Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease

Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive "designer" theophylline, the archetypal non-selective phosphodiesterase inhibitor.     

Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review. RECENT FINDINGS: Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life. SUMMARY: Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.     

The preclinical pharmacology of roflumilast – A selective,oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease

After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A–D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500-μg tablet of roflumilast.The molecular mode of action of roflumilast – PDE4 inhibition and subsequent enhancement of cAMP levels – is well established. To further understand its functional mode of action in chronic obstructive pulmonary disease (COPD), for which roflumilast is being developed, a series of in vitro and in vivo preclinical studies has been performed.COPD is a progressive, devastating condition of the lung associated with an abnormal inflammatory response to noxious particles and gases, particularly tobacco smoke. In addition, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), significant extrapulmonary effects, including comorbidities, may add to the severity of the disease in individual patients, and which may be addressed preferentially by orally administered remedies. COPD shows an increasing prevalence and mortality, and its treatment remains a high, unmet medical need.In vivo, roflumilast mitigates key COPD-related disease mechanisms such as tobacco smoke-induced lung inflammation, mucociliary malfunction, lung fibrotic and emphysematous remodelling, oxidative stress, pulmonary vascular remodelling and pulmonary hypertension. In vitro, roflumilast N-oxide has been demonstrated to affect the functions of many cell types, including neutrophils, monocytes/macrophages, CD4+ and CD8+ T-cells, endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. These cellular effects are thought to be responsible for the beneficial effects of roflumilast on the disease mechanisms of COPD, which translate into reduced exacerbations and improved lung function. As a multicomponent disease, COPD requires a broad therapeutic approach that might be achieved by PDE4 inhibition. However, as a PDE4 inhibitor, roflumilast is not a direct bronchodilator.In summary, roflumilast may be the first-in-class PDE4 inhibitor for COPD therapy. In addition to being a non-steroid, anti-inflammatory drug designed to target pulmonary inflammation, the preclinical pharmacology described in this review points to a broad functional mode of action of roflumilast that putatively addresses additional COPD mechanisms. This enables roflumilast to offer effective, oral maintenance treatment for COPD, with an acceptable tolerability profile and the potential to favourably affect the extrapulmonary effects of the disease.     

The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism

Xanthines such as theophylline have been used in the treatment of lung diseases since the early 1900’s, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. This means that plasma levels have to be measured regularly and can make the use of theophylline problematic. With the increasing availability of other classes of drugs for the treatment of respiratory diseases, this has limited the use of xanthines, despite their clear clinical benefit in the treatment of patients with asthma and COPD. Doxofylline is a xanthine molecule having both bronchodilator and anti-inflammatory activity with an improved therapeutic window over conventional xanthines such as theophylline. However, the mechanistic basis of this improved therapeutic window is not understood. The present study has investigated some pharmacological activities of doxofylline in comparison with theophylline. Doxofylline does not directly inhibit any of the known HDAC enzymes, and did not inhibit any PDE enzyme sub types or act as an antagonist at any of the known adenosine receptors, except for PDE2A₁, and adenosine A_2A and only at the highest tested concentration (10^?4 M). These results may explain the improved tolerability profile of doxofylline compared with theophylline.     

Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD

BackgroundInhibition of phosphodiesterase 4 (PDE4) represents an approach to anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). GSK256066 is a potent and selective inhaled PDE4 inhibitor. The aim of this study was to investigate the safety and tolerability of 28 days repeat inhaled dosing with GSK256066 in moderate COPD.MethodsThis was a Phase IIa, multicenter, parallel-group, double-blind, three-arm, placebo-controlled, four-week, randomized study with two doses of GSK256066 (25 μg, 87.5 μg). The primary endpoint was safety and tolerability. Secondary endpoints included changes in inflammatory markers in induced sputum and blood, lung function (spirometry, body plethysmography, impulse oscillometry), and pharmacokinetics.Results104 patients were randomized and 94 patients completed the study. The incidence and intensity of treatment-related adverse events were similar between treatment groups. The most frequent adverse event was nasopharyngitis and there were no serious adverse events in patients receiving GSK256066. The overall incidence of gastrointestinal adverse events was low in all treatment groups. There were no statistically significant changes in inflammatory markers in induced sputum and blood following treatment with GSK256066. Analysis of sputum mRNA suggested engagement of pharmacology, based on increased expression of cAMP-dependent genes including amphiregulin and CREM in subjects receiving GSK256066. There was a trend for an increase in post-bronchodilator FEV1 for both doses of GSK256066; in addition, for the 87.5 μg group, there was a mean reduction in residual volume of 0.367 L (95% confidence interval: 0.112, 0.622 L) relative to placebo.ConclusionsAdministration of inhaled GSK256066 was well-tolerated in patients with moderate COPD. Further studies would be required to confirm the favorable safety profile and to demonstrate clinical efficacy of this compound.(ClinicalTrials.gov identifier: NCT00549679).     

MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers

BACKGROUND: MK-0873 is a novel selective phosphodiesterase-4 inhibitor, which has been in development for the treatment of chronic obstructive pulmonary disease (COPD). In this indication, theophylline is still an important treatment, despite its relatively small therapeutic window. In view of this, it is important to investigate whether MK-0873 could affect the pharmacokinetics, safety and tolerability of theophylline, when both drugs are given concomitantly. AIM: The objective of this study was to investigate the effect of multiple doses of oral MK-0873, a selective phosphodiesterase-4 inhibitor, on the pharmacokinetics, safety and tolerability profile of orally administered theophylline in healthy volunteers. METHODS: Eight healthy, non-smoking male subjects participated in this randomized, open-label, 2-period, cross-over study. In one period subjects received an oral dose of 2.5mg MK-0873 for 6 days co-administered with a single oral dose of 250 mg theophylline on day 5. The other period consisted of a single dose of 250 mg theophylline on day 1. In each period, blood samples were collected at predefined time points to evaluate theophylline pharmacokinetics. RESULTS: All subjects completed the study. The study medications were generally well tolerated and no clinically relevant changes were observed in either treatment periods. No significant difference was found in the AUC 0-infinity (77.7 vs. 83.8h ng/ml; p=0.280) and Cmax (6.70 vs. 7.77 ng/ml; p=0.125) of theophylline between the MK-0873+theophylline and theophylline only treatment, and bioequivalence was demonstrated for AUC0-infinity (geometric mean ratio with 90% confidence interval: 0.930 (0.826, 1.047)). CONCLUSION: In this study, in a limited number of subjects, co-administration of oral MK-0873 did not affect the pharmacokinetics, safety, and tolerability of oral theophylline in non-smoking healthy male subjects.     

Formoterol in the management of chronic obstructive pulmonary disease

Bronchodilators represent the hallmark of symptomatic treatment of Chronic Obstructive Pulmonary Disease (COPD). There are four categories of bronchodilators: anticholinergics, methylxanthines, short-acting β₂-agonists, and long-acting β₂-agonists such as formoterol. Significant research has been performed to investigate the efficacy, safety and tolerability of formoterol in the therapeutic field of COPD. Formoterol exhibits a rapid onset of bronchodilation similar to that observed with salbutamol, yet its long bronchodilatory duration is comparable to salmeterol. In addition, formoterol presents with a clear superiority in lung function improvement compared with either ipratropium bromide or oral theophylline, while its efficacy improves when administered in combination with ipratropium. Formoterol has been shown to better reduce dynamic hyperinflation, which is responsible for exercise intolerance and dyspnea in COPD patients, compared with other bronchodilators, whereas it exerts synergistic effect with tiotropium. Moreover, formoterol reduces exacerbations, increases days free of use of rescue medication and improves patients’ quality of life and disease symptoms. Formoterol has a favorable safety profile and is better tolerated than theophylline. Collectively, data extracted from multicenter clinical trials support formoterol as a valid therapeutic option in the treatment of COPD.     

NVA237, a long-acting muscarinic antagonist, as an emerging therapy for chronic obstructive pulmonary disease

Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting β(2)-agonist is central to the management of chronic obstructive pulmonary disease (COPD). Tiotropium, the first LAMA available for use in COPD, has been shown to be an effective bronchodilator and is generally safe and well tolerated. However, tiotropium has limitations that include a high incidence of dry mouth, slow onset of action and, in some studies, a part of the patient population did not achieve clinically significant bronchodilation. It also remains unclear whether tiotropium reduces progressive deterioration of lung function in patients with COPD. An ideal LAMA would provide clinically meaningful bronchodilation, deliver symptom relief, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations and reduce mortality risk. A 24-h duration of action, rapid onset of action and a good safety and tolerability profile are also desirable. The once-daily LAMA, NVA237 (glycopyrronium bromide), may meet some of these characteristics. NVA237 has high selectivity for the muscarinic type-3 (M(3)) receptor which might potentially result in a higher therapeutic index than tiotropium, which is less selective for M(3). Phase II studies showed that NVA237 once daily provides clinically significant 24-h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile. Phase III studies are ongoing that will assess the long-term safety and efficacy of NVA237.     

The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-alpha production in whole blood from COPD patients

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-alpha release with IC(50) values of 1.3+/-0.7, 2.8+/-0.9 microM, higher to 10 microM and lesser than 0.03 microM for CI-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a similar inhibition in the whole blood from healthy volunteers with, however, higher IC(50) values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-alpha release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD.     

Phosphodiesterase 4-selective inhibition: novel therapy for the inflammation of COPD

Chronic obstructive pulmonary disease (COPD), which is increasing in prevalence and a leading cause of death worldwide, is characterised by an 'abnormal' inflammatory response. There is a predominance of CD8(+) T cells, CD68(+) macrophages and, in exacerbations-neutrophils, in both conducting airways and lung parenchyma. Smoking is the most common etiological factor leading to COPD and smoking cessation is the most effective approach to the management of COPD, but it does not resolve the underlying inflammation of COPD, which persists, even in ex-smokers. The presence of mucosal inflammation serves as the rationale for anti-inflammatory therapy. However, while there are reductions in the numbers of mast cells following treatment with inhaled steroids, CD8(+), CD68(+) cells and neutrophils are refractory to such treatment, highlighting a need for additional, more targeted interventions. Phosphodiesterase 4 (PDE4) inhibitors are a promising and novel drug class that have potent activity against several key components of the inflammatory process in COPD. A recently published study has shown that the selective PDE4 inhibitor, cilomilast, reduces the numbers of bronchial mucosal CD8(+) and CD68(+) cells and neutrophils. This review focuses on the nature of the inflammation in COPD and considers how selective PDE4 inhibitors may optimize and advance our treatment of this chronic condition.     

Evaluation of PDE4 inhibition for COPD

Targeting type 4 phosphodiesterase (PDE4) for treatment of COPD has multilevel benefits to patients by reducing inflammation, relieving bronchoconstriction, and improving pulmonary circulation. The isoenzyme-specific narrow spectrum PDE4 inhibitors such as cilomilast and roflumilast may have limited clinical efficacy in managing severe and very severe COPD. Development of dual therapy by combining PDE4 inhibition with Ca²⁺ channel antagonism may introduce an effective novel armory for physicians to manage patients with severe COPD.     

The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications

Asthma and COPD are two chronic inflammatory disorders of the airway characterized by airflow limitation. While many similarities exist between these two diseases, they are pathologically distinct due to the involvement of different inflammatory cells; predominantly neutrophils, CD8 lymphocytes in COPD and eosinophils and CD4 lymphocytes in asthma. Cigarette smoking is associated with accelerated decline of lung function, increased mortality, and worsening of symptoms in both asthma and COPD. Furthermore, exposure to cigarette smoke can alter the inflammatory mechanisms in asthma to become similar to that seen in COPD with increasing CD8 cells and neutrophils and may therefore alter the response to therapy. Cigarette smoke exposure has been associated with a poor response to inhaled corticosteroids which are recommended as first line anti-inflammatory medications in asthma and as an add-on therapy in patients with severe COPD with history of exacerbations. While the main proposed mechanism for this altered response is the reduction of the histone deacetylase 2 (HDAC2) enzyme system, other possible mechanisms include the overexpression of GR-β, activation of p38 MAPK pathway and increased production of inflammatory cytokines such as IL-2, 4, 8, TNF-α and NF-K?. Few clinical trials suggest that leukotriene modifiers may be an alternative to corticosteroids in smokers with asthma but there are currently no drugs which effectively reduce the progression of inflammation in smokers with COPD. However, several HDAC2 enhancers including low dose theophylline and other potential anti-inflammatory therapies including PDE4 inhibitors and p38 MAPK inhibitors are being evaluated.     

Management of asthma and chronic airflow limitation. Are methylxanthines obsolete?

After almost 50 years as first-line drugs in the management of asthma and COPD, methylxanthines have been largely superceded by inhaled adrenoceptor agonist and anticholinergic bronchodilators which are more potent and far less toxic. Accumulating evidence indicates that intravenous theophylline contributes side effects, but is rarely of benefit in acute exacerbations of asthma or COPD. In the maintenance therapy of asthma, first-line therapy is dose-optimized inhaled steroids, reducing the need for bronchodilators. Inhaled adrenoceptor agonists are second line medications, anticholinergic aerosols third line, and theophylline, if needed at all, may fulfill a minor systemic steroid-sparing function in severe asthmatics on maximum doses of the inhaled medications. In the maintenance therapy of some patients with COPD, theophylline sometimes may be useful but these responders should be identified by objectively establishing therapeutic benefit. Since many patients have side effects from the methylxanthines, while their therapeutic benefit over and above dose-optimized inhaled therapy is marginal, their continued almost routine use in the management of reversible airflow obstruction is hard to justify, although this class of drugs may be useful in selected patients in whom both subjective and objective benefit can be demonstrated. In COPD, theophylline may improve exercise capacity in some patients by still incompletely understood mechanisms probably unrelated to bronchodilation.     

Inhibition by reproterol of cAMP PDE in intact mastocytoma P-815 cells

In vitro studies in rat mastocytes and human monocytes suggested that reproterol (a selective beta(2)-adrenoceptor agonist with a theophylline moiety) exerts anti-inflammatory actions through inhibition of cyclic AMP (cAMP) PDE activity. Thus, reproterol was tested for its ability to inhibit cAMP PDE in cultured mouse mastocytoma P-815 cells. cAMP PDE activity was measured in intact cells by spectrofluorometry using the fluorescent substrate 2'-O-anthraniloyl cAMP. Reproterol was more potent than theophylline to inhibit cAMP PDE (pIC(50)=4.28+/-0.25 vs. 3.16+/-0.05). This contrasted with disrupted cells, where the PDE inhibitory potency of reproterol was low (pIC(50)=2.85+/-0.03) and similar to that of theophylline (pIC(50)=2.66+/-0.19). No cAMP PDE inhibition was found with other beta(2)-agonists tested (fenoterol, salbutamol, salmeterol and formoterol). Finally, the selective PDE inhibitors calmidazolium (100 nM), milrinone (5 microM) and rolipram (50 microM) inhibited cAMP PDE activity by approximately 20, 30 and 25% respectively. In conclusion, reproterol potently and non-specifically inhibited intracellular cAMP phosphodiesterases in intact mastocytoma cells. This can explain the previously reported beta(2)-adrenoceptor-independent anti-inflammatory actions of reproterol in vitro. Further studies are required to define the anti-inflammatory potential of reproterol in asthma.     

The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro

Neutrophil-derived proteases such as neutrophil elastase (NE) and matrix metalloproteinase (MMP) are implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). In this study, the effects of selective phosphodiesterase (PDE) inhibition on NE and MMP-9 release, as well as Myeloperoxidase (MPO) activity and integrin-mediated neutrophil adhesion to human umbilical vein endothelial cells (HUVECs), were investigated. Human neutrophils were treated with PDE inhibitors (10(-11)-10(-4)M) in the absence and presence of TNF-alpha (tumour necrosis factor) (100 U ml(-1)) for 30 min, prior to fMLP activation. After 45 min, the cells were removed and NE, MPO and MMP-9 release assessed. In the adhesion studies, the neutrophils were radio-labelled with 51Cr, stimulated and immediately transferred to cultured HUVEC monolayers for 30 min, prior to assessment of adhesion. TNF-alpha (100 U ml(-1)) acted synergistically with fMLP in stimulating azurophil degranulation with respect to both MPO activity (P<0.01) and NE release (P<0.01). In contrast, an additive effect was observed with TNF-alpha and fMLP with regard to MMP-9 release and neutrophil adhesion to HUVECs. The PDE4 inhibitors, roflumilast, roflumilast N-oxide, cilomilast and rolipram significantly suppressed MPO, NE and MMP-9 release in both the presence and absence of TNF-alpha (P<0.05; n=6-10) and also reduced neutrophil adhesion to HUVECs. In contrast, milrinone, a PDE3 inhibitor and the non-selective PDE inhibitor, theophylline did not inhibit azurophil degranulation under any of the experimental conditions. These data provide further evidence that selective PDE4 isoenzyme inhibitors can inhibit neutrophil degranulation, effects not shared by PDE3 inhibitors or theophylline.     

New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease

Phosphodiesterase 4 (PDE4) is a member of the growing family cyclic AMP and cyclic GMP. Earliest described inhibitors of PDE4, such as rolipram, demonstrate marked anti-inflammatory and bronchodilatory effects in vitro and in vivo. The clinical utility of these earlier compounds was limited by their propensity to elicit gastrointestinal side effects. This has led to an extensive effort to identify novel PDE4 inhibitors that maintain the anti-inflammatory activity and bronchodilatory activity of rolipram but with a reduced potential to produce side effects. This article summarizes the evidence supporting the utility of selective PDE4 inhibitors in the treatment of asthma and chronic obstructive pulmonary disease, discusses the recent results obtained in clinical trials with second-generation inhibitors, and presents two approaches designed to identify additional novel selective PDE4 inhibitors.     

Pharmacological aspects of successful long-term analgesia

Persistent pain represents a major quality-of-life burden for patients and a challenge for their physician. Chronic pain often arises from multiple tissue sources and involves multiple chemical mediators and pain transmission pathways. Successful long-term pain management requires analgesic regimens that can treat pains of multiple origin and type. Safety and tolerability are also a high priority when prescribing chronic therapy. Recent publications and regulatory developments affecting anti-inflammatory drugs have limited the options available for the management of chronic pain. Major concerns in long-term use of anti-inflammatory drugs include renal toxicity, gastrointestinal ulceration and bleeding and cardiovascular events, which can be of particular concern for elderly patients. Opioid agents avoid the end-organ toxicity seen with anti-inflammatory drugs, but their use may be limited, especially in the long term, by side effects such as constipation or sedation and by concerns about the potential for physical or psychological dependence. Paracetamol (acetaminophen) has a favourable safety and tolerability profile, although exceeding the recommended dose (up to 4 g/day) carries a risk of liver damage. It exerts simultaneous anti-nociception at both spinal and supra-spinal sites, and has shown self-synergy between these two routes of activity. Tramadol, an atypical weak opioid with a multi-modal mechanism of action, inhibits re-uptake of multiple neurotransmitters and has an improved safety and tolerability profile compared with traditional opioids. Rational combinations of analgesic drugs offer a viable approach to managing persistent pain that involves multiple sites or pathways. The combination of paracetamol plus tramadol brings together two well-known analgesics that have different but complementary mechanisms of analgesic action. Laboratory studies have demonstrated that these agents interact to produce synergistic analgesia with a desirable safety/efficacy profile.     

磷酸二酯酶抑制剂与呼吸道疾病

磷酸二酯酶(PDE)存在于许多炎症细胞及结构细胞中,目前已发现11种.PDE抑制剂主要抑制体内环磷酸腺苷(cAMP)及环磷酸鸟苷(cGMP)水解,使细胞内cAMP及cGMP浓度增加,引起一系列生理功能,如平滑肌舒张、减轻细胞炎症及免疫反应等.PDE4特异性水解cAMP,选择性PDE4抑制剂具有广泛抗炎作用,如抑制细胞趋化,抑制中性粒细胞、嗜酸粒细胞、巨噬细胞及T细胞细胞因子及化学趋化物质释放.第二代PDE4抑制剂Cilomilast和Roflumilast已进入临床实验阶段,并已证实对支气管哮喘(简称哮喘)及慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)有效.由于胃肠道副作用,这类药物临床应用受到一定限制.PDE5可特异性水解cGMP,对缺氧性肺动脉高压和血管重塑有效.PDE3和PDE7特异性水解cAMP,PDE7参与T细胞激活.目前其他PDE抑制剂与PDE4抑制剂混合制剂正在研发中.PDE4-PDE7双重抑制剂可能对哮喘及COPD更有效.PDE3-PDE4双重抑制剂具有更强的支气管舒张作用及气道保护作用.     

PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast

Chronic obstructive pulmonary disease is characterized by a rapid decline in lung function due to small airway fibrosis, mucus hypersecretion and emphysema. The major causative factor for COPD is cigarette smoking that drives an inflammatory process that gives rise to leukocyte recruitment, imbalance in protease levels and consequently matrix remodeling resulting in small airway fibrosis and loss of alveolar tissue. Current drug treatment improves symptoms but do not alter the underlying progression of this disease. The failure of anti-inflammatory drugs like glucocorticosteroids to have a major impact in this disease has hastened the need to develop novel therapeutic strategies. Phosphodiesterase (PDE)4 inhibitors are novel anti-inflammatory drugs that have recently been show to document clinical efficacy in this disease, although their utility is hampered by class related side-effects of nausea, emesis and diarrhea. Whilst it is not yet clear whether such drugs will prevent emphysema, this is a distinct possibility provided experimental observations from preclinical studies translate to man. This review will discuss the current standing of PDE4 inhibitors like roflumilast as novel treatments for COPD and the potential for developing nonemetic anti-inflammatory drugs.     

Pharmacological aspects of successful long-term analgesia

Persistent pain represents a major quality-of-life burden for patients and a challenge for their physician. Chronic pain often arises from multiple tissue sources and involves multiple chemical mediators and pain transmission pathways. Successful long-term pain management requires analgesic regimens that can treat pains of multiple origin and type. Safety and tolerability are also a high priority when prescribing chronic therapy. Recent publications and regulatory developments affecting anti-inflammatory drugs have limited the options available for the management of chronic pain. Major concerns in long-term use of anti-inflammatory drugs include renal toxicity, gastrointestinal ulceration and bleeding and cardiovascular events, which can be of particular concern for elderly patients. Opioid agents avoid the end-organ toxicity seen with anti-inflammatory drugs, but their use may be limited, especially in the long term, by side effects such as constipation or sedation and by concerns about the potential for physical or psychological dependence. Paracetamol (acetaminophen) has a favourable safety and tolerability profile, although exceeding the recommended dose (up to 4 g/day) carries a risk of liver damage. It exerts simultaneous anti-nociception at both spinal and supra-spinal sites, and has shown self-synergy between these two routes of activity. Tramadol, an atypical weak opioid with a multi-modal mechanism of action, inhibits re-uptake of multiple neurotransmitters and has an improved safety and tolerability profile compared with traditional opioids. Rational combinations of analgesic drugs offer a viable approach to managing persistent pain that involves multiple sites or pathways. The combination of paracetamol plus tramadol brings together two well-known analgesics that have different but complementary mechanisms of analgesic action. Laboratory studies have demonstrated that these agents interact to produce synergistic analgesia with a desirable safety/efficacy profile.