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Biomedical subjects

N J Snell

Publications and source records attributed to N J Snell.

At least 19 recordsLinked to original sources
PubMed2001

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).

Animals↗
PubMed1999

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.

Administration, Inhalation↗
PubMed1999

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.

Animals↗
PubMed1996

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.

Ambroxol↗
PubMed1990

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.

Administration, Inhalation↗
PubMed1990

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.

Aged↗
PubMed1989

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.

Adult↗
PubMed1982

A trial of prophylactic mexiletine in home coronary care.

A double blind randomised study was undertaken comparing the effects of oral mexiletine and placebo given by general practitioners at home in the early stages of suspected acute myocardial infarction, and continued for six weeks. The study comprised 216 patients. In 59 the diagnosis of acute myocardial infarction was not confirmed. Of the 72 patients with confirmed myocardial infarction treated with mexiletine, 11 (15.3%) died, compared with 19 (22.4%) of the 85 patients given the placebo, and significantly fewer of the former compared with the latter had frequent ventricular ectopics or ventricular tachycardia recorded on 24 hour electrocardiograms. Numbers of patients transferred to hospital or withdrawn from the trial because of arrhythmia or heart failure were similar in the two treated groups. Ten (13.9%) of the patients taking mexiletine had the drug withdrawn because of side effects attributed to it, compared with three (3.5%) of the group taking the placebo. A further five patients (all on mexiletine) also had treatment withdrawn because of side effects but infarction was not later confirmed. The results indicate that oral mexiletine can be given safely to patients with suspected myocardial infarction at home by their general practitioners in the absence of a positive electrocardiographic diagnosis. The frequency of ventricular tachycardia is significantly reduced; but there is no evidence of reduced mortality.

Aged↗