Characterization of Solid Dispersions of Itraconazole and Hydroxypropylmethylcellulose Prepared by Melt Extrusion,Part II

Purpose. This study was done to elucidate the physical and pharmaceutical properties of itraconazole-HPMC dispersions and the influence of water on the phase separation. Methods. Extrudates were prepared using a corotating twin-screw hot-stage extruder with fixed process parameters. Modulated-temperature differential scanning calorimetry (MTDSC) and DSC 111 were used to examine the mixing behavior of itraconazole and the carrier by evaluation of the glass transition region. High temperature diffuse reflectance infrared transform spectroscopy (HT-DRIFT) was performed to reveal interactions between itraconazole and HPMC. Dissolution was performed to investigate the pharmaceutical performance of the dispersions. Results. Although the dissolution rate of itraconazole significantly increased, we found that the solid dispersions do not form a homogeneous system. A different picture was obtained depending on the way MTDSC analysis was performed, i.e., using open or closed sample pans. Water can evaporate in open pans, which allows itraconazole to interact with HPMC and leads to a partially mixed phase. Analysis in hermetically closed pans revealed a further phase separation as water remains on the sample and impedes the interaction between drug and polymer. Conclusions. Solid dispersions of itraconazole and HPMC do not form a homogeneous phase.     

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Effect of transcoronary ablation of septal hypertrophy on clinical outcome in hypertrophic obstructive cardiomyopathy associated with atrial fibrillation

Summary Background Relatively few reports on the clinical impact of atrial fibrillation (AF) in hypertrophic obstructive cardiomyopathy (HOCM) are available. The aims of our study are to report the effect of transcoronary ablation of septal hypertrophy (TASH) on clinical outcome in HOCM associated with AF and to evaluate the influence of AF on symptoms and quality of life in HOCM. Patient and methods In 80 consecutive patients (38 f, mean age 56 ± 17 years) with severely symptomatic HOCM referred for interventional treatment, we analyzed the prevalence of AF based on 240 Holter ECG recordings and patients’ history, retrospectively. Symptoms, quality of life, number of hospital admissions and hemodynamic performance were obtained in all patients before and after TASH. Mortality was additionally investigated by letter and telephone contact. Results The overall prevalence of AF was 29%. Paroxysmal AF was detected in 17 pts (21.3%), persistent AF in 5 pts (6.3%). Only 1 pt (1.3%) suffered from permanent AF. Symptoms due to AF were present in 52.6% of the AF patients. Quality of life score was markedly improved after TASH (15.9 ± 3.8 vs. 20.7 ± 3.8, p < 0.001) with no difference between sinus rhythm and atrial fibrillation. However, hospital admissions were more frequent in the AF group (0.85 ± 1.84 vs. 0.28 ± 0.81, p = 0.03) in 32 ± 13 months. AF patients suffered more often from syncope before TASH (30 ± 70% vs. 10 ± 30%, p = 0.008). Two patients with sinus rhythm at baseline died after 32 ± 13 months from cardiovascular cause. Conclusions Atrial fibrillation is the major cardiac arrhythmia in severe HOCM. The majority of AF patients demonstrate AF specific symptoms. The paroxysmal type of atrial fibrillation dominates by far. Both patients with and without atrial fibrillation showed similar quality of life with marked improvement after TASH.     

Acute and long-term results after transcoronary ablation of septal hypertrophy (TASH). Catheter interventional treatment for hypertrophic obstructive cardiomyopathy.

Aims: To evaluate acute and long-term symptomatic, haemodynamic (at rest and during exercise) and electrophysiological results of transcoronary ablation of septal hypertrophy (TASH), a catheter interventional treatment for hypertrophic obstructive cardiomyopathy. Methods and Results: Sixty-two transcoronary ablations of septal hypertrophy were performed by injection of 4.6+/-2.6 ml 96% ethanol into septal branches in 50 patients with hypertrophic obstructive cardiomyopathy and severe symptoms. Serial left and right heart catheterization, transoesophageal echocardiography and electrophysiological investigations were repeated 2 weeks and 7+/-1 months (n=37) after intervention. Transcoronary ablation of septal hypertrophy led to a reduction in septal thickness, sustained elimination of the outflow obstruction (51+/-41 vs 6+/-10 mmHg at rest, P<0.001; 134+/-48 vs 28+/-32 mmHg, P<0.001, post-extrasystolic), a decrease in left ventricular filling pressures at rest and during exercise and a pronounced clinical improvement. There was no evidence for the creation of an arrhythmogenic substrate as assessed by serial programmed electrical stimulation in 39 patients. However, permanent high-grade atrioventricular block occurred in 17% of the patients. There were two early, but no late deaths during a mean follow-up time of 10. 6+/-5.6 months. Conclusion: Transcoronary ablation of septal hypertrophy is a promising new treatment for hypertrophic obstructive cardiomyopathy in patients with severe symptoms. It should now be compared with alternative treatment strategies in prospective randomized studies.     

Diminished adult neurogenesis in the marmoset brain precedes old age

With aging there is a decline in the number of newly generated neurons in the dentate gyrus of the hippocampus. In rodents and tree shrews, this age-related decrease in neurogenesis is evident long before the animals become aged. No previous studies have investigated whether primates exhibit a similar decline in hippocampal neurogenesis with aging. To investigate this possibility, young to middle aged adult common marmosets (Callithrix jacchus) were injected with BrdU and perfused 3 weeks later. The number of newly generated cells in the subgranular zone/granule cell layer of the dentate gyrus was significantly lower in older animals and decreased linearly with age. A similar age-related decline in new cells was observed in the subventricular zone but not in the hilar region of the dentate gyrus. These data demonstrate that a substantial decrease in neurogenesis occurs before the onset of old age in the adult marmoset brain, suggesting the possibility that similar alterations occur in the human brain.