Acute and long-term efficacy of propafenone in patients with sustained ventricular tachyarrhythmias: assessment with programmed ventricular stimulation

To determine the electrophysiological properties of oral propafenone, 50 patients (39 male and 11 female, aged 31 to 80 years) with sustained ventricular tachycardia or ventricular fibrillation underwent serial electrophysiological drug testing, using propafenone (750 to 900 mg daily) as the anti-arrhythmic regimen of first choice. During baseline study, all patients had inducible sustained ventricular tachyarrhythmias. After oral loading of propafenone, 37 patients (74%) remained inducible whereas 13 were rendered non-inducible. Among the still inducible patients, the mean VT rate decreased from 223 +/- 38 b.min-1 (baseline) to 172 +/- 32 b.min +/- 1 (P less than 0.001). Four patients showed an increase of VT rate during propafenone compared to the VT rate at control. Non-inducible patients were discharged on propafenone. During a mean follow-up period of 20 +/- 15 months, there were three non-fatal VT recurrences among the responders, two of them due to non-compliance. Thus, propafenone used as the anti-arrhythmic agent of first choice among patients undergoing serial electrophysiological drug testing for ventricular tachyarrhythmias proved effective in suppressing VT induction in 26%. With regard to arrhythmic events, these patients have a favourable outcome.     

Acute and long-term efficacy of oral propafenone in patients with ventricular tachyarrhythmias.

The class Ic antiarrhythmic agent propafenone was studied by repeated electrophysiologic testing in 54 patients (43 male, aged 54 +/- 10 years, mean ejection fraction of 37.3 +/- 16.9%) with ventricular tachyarrhythmias. Forty patients (74%) had coronary artery disease. Programmed ventricular stimulation (S2, S2S3 during sinus rhythm and/or during S1S1 = 500, 430, 370, and 330 ms) off antiarrhythmic drugs induced sustained ventricular tachycardia, flutter, or fibrillation in all patients. After 450-900 mg of oral propafenone/day for 4-7 days, 51 patients were restudied. In the remaining three patients, spontaneous ventricular tachycardia occurred on drug therapy. Tachycardia induction was suppressed in 9 of 51 patients restudied (18%) and rendered more difficult to induce (basic stimulation drive greater than or equal to 40 beats/min higher than at control study) in another 7 patients (14%) (overall efficacy of 31%). The tachycardia rate decreased from 220 +/- 43 to 177 +/- 44 beats/min (p less than 0.01). The right ventricular effective refractory period increased from 232 +/- 22 to 252 +/- 22 ms (p less than 0.001). Responders to propafenone therapy had higher rates of inducible ventricular tachycardia at control (greater than 230 beats/min: 43%; less than or equal to 230 beats/min: 21%; p less than 0.05), higher ejection fractions, and lower left ventricular end-diastolic pressures than nonresponders. Eleven of the 16 patients showing a positive response to propafenone therapy in electrophysiologic testing were discharged on propafenone alone. During follow-up (17 +/- 12 months), nine patients remained free from ventricular tachycardia, one patient had a relapse, and one patient died of noncardiac death.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adverse selection and regulation in health insurance markets

In this paper we look at various ways to regulate the health insurance market and ask whether they provide an answer to the problem of adverse selection. To avoid inefficiency, government policy must either effectuate some cross-subsidization of insurance policies within the state sector or grant private insurance firms an exclusive right to serve certain groups of the population. Recent reforms in the Netherlands and Germany and President Clinton's proposals for the US could be adapted to fulfil these requirements. Efficiency cannot be achieved, on the other hand, if the regulator tries to "prescribe" cross-subsidization within the private sector.     

The rheological properties of self-emulsifying systems, water and microcrystalline cellulose.

The rheological properties of mixtures of equal parts of a range of ratios of a self-emulsifying system (MP) and water (W) added to microcrystalline cellulose (MCC), have been measured by an extrusion capillary rheometer. These measurements allow assessment of both the shear and tension components of flow plus the elastic behaviour of the wet powder masses, although the results for the estimation of shear stress require careful interpretation due to the limitation of the measuring system and the assumptions made in their derivation. The results indicate that there are three regions of behaviour of the systems, which are all significantly different from the mixtures containing only W and MCC. At low MP contents (1.5--23%), the masses increase in their resistance to shear and elongational flow and have lower elasticity. These similarities in behaviour occur in spite of considerable increase in the viscosity of the MPW mixtures and a change to non-Newtonian flow of the fluid. The behaviour of the 46% MP system is intermediate between these systems and the high MP concentrations (69, 80 and 92%). These latter systems show less resistance to shear and elongational flow than the first group of concentrations, but show considerably higher levels of elasticity. As the resistance to shear decreases, so does the impairment of the surface of the extrudate. There is clear evidence of a systematic change in behaviour of the wet powder masses as the values for the angle of entry of the wet mass into the die when plotted against the ratio of the resistance to die entry (upstream pressure loss) to the shear stress within the die, is linear on a log/log scale. Also, the values of compliance of the systems as a function of shear stress fall on a common curve. Changes in the ratio of the MPW to MCC for a system for a single level of MP (46%) resulted in a change in the values of the rheological parameters but not the type of behaviour. As all these wet powder masses had been shown previously to form pellets by the process of extrusion/spheronization, it is clear that systems with a wide range of rheological characteristics can be processed and no single rheological parameter can be used to provide complete characterisation of the processability of such systems.     

Feasibility study for the rapid determination of the amylose content in starch by near-infrared spectroscopy.

Near-infrared (NIR) spectroscopy was used to determine the amylose content in six different starches, whose declared amylose contents ranged from 2 to 95% m/m. The amylose content of starches can vary considerably between batches depending on growth conditions and time of harvesting. An NIR calibration model was developed for amylose using simple laboratory produced mixtures of amylose and amylopectin in different ratios. The spectral region at 1700-1800nm showed a good correlation to the amylose content of these mixtures. A simple absorbance ratio calibration model using standard normal variate and first derivative pre-treated spectra gave a root mean standard error of prediction of 1.2% m/m. Application to real samples gave amylose contents in reasonable agreement with the average values stated by the supplier. NIR spectroscopy provides a rapid and non-destructive method for the quantitative determination and standardisation of amylose in starch and could make a suitable alternative to traditional techniques, such as complex formation of starch with iodine or n-butanol.     

The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture

A method of converting self-emulsifying drug delivery systems to a pellet form has been studied. Formulations with varied relative quantities of an oil/surfactant mixture, water, microcrystalline cellulose (MCC), and lactose were chosen in a statistical design after preliminary ranging experiments. Pellets were produced by extrusion/spheronization. The characteristics of the pellets were studied by sieving, disintegration testing, diametral compression, image analysis, non-contact laser profilometry, and scanning electron microscopy. The effects of the formulation variables on pellet properties were evaluated by analysis of variance. It was possible to relate the formulation variables to all the quantified pellet properties except the shape. The relative quantities of oil/surfactant and water had an effect on the amount of liquid and oil/surfactant that could be incorporated into the powder, extrusion force, median diameter, size spread, disintegration time, tensile strength, and surface roughness. The relative quantities of lactose and MCC had an effect on the amount of liquid and oil/surfactant that could be incorporated into the powder, tensile strength, and roughness only. Water was an essential element of the formulations. The maximum quantity of the specific oil/surfactant combination studied that can be incorporated was 42% of the dry pellet weight.     

Theoretical and experimental investigations into the delamination tendencies of bilayer tablets

A controlled release resinate beads of betahistine diHCl (BHCl), a short half-life freely water soluble drug, was developed to allow once-daily administration to improve patient compliance and eliminate the risk of intolerance of the drug. BHCl-resin complex was subsequently coated with Eudragit RS100. A 2(4) full factorial design was employed for optimization and to explore the effect of Eudragit RS100 concentration in the coating solution (X(1)), the coating percentage (X(2)), the speed of rotation (X(3)) and the concentration of plasticizer (PEG 400) (X(4)) on the release rate of the drug from the microcapsules. The extent of coating (Y(1)), and the percentage drug released at given times (Y(2), Y(3) and Y(4)) were selected as dependent variables. The optimization process was performed for X(1), X(2), X(3) and X(4) using target ranges of these responses determined based on target release model deduced form zero-order dissolution profile of BHCl for once-daily administration. The levels of X(1), X(2), X(3) and X(4) of optimized BHCl microcapsules are 14.42%, 50.63%, 1495rpm and 9.94%, respectively. The calculated value of f(2) for the optimized BHCl microcapsules filled into hard gelatin capsules was 67.03 indicating that the dissolution profiles of the optimized formulation is comparable to that of the target release model. It could be concluded that a promising once-daily extended-release microcapsules of the highly water soluble drug, BHCl, was successfully designed.     

The influence of plate design on the properties of pellets produced by extrusion and spheronization

The aim of this work was to produce pellets using a standard formulation by means of extrusion and spheronization. Three different spheroniser friction plate patterns (i.e. cross-hatch, radial, striated edge pattern) have been used in order to investigate whether the plate pattern affects physical properties of the pellets such as pellet size distribution, yield, shape, mechanical strength, density and drug dissolution. Extrusion was performed with a screen extruder and the screen size was varied to determine whether the extrudate produced could affect the physical properties of pellets. The plate load was also varied. Diclofenac sodium was chosen as a model drug. The pattern of the friction plate used in the spheronization of extrudates affected the properties of the pellets. Yield values varied by up to 20%, and for an otherwise optimised formulation the use of a striated edge plate appeared advantageous in this respect. However, these pellets had a reduced mechanical strength despite their lower porosity, which might be disadvantageous. In addition, other factors such as the amount of extrudate loaded into the spheroniser, the maintenance of a constant moisture content within the spheroniser and the size of the extruder screen influenced these findings significantly. The only physical property of the pellets that did not respond to the various changes in the manufacturing process of the pellets is the pellet shape, which remained spherical. The dissolution of the drug appeared to be related to the median pellet size and was only marginally affected by changes in the spheronization process.     

The rheological properties of modified microcrystalline cellulose containing high levels of model drugs

The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.