Soft drugs for future treatment of chronic obstructive pulmonary disease (COPD)

COPD is a major cause of chronic morbidity and mortality worldwide. Current treatment is aimed at symptomatic relief. In contrast to bronchial asthma, glucocorticoid treatment strategies have proved disappointing. Consequently, there is a need to develop more effective therapeutic strategies to replace present treatment. Advances in understanding the pathogenesis of COPD have the potential for identifying new therapeutic targets. Additionally, forgotten old compounds might undergo a revival by means of novel pharmaceutical technology.     

Pharmacokinetics of inhaled drugs

1A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively low levels of systemic absorption. 2Pharmacokinetic evaluation of drug absorption from the lungs provides an accurate and reproducible method for comparing different inhaler delivery systems, as well as for evaluating bioequivalence of generic drug formulations. 3The measurement of drug absorption from the lungs may also be applied to assess the effects of inhalation technique on drug delivery in vivo. For example with salbutamol delivered via a large volume spacer, lung bioavailability has been shown to be altered by factors such as the number of actuated puffs, inhalation-actuation delay and washing procedure. 4Differences in drug delivery to the lungs between dry powder reservoir and pressurised metered-dose aerosol devices translate directly into commensurate differences in clinical efficacy for delivery of both inhaled β₂-adrenoceptor agonists and corticosteroids. 5For inhaled corticosteroids, pharmacokinetic evaluation using oral charcoal to obviate alimentary absorption may be applied to quantify the relative gut and lung components of systemic bioavailability. In tandem with information on receptor potency and affinity, drug elimination and distribution, these data may help in part to explain observed differences between different inhaled corticosteroids in terms of their systemic bioactivity profiles. 6Studies are required to evaluate whether pharmacokinetic evaluation of lung absorption is a suitable way of quantifying delivery of nebulised aminoglycoside antibiotics, as for example in patients with cystic fibrosis. 7Pharmacokinetic evaluation appears to have an established role in the quantification of drug delivery to the lungs and provides important information which is complimentary to other techniques such as radiolabelled deposition. The next decade of research into pharmacokinetics of established and novel drugs and delivery systems is awaited with keen interest, and will hopefully provide a greater understanding into ways of optimising the benefit-risk ratio for inhaled drugs.     

Absolute oral versus inhaled bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids.

Orally inhaled drugs provide great benefit in the treatment of asthma as they are delivered directly to the site of action, i.e. the lung. The absolute oral inhaled bioavailability of a glucocorticoid results from the combination of the bioavailability of the dose delivered to the lung and the bioavailability of the dose delivered into the gastrointestinal (GI) tract. The majority of the dose delivered to the lung is absorbed and available systemically. For the portion of the glucocorticoid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass/pre-systemic metabolism in the GI tissue and liver. Since this oral component of the delivered dose does not provide any beneficial therapeutic effect but can contribute to the systemic side effects, it is desirable for the absolute oral bioavailability of inhaled glucocorticoids to be relatively low (which is the case with most of the glucocorticoids, < 25%). Another approach to limiting systemic exposure from inhaled delivery is to improve the effectiveness of the oral inhaled formulation and delivery device, by increasing the fraction of the total inhaled dose which reaches the lung. Since current inhalation technology can provide respirable fractions in the range of 30-50%, what is the significance of the oral component of systemic exposure in relation to the overall systemic exposure following the oral inhalation administration of glucocorticoids? Below a certain point (approximately 25%), lower oral bioavailability of inhaled drugs may not be clinically important with respect to systemic exposure if the lung targeting is good (30%).     

Emerging inhaled long-acting beta-2 adrenoceptor agonists for the treatment of COPD

Introduction: Chronic obstructive pulmonary disease (COPD), characterized by persistent and partially reversible airflow obstruction, is a leading cause of morbidity and mortality worldwide. Long-acting inhaled bronchodilators form the backbone for the maintenance therapy for this disease. The ultra-long-acting β₂-agonists (ultra-LABAs) represent novel pharmacologic agents with interesting potential benefits as stand-alone therapy or in combination with other therapies for the treatment of COPD.

Areas covered: In this review, we will focus newly developed ultra-LABAs, describing currently available evidence of their clinical effect and safety, their comparison relative to older long-acting β₂-agonists, and their potential niche in the maintenance treatment of COPD. We also provide an overview of the current landscape of available LABAs, and discuss the present understanding of the disease, and suggest possible future directions for COPD therapy.

Expert opinion: Ultra-LABAs are pivotal bronchodilators in the maintenance therapy of COPD as monotherapy or in combination with other agents. Their long-acting effect permits once daily dosing and their improved delivery using novel devices and their safety profile represent an important advancement in management of this disease.     

The self-administration of inhaled beta agonist drugs during severe asthma

Interviews were conducted with 101 consecutive adult patients admitted to Wellington Hospital with a diagnosis of asthma to assess the extent to which beta agonist drugs are self-administered by asthmatic patients during severe asthma. The 99 patients prescribed an inhaled beta agonist were subdivided into two groups: group A comprising 79 patients prescribed a beta agonist for inhalation via an inhaler (metered dose aerosol or dry powder device) alone; group B comprising 20 patients prescribed beta agonist for inhalation via both an inhaler and nebuliser. In group A, the attacks of asthma lasted greater than 24 hours in 64/79 patients, and 22% of these patients reported taking more than 60 doses of their inhaler, and 52% more than 30 doses during the 24 hr period prior to admission. In group B, the attacks of asthma lasted greater than 24 h in 17/20 patients, and 35% of these patients self-administered their nebuliser more than six times, and 76% more than four times during the 24 h period prior to admission. In addition to their nebuliser use, these patients also took a median 23 doses of their inhaler during this 24 h period. This use of inhaled beta agonist contrasts with the recommended practice in both the USA and Europe, where most physicians recommend no more than 15 doses of a beta agonist as the maximal dose per day. We conclude that asthmatic patients in New Zealand self-administer high doses of inhaled beta 2 agonist drugs during severe exacerbations of asthma.     

Establishing bioequivalence for inhaled drugs; weighing the evidence

INTRODUCTION: During drug development and product life-cycle management, it may be necessary to establish bioequivalence between two pharmaceutical products. Methodologies to determine bioequivalence are well established for oral, systemically acting formulations. However, for inhaled drugs, there is currently no universally adopted methodology, and regulatory guidance in this area has been subject to debate. AREAS COVERED: This paper covers the current status of regulatory guidance on establishing the bioequivalence of topically acting, orally inhaled drugs, the value and limitations of in vitro and in vivo bioequivalence testing, and the practical issues associated with various approaches. The reader will gain an understanding of the issues pertaining to bioequivalence testing of orally inhaled drugs, and the current status of regulatory approaches to establishing bioequivalence in different regions. EXPERT OPINION: Establishing bioequivalence of inhaled drug products involves a multistep process; however, methodologies for each step have yet to be fully validated. Our lack of understanding about the relationship between in vitro, in vivo and clinical data suggests that in most cases, unless there is a high degree of pharmaceutical equivalence between the test and reference products, consideration of a combination of preclinical and clinical data may be preferable to abridged approaches relying on in vitro data alone.     

Establishing bioequivalence for inhaled drugs; weighing the evidence

Introduction: During drug development and product life-cycle management, it may be necessary to establish bioequivalence between two pharmaceutical products. Methodologies to determine bioequivalence are well established for oral, systemically acting formulations. However, for inhaled drugs, there is currently no universally adopted methodology, and regulatory guidance in this area has been subject to debate.

Areas covered: This paper covers the current status of regulatory guidance on establishing the bioequivalence of topically acting, orally inhaled drugs, the value and limitations of in vitro and in vivo bioequivalence testing, and the practical issues associated with various approaches. The reader will gain an understanding of the issues pertaining to bioequivalence testing of orally inhaled drugs, and the current status of regulatory approaches to establishing bioequivalence in different regions.

Expert opinion: Establishing bioequivalence of inhaled drug products involves a multistep process; however, methodologies for each step have yet to be fully validated. Our lack of understanding about the relationship between in vitro, in vivo and clinical data suggests that in most cases, unless there is a high degree of pharmaceutical equivalence between the test and reference products, consideration of a combination of preclinical and clinical data may be preferable to abridged approaches relying on in vitro data alone.     

The future of antibodies as cancer drugs

Targeted therapeutics such as monoclonal antibodies (mAbs) have proven successful as cancer drugs. To profile products that could be marketed in the future, we examined the current commercial clinical pipeline of mAb candidates for cancer. Our analysis revealed trends toward development of a variety of noncanonical mAbs, including antibody-drug conjugates (ADCs), bispecific antibodies, engineered antibodies and antibody fragments and/or domains. We found substantial diversity in the antibody sequence source, isotype, carbohydrate residues, targets and mechanisms of action (MOA). Although well-validated targets, such as epidermal growth factor receptor (EGFR) and CD20, continue to provide opportunities for companies, we found notable trends toward targeting less-well-validated antigens and exploration of innovative MOA such as the generation of anticancer immune responses or recruitment of cytotoxic T cells.     

The scientific rationale of combining inhaled glucocorticoids and long acting beta 2 adrenoceptor agonists

Asthma is characterised by a chronic inflammatory process involving the airway wall leading to airflow limitation and bronchial hyperresponsiveness. This review describes the cellular molecular events underlying airway inflammation and remodelling in asthma and focuses on the distinct mechanisms of action of corticosteroids in beta agonists in asthma pathophysiology. In particular it discusses the evidence from studies both in vitro and in vivo to suggest that there is a complimentary beneficial interaction of these agents on the asthma process.     

Developing inhaled drugs for respiratory diseases: A medicinal chemistry perspective

Despite the devastating impact of many lung diseases on human health, there is still a significant unmet medical need in respiratory diseases, for which inhaled delivery represents a crucial strategy. More guidance on how to design and carry out multidisciplinary inhaled projects is needed. When designing inhaled drugs, the medicinal chemist must carefully balance the physicochemical properties of the molecule to achieve optimal target engagement in the lung. Although the medicinal chemistry strategy is unique for each project, and will change depending on multiple factors, such as the disease, target, systemic risk, delivery device, and formulation, general guidelines aiding inhaled drug design can be applied and are summarised in this review.     

未来畅销新制剂

开发药物新制剂不但可满足患者治疗和提高生活质量的需要,而且还可获得丰厚的经济收益。例如,强生公司开发出芬太尼透皮控释贴片（商品名：Duragesic）,使原只能在医院内受控使用的药品转而可让患者方便地携带出医院使用,2004年的全球年销售额达21亿美元。     

糖尿病治疗药的现况和今后发展方向

将治疗糖尿病的药物分类为胰岛素类,胰岛素分泌促进剂,胰岛素增敏剂,一氧化氮合酶抑制剂,糖原异生抑制剂,影响碳水化合物吸收的药物,中药类等类别分别进行综述,并指出今后发展方向.对今后中药的发展提出了看法.