Terodiline, emepronium bromide or placebo for treatment of female detrusor overactivity? A randomised, double-blind, cross-over study

In a randomised, double-blind study, 20 women with idiopathic detrusor instability and associated symptoms were treated with terodiline 25 mg bd, placebo, and emepronium bromide 200 mg tds--each drug being given for 3 weeks with placebo as wash-out period before cross-over. The results were evaluated according to drug preference, frequency charts and elimination of detrusor instability on cystometry. Serum levels of both drugs were monitored as control of tablet intake. The preference for terodiline to placebo was statistically significant: 14/3 women (P less than 0.05), and the majority of women (12/4) preferred terodiline to emepronium. Terodiline also gave a small but significant reduction in 24 h micturition frequency and eliminated detrusor instability in almost 50% of the patients (P less than 0.05). Side effects were frequent but mild in all three treatment periods. It was concluded that terodiline offers an alternative in the treatment of female detrusor instability.     

Effect of diffusion chamber pore size on differentiation and proliferation of periosteal cells. An experimental study

The influence of the pore size of Nucleopore diffusion-chamber filters on the rate of proliferation and differentiation of periosteal cells in muscle was studied in 44 growing rabbits. Periosteal grafts were placed in chambers (16-19 in each experimental group) sealed with filters with a pore size of 0.4, 0.6, 0.8, 1.0, or 2.0 micron. Each chamber was implanted into the paraspinal muscle of the rabbit, where it remained for 16 weeks. The osteochondrogenic activity of the graft grew linearly when the pore size increased from 0.4 to 1.0 micron. In the chambers with a pore size of 2.0 micron, both bone and cartilage were found in only one chamber. Bone and cartilage were not found outside any of the chambers. The present results showed that the pore size of the filters significantly affected the ability of the periosteal graft to form bone and cartilage.     

Modeling in Frequency Domain Used for Assessment of In Vivo Dissolution Profile

Purpose. To present a model-dependent approach for the assessment of the in vivo drug dissolution profile based on in vitrodata for the multiple unit dosage form, as an alternative to the numerical method proposed in the study by Hayashi et al, Pharm. Res. 12:1333–1337 (1995). Methods. The data for aspirin granules administered to healthy subjects obtained in the above mentioned study were re-evaluated. The subject dissolution system was considered to consist of two subsystems connected in series, i.e. the subsystem describing the gastric-emptying process and the subsystem describing the intestinal dissolution process. The frequency response method was used to model the subject dissolution system. Results. The model in vivodissolution profile of aspirin, assessed as the integral of the model weighting function of the subject dissolution system, was in agreement with the in vivo cumulative absorption profile calculated by the Wagner-Nelson method. Conclusions. Comparison of dynamic properties of the subject dissolution system with the subsystem describing the gastric-emptying process yielded quantitative confirmation of the decisive role of the gastric-emptying process in the in vivodrug dissolution after administration in the multi unit dosage form.     

Effects of erythromycin on the propulsive motility of upper gastrointestinal tract in rats

The differences between the postprandial mixing or propulsion and the interdigestive motility of the gastrointestinal (GI) tract are already known. Earlier studies showed dose-dependent differences in the effects of erythromycin on interdigestive motility. The various GI side-effects (vomiting, diarrhoea) also suggest that there are different effects of erythromycin on the GI motility. The aim of our study was to examine postprandially the propulsive effects of different doses of erythromycin on the movement of intraluminal contents in the upper GI tract of the rat. The animals were fasted for 24 h before the experiments but water was given freely. The rats received 1.5 ml 1.5% methylcellulose painted with 0.05% phenol-red intragastrically (test solution). Erythromycin(E. lactobionate) was given intravenously at doses of 0.05, 0.1, 0.25, 0.5, 1.0 and 5.0 mg/kg 15 min before the administration of a test solution. The animals were sacrificed 20,60 and 120 min after administration of methylcellulose, when the distance between the front of the painted intraluminal contents and the pylorus was measured and expressed as a percentage of the total length of small intestine. The phenol-red content in the stomach and small intestine was measured spectrophotometrically and the gastric emptying was calculated from the ratio of the measured total and intestinal phenol-red content. Our results showed that the small doses of erythromycin (0.1 and 0.25 mg/kg) accelerated gastric emptying after 20 min but did not change significantly the propulsive motility of upper small intestine; however, large doses of erythromycin (1.0 and 5.0 mg/kg) decreased gastric emptying and upper GI motility after 20 and 60 min. In summary, the prokinetic action of small doses of erythromycin was demonstrated, but its effecttime on GI motility is short and the ratio of the stimulating and inhibitory doses is 1:10. This paper was presented at the Section of IUPHAR GI Pharmacology Symposium on ’Biochemical pharmacology as an approach to gastrointestinal disorders (basic science to clinical perspectives)‘, October 12-14, 1995, Pécs, Hungary.     

Combined anti-bradycardia/anti-tachycardia pacemaker-cardioverter-defibrillator systems in patients with recurrent ventricular tachyarrhythmias]

In 41 patients with recurrent sustained ventricular tachycardia and/or ventricular fibrillation an integrated pacemaker-defibrillator-system (PCD, Medtronic, model 7216 A or 7217 B) was implanted. In 21 out of 24 (88%) patients a new transvenous implantation technique in combination with a subcutaneous patch electrode was used. The implanted devices comprise antibradycardiac pacemaker functions, two different forms of antitachycardiac pacemaker functions (ramp and burst pacing), and internal cardioversion or defibrillation capabilities. During a mean follow-up of 8 months 147 episodes of ventricular tachycardia were detected, 131 of them were terminated successfully by antitachycardiac pacing; in 13 episodes internal cardioversion was applied to revert ventricular tachycardia. Twenty-seven episodes of ventricular fibrillation or rapid ventricular tachycardia (greater than 200/min) were detected and successfully terminated by internal defibrillation. In six patients with intermittent rapid atrial fibrillation, change of antiarrhythmic therapy was required to avoid activation of the device. The new integrated pacemaker-defibrillator systems improve therapy in patients with life-threatening tachyarrhythmias by reducing the number of internal cardioversions/defibrillations; the non-thoracotomy approach reduces the post operative risk.     

A chimeric EGFR/neu receptor in functional analysis of the neu oncoprotein.

As the factor binding to the neu protein has been unknown, it has not been possible to confirm experimentally the proposed growth-factor receptor like functions of the neu protein. To approach this problem we constructed a recombinant receptor which enabled ligand regulation of the neu tyrosine kinase. The hybrid receptor consisted of the extracellular ligand binding, transmembrane and protein kinase C-substrate domains joined to the intracellular tyrosine kinase and carboxyl-terminal domains of the neu protein. Several properties of NIH3T3 cells carrying this construct were tested. We obtained the first experimental evidence that the neu proto-oncogene has mitogenic and transforming activities only in the presence of a ligand stimulating its tyrosine kinase activity. Various cellular and molecular biological parameters indicated that the chimeric receptor behaved very similarly to the EGFR. Also, this chimeric receptor has allowed us to compare the constitutive oncogenic and the ligand-activated non-oncogenic activities of the neu tyrosine kinase. In the future we plan to focus on characterization of possible differences between EGFR and neu signalling in more differentiated cellular backgrounds.     

The relation of the accumulation of cadmium in human placenta to the intake of high-fibre grains and maternal iron status.

Exposure to cadmium via the diet is known to depend to a large extent on the intake of cereal grains, particularly the high-fibre fractions of wheat. Subjects with low iron status absorb more cadmium than those with better iron status. The purpose of the present study was to determine to what extent cadmium accumulation in human placenta is affected by the intake of grain fibre and maternal iron status during pregnancy. Thirty-nine pregnant women participated in the study. In each trimester the women were requested to complete a dietary history and to allow blood samples to be taken for haemoglobin, serum ferritin and serum thiocyanate determinations, the latter as a marker for smoking. At delivery the whole placenta was taken for the determination of the cadmium concentration. The 32 women who had serum thiocyanate levels less than 70 mumol/l, who had completed at least one dietary history and from whom a blood sample was obtained in the third trimester, were included in the final statistical analyses. In the group of women who consumed less than the median intake of grain fibre and had more than 15 micrograms ferritin/l serum in the third trimester, the placenta cadmium concentration was nearly half that in the placentae of women who had consumed more grain fibre or had lower iron status in late pregnancy.     

Possible anatomical base of snoring

Variations of the medial and inferior choanal limits may facilitate snoring. These are: 1) short vomer without crista choanalis vomeris and adaptational formations, 2) extremely concave posterior margin of the hard palate leading to disproportion between the muscular and aponeurotic part of m. tensor veli palatini and hence to a flabby soft palate especially during sleep, and 3) neonatal relation of the height and width of the choane resulting in a very large choanal region instead of relative reduction of choanal width compared to its increasing height. All these variations result in a flabby soft palate especially during sleep and may lead to formation of whirles of inspired air and snoring.     

Development of an auxotrophic oral live Shigella flexneri vaccine

An oral live attenuated Shigella flexneri vaccine candidate strain was constructed by making it auxotrophic and dependent on aromatic metabolites not available in mammalian tissues. An aroD gene of Escherichia coli K12 strain NK 5131, inactivated by insertion in it of the Tn 10 transposon, was transduced using phage P1 into a virulent S. flexneri serotype Y strain (Sfl 1) isolated from a patient with bacillary dysentery. One of the transductant strains Sfl 114 was found to invade HeLa cells in vitro, to cause plaque formation in HeLa monolayers (i.e. maintain intracellular multiplication in vitro), but to be unable to cause keratoconjunctivitis in guinea-pig eyes. When the strain was fed to Macacca fascicularis monkeys it was well tolerated, excreted for 1-4 days, and found to elicit a local intestinal sIgA and serum IgA, IgM and IgG responses. Monkeys challenged with 100 ID50 dose (1 X 10(11) bacteria) of the virulent parent Sfl 1 strain were completely protected from development of diarrhoea. Coloscopy of the monkeys and the sampling of intestinal biopsies showed that the vaccine protected against the surface epithelial erosions and ulcerations seen in unimmunized monkeys. Killing of invading virulent shigellae apparently took place intracellularly in the mucosa suggesting that cellular immune mechanisms played a role in the elicited host defence. The constructed S. flexneri Sfl 114 strain has the properties of a promising shigella vaccine and will next be the subject of studies with human volunteers.