摘要:

In patients with cystic fibrosis (CF), the poor clearance of airway secretions promotes recurrent cycles of pulmonary infection and inflammation. In recent years, novel drugs have been developed to alter the properties of the secretions in an attempt to aid chest physiotherapy in improving airway clearance. Once-daily nebulised recombinant human deoxyribonuclease (rhDNase; dornase alfa; Pulmozyme®) is the most widely used mucoactive therapy in patients with CF. It has been shown to reduce the viscoelasticity of sputum from patients with CF and enhance the clearance of secretions. Clinical trials have shown rhDNase to be a well tolerated treatment that improves pulmonary function and reduces respiratory exacerbations. However, the response to treatment is heterogeneous and only a proportion of patients with CF actually benefit from the treatment. At present, we are unable to predict which patients will benefit from rhDNase. Many CF centers have developed formal n-of-1 trials of treatment to find out who benefits and to justify prescribing the agent. rhDNase is an expensive therapy and is mainly used in patients over the age of 5 years with moderate to severe lung disease. However, studies have shown that rhDNase may be useful in patients with milder lung disease. Comparisons with another mucoactive drug, hypertonic saline, have shown rhDNase to be more effective. Recently, it has been shown that giving rhDNase on an alternate-day basis, rather than daily, is equally effective, potentially reducing costs and treatment time.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

There has been an exponential growth in the development of radiolabeled peptides for diagnostic and therapeutic applications in the last decade. The automated means of synthesizing these compounds in large quantities and the simplified methods of purifying, characterizing, and optimizing them have kindled attention to peptides as carrier molecules. These new techniques have accelerated the commercial development of radiolabelled peptides, which has provided additional radiopharmaceuticals for the nuclear medicine community.Peptides have many key properties including fast clearance, rapid tissue penetration, and low antigenicity, and can be produced easily and inexpensively. However, there may be problems within vivocatabolism, unwanted physiologic effects, and chelate attachment. Radiolabeled peptides have made their greatest impact in the management of relatively rare neuroendocrine malignancies. Indeed, Indium-111 (111In)-pentetreotide (111In-DTPA-octreotide, Octreoscan®), which binds to somatostatin receptors (SSTRs), has become the diagnostic ‘gold standard’ in these diseases. However,111In-pentetreotide has been less successful in the diagnosis of other more prevalent diseases in which SSTRs are upregulated. Technetium-99m (99mTc)-depreotide (NeoTect™), a99mTc-labeled SSTR-analog, could have wider impact since it has high sensitivity and specificity for lung cancer lesion detection. However, this impact may be minimized by the increased availability of positron emission tomography imaging with Fluorine-18 (18F)-flourodeoxyglucose, which has similar sensitivity and specificity for lesion identification in this disease, and is currently more widely used. The receptors for bombesin,α-melanocyte-stimulating hormone, neurotensin, and the integrin αvβ3, are under active investigation as targets for radiolabelled peptides, but are still in the pre-clinical stage. Compounds directed at the cholecystokinin-B/gastrin receptor have shown promising results in clinical trials in humans.Radiolabelled peptide therapy is usually indicated for patients with widespread disease that is not amenable to focused radiation therapy or is refractory to chemotherapy. Phase I/II studies using various radiolabelled peptides (including111In-pentetreotide, Yttrium-90 [90Y]-DOTA-Phe1-Tyr3-octreotide,90Y-DOTA-lanreotide, and Lutetium-177 [177Lu]-DOTA-octreotate) for the treatment of patients with neuroendocrine malignancy are in progress. Over 400 patients have been treated, and the response rate has ranged from 60% to 75%, although few patients have had a complete response. Patients have been given individual doses ranging from 2 to 11 GBq with a slow infusion every 4–8 weeks (up to 12 times). The kidney is the dose-limiting organ and most patients experience a transient decline in blood cell counts. A concomitant infusion of an amino acid mixture can reduce kidney toxicity and increase the effective tumor dose. Other peptides currently under investigation, some of which have shown promising results, include Rhenium-188 (188Re)-P2045 and90Y-αvβ3antagonist.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

A wide variety of peptide drugs are now produced on a commercial scale as a result of advances in the biotechnology field. Most of these therapeutic peptides are still administered by the parenteral route because of insufficient absorption from the gastrointestinal tract. Peptide drugs are usually indicated for chronic conditions, and the use of injections on a daily basis during long-term treatment has obvious drawbacks. In contrast to this inconvenient and potentially problematic method of drug administration, the oral route offers the advantages of self-administration with a high degree of patient acceptability and compliance. The main reasons for the low oral bioavailability of peptide drugs are pre-systemic enzymatic degradation and poor penetration of the intestinal mucosa. A considerable amount of research has focused on overcoming the challenges presented by these intestinal absorption barriers to provide effective oral delivery of peptide and protein drugs. Attempts to improve the oral bioavailability of peptide drugs have ranged from changing the physicochemical properties of peptide molecules to the inclusion of functional excipients in specially adapted drug delivery systems. However, the progress in developing an effective peptide delivery system has been hampered by factors such as the inherent toxicities of absorption-enhancing excipients, variation in absorption between individuals, and potentially high manufacturing costs. This review focuses on the intestinal barriers that compromise the systemic absorption of intact peptide and protein molecules and on the advanced technologies that have been developed to overcome the barriers to peptide drug absorption.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Cachexia, usually defined as the loss of >5% of an individual’s baseline bodyweight over 2–6 months, occurs with a number of diseases that includes not only AIDS and advanced cancer but also chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease, Crohn disease, and renal failure. Anorexia is considered a key component of the anorexia-cachexia syndrome. Progestogens, particularly megestrol acetate, are commonly used to treat anorexia-cachexia. The mechanism of action of megestrol is believed to involve stimulation of appetite by both direct and indirect pathways and antagonism of the metabolic effects of the principal catabolic cytokines. Because the bioavailability of megestrol acetate directly affects its efficacy and safety, the formulation was refined to enhance its pharmacokinetics.Such efforts yielded megestrol acetate in a tablet form, followed by a concentrated oral suspension form, and an oral suspension form developed using nanocrystal technology. Nanocrystal technology was designed specifically to optimize drug delivery and enhance the bioavailability of drugs that have poor solubility in water. Megestrol acetate nanocrystal oral suspension is currently under review by the US FDA for the treatment of cachexia in patients with AIDS. Preclinical pharmacokinetic data suggest that the new megestrol acetate formulation has the potential to significantly shorten the time to clinical response and thus may improve outcomes in patients with anorexia-cachexia.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Anakinra (Kineret®) is the first biologic drug that has been developed specifically as an interleukin (IL)-1 receptor antagonist (Ra) and is derived from an endogenous IL-1Ra. The drug blocks the activity of IL-1 in synovial joints, reducing the inflammatory and joint destructive processes associated with rheumatoid arthritis (RA). In randomized, placebo-controlled trials of up to 52 weeks' duration, anakinra has shown efficacy both as monotherapy and in combination with other disease-modifying antirheumatic drugs (DMARDs) in adults with RA. It is subcutaneously administered and is generally well tolerated. Anakinra offers a useful addition to the range of drugs available for the treatment of RA.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS