Biomedical subjects
Publications and source records attributed to Mark Parry-Billings.
The publisher regrets that this is an accidental duplication of an article that has already been published inPulm. Pharmacol. Ther., 16 (2003) 79-95, doi:10.1016/S1094-5539(02)00147-5. The duplicate article has therefore been withdrawn.
The growth of clinical guidelines has helped to improve the standard of patient care with the archetypal document being the British Thoracic Society's guidelines on asthma management. In recent years however the fashion has evolved to style guidelines according to the tenants of 'evidence based medicine'. We examine the evidence behind this fashion and conclude that there is a grave danger of bias and distortion of the data from this approach.
Dry powder inhalers (DPIs) are increasingly being used to deliver drugs for the treatment of asthma. Both the aerosolization and delivery of the drug from a DPI to the lung are dependent on an adequate inspiratory effort from the patient, and it is well-known that the air flow achieved early in the inspiratory profile is important in determining particle size distribution from the inhaler. The present study assessed the peak inspiratory flow (PIF) generated through the Clickhaler DPI, and the early inspiratory flow at 150 mL of inspired volume (IF(150)), in asthmatic children. These measurements were made in a well-controlled setting, and two attempts were recorded to establish maximum achievement. Results were obtained from 57 children aged 6-17 years, showing a (mean +/- SD) best PIF of 60.5 +/- 18.7 L/min (range, 26.8-97.0). The mean PIF overall was 54.2 +/- 20.8 L/min (7.9-97.0). For children aged 6-8 years, the mean best PIF was 46.5 +/- 14.6 L/min (26.8-71.1); for those aged 9 years or more, it was >65 L/min (30.3-97.0). PIF values were unrelated to % predicted FEV(1) measurements. Best IF(150) (mean +/- SD) was 42.9 +/- 13.6 L/min (23.1-66.6) in children aged 6-8 years, and >55 L/min (28.0-86.4) for the older children, showing that high flow rates were achieved early in the inspiratory profile. These data indicate that children with stable asthma can generate adequate inspiratory flow rates to operate the Clickhaler effectively.
International agreements to ban the use of environmentally damaging chlorofluorocarbons (CFCs) have signalled an end to the traditional CFC-propelled pressurised metered dose inhaler (pMDI) which has long been the mainstay of topical asthma therapy. The need for acceptable and cost-effective replacement inhalers, combined with opportunities to develop generic formulations of patent-expired drugs, has fueled a lively response from the pharmaceutical industry. Improvements in pMDI design and reformulation with propellants such as hydrofluoroalkanes may offer significant advantages over CFC-pMDIs and prolong the widespread use of pressurised drug delivery systems for many years to come. In the longer term, however, another likely candidate for success in providing economical, efficient and acceptable inhaled therapies is the breath-actuated, multiple-dose dry powder inhaler (DPI). This review concentrates on the multiple-dose DPIs available within Europe today.
A new chemical entity (NCE) was evaluated in the Clickhaler (Innovata Biomed Ltd.) dry powder inhaler, a reservoir-based multidose delivery system. The standard device metering system was modified to handle higher doses (nominally 20 mm(3) of lactose based blend). The micronized drug was formulated at 12.5% w/w in lactose monohydrate (Pharmatose 325M, DMV) equivalent to a nominal dose of approximately 1 mg. Delivered shot weight (mg of blend) and emitted dose (microg drug) averaged 7.4 mg and 905 microg, respectively, and were consistent (within +/-20 to 25% of mean) through the life of the inhaler. The fine particle fraction (FPF) (Andersen cascade impactor) was typically 60%. A short stability study (i.e. 3 months at room temperature, 53 or 75% RH, unpacked) showed that the in vitro performance was maintained. The results of these studies provide in vitro proof of principle for this novel drug/device combination.
A scintigraphic study was carried out to compare the lung deposition of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in healthy volunteers. Validation of Technetium-99m ((99m)Tc) radiolabeling of the budesonide/lactose blend used in the Clickhaler and excipient-free budesonide used in the Turbuhaler was carried out using a multistage liquid impinger, and compared with reference unlabeled devices. Budesonide was quantified using high-performance liquid chromatography and (99m)Tc by scintillation counting. The percentages (SD) of fine particles (<5.5 microm diameter) from radiolabeled and unlabeled devices were not significantly different (p > 0.05). Mean values for drug and radiolabel, respectively, were 34.6% (2.5) and 31.6% (3.8) for the Clickhaler, and 29.8% (5.5) and 31.4% (5 6) for the Turbuhaler. Fifteen healthy male volunteers received a single dose (2 x 200 microg actuations) from both devices in a double-blinded, double dummy, crossover study. During dosing, each inhalation maneuver was recorded using a computer-linked pressure transducer. To permit accurate determination of radiolabeled drug deposition, the lung margins of each volunteer were determined by Krypton-81m ((81m)Kr) gas imaging. Mean [SD] lung deposition for the Clickhaler (26.8% [6.8], RSD 25.2) was significantly greater (p < 0.001) than for the Turbuhaler (15.8% [6.6], RSD 42.2). Inspiratory flow rate parameters were similar for both devices with peak and mean values of 73 and 51 L/min for the Clickhaler, and 73 and 47 L/min for the Turbuhaler, respectively. These results indicate that, in healthy volunteers, budesonide lung deposition was higher and more consistent with the Clickhaler than with the Turbuhaler.