Therapeutic Potential of Antileukotriene Drug-Camellia sinensis Extract Co-Formulation on Histamine Induced Asthma in Guinea Pigs.

BACKGROUND/OBJECTIVE: To study the therapeutic potential of Antileukotriene drug- Camellia sinensis extract co-formulation on histamine induced asthma in guinea pigs. METHODS: SRSD of Montelukast sodium was prepared by the solvent evaporation method. Lyophilized aqueous extract of Camellia sinensis leaves and SRSD mixture was filled in capsule and the capsule shell was coated to achieve initial release lag time. In vitro and pharmacokinetic study of capsules was performed and compared with commercial tablets. A further role of green tea, as an antioxidant adjunct for asthma management, has been analyzed by lung histology, mast cell count and oxidative stress assay in the serum of control and experimental animals. RESULTS: The drug release from the commercial tablet was immediate and rapid, but capsule has shown an initial 3.5 hr lag time followed by sustained action up to 8 hr. Pharmacokinetic results show that studied formulations are bioequivalent with respect to Cmax and AUC, while rest parameters showed asignificant difference. Mast cells count in lung tissue were increased (p<0.001) in the experimental group along with glycoprotein deposition in asthmatic bronchioles. Levels of SOD and GPX were decreased (p<0.05) while CAT was increased (p<0.04) in the asthma group in comparison to control. CONCLUSION: In the experimental animal model, co-formulation was effective in modulating allergic inflammation and contributing to better control of the inflammatory response. Our findings suggest that Camellia sinensis leaves extract may be used as an adjunct for future improvements in asthma treatment and prevention.

Chronopharmacokinetic Evaluation of Budesonide Multiparticulate Systems.

BACKGROUND: Poor oral absorption of budesonide limits the design of its solid oral dosage form. With this context, multiparticulate pulsatile system of budesonide for chronotherapy of nocturnal asthma was aimed in this study. METHODS: Initially, solid dispersions of budesonide (BD) using sodium starch glycolate (SSG) and guar gum (GG) were developed and characterized. Uniform sized non-pareil seeds (~400 µm) were coated with solid dispersions to obtain immediate (BMP) and controlled release pellets by solution layering technique. Rationale of selection of BD in this research was based on recent patents such as diltiazem HCl (US5914134) and multipar-ticulate systems (US5017381). Pulsatile drug release pellets (BMPP) of BD were obtained by coating the controlled release pellets with Eudragit L100 and RS 100. Pellets were assessed by saturation sol-ubility, FTIR, DSC, micromeritic, SEM, drug content, drug release, pharmacokinetic and stability studies. RESULTS: Solubility of BD was increased by 22 folds due to inter-particle distribution of BD and polymers in solid dispersions. No changes in characteristic functional groups of BD had indicated the compatibility of drug with polymers as noticed in FTIR and DSC. Fluidized bed processor enabled the production of spherical and uniformly distributed pellets with optimum angle of repose (12-19°) and friability (<1%). Solution layering technique employed in preparation of pellets had facilitated with moderately high BD content (91.5-99.6%) and 100% drug release at the end of 12hr. The pulsatile release pellets (BMPP) produced 6hr lag phase followed by 12hr controlled release. Promised pharmacokinetics was resulted as Cmax of 380ng/ml for BMP-2 and 162ng/ml for BMPP-5 and Tmax of 5 hr for BMP-2 and 12hr for BMPP-5. Increased pharmacokinetics was the direct results of increased solubility of BD due to application of solid dispersion and solution layering on pellets. CONCLUSIONS: Chronopharmacokinetics of BD were achieved with the help of Eudragit coatings on pellets. The BMP and BMPP formulations were found to be reasonably stable over a period of time. Thus, optimal chronopharmacokinetics of BD was achieved successfully by multiparticulate pulsatile technology.

In vitro and in vivo evaluation of multilayered pastilles for chronotherapeutic management of nocturnal asthma.

OBJECTIVE: The present work was undertaken with an objective to design a multilayered dosage form of doxofylline, using pastillation technology, for the chronotherapeutic management of nocturnal asthma. RESEARCH DESIGN & METHODS: Pastilles consisting of the drug, polyethylene glycol and colloidal silicon dioxide, were generated using an in-house laboratory-scale pastillation device. The pastilles were further coated with enteric polymers and a floating layer, using conventional coater. The pastilles were subjected to physicochemical analysis, morphological characterization, in vitro drug release studies and in vivo pharmacokinetic studies in rats. RESULTS: It was observed that colloidal silicon dioxide was instrumental in improving the contact angle of the pastilles. The uncoated pastilles released the drug immediately, while the enteric-coated (10% w/w) pastilles were found to have sufficient acid resistance when the coat is applied with 5% (v/v) triethyl citrate as plasticizer. The in vivo blood serum profile indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release required for the chronotherapeutic treatment of nocturnal asthma. CONCLUSION: The present work opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate-release and modified-release drug delivery systems.

Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma.

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.

Antiasthmatic effects of Gleditsia sinensis in an ovalbumin-induced murine model of asthma.

This study evaluated the antiasthmatic effects of Gleditsia sinensis ethanolic extract (GSEE) and its underlying mechanisms, using an in vivo murine model of asthma. Female BALB/c mice were sensitized, challenged with ovalbumin, and then examined for asthmatic reactions. The results showed that GSEE exerted profound inhibitory effects on the accumulation of eosinophils in the airways and reduced the levels of interleukin (IL)-4 and IL-5 in bronchoalveolar lavage fluid (BALF) and immunoglobulin E (IgE) in BALF and plasma. Gleditsia sinensis ethanolic extract also suppressed the production of reactive oxygen species in BALF and inflammatory infiltration, in a dose-dependent manner, and it inhibited goblet-cell hyperplasia in lung tissue. Thus, GSEE shows antiasthmatic effects in a murine model of allergic asthma, which appeared to be mediated partially by the reduction of oxidative stress and airway inflammation. These results indicate that GSEE could be an effective novel therapeutic agent for the treatment of allergic asthma.

A new pressure-controlled colon delivery capsule for chronotherapeutic treatment of nocturnal asthma.

The purpose of this study was to prepare a pressure-controlled colon delivery capsule (PCDC) containing theophylline (TPH) dispersion in a lipid matrix as a chronotherapeutic drug delivery system for the treatment of nocturnal asthma. The system was made by film coating using Eudragit S100- based formula over the sealed-hard gelatin capsules containing the drug-lipid dispersion. The lipid formula was composed mainly of Gelucire 33/01 (G33) with different ratios of surfactants (1-10%). The efficiency of the prepared system was evaluated in vitro for its ability to withstand both the gastric and intestinal medium. In addition, the drug plasma concentrations were monitored after single administration to Beagle dogs and compared to that obtained after administration of a reference marketed, generic, sustained-release TPH tablets, Avolen(®) SR. It was found that the optimum lipid formula was GL2 containing 90% G33 and 10% Labrasol. The film-coated capsules showed complete resistance to both the acidic environment (pH 1.2) for 2 hours and phosphate buffer pH 6.8 for 3 hours at 37°C. In vivo evaluation of the TPH-based PCDCs showed longer lag time compared TO the marketed formula followed by sudden increase in TPH blood levels, which recommends the high potential of this system as a chronotherapeutic drug delivery for nocturnal asthma. The prepared PCDCs exhibited a significantly higher C(max) and T(max) and a nonsignificantly different AUC compared with Avolen(®) SR. Higher TPH blood levels from 1 to 8 hours postadministration was detected in the case of the prepared PCDCs.

Pitrakinra for asthma.

IMPORTANCE OF THE FIELD: In asthma IL-4 and IL-13 have been demonstrated to play major pathogenic roles and therefore their blockade would potentially represent a plausible therapeutic approach. AREAS COVERED IN THIS REVIEW: Pitrakinra is a dual IL-4/IL-13 inhibitor currently under development for asthma and the existing preclinical and clinical data are discussed. WHAT THE READER WILL GAIN: Inhaled pitrakinra demonstrated a good anti-inflammatory potential and a good safety profile on a short-term basis but its place in asthma therapy is still to be found. TAKE HOME MESSAGE: Specific anticytokine therapies might in the near future reshape asthma therapy.

The preclinical testing strategy for the development of novel chemical entities for the treatment of asthma.

Identifying and developing novel chemical entities (NCE) for the treatment of asthma is a time-consuming process and liabilities that endanger the successful progression of a compound from research into the patient are found throughout all phases of drug discovery. In particular the failure of advanced compounds in clinical studies due to lack of efficacy and/or safety concerns is tremendously costly. Therefore, in order to try and reduce the failure rate in clinical trials various in vitro and in vivo tests are performed during preclinical development, to rapidly identify liabilities, eliminate high risk compounds and promote promising potential drug candidates. To achieve this objective, numerous prerequisites have to be met regarding the physico-chemical properties of the compound, and bioactivity or model systems are needed to rate the therapeutic potential of new compounds. Drug liabilities such as target and species specificity, formulation issues, pharmacokinetics as well as pharmacodynamics and the toxic potential of the compound have to be analyzed in great detail before a compound can enter a clinical trial. A particularly challenging aspect of developing novel NCEs for the treatment of asthma is choosing and setting up in vivo models believed to be predictive for human disease. Numerous companies have in the past and are currently developing NCEs targeting many different pathways and cells with the aim to treat asthma. However, currently the only NCE having a significant market share are long-acting beta-agonists (LABA), inhaled and orally active steroids and leukotriene receptor antagonists. In the past many novel NCE for the treatment of asthma were effective in animal models but failed in the clinic. In this review we outline the prerequisites of novel NCE needed for clinical development.

Intracellular delivery of nanoparticles of an antiasthmatic drug.

The aim of the investigation was to prepare and characterize wheat germ agglutinin(WGA)-conjugated poly(D: ,L-lactic-co-glycolic) acid nanoparticles encapsulating mometasone furoate (MF) as a model drug and assess changes in its fate in terms of cellular interactions. MF loaded nanoparticles were prepared using emulsion-solvent evaporation technique. WGA-conjugation was done by carbodiimide coupling method. The nanoparticles were characterized for size, zeta potential, entrapment efficiency and in-vitro drug release. The intracellular uptake of nanoparticles, drug cellular levels, and anti-proliferative activity studies of wheat germ agglutinin-conjugated and unconjugated nanoparticles were assessed on alveolar epithelial (A549) cells to establish cellular interactions. Prepared nanoparticles were spherical with 10-15 microg/mg of WGA conjugated on nanoparticles. The size of nanoparticles increased after conjugation and drug entrapment and zeta potential reduced from 78 +/- 5.5% to 60 +/- 2.5% and -15.3 +/- 1.9 to -2.59 +/- 2.1 mV respectively after conjugation. From the cellular drug concentration-time plot, AUC was found to be 0.4745, 0.6791 and 1.24 for MF, MF-nanoparticles and wheat germ agglutinin-MF-nanoparticles respectively. The in-vitro antiproliferative activity was improved and prolonged significantly after wheat germ agglutinin-conjugation. The results conclusively demonstrate improved availability and efficacy of antiasthmatic drug in alveolar epithelial cell lines. Hence, a drug once formulated as mucoadhesive nanoparticles and incorporated in dry powder inhaler formulation may be used for targeting any segment of lungs for more improved therapeutic response in other lung disorders as well.

[Cutaneous permeation comparison of Kechuan acupoint patch and power].

OBJECTIVE: To compare the cutaneous permeation of Kechuan acupoint patch and power, and evaluate the possibility of dosage form reform of Kechuan recipe. METHOD: Take the Eugend and Ephedrine as the indexes, HPLC was employed to determine their contents, the pond with Franz diffusion were used to measured the cutaneous. RESULT: The permeation of Patch matched with Higuchi Equation. Take Eugend as the index, the permeation rate of total of Patch is 2.319 and 1.738 times of the powder, and 1.784 and 1.215 times of the powder with the Ephedrineas as index. CONCLUSION: The permeation rate of Kechuan acupoint patch was more rapid than the powder. Moreover, the total quantity of permeation of patch was also more than the powder.

Inhibición in vitro de la desgranulación de basófilos por drogas utilizadas habitualmente en el tratamiento del asma: comparación con productos vegetales inmunomoduladores / In vitro basophils degranulation inhibition by drugs habitually used in the asthma treatment: comparison with inmunomodulator vegetal products

Antecedentes. Los derivados de Achyrocline satureioides (A.s.) y Minthostachys verticillata (M.v.) han sido utilizados tradicionalmente por sus propiedades antiinflamatorias y broncodilatadoras en el asma. Objetivos. Comparar la inhibición de basófilos in vitro por dexametasona, teofilina, cromoglicato disódico, bromuro de ipratropio + salbutamol con la de decocciones de hojas/flores de A.s. y decocción/aceite esencial de M.v., mediante el dosaje de B-hexosaminidasa, un marcador de la reacción alérgica inmediata. Evaluar los efectos inmunomoduladores de la decocción/aceite esencial de M.v. sobre la producción de IFN-y. Metodologia. Se estudiaron 38 pacientes alérgicos a hongos anemófilos. Se realizó prick y dosaje de IgE total por EIA. La liberación de B-hexosaminidasa se evaluó con el alergeno solo y el alergeno adicionado de las drogas comerciales o cada derivado vegetal, por EIA. Los niveles de IFN-y fueron cuarificados por EIA en los sobrenadantes de cultivos de linfocitos estimulados con decocción o aceite esencial de M.v. Resultados. Todos los pacientes mostraron reactividad cutánea. Los basófilos desafiados in vitro por el alergeno, liberanon B-hexosaminidasa. La liberación de la enzima fue disminuida por cada droga o derivado vegetal (p<0,05). La producción de IFN-y fue significativamente menor en los alérgicos que en los controles (p<0,02). La decocción o el aceite esencial de M.v. estimularon la síntesis de IFN-y en las muestras de pacientes alérgicos (p<0,02). Conclusiones. La prueba de liberación de B-hexosaminidasa demostró ser una técnica accesible y de fácil realización que podría reemplazar o complementar las prácticas diagnósticas habituales. Bromuro de ipratropio + salbutamol resultó la droga más eficaz in vitro. Las decocciones de flores de A.s. y de hojas de M.v. mostraron potencia reguladora sobre la desgranulación in vitro. Cecocción de hojas y aceite esencial de M.v., fueron inmunomoduladores para la procucción de IFN-y.

Herb-drug interactions: an overview of the clinical evidence.

Herbal medicines are mixtures of more than one active ingredient. The multitude of pharmacologically active compounds obviously increases the likelihood of interactions taking place. Hence, the likelihood of herb-drug interactions is theoretically higher than drug-drug interactions, if only because synthetic drugs usually contain single chemical entities. Case reports and clinical studies have highlighted the existence of a number of clinically important interactions, although cause-and-effect relationships have not always been established. Herbs and drugs may interact either pharmacokinetically or pharmacodynamically. Through induction of cytochrome P450 enzymes and/or P-glycoprotein, some herbal products (e.g. St John's wort) have been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of conventional drugs, including cyclosporine, indinavir, irinotecan, nevirapine, oral contraceptives and digoxin. The majority of such interactions involves medicines that require regular monitoring of blood levels. To date there is less evidence relating to the pharmacodynamic interaction. However, for many of the interactions discussed here, the understanding of the mechanisms involved is incomplete. Taking herbal agents may represent a potential risk to patients under conventional pharmacotherapy.

Safety of the newer inhaled corticosteroids in childhood asthma.

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns have been raised about their potential adverse effects in children. This review examines the safety data on three new ICS - fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a) propellant (QVAR The use of tradenames is for product identification purposes only and does not imply endorsement. formulation) in relation to the older corticosteroids. Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and maintaining good dental hygiene to minimize this risk. Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data available do not show any significant compromise of final adult height. The effect on growth of fluticasone propionate may not be as great as with the older ICS, but the studies have been short term and only used low doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in children did not show any adverse effects, but there may be an increased risk of fractures. Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclomethasone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in children.ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used to achieve symptom control, thus minimizing the risk of serious adverse effects.

Pharmacokinetics of a novel anti-asthmatic, scoparone, in the rabbit serum assessed by a simple HPLC method.

The pharmacokinetics of scoparone (Sco), an anti-asthmatic coumarin derivative extracted from the traditional Chinese herb "Yin Chen", was determined in rabbit plasma by a high performance liquid chromatography (HPLC) method which was newly developed using a Nova-Pak Silica C(18) column and a mobile phase of acetonitrile-water (20:80, v/v). After intravenous administration of Sco at a dose of 2.0 or 3.6 mg/kg, the time course of the plasma concentration of Sco was found to fit an open two-compartment model. AUC values increased, dose-dependently. Mean T(1/2) values showed that half-life was dosage independent. Distribution and elimination of Sco in rabbit plasma were both relatively rapid. These results indicate that Sco could be easily administrated by spray inhalers and is expected to have few associated side effects.

Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma.

The type 2 helper T cell (T(H)2) cytokine interleukin (IL)-4 is thought to play a central role in the early stages of asthma. In an effort to develop an antibody treatment for asthma that neutralizes the effects of IL-4, a murine monoclonal antibody, 3B9, was generated with specificity for human IL-4. In vitro studies demonstrated that 3B9 inhibited IL-4-dependent events including IL-5 synthesis, (T(H)2) cell activation and up-regulation of immunoglobulin E expression. 3B9 was then humanized (pascolizumab, SB 240683) to reduce immunogenicity in humans. SB 240683 demonstrated species specificity for both monkey and human IL-4 with no reactivity to mouse, rat, cow, goat or horse IL-4. Pascolizumab inhibited the response of human and monkey T cells to monkey IL-4 and effectively neutralized IL-4 bioactivity when tested against several IL-4-responsive human cell lines. Affinity studies demonstrated rapid IL-4 binding by pascolizumab with a slow dissociation rate. In vivo pharmacokinetic and chronic safety testing in cynomolgus monkeys demonstrated that pascolizumab was well tolerated, and no adverse clinical responses occurred after up to 9 months of treatment. Three monkeys developed an anti-idiotypic response that resulted in rapid pascolizumab clearance. However, in the chronic dosing study the antibody response was transient and not associated with clinical events. In conclusion, pascolizumab is a humanized anti-IL-4 monoclonal antibody that can inhibit upstream and downstream events associated with asthma, including (T(H)2) cell activation and immunoglobulin E production. Clinical trials are under way to test the clinical efficacy of pascolizumab for asthma.

[Projection of new antihistamines]. / Proyección de los nuevos antihistamínicos.

The metabolic fate of most antihistamines is not clearly established. The drugs usually appear to be extensively metabolized,mainly in the liver. Some second generation antihistamines are metabolized principally by the cytochrome P-450 microsomal enzyme system, mainly by the isoenzyme 3A4 (CYP3A4), although other isoenzyme,including CYP1A2 and CYP2D6, also may be involved. However,other second generation antihistamines appear to be only minimally metabolized in the liver. Serious cardiac effects (prolongation of the QT interval, arrhythmias, torsades de pointes, ventricular fibrillation, arrest, hypotension, palpitations, syncope, dizziness, and/or death) have been reported rarely in patients receiving terfenadine or astemizole. Cardiotoxic effects ussually were associated with higher than recommended dosages and/or increased plasma concentrations of the drugs and their active metabolites. No clinically important adverse effects or changes in the QT intervals were reported after concomitant administration of ketoconazole with fexofenadine. Patients receiving an azole, antifungal, a macrolide, quinine or grapefruit juice also appear to be at substantial risk of such toxicity, probably secondary to interference with metabolism of the antihistamine. Second-generation H1 receptor antagonist have been studied extensively in the treatment of asthma. Many of these drugs have been reported to inhibit eosinophil and basophil chemotaxis and therefore might have an effect on the inflammatory reactions that characterise this disease. Safe use of antihistamines during pregnancy has not been established; therefore, the drugs should not be used in women who are or may become pregnant unless the potential benefits justify the possible risks to the fetus. Antihistamines should not be administered to premature or full-term neonates. Young children may be more susceptible than adults to the toxic effects of antihistamines.

Circadian rhythms in the pharmacokinetics and clinical effects of beta-agonist, theophylline, and anticholinergic medications in the treatment of nocturnal asthma.

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.

Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers.

AIMS: To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration. METHODS: Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed. RESULTS: Statistically significant (P < 0.05) increases were noted in AUC(o,t) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71-1.84). CONCLUSIONS: Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.