PIFR is mostly achieved after the release of the powder, slope of the pressure profile is also described as an important determinant. The aim of the present study was to assess whether the PIFR while using Diskus it and Turbuhaler it inhalers could be used to predict the slope of the inhalation pressure profile. In a group of 10 stable asthma patients and three groups (mild, moderate and severe) of 16 chronic obstructive pulmonary disease (COPD) patients, lung function was measured, and for each device, 18 inhalation profiles were recorded with the inhalation profile recorder during six sessions over 10 weeks. The values for the pressure slope and PIFR of both Diskus and Turbuhaler, were significantly correlated. The r-values were 0.865 and 0.882, respectively (p<0.01). Percentage explained variance was 74.8% for Diskus and 77.8% for Turbuhaler. Significant correlations were found between peak inspiratory flow rates and slopes. It has been shown for two different dry powder inhalers that peak inspiratory flow rate and slope correlate well in a wide range of patient groups.

Comparison of salmeterol with beclomethasone in adult patients with mild persistent asthma who are already on low-dose inhaled steroids.

Current guidelines on asthma management recommend the early use of inhaled corticosteroids. Recent studies of patients with moderate to severe asthma show that the addition of salmeterol is superior to a further increase of the steroids. In this study with adult, mild persistent asthma patients, we compared the effects of adding salmeterol 50 microg b.i.d. versus beclomethasone dipropionate (BDP) 200 microg b.i.d. (both via Diskhaler dry powder inhaler) to the low-dose inhaled steroids. A double-blind, randomized, parallel-group study was conducted with a run-in period of 2 weeks and a treatment period of 12 weeks. Patients (n = 233) were randomized with a peak expiratory flow (PEF) reversibility of 22 +/- 10% (mean +/- SD) in the run-in period. The morning PEF was 84 +/- 17% predicted and the age was 42 +/- 14 years (45% males). The average prestudy inhaled steroid dose was 361 microg daily. Within a week of salmeterol treatment the daily PEF recordings reached maximal levels. At the end of the treatment period the evening PEF remained significantly better in the salmeterol group than in the BDP group (p = 0.036). The PEFs, measured at the general practitioners' (GPs') office, were at least 95% of the predicted values and the post-salbutamol values at the end of both treatments. However, the salmeterol group had already obtained this level after 2 weeks and differed significantly from the beclomethasone group (p = 0.003 for percent predicted and p = 0.0007 for post-salbutamol PEF values). The symptom scores and the use of rescue medication showed a similar profile. Quality of life improved with both treatments, but without significant statistical differences between the groups. The frequency of adverse events, typical for beta2-agonists, was low and showed no differences between the groups. These results showed that the addition of salmeterol is at least as effective as adding beclomethasone in normalizing peak flows and improving asthma control in mild persistent asthma patients. Furthermore, salmeterol has a much faster onset of action.

Handling of a spacer (Babyhaler) for inhalation therapy in 0- to 3-year-old children.

The handling of the Babyhaler spacer for inhalation therapy in children 0-3 years old with asthma was tested and the perceptions of the investigators with the instruction of this device to the parents was investigated. It was an open, multicenter study of 182 patients with a treatment period of 2 weeks and a 2-week follow-up period. Thirty pediatricians in Dutch local and university hospitals participated. Using a standardized instruction, the purpose and the application of the Babyhaler were explained and demonstrated, and parents were asked to use the Babyhaler on their own child. The quality of the demonstration was scored and, if necessary, additional instruction was given. In the following treatment period of 2 weeks record card was completed; the convenience score of the Babyhaler and the symptom score were recorded. At the following evaluation visit the handling of the Babyhaler by the parents was re-evaluated. Eighty-nine percent of the parents could use the Babyhaler correctly after one instruction. The instructions of the Babyhaler were considered to be easy in 83% of the cases by the parents and the investigators. During the treatment period the handling score (6 = impossible to use, 1 = very easy) improved from 2.4 to 1.7. At the evaluation visit the correct use was similar to the result at the instruction visit (87%). No differences were found in the ease of handling between the three age groups (0-1, 1-2, and 2-3 years). The application of inhalation therapy via the Babyhaler was favored by 92% of the parents as compared to the former treatment method. We demonstrated that the Babyhaler is easy to use by the parents and that the instruction of the device by practitioners is also perceived as easy.

Pharmacological profile of a chromanamine analogue (DP-6OH-3CA) of the selective presynaptic dopamine agonist N,N-dipropyl-7-hydroxy-2-aminotetralin.

The pharmacological profile of an oxygen isostere of the selective presynaptic dopamine agonist DP-7OH-AT, i.e. dipropyl-6-hydroxy-3-chromanamine (DP-6OH-3CA) has been evaluated in various receptor binding, neurobiochemical and behavioural experiments. The chromanamine displaced the 3H-labelled dopamine ligands, 5,6-DPAT and N-0437, with Ki values of 106 and 143 nM, respectively. In in-vivo biochemical models for presynaptic activity the chromanamine induced a half-maximal effect in the gamma-butyrolactone reversal test at 6.8 mumol kg-1 and had an ED70 value of 40 mumol kg-1 for HVA decrease in the striatum. In behavioural models for postsynaptic dopaminergic activity a half-maximal effect for the induction of stereotypy was reached at 100 mumol kg-1 and reversal of the effects of reserpine to a level of 200 counts was induced at 11 mumol kg-1. On comparison of these results with the results obtained with the carbon analogue of DP-6OH-3CA, i.e. DP-7OH-AT, it is apparent that the chromanamine has a reduced potency for dopamine D2 receptors in in-vitro and in-vivo models. The selectivity for presynaptic dopamine receptors was lower than with DP-7OH-AT and the isomeric chromanamine, DP-8OH-3CA, indicating that the optimal position of the hydroxyl group for presynaptic selectivity is in the 8 and not in the 6 position for the chromanamines.

Pharmacological profile of N,N dipropyl-8-hydroxy-3-chromanamine, an oxygen isostere of the dopamine agonist N,N dipropyl-5-hydroxy-2-aminotetralin with enhanced presynaptic selectivity.

The pharmacological profile of N,N dipropyl-8-hydroxy-3-chromanamine (DP-8OH-3CA), the oxygen isostere of N,N dipropyl-5-hydroxy-2-aminotetralin (DP-5OH-AT), was studied and the results compared to its carbon analogue and apomorphine. The chromanamine was found to displace the D2-dopaminergic ligand [3H] 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin with a higher potency than apomorphine and DP-5OH-AT; the IC50 values were 8, 11 and 16 nM, respectively. Experiments investigating the effects of these compounds on dopamine metabolism following oral (o.a.) and intraperitoneal administration (i.p.) showed that the chromanamine had an excellent o.a./i.p. ratio. The presynaptic actions on D2-dopamine receptors, which were studied using tyrosine hydroxylase inhibition, modulation of dopamine metabolism, prevention of alpha-methyl-p-tyrosine induced dopamine depletion in rats and hypomotility in mice, showed that the chromanamine acts as a D2-agonist with half maximal effects between 0.1 and 0.4 mumol/kg (i.p.) DP-8OH-3CA was found to evoke obvious postsynaptic effects when studied in such models as stereotyped behaviour, hyperlocomotion, turning behaviour in 6 hydroxydopamine lesioned rats and reserpine reversal. Stereotypy and the accompanying hyperlocomotion were found to be induced at a half maximal dose of 17 mumol/kg (i.p.). Both with the stereotyped and turning behaviours, a long duration of action was evident. The selectivity for presynaptic receptors was found to be 6.7 times higher than that of DP-5OH-AT, indicating that oxygen substitution can cause an enhancement of selectivity for presynaptic D2-dopamine receptors. Experiments on noradrenaline release and on serotonin synthesis showed that DP-8OH-3CA had only moderate affinity for 5-hydroxytryptamine and noradrenaline receptors. It is concluded that DP-8OH-3CA is a potent D2-agonist with an excellent o.a./i.p. ratio and enhanced selectivity for presynaptic dopamine receptors.

The prostaglandin response in guinea-pig taenia caeci and trachea smooth muscle of different ages.

The concentration-response curves for the carbachol-induced contraction of smooth muscle cells of guinea-pig taenia caeci and trachea were not dependent on tissue age. The prostaglandin E2 and F2 alpha responses increased with age in taenia caeci in contrast with the PGE2 response evoked in trachea. The high-potassium responses evoked in taenia caeci and trachea both increased at higher tissue age. Methoxyverapamil only inhibited the age-dependent responses. The results suggest that it is mainly the voltage-dependent calcium channels that are involved in the age-dependent prostaglandin response.

Desensitization of PGE2 and PGI2 induced contractions in different smooth muscles of guinea-pig unmasking relaxing properties of prostanoids.

Prostaglandin E2 (PGE2) and 16,16-dimethyl PGE2 (16,16-dm PGE2) caused contraction of guinea-pig taenia caeci, contraction and at higher concentrations relaxation of trachea and relaxation of ureter smooth muscle. The prostacyclin derivative iloprost induced contraction of taenia caecum, while it was inactive in the other preparations. After pretreatment of the smooth muscles with 16,16-dm PGE2, stimulation of the PGE2 receptors in taenia caeci and trachea and of PGI2 receptors in taenia caeci caused relaxation. The results indicate that the prostanoid receptor mediating contraction is selectively vulnerable for desensitization in contrast with the receptor mediating smooth muscle relaxation.

The action of prostaglandins on ureter smooth muscle of guinea-pig.

Prostaglandins of the E type (PGE) relaxed guinea-pig ureter but prostaglandins of the F type (PGF) did not affect smooth muscle contraction. Hyperpolarization and relaxation of the muscle cells caused by the PGEs were achieved at concentrations in a different range, a feature also observed in the presence of forskolin or iso-butyl-methyl-xanthine (IBMX). Hyperpolarization was inhibited in the presence of k-strophanthoside. The c-AMP content of ureter smooth muscle cells was increased in the presence of PGE2. These observations suggest that the PGE-induced hyperpolarization is caused by activation of the sodium-potassium pump and that enhancement of the cellular c-AMP level plays a major role in the PGE-induced relaxation.

Energetics of smooth muscle taenia caecum of guinea-pig: a 31P-NMR study.

Smooth muscle cell energetics of taenia caeci during relaxation, spontaneous activity and maximal contraction were investigated using 31P-NMR. In relaxed muscle obtained in calcium-free medium, [ATP], [phosphocreatine] and [sugar phosphate] were 4.4 mM, 7.7 mM and 2.8 mM, respectively. There was only a small difference in the energetics of spontaneously active and maximally contracted muscles, but under both conditions substantial changes occurred as compared with relaxed muscles. The internal pH in relaxed muscle was found to be 7.05, which acidified to 6.5 during contraction. The level of sugar phosphates was found to be not a limiting factor in energetics.

Microelectrode measurement of intracellular chloride activity in smooth muscle cells of guinea-pig ureter.

The intracellular Cl activity (aiCl) of smooth muscle cells in the guinea-pig ureter was measured using double-barrelled Cl-sensitive microelectrodes. The mean aiCl in normal Krebs solution was 51.1 mM, equivalent to an ECl of -18.6 mV, with a mean Em of -48.7 mV. Thus aiCl was three times higher than predicted from a passive distribution, aiCl exceeded the extracellular activity by nearly 10 mM in 10%-Cl solution. Complete removal of extracellular Cl (Cl0) caused a decline in aiCl to an apparent level of 3.3 mM with a mean time constant of 6.7 min. Cl ions were reaccumulated against their electrochemical gradient on readmission of Cl0 with a mean time constant of 6.6 min. Both the reaccumulation and loss of Cl ions on changing Cl0 were slowed about three-fold by the presence of the anion exchange inhibitor DIDS. It is therefore concluded that most of the transmembrane Cl movements are mediated by a reversible anion exchange carrier and that PCl is very low. These results are similar to those obtained in vas deferens and may be a general feature of smooth muscle cells.