Anti-inflammatory Effects Of Theophylline Research Articles

Chinese herbal component, Praeruptorin E, enhances anti-asthma efficacy and prevents toxicity of aminophylline by targeting the NF-κB/PXR/CYP3A4 pathway

BackgroundAminophylline is widely used for the treatment of asthma, but the therapeutic dose is very close to the toxic dose, which makes this drug prone to accumulation poisoning. In the present study, we explored whether the Chinese herbal component, Praeruptorin E (PE), enhances anti-asthma efficacy and prevents the toxicity of aminophylline.MethodsFirst, an ovalbumin (OVA)-induced mouse model of asthma, immunohistochemistry, pathological staining, and bronchoalveolar lavage fluid (BALF) were used to detect the lung condition of asthmatic mice. The content of Th2 cytokines in serum was measured by enzyme-linked immunosorbent assay (ELISA), and the expression of related proteins was detected by Western blotting and immunofluorescence. Concentrations of theophylline and its metabolites in rat serum were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). siRNA transfection and chromatin immunoprecipitation (ChIP) were used to investigate the mechanism of PE.ResultsPE was found to synergize with aminophylline to reduce the infiltration of inflammatory cells, collagen deposition, and mucus hyperplasia in the lungs of asthmatic mice. It inhibited the expression of Th2 cytokines, interleukin (IL)-4, IL-5, and IL-13; promoted lung tissue repair; and reduced the toxic effect of aminophylline on the heart. Moreover, LC-MS/MS analysis showed that PE reduced the plasma concentration of the parent theophylline and its metabolite 1,3-dimethyluric acid (1,3-DMU). PE facilitated aminophylline’s suppression of nuclear factor-κB (NF-κB), and increased the expression of the xenobiotic nuclear receptor pregnane X receptor (PXR) and its primary target gene, CYP3A11 [this is the mouse homolog of cytochrome P450 3A (CYP3A)] in the asthmatic mouse liver and in the L-02 human fetal hepatocyte cell culture model. In addition, the ChIP assay revealed that PE attenuated the binding of NF-κB to the promoter region of the PXR gene and prevented the suppression of PXR gene expression by NF-κB.ConclusionsPE has a dual function in enhancing the immune regulation and anti-inflammatory effects of theophylline, as well as preventing theophylline toxicity by targeting the NF-κB/PXR/CYP3A4 axis. PE is a promising herbal medicine that will benefit asthmatics taking theophylline.

Optimization of Spray-Drying Conditions and Pharmacodynamics Study of Theophylline/Chitosan/β-Cyclodextrin Microspheres

Theophylline has been reported to have considerable pharmacological activity for asthma, which is partly mediated by the anti-inflammatory effects of theophylline. Nevertheless, the wide application of theophylline was hampered due to its rapid metabolization and the poor patient compliance. Microspheres can be applied as targeted and sustained drug-release carriers. The purposes of the present study were to optimize spray-drying conditions and summarize the anti-asthma pharmacodynamics of the theophylline/chitosan/β-cyclodextrin microspheres. The yield, encapsulation efficiency, drug load, and water content were evaluated using ultraviolet spectrophotometry. The morphology of microspheres was observed by scanning electron microscope. Histopathological assessment of microspheres in a murine model of asthma was measured by H&E staining and immunohistochemistry. Levels of IL-4 and TNF-α protein in bronchoalveolar lavage fluid were measured using enzyme-linked immunosorbent assays. The optimal spray-drying conditions (T gi = 150°C, W ff = 8 mL/min, W af = 400 m3/h, and M w = 13 × 105) were selected by orthogonal experiment. The yield, encapsulation efficiency, drug load, and water content of the microspheres were 39.3 ± 1.2%, 76.0 ± 0.8%, 19.5 ± 1.5%, and 10.3 ± 0.6%, respectively. A scanning electron micrograph showed that the microspheres were predominantly spherical with smooth surface or slightly wrinkled. Theophylline/chitosan/β-cyclodextrin microspheres markedly decreased the number of infiltrated inflammatory cells, the levels of IL-4, and TNF-α protein in animal models. Based on lung histopathological studies, inflammatory cells, goblet cells, and NF-κB positive cells were inhibited in the theophylline/chitosan/β-cyclodextrin microspheres group compared with those in the model group. These results indicate that optimized theophylline/chitosan/β-cyclodextrin microspheres may be useful as a novelty pulmonary drug-delivery system in therapy for the treatment of bronchial asthma.

Inhibitory effects of theophylline on the peroxynitrite-augmented release of matrix metalloproteinases by lung fibroblasts

The anti-inflammatory effects of theophylline have been reported to include inhibition of the release of proinflammatory mediators from macrophages and neutrophils. Overproduction of reactive nitrogen species (RNS) has been reported in the airways of patients with chronic obstructive pulmonary disease (COPD), and this causes tissue inflammation and injury. We investigated whether peroxynitrite stimulated the release of matrix metalloproteinases 2 and 9 (MMP-2 and -9; gelatinases) from human fetal lung fibroblasts (HFL-1 cell line) and whether theophylline inhibited the peroxynitrite-augmented release of MMPs. HFL-1 cells and primary lung fibroblasts were treated with peroxynitrite (an RNS), and gelatinases levels were evaluated by gelatin zymography. The inhibitory effect of theophylline on the peroxynitrite-augmented release of MMP-2 and MMP-9 was also investigated. To explore the cell signaling pathways involved in the peroxynitrite-induced gelatinases release and the inhibitory effect of theophylline, transforming growth factor-β(1) (TGF-β(1)), nuclear factor-κB (NF-κB), and histone deacetylase (HDAC) were measured. Peroxynitrite significantly augmented the release of MMP-2 and MMP-9 by fibroblasts (P < 0.01), as well as TGF-β(1) release (P < 0.01), NF-κB activation (P < 0.01), and HDAC2 inactivation (P < 0.01). An NF-κB inhibitor diminished the RNS-augmented release of MMPs and TGF-β(1) (P < 0.01), and a neutralizing TGF-β antibody also diminished MMP release (P < 0.01). Theophylline significantly inhibited the peroxynitrite-augmented release of MMP-2 and MMP-9 in HFL-1 cells and normal adult lung fibroblasts, and it also inhibited the peroxynitrite-mediated HDAC2 inactivation, NF-κB activation, and TGF-β(1) release in HFL-1 cells (all P < 0.01). These results suggest that peroxynitrite can influence tissue remodeling by promoting gelatinases release, while theophylline suppresses peroxynitrite-induced tissue remodeling via pathways involving NF-κB/TGF-β(1) and/or HDAC in the HFL-1 cell line.

Low dose oral theophylline effects on HS-CRP in stable COPD patients

Background: Low dose theophylline may have some anti-inflammatory effects on COPD patients. This study was conducted to determine the effect of oral low dose theophylline on serum CRP level in patients with stable COPD. Methods: In this double blind randomized clinical trail study, 50 patients (25 in experimental and 25 in placebo group) were enrolled into the study by randomized blocking method. Serum HS-CRP using ELISA method was measured before and after the study. Data was analyzed using t-test and paired t-test. Results: There was no significant difference in gender, age, smoking and spirometry variables before study between two groups. Serum HS-CRP level remained the same between two groups before and after the intervention. Conclusion: More studies with large sample size needed to find anti-inflammatory effect of theophylline on macrophages and neutrophils and their derivative inflammatory materials in COPD patients.

Can β2‐adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?

Chronic obstructive pulmonary disease (COPD) has become a global epidemic disease with an increased morbidity and mortality in the world. Inflammatory process progresses and contributes to irreversible airflow limitation. However, there is no available therapy to better control the inflammatory progression and therefore to reduce the exacerbations and mortality. Thus, the development of efficient anti-inflammatory therapies is a priority for patients with COPD. β(2) -Adrenoceptor agonists and anticholinergic agents are widely used as first line drugs in management of COPD because of their efficient bronchodilator properties. At present, many studies in vitro and some data obtained in laboratory animals reveal the potential anti-inflammatory effects of these bronchodilators but their protective role against chronic inflammation and the development of emphysema in patients with COPD remains to be investigated. The anti-inflammatory effects of theophylline at low doses have also been identified. Beneficial interactions between glucocorticoids and bronchodilators have been reported, and signaling pathways explaining these synergistic effects begin to be understood, especially for theophylline. Recent data demonstrating interactions between anticholinergics with β(2) -adrenoceptor agonists aiming to better control the pulmonary inflammation and the development of emphysema in animal models of COPD justify the priority to investigate the interactive effects of a tritherapy associating corticoids with the two main categories of bronchodilators.

Anti-inflammatory Effect of Theophylline in Rats and Its Involvement of the Glucocorticoid–Glucocorticoid Receptor System

Although theophylline has been suggested to have an anti-inflammatory effect, there have been few reports to show the in vivo effect and the mechanism of anti-inflammatory activity of theophylline experimentally. To reveal the anti-inflammatory activity of theophylline, we studied the effect of theophylline and its metabolites on carrageenan-induced edema in rat foot pad. Subcutaneous injection of theophylline (5 –100 mg/kg) inhibited carrageenan-induced edema dose-dependently. Theophylline metabolites, that is, 1-methylxanthine, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid (equimolar dose to 50 mg/kg of theophylline), did not inhibit the edema significantly. The inhibitory effect of theophylline on carrageenan-induced edema disappeared by pretreatment with aminoglutethimide, an inhibitor of glucocorticoid synthesis and with mefepristone, an antagonist of the glucocorticoid receptor. These results suggest that theophylline itself has anti-inflammatory activity and the glucocorticoid–glucocorticoid receptor system is involved in the anti-inflammatory activity of theophylline.

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Purpose : Theophylline has recently been reported to have concurrent anti-inflammatory effects at low therapeutic plasma concentrations which are below the doses at which significants, clinically useful bronchodilatation is evident. Sustained-release formulation in capsule and dry syrup forms were developed to reduce its adverse effects and improve its clinical effects. We compared the therapeutic effects of theophylline dry syrup and capsules in children with mild asthma. Methods : Ninety children with mild asthma were randomized to receive either theophylline dry syrup (n=44) or theophylline capsules (n=46); 4 mg per kilogram of body weight, twice a day, for 12 weeks. Baseline and serial measurements of daytime and nighttime asthma symptom score were performed. Compliance scores, drug swallowing scores, and drug usability scores were measured every 4 weeks. Each scoring was rated on a scale of 0-4. Serum theophylline concentration were measured at 4 and at 12 weeks. To examine the anti-inflammatory effect of theophylline on asthma, Serum eosinophilic cationic protein as a marker of airway inflammation caused by eosinophil was measured 12 weeks pre- and post-administration. Results : The daytime and nighttime asthma symptom scores of the two groups after 4 weeks significantly improved over the baseline score. Daytime and nighttime asthma symptom scores in the dry syrup group were statistically lower at all time points except for the nighttime symptom scores at 4 weeks. Compliance scores, drug swallowing scores, and drug usability scores in the dry syrup group were significantly higher at the end time point. Only in the dry syrup group was the serum ECP at the end time point statistically lower than baseline. Conclusion : Low-dose sustained-release theophylline may be safe and effective in bronchial asthma and this effect may be mediated by its anti-inflammatory action mechanisms. Especially, when used in children with asthma, dry syrup formulation is recommended because of its higher compliance than capsule formulation.

Theophylline and Dexamethasone Induce Peroxisome Proliferator-Activated Receptor-γ Expression in Human Eosinophils

Eosinophils are major effector cells in allergic diseases including asthma. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor that regulates immune reaction. We have previously demonstrated that human eosinophils express PPARγ and that stimulation with a synthetic agonist for PPARγ attenuated the factor-induced eosinophil survival and chemotaxis. However, the modulator of the eosinophil PPARγ expression has not yet been studied. In this study, we investigated the effect of theophylline and dexamethasone (widely used drugs in the treatment of asthma) on PPARγ expression in eosinophils. Purified human peripheral blood eosinophils were cultured, and therapeutic concentrations of theophylline and dexamethasone were added. Subsequently, PPARγ was measured using quantitative real-time RT-PCR and flow cytometry. Theophylline and dexamethasone markedly enhanced both mRNA and protein levels of PPARγ. These findings suggest that the increase in PPARγ expression on eosinophils may play a role in the anti-inflammatory effects of theophylline and dexamethasone.

IN VITRO EFFECTS OF THEOPHYLLINE AND FUROSEMIDE ON PLA2-ACTIVITY

S543 INTRODUCTION: Theophylline is a phosphodiesterase inhibitor and adenosine receptor blocker used in asthma therapy. The loop diuretic furosemide can also applied endotracheally in emergency treatment of asthma [1]. The putative mechanism of action is inhibition of the Na+/2Cl-/K+ cotransport. An additional anti-inflammatory effect is assumed for both drugs. Phospholipase A2 (PLA2) plays a major role in the eicosanoid-pathway. The anti-inflammatory effects of theophylline and / or furosemide may be due to inhibition of PLA2. PURPOSE OF THE STUDY: To establish the effects of theophylline and furosemide on PLA2 activity in an in vitro model. MATERIALS & METHODS: PLA2 (human platelet membranes) is incubated for 30 min with: 1) TRIS-buffer (native platelets); 2) Theophylline 1, 10, and 100[micro sign]g; 3) Furosemide 1, 10, and 100[micro sign]g; PLA2 activity is measured by a radioactive assay according to Flesch [2] and Sundaram [3]. Native activities are considered to be 100% (baseline). Data is analysed with Mann-Whitney rank order test. Statistical significance is assumed for p <or=to 0.05. RESULTS: Theophylline treated platelets show a small increase in PLA (2) activity. In contrast, furosemide causes a significant decrease in PLA2 activity, when high doses (10 - 100 [micro sign]g) are used. (Table 1 and Figure 1)Table 1: Mean values +/- standard deviation in % (brackets absolute values):Figure 1CONCLUSION: The anti -inflammatory effect of theophylline is not due to PLA2 inhibition. In contrast, furosemide decreases PLA2 activity. This might explain in part its positive effects in asthma therapy.

Bronchodilators

After complete abstinence, regular use of short-acting beta 2-agonists results in an increase in early and late asthmatic (allergen) response, exercise-induced bronchoconstriction, and nonspecific airways responsiveness (methacholine). Regular use of long-acting beta 2-agonists also results in increased nonspecific airways responsiveness (methacholine) with or without concomitant inhaled corticosteroids and attenuates the response to escalating doses of inhaled short-acting beta 2-agonists such as might be used in an acute exacerbation. In spite of these findings, symptom control and bronchodilation are improved more with the addition of salmeterol than with a doubling of inhaled corticosteroid dose. Selective cyclic nucleotide phosphodiesterase inhibitors show promise in expanding the bronchodilator and anti-inflammatory effects of theophylline.

Anti-inflammatory Effects of Theophylline: Modulation of Cytokine Production

The basis for the efficacy of theophylline in the treatment of asthma remains enigmatic. Although commonly classified as a bronchodilator, its ability to dilate smooth muscle is considered fairly poor and clinical responses are often independent of bronchodilation. Recent studies have suggested that immunomodulatory activities may contribute to the therapeutic benefit mediated by theophylline. We performed these preliminary studies to determine whether theophylline modulates cytokine production by peripheral blood mononuclear cells. Peripheral blood mononuclear cells were obtained from 24 asthmatic subjects and were left in a resting state or stimulated with either mitogens (phytohemagglutinin, lipopolysaccharide) or antigen (tetanus, cat) with or without the additional presence of theophylline (15 micrograms/dL). Supernatants were collected and evaluated for cytokine concentration by ELISA. Theophylline neither inhibited production of allergenic cytokines such as IL-4 nor modulated the repertoire of cytokines produced by TH cells. A statistically significant inhibition of spontaneous interferon-gamma synthesis was observed (24.5 +/- 8.6 to 13.4 +/- 4.2; P < .05). Theophylline did have anti-inflammatory effects on cytokines primarily produced by mononuclear phagocytic cells. Theophylline mediated a slight inhibition of TNF-alpha production (0.26 +/- 0.08 to 0.21 +/- 0.06; P < .05). Theophylline was also associated with a 2.8-fold increase in spontaneous production of the anti-inflammatory cytokine IL-10 (0.35 +/- 0.08 to 0.98 +/- 0.16 ng; P < .01). A relative absence of IL-10 characterizes the asthmatic airways and may contribute to the development and severity of allergic inflammation. Induction of IL-10 production by theophylline may therefore mitigate inflammation and contribute to the clinical efficacy of this class of medications.

Anti-inflammatory effects of theophylline, cromolyn and salbutamol in a murine model of pleurisy.

1. The aim of this study was to examine the effect of theophylline, cromolyn and salbutamol, three well-known anti-asthmatic drugs, on the early (4 h) and late (48 h) phases of cell migration and fluid leakage induced by carrageenin in the pleural cavity of mice. 2. In the first set of experiments, animals were pretreated (30 min) with different doses of theophylline (0.5-50 mg kg-1, i.p.), cromolyn (0.02-0.2 mg per pleural cavity) or salbutamol (0.05-50 mg kg-1, i.p.); the total and differential cell content, and also the exudate were analysed 4 h after carrageenin (1%) administration. Afterwards, in order to evaluate the time course effects of these drugs on both phases of the inflammatory reaction, one dose employed in the above protocol was chosen, to pretreat (0.5-24 h) different groups of animals. The studied parameters were evaluated 4 and 48 h after pleurisy induction. 3. Acute administration of theophylline (1-50 mg kg-1, i.p.) cromolyn (0.02-0.2 mg per pleural cavity) and salbutamol (0.5-50 mg kg-1, i.p.), 30 min prior to carrageenin, caused significant inhibition of total cell and fluid leakage in the pleural cavity at 4 h (P < 0.01). All drugs exerted a long-lasting inhibitory effect on both exudation and cell migration (P < 0.01) when administered 0.5-8 h before pleurisy induction. However, the temporal profile of the inhibitory effect induced by these drugs on the first phase of the inflammatory reaction was clearly different. Thus, the inhibitory effect induced by theophylline and cromolyn on exudation was significantly longer (up to 24 h) in comparison to their effects on cell migration (only up to 8 h). In contrast, although salbutamol when administered 30 min before pleurisy induction abolished fluid leakage (P < 0.01), this effect was not sustained in the groups pretreated for 4-8 h. In these latter groups, a significant but much smaller reduction of exudation was observed (P < 0.01), whereas the magnitude of cell migration inhibition did not vary. 4. The second phase (48 h) of the inflammatory reaction induced by carrageenin (1%) was significantly inhibited by cromolyn (0.02 mg per pleural cavity) when this drug was administered 0.5-24 h before pleurisy induction (P < 0.01). Similar results were observed when theophylline (50 mg kg-1, i.p.) was administered 0.5-4 h before the injection of the phlogistic agent (P < 0.01). Treatment of the animals with salbutamol (5 mg kg-1, i.p.), 0.5-24 h before pleurisy induction, did not inhibit either cell migration or fluid leakage. In this condition, a significant increase of these parameters was observed in the group pretreated with salbutamol 8-24 h before pleurisy induction (P < 0.01). 5. These results indicate that theophylline and cromolyn were able to inhibit the early (4 h) and late (48 h) phases of the inflammatory reaction induced by carrageenin in a murine model of pleurisy. Salbutamol was effective only against the early phase. The inhibitory effects of theophylline, cromolyn and salbutamol on the early phase of this inflammatory reaction were long-lasting, although a distinct profile of inhibition was observed among them. These findings confirm and extend previous results described in other models of asthma and support both clinical and experimental evidence suggesting that these anti-asthmatic agents exhibit marked anti-inflammatory properties.

REASSESSING THE THERAPEUTIC RANGE FOR THEOPHYLLINE ON LABORATORY REPORT FORMS: ANOTHER VIEWPOINT

The therapeutic utility of theophylline and the recommended range for serum concentrations are debated in a series of three editorials by noted contributors in this area. In the first, it is pointed out that the role of theophylline has evolved into an "adjunctive" therapy for asthma and chronic obstructive pulmonary disease. Serum concentrations of 10 to 15 µg/mL do not sacrifice significant clinical benefit, whereas there is increased risk for adverse effects at higher concentrations. Changing laboratry report forms to designate a lower therapeutic range of 5 to 15 µg/mL for an increased margin of safety (with &amp;gt;20 µg/mL continuing as the lower limit of the toxic range) is advocated and a stepwise approach for implementing this change is proposed. The second paper supports the view that theophylline remains more important than a third- or fourth-line agent in the treatment of asthma, particularly in selected patients. A higher target serum concentration range of 10 to 15 µg/mL may be desirable in more severe asthmatics (requiring oral steroids despite treatment with inhaled steroid), those with nocturnal symptoms, acute exacerbations requiring hospitalization and mechanical ventilation, and in patients for whom this is a more economical or preferable therapy. In these patients a serum concentration of 5 µg/mL may be too low to achieve sufficient benefit. Designation of "10 to 15 µg/mL (5 to 20)" as the therapeutic range is suggested to emphasize the midrange as the target while indicating that levels between 5 and 20 µg/mL are acceptable, although not ideal from either an efficacy or safety standpoint. In the third and final viewpoint presented, much data supporting the efficacy of theophylline in the treatment of chronic asthma and its relationship to serum concentrations are presented. Evidence for potential anti-inflammatory effects of theophylline is also reviewed. Severe toxicity, a rare event, is noted to be not a result of serum concentrations slightly above the therapeutic range, but from massive overdosage and/or drug interactions or concomitant illnesses that alter elimination of the drug. No changes in the recommended therapeutic range of theopylline, which might alter its effectiveness, are proposed. Rather, more careful use and monitoring through education of prescribers is advocated.

REASSESSING THE THERAPEUTIC RANGE FOR THEOPHYLLINE ON LABORATORY REPORT FORMS: ANOTHER PERSPECTIVE

The therapeutic utility of theophylline and the recommended range for serum concentrations are debated in a series of three editorials by noted contributors in this area. In the first, it is pointed out that the role of theophylline has evolved into an "adjunctive" therapy for asthma and chronic obstructive pulmonary disease. Serum concentrations of 10 to 15 µg/mL do not sacrifice significant clinical benefit, whereas there is increased risk for adverse effects at higher concentrations. Changing laboratry report forms to designate a lower therapeutic range of 5 to 15 µg/mL for an increased margin of safety (with &amp;gt;20 µg/mL continuing as the lower limit of the toxic range) is advocated and a stepwise approach for implementing this change is proposed. The second paper supports the view that theophylline remains more important than a third- or fourth-line agent in the treatment of asthma, particularly in selected patients. A higher target serum concentration range of 10 to 15 µg/mL may be desirable in more severe asthmatics (requiring oral steroids despite treatment with inhaled steroid), those with nocturnal symptoms, acute exacerbations requiring hospitalization and mechanical ventilation, and in patients for whom this is a more economical or preferable therapy. In these patients a serum concentration of 5 µg/mL may be too low to achieve sufficient benefit. Designation of "10 to 15 µg/mL (5 to 20)" as the therapeutic range is suggested to emphasize the midrange as the target while indicating that levels between 5 and 20 µg/mL are acceptable, although not ideal from either an efficacy or safety standpoint. In the third and final viewpoint presented, much data supporting the efficacy of theophylline in the treatment of chronic asthma and its relationship to serum concentrations are presented. Evidence for potential anti-inflammatory effects of theophylline is also reviewed. Severe toxicity, a rare event, is noted to be not a result of serum concentrations slightly above the therapeutic range, but from massive overdosage and/or drug interactions or concomitant illnesses that alter elimination of the drug. No changes in the recommended therapeutic range of theopylline, which might alter its effectiveness, are proposed. Rather, more careful use and monitoring through education of prescribers is advocated.

REASSESSING THE THERAPEUTIC RANGE FOR THEOPHYLLINE ON LABORATORY REPORT FORMS: THE IMPORTANCE OF 5-15 µg/mL

The therapeutic utility of theophylline and the recommended range for serum concentrations are debated in a series of three editorials by noted contributors in this area. In the first, it is pointed out that the role of theophylline has evolved into an "adjunctive" therapy for asthma and chronic obstructive pulmonary disease. Serum concentrations of 10 to 15 µg/mL do not sacrifice significant clinical benefit, whereas there is increased risk for adverse effects at higher concentrations. Changing laboratry report forms to designate a lower therapeutic range of 5 to 15 µg/mL for an increased margin of safety (with &amp;gt;20 µg/mL continuing as the lower limit of the toxic range) is advocated and a stepwise approach for implementing this change is proposed. The second paper supports the view that theophylline remains more important than a third- or fourth-line agent in the treatment of asthma, particularly in selected patients. A higher target serum concentration range of 10 to 15 µg/mL may be desirable in more severe asthmatics (requiring oral steroids despite treatment with inhaled steroid), those with nocturnal symptoms, acute exacerbations requiring hospitalization and mechanical ventilation, and in patients for whom this is a more economical or preferable therapy. In these patients a serum concentration of 5 µg/mL may be too low to achieve sufficient benefit. Designation of "10 to 15 µg/mL (5 to 20)" as the therapeutic range is suggested to emphasize the midrange as the target while indicating that levels between 5 and 20 µg/mL are acceptable, although not ideal from either an efficacy or safety standpoint. In the third and final viewpoint presented, much data supporting the efficacy of theophylline in the treatment of chronic asthma and its relationship to serum concentrations are presented. Evidence for potential anti-inflammatory effects of theophylline is also reviewed. Severe toxicity, a rare event, is noted to be not a result of serum concentrations slightly above the therapeutic range, but from massive overdosage and/or drug interactions or concomitant illnesses that alter elimination of the drug. No changes in the recommended therapeutic range of theopylline, which might alter its effectiveness, are proposed. Rather, more careful use and monitoring through education of prescribers is advocated.

Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol.

The effects of theophylline on allergen-induced airway obstruction and bronchial hyperresponsiveness were investigated in allergic rabbits. This allergic rabbit model was developed in our laboratory and stimulates the human model of allergic asthma in several aspects. Four allergic rabbits with hyperreactive airways were challenged with ragweed to elicit early- and late-phase asthmatic responses and subsequent increased airway responsiveness. Two to three weeks later, the rabbits received theophylline (5 mg/ml, nebulized for 3 min) prior to a second allergen challenge. Theophylline significantly inhibited the allergen-induced early- and late-phase asthmatic responses by 38% (P < 0.05) and 49% (P < 0.05), respectively. Further theophylline inhibited the allergen-induced increase in lung resistance by 42% (P < 0.05) during the late-phase responses. Theophylline also inhibited the allergen-induced bronchial hyperresponsiveness by 39% (P < 0.05) at 24 h. These data suggest a potential anti-inflammatory effect of theophylline in preventing allergen-induced asthmatic responses and bronchial hyperresponsiveness.