Host defenses against respiratory tract infection: implications for anti-inflammatory drug development and treatment.

The human respiratory tract is exposed to a constantly changing environment which may bring it into contact with a variety of pathogenic organisms. A range of innate and acquired defence mechanisms have evolved to counter these threats. Several new classes of therapeutic agent which may interfere with these defence mechanisms have recently been marketed or are under clinical development; this paper reviews some key examples, with the potential implications for disease management.

Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma.

With new drugs being introduced to treat asthma it is timely to review criteria that can be used to assess efficacy in clinical trials. Anti-asthma drugs are classified into symptoms-modifying, symptom preventers and disease modifying agents. Attention is drawn to the types of experimental evidence required in preclinical studies to support further clinical development of a new therapy. Clinical trials demand careful selection of patients to maximise the strength of the efficacy signal according to the type of trial being designed. While provocation tests are useful in suggesting efficacy, negative tests do not necessarily indicate lack of anti-asthma activity. Therapeutic trial designs need to take account of duration of treatment, dose-response relationships and confirmatory trials. Outcome measures include symptoms, lung function, reduction in concomitant medication, exacerbations, quality of life and measures of inflammation. Interpretation of results need to include the clinical relevance of any changes as well as statistical significance. Special consideration needs to be given to the evaluation of drugs for acute severe asthma, asthma in children and older people, co-morbidity such as rhinitis, and inhaler devices. As with all drugs introduced into practice, careful attention needs to be paid to both short- and long-term safety.

Ribavirin--current status of a broad spectrum antiviral agent.

Ribavirin is a very broad-spectrum virustatic antiviral agent, first synthesised in 1972. It is characterised by low toxicity apart from reversible anaemia, usually mild. Its multiple mechanisms of action mean that viral resistance rarely develops. It can be administered orally, intravenously, or via a nebuliser. It has shown varying degrees of clinical efficacy in a variety of human diseases including respiratory tract infections due to respiratory syncytial virus and influenza, measles, herpesvirus infections, HIV infection, Lassa fever, haemorrhagic fever with renal syndrome, and (in combination with IFN-alpha) chronic hepatitis C infection. It may well prove of value against other emerging exotic infections (e.g., West Nile virus, Nipah virus).

Assessing lung deposition of inhaled medications. Consensus statement from a workshop of the British Association for Lung Research, held at the Institute of Biology, London, U.K. on 17 April 1998.

In vitro measurements of aerosol fine particle fraction (FPF) using particle-sizing apparatus (e.g. the twin impinger, multi-stage liquid impingers, cascade impactors) have a key role to play in the development of new pharmaceutical products and in quality control. However, use of in vitro methodology to attempt to predict lung deposition in vivo is of limited value due, in part, to the inability of current apparatus to mimic upper and lower airway anatomy satisfactorily. Estimates of FPF based on cut-off points ranging from 5-7 microns generally overestimate lung deposition as measured in vivo by gamma scintigraphy. We recommend that: 1. multistage apparatus (minimum five stages) be used to characterize particle size distribution adequately, over the range 0.5-5.0 microns; 2. where possible, measurements should be made at a range of rates and profiles of flow reflecting those likely to be generated using the inhalation device in clinical practice (including use by young and elderly patients with varying degrees of airflow obstruction); 3. encouragement should be given to the further development, standardization, and validation of apparatus with a 'throat' which more closely resembles the human oropharynx and larynx. Pharmacokinetic methods can give a good estimate of total, but not regional, lung deposition, with drugs which are either not absorbed via the gastrointestinal tract, or whose absorption can be blocked by co-administration of charcoal, thus avoiding confounding by absorption of drug substance deposited in the oropharynx and subsequently swallowed. Techniques which rely on evaluation of a timed fractional output of drug substance in the urine are susceptible to the inherent variability of rate of absorption across the respiratory epithelium. We recommend that consideration should be given to the further refinement and validation of PK methods which would more clearly identify the fractional dose deposited in the lung. Lung-imaging methodology, e.g. gamma scintigraphy, employing formulations radiolabelled with gamma-ray-emitting radionuclides such as 99mTc, can measure total lung deposition and oropharyngeal deposition, provided that the radiolabelling process is appropriately validated and suitable corrections are made for attenuation of gamma rays by body tissues. An estimate of regional lung deposition can be made by drawing 'regions of interest' on the scintigraphic image; the precision of this measure is limited by the two-dimensional (2-D) nature of most images which mean that there is an overlay of structures of interest (alveoli, small and large airways), which is most marked centrally. Three-dimensional (3-D) imaging techniques (e.g. single photon emission computed tomography, SPECT, and positron emission tomography, PET) have the potential to give more detailed data on regional lung deposition, but are currently more expensive, employ higher radiation doses, and are less well validated than 2-D (planar) imaging. We consider that, of the available imaging modalities, planar gamma scintigraphy represents current best practice for the assessment of lung deposition from inhaler devices where regional differences may be important. The methodology should be optimized by the adoption of generally accepted standards for radiolabelling, imaging, attenuation correction, and interpretation. It is important that deposition in all sites (device, oropharynx, lungs, stomach) should be quantified. Consideration should be given to refining the concept of regions of interest to coincide more closely with anatomical lung structures. Statistical methods to compare the size distributions of drug and radiolabel in validation experiments should be developed. In the longer term it is envisaged that three-dimensional imaging may play a more important part in evaluating lung deposition; an optimal three-dimensional anatomical model of lung zones of interest needs to be developed.

Current management of tuberculosis.

Current chemotherapeutic regimens against tuberculosis give excellent cure rates and low relapse rates if implemented and monitored correctly. This is fortunate since only two new drugs have been approved for use in this condition in the last 30 years. However, shortcomings in management and in patient compliance have resulted in an increasing prevalence of drug-resistant organisms. The global decline in the disease has been reversed due to a combination of factors including the HIV epidemic, ageing populations, poverty, and translocation of refugee populations due to conflict.

The treatment of tuberculosis: current status and future prospects.

Although a vaccine and effective chemotherapy against tuberculosis (TB) have been available for more than half a century, TB was declared a global emergency in 1993. Current chemotherapeutic regimens are being undermined by lack of resources for proper implementation and control, and the emergence of multi-drug resistant strains of Mycobacterium tuberculosis. Several new chemotherapeutic agents are under development, mainly derived from existing anti-TB drugs or broad-spectrum antibiotics. New experimental agents include immunomodulants and drugs directed against novel cellular targets.

New developments in the treatment of viral respiratory tract infections.

Most respiratory tract infections are viral in origin, yet until recently only a few effective therapies had been developed. This reflected the large number of causative agents and the generally benign course of most infections. However, increasing numbers of serious respiratory infections have been seen in recent years, due to the rising prevalence of immunodeficient patients and the emergence of previously unrecognised pathogens. Better understanding of viral structure, and novel methods of drug design and discovery are leading to the development of potentially valuable new treatments, particularly for influenza and respiratory syncytial virus infection.

Activity of bromhexine and ambroxol, semi-synthetic derivatives of vasicine from the Indian shrub Adhatoda vasica, against Mycobacterium tuberculosis in vitro.

The benzylamines, bromhexine and ambroxol, widely used as mucolytics, have a pH-dependent growth-inhibitory effect on Mycobacterium tuberculosis. As these compounds are concentrated in macrophages, they might exert a clinically useful effect on intracellular tubercle bacilli. This, combined with indirect effects including enhancement of lysozyme levels in bronchial secretions and levels of rifampicin in lung tissue and sputum, and possibly clearance of bacilli-laden mucus from cavities and bronchi, suggests a potentially useful adjunctive function for these agents in the therapy of tuberculosis, and adds credibility to early reports of the beneficial effect of benzylamines in this disease.

Pediatric tuberculosis in immigrants to the United Kingdom from the Indian sub-continent.

Tuberculosis (TB) is now an uncommon disease in the United Kingdom (U.K.) and its overall incidence is declining. However, the incidence of TB in immigrants from India, Pakistan, and Bangladesh (the Indian sub-continent, ISC) is much higher than in the native white population or immigrant groups from other areas, and this is so even for children of ISC ethnic origin born in the U.K. The clinical pattern of the disease also differs, extrapulmonary involvement being commoner in ISC patients than white patients. The epidemiology and management of TB in pediatric patients of ISC origin is reviewed and reasons for differences from other ethnic groups in the U.K. are discussed.

In vitro and in vivo effects of ribavirin on human respiratory epithelium.

The effects of ribavirin, a broad spectrum antiviral agent, on the structure and function of normal human nasal epithelium have been studied in vitro, as has also the in vivo effect of treatment with nebulised ribavirin on nasal mucociliary clearance of saccharin in four patients. Ciliary beat frequency was measured by a photometric technique, and changes in epithelial and ciliary ultrastructure were assessed by transmission electron microscopy. Ribavirin solution at the recommended concentration of 20 mg/ml had no adverse effects on ciliary activity in vitro; at concentrations of 50 mg/ml and above it slowed ciliary beating significantly and at 60 mg/ml caused ciliostasis associated with epithelial disruption. Nasal inhalation of ribavirin at 60 mg/ml for up to 20 minutes, however, did not slow nasal mucociliary clearance, nor did it adversely affect the ciliary beating or structure of nasal ciliated epithelium examined in vitro immediately after inhalation.

Economic and long-term benefits of ribavirin therapy on respiratory syncytial virus infection.

Ribavirin is a broad-spectrum antiviral agent. Administered as an aerosol, it has been shown to be clinically effective in improving the signs and symptoms of viral bronchiolitis in infancy, particularly cases due to respiratory syncytial virus (RSV). This paper reviews the evidence for economic and/or long-term clinical benefits from using ribavirin in the acute illness. There are data to suggest that use of ribavirin may lead to a reduction in therapeutic interventions and duration of hospital stay, with associated savings in hospital costs. Ribavirin reduces the production of RSV-specific IgE, and (in vitro) inhibits the release of inflammatory mediators from mast cells, suggesting that there could be beneficial effects on the incidence of postbronchiolitis wheezing. Confirmatory studies are in progress.

Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis.

In a randomised, controlled study alternate day prednisolone with an initial high dose phase ("prednisolone only series") has been compared with cyclophosphamide plus alternate day low dose prednisolone ("cyclophosphamide-prednisolone series") in 43 patients with previously untreated fibrosing alveolitis (five patients had received prednisolone in minimal dosage). In the prednisolone only series prednisolone 60 mg daily was given for one month and then reduced by 5 mg a week to 20 mg on alternate days or the minimum dose to maintain early improvement. Patients in the cyclophosphamide-prednisolone series received 100, 110, or 120 mg cyclophosphamide daily (depending on body weight) plus 20 mg prednisolone on alternate days. Treatment was continued indefinitely, or changed to the alternative regimen if the patient deteriorated, failed to improve, or developed drug toxicity. For response to treatment (as judged by change in breathlessness score, radiographic appearance, and lung function) patients were classified as improved, stable, or deteriorating. Deaths from cryptogenic fibrosing alveolitis were also analysed. Improvement had occurred at one or more assessments in seven of the 22 patients in the prednisolone only series and in five of the 21 patients in the cyclophosphamide-prednisolone series. At three years, however, only two of the 22 patients in the prednisolone only series were still improved and three stable, compared with one and seven of the 21 patients in the cyclophosphamide-prednisolone series (three of the seven had stopped treatment because of toxicity). Life table analysis suggested better survival in patients in the cyclophosphamide-prednisolone series but this was not significant. At three years 10 of 22 patients in the prednisolone only series had died compared with three of 21 patients in the cyclophosphamide-prednisolone series. With death or failure of first treatment regimen as outcome there was a significant advantage to the patients having cyclophosphamide-prednisolone. This advantage was explained in part by the better lung volumes in this group on admission. After allowance had been made for total lung capacity (TLC), no other factor was predictive of outcome. Analyses of subgroups according to TLC on admission showed that patients with a TLC below 60% predicted did badly and those with a TLC of 80% or more predicted did well with both regimens. Patients with an initial TLC of 60-79% predicted did better with the cyclophosphamide-prednisolone regimen. Side effects were uncommon in both series and those due to cyclophosphamide resolved when treatment was stopped. The combination of cyclophosphamide with prednisolone may be an alternative to prednisolone alone with an initial high dose phase. Many patients, however, failed to respond to either treatment.