Advances in inhaled technologies: understanding the therapeutic challenge, predicting clinical performance, and designing the optimal inhaled product.

Inhaled medicines are designed mainly to provide safe and efficacious treatment of respiratory diseases, offering the potential advantages of targeted drug delivery such as reduced onset time and increased therapeutic ratio. However, as a flipside of targeted drug delivery, drug levels in the relevant effect compartment cannot be easily assessed. In combination with technical challenges associated with aerosolizing and administering an inhaled medicine, this renders inhalation product development demanding in the regulatory aspect as well. Emerging technologies that could address some of these challenges include (i) mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling, which in combination with experimental techniques such as positron emission tomography could provide information on local target engagement; (ii) patient-feedback features in combination with electronic monitoring, which may improve patient adherence as well as patient handling; and (iii) controlled-release formulations and nanotechnology-based formulations with high drug load, which may expand the scope of development of compounds and targets suitable for inhalation product development.

An edge-sensitive noise reduction algorithm for image processing.

An edge-sensitive noise reduction algorithm for digital image processing is proposed. It is designed as C-DLL to run as a macro command under Image-Pro Plus. Its properties are compared to the median filter and a simple smoothing kernel.

The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine.

OBJECTIVE: The primary aim of the present study was to investigate the effect of ketoconazole on the pharmacokinetics of nisoldipine. METHODS: A single dose of nisoldipine 5 mg immediate-release tablet was administered either alone or in combination with ketoconazole 200 mg (4 days pretreatment and concomitant administration) in a randomized crossover trial in seven healthy male Caucasian volunteers. Plasma concentration-versus-time profiles of nisoldipine and its metabolite M9 were determined. RESULTS: Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold, increase in mean AUC and Cmax of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. The ketoconazole-induced increase in plasma concentration of the metabolite M9 was of similar magnitude. CONCLUSION: The interaction is attributed to inhibition of cytochrome 3A4-mediated first-pass metabolism. Ketoconazole and other antifungal drugs of the substituted imidazole type as well as other potent inhibitors of cytochrome 3A4 should not be used concomitantly with nisoldipine.

Design of a PC-based system for time-domain and spectral analysis of heart rate variability.

Investigation of heart rate variability is the subject of considerable interest in physiology, clinical medicine, and clinical pharmacology. The functional assessment of the autonomic nerve system by observation of its main actors, the sympathetic and parasympathetic branch, is emphasizing the importance of autonomic regulation under different physiological circumstances, in several disease states, and under drug therapy. This paper describes a PC-based system designed with LabView that performs time-domain and frequency-domain analyses of heart rate variability as suggested by the guidelines of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Examples for heart rate variability are given for different physiological states along with an analysis and evaluation by the system described.

Butterworth equations for homomorphic filtering of images.

In digital image processing, the homomorphic filtering approach is derived from an illumination-reflectance model of the image. Homomorphic filtering can perform simultaneous dynamic range compression and contrast enhancement. Crucial for the success of the homomorphic approach is the selection of an appropriate frequency-domain filter function in order to modify the illumination and reflectance components of an image differently. The author found Butterworth type highpass equations far superior to other frequency-domain filter functions, including Gaussian equations, making the Butterworth highpass suitable for use with the homomorphic filtering approach. The program was written in Microsoft (MS) Visual C++ (filter) as well as MS Visual Basic (user interface) to run as a module under the image processing software package Image-Pro Plus.

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form.

OBJECTIVE: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. METHODS: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. RESULTS: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 micrograms.l-1 with a pronounced interindividual variability (% CV) of 89.5-108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 micrograms.l-1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 micrograms.l-1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. CONCLUSION: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.