Importance of programmed ventricular stimulation in patients with ventricular salvos

The yield of programmed ventricular stimulation in asymptomatic patients with documented ventricular salvoes is not definitely known. Therefore, we retrospectively evaluated the data of 57 patients in whom ventricular salvoes had been observed, either during resting ECG or 24-hour ECG monitoring, and who had been studied using programmed ventricular stimulation. Of these patients, 63% were male, with a mean age of 49 years. 28% had coronary artery disease, 21% dilated cardiomyopathy, 16% mitral valve prolapse, 9% hypertrophic cardiomyopathy, 9% valvular heart disease and 14% had no structural heart disease. Using a maximum of two premature ventricular extrastimuli during programmed ventricular stimulation, sustained ventricular tachycardia or ventricular fibrillation was induced in nine patients (16%). In 30 patients (53%) nonsustained ventricular tachycardia was induced (3-35 ventricular echo beats), in 18 patients only one to two ventricular echo beats could be induced. In 8/16 patients (50%) with coronary artery disease, sustained ventricular tachycardia/ventricular fibrillation could be induced. Mean left ventricular ejection fraction did not differ between patients with inducible sustained ventricular tachyarrhythmia and those with inducible non-sustained ventricular tachycardia or those with a normal result during programmed ventricular stimulation. 33 patients were treated with antiarrhythmic drugs; the efficacy of antiarrhythmic therapy was either controlled by "serial electrophysiologic testing" in four patients, or by repeated 24-hour long-term ECG in 29 patients. During a mean follow-up period of 31 +/- 24 months five patients died, two of them suddenly. None of the remaining patients had experienced a symptomatic sustained ventricular tachycardia or a syncope.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of non-disintegrating tablet dimensions and density on their gastric emptying in fasted volunteers

The aim of this work was to identify the influence of tablet density on their gastric emptying in fasted subjects and to compare the findings with those of a previous study using the same subjects with tablets of a larger diameter. Tablets of 6.6 mm diameter and densities of 1.41 and 2.85 g cm-3 were labelled with 99mTc and 111In. They were coated with ethyl cellulose to ensure that they remained intact within the gastrointestinal tract. Their position within the gastrointestinal tract of fasted healthy subjects was monitored with a double-headed gamma camera at 1-min time intervals. The median gastric emptying time and the interquartile range were derived from the Bernoulli random event distribution. It was found that the dense tablets had a significantly longer gastric emptying time than the light tablets. Comparison with the results from the previous study gave a clear indication that irrespective of tablet density, the 6.6-mm tablets had longer gastric emptying times than the 12.0-mm tablets.     

Gastrointestinal transit of model mini-tablet controlled release oral dosage forms in fasted human volunteers

The aim of this study was to compare the gastrointestinal transit of multiple unit, small diameter (3.2 mm), non-disintegrating tablets of differing densities with results previously reported in the same volunteers in the fasted state for larger diameter (6.6 and 12.2 mm) tablets. The gastrointestinal transit was observed with gamma-scintigraphy at various intervals over a 9-h period to give an accurate assessment of the transit characteristics. The value for the median emptying time of the first light tablet was significantly shorter than that for the dense tablet, but the total emptying time and the time for the last tablet to empty for both sets of tablets were not statistically different. The value of the median time for initial and final emptying of the small tablets from the stomach was significantly longer than that for the larger diameter tablets. The 9-h time limit of the observations limited the estimation of the time taken to enter the caecum and consequently the small intestine transit times. There was clear evidence that for the dense tablets of all sizes, the value for the small intestine transit time was longer than the 3-4 h reported in the literature. The only tablet system to enter the caecum within the time limit of the study was the normal density 12.2-mm tablets.     

Starch-based coatings for colon-specific delivery. Part II: Physicochemical properties and in vitro drug release from high amylose maize starch films

This work reports an investigation into free-film properties of a high amylose maize starch-based film coating that has been used in the preparation of formulations for drug delivery to the colon (WO 2008/012573 A1) and relates these properties to in vitro drug release from pellets.Maize starch/ethylcellulose free films were prepared and characterised by scanning electron microscopy (SEM), light microscopy, modulated differential scanning calorimetry (mDSC), Fourier-transform infrared (FT-IR), X-ray and % swelling in aqueous fluids with pH conditions similar to the stomach and small intestine. 5-ASA release from film-coated pellets was tested in enzyme free simulated gastric fluid and phosphate buffer pH 7.2. Selected formulations were further assessed in simulated gastric and intestinal fluids containing pepsin and pancreatin, respectively.The free films prepared were smooth and homogeneous in their appearance. The two polymers are immiscible, and neither mDSC nor FT-IR could detect interactions between them. Films made from high amylose starches were found to have a considerably lower swelling ability than high amylopectin-based films, and they suppressed drug release in the enzyme free media successfully.5-ASA release from pellets coated with mixtures of high amylose starches (Hylon^® VII, Hylon^® V or LAPS) and Surelease^® in a ratio of 1 to 2 w/w was found to be minimal in simulated gastric and intestinal fluids. This suggests that these mixed films provide starch domains that are resistant to the enzymes present in the upper GI tract and thus can potentially be used in the preparation of colon-specific delivery devices. Starches with a minimum amylose content of 56% such as the starches used in this study (Hylon^® VII and Hylon^® V) are preferred, and although pure amylose can also be used this is not essential.     

Characterization of microcrystalline cellulose and silicified microcrystalline cellulose wet masses using a powder rheometer.

A powder rheometer has been used to study the properties of wet powder masses and the results have been compared to the mixer torque rheometer (MTR). Two different microcrystalline cellulose (MCC) grades (Avicel and Emcocel) and silicified microcrystalline cellulose (SMCC, Prosolv) were used as model powders. The wet massing behaviour of one material (Prosolv) was studied by the powder rheometer using liquid addition experiments, while the rheological properties of wet granules were studied using both the powder rheometer and the MTR. In water addition measurements the torque behaved in a similar way to MTR measurements and the maximum value of ZTL (zero torque limit) was achieved at the capillary state of wet mass. The wet granules exhibited different behaviour in the powder rheometer and the MTR experiments, which indicates that these rheometers involve different shear forces or they measure different properties of the wet granules. Emcocel wet masses achieved the capillary state at lower liquid amount than Avicel and Prosolv masses, which indicates that Emcocel is not able to hold as much water in the internal structure as Avicel and Prosolv. The powder rheometer proved to be a sensitive piece of equipment, which can be used to study both dry and wet powder masses. It was able to distinguish wet granules from wet powder masses after liquid addition, whereas the MTR could not. However, before the powder rheometer can be properly utilised in wet powder mass studies, the problem of torque overload requires resolution.     

Application of dynamic mechanical analysis (DMA) to the determination of the mechanical properties of coated pellets

Pellets containing a model drug, paracetamol, and microcrystalline cellulose (MCC) were designed to vary their mechanical properties by the incorporation of lactose, glyceryl monostearate (GMS), ethanol, or glycerol, and were produced by the process of extrusion and spheronization. The pellets were coated with an aqueous dispersion of ethyl cellulose (Surelease) to different levels of weight gain (5, 10, and 20%). The tensile strength, deformability, linear strain, elastic modulus, and shear strength of the coated and uncoated pellets were determined by conventional techniques, which are obtained from diametral compression test of individual pellets and compaction of a bed of pellets. Dynamic Mechanical Analysis (DMA) was performed on single pellets to determine the storage modulus and phase angle of the coated pellets. This work demonstrated that the coating film affected the mechanical properties of the pellets differently depending on the properties of the core pellets. Analysis of variance established a significant increase in the strength of the soft GMS- or glycerol-containing pellets with coating, while the effect of the coating material was not significant with respect to the elastic modulus, storage modulus, and phase angle of such pellets. The effects of the coating material on the elastic modulus, deformability, storage modulus, and phase angle of the rigid lactose-containing pellets were significant. The sinusoidal stress-relaxation cycle of the DMA illustrated the increase in the viscoelasticity of all the pellets after coating. Finally, the work demonstrate the advantages of DMA in determining the reversible or dissipated energy by means of storage modulus or phase angle when compared with the irreversible structural destruction of the pellets by conventional techniques.     

Characterisation of the mechanical properties of polymer films formed from aqueous polymer dispersions by creep testing

The mechanical properties of films formed from an aqueous dispersion of polymethlymethacrylate (Eudragit NE30D) and as mixture with an aqueous dispersion of ethylcellulose (Aquacoat ECD30), have been assessed by applying creep tests at different temperatures, using a dynamic mechanical analyser. In the region of linear creep, the film prepared from 100% Eudragit was far less elastic than when 60% Aquacoat was present. In this region, when the applied stress was doubled, the strain response was doubled. In the non-linear region of behaviour, there is clear evidence that the mixed film is more elastic than the film containing only Eudragit.     

Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables

Pellets comprising chitosan, cellulose microcrystalline, povidone, filler excipient and diclofenac sodium as model drug were prepared by extrusion-spheronisation. The effects of chitosan load (zero, 0%, low, 4% and high, 16% levels), type of filler (lactose, tribasic calcium phosphate and beta-cyclodextrin) and composition of the binding liquid (ethanol/water mixtures 20 and 50%) on physical characteristics of pellets were evaluated. A three-factor factorial design was employed in the study. Analysis of variance (ANOVA) indicated that single factors had significant effect on the physical characteristics of the pellets. The type of filler followed by polymer load markedly affected the density. The type of binding liquid had negligible effect on the shape and surface roughness of the pellets. Increase in the chitosan load resulted in pellets of lower porosity values. This could be attributed to the binding capacity of chitosan and povidone leading to more compacted structures. Chitosan load and type of filler had significant influence on the surface roughness. The surface of pellets became rougher as the chitosan load increased, however, there was no significant difference between zero and low contents of chitosan. Pellets prepared using tribasic calcium phosphate showed a smoother surface when compared with formulations including lactose or beta-cyclodextrin. Chitosan was useful to provide pellets of acceptable physical characteristics when employing an alcohol/water mixture 50% (v/v) as binding liquid for the extrusion-spheronisation process.     

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine

Purpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and C_max parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.