Systemic absorption of rifamycin SV MMX administered as modified-release tablets in healthy volunteers.

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410±0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed.

Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers.

OBJECTIVE: To assess the pharmacokinetic and pharmacodynamic interactions of emedastine difumarate, a new antihistamine drug and ketoconazole. MATERIAL: Twelve healthy Caucasian volunteers were administered emedastine difumarate 4 mg oral capsules once daily for 10 consecutive days. From day 6 to day 10, ketoconazole 200 mg were co-administered twice daily. METHODS: The effects of multiple ketoconazole administration on emedastine kinetics were evaluated by comparing values obtained for pharmacokinetic parameters at steady state, with and without ketoconazole. C(ss,max), C(ss,min), tmax, AUCss, t(1/2) and Cl(ss)/F values, obtained after both treatments, were compared. Significant difference was defined as p < 0.05. QTc intervals from ECGs at baseline, after emedastine treatment and after emedastine-ketoconazole co-treatment were statistically compared. RESULTS: Emedastine steady state pharmacokinetics were slightly altered as a result of the ketoconazole co-treatment. AUCss rose by about 33% (increase ranging from 0.96 to 66.86, p < 0.001) and total clearance decreased by about 30% (ranging from 0.96 to 40.08, p < 0.001) with no change in the half-life. These events did not lead to relevant pharmacodynamic changes, i.e. maximum prolongation of the corrected QT interval (QTc) observed after 5 days co-treatment (day 10) was of about 4%. Rate and severity of anti-H 1 sedation episodes also did not increase on ketoconazole co-treatment. CONCLUSIONS: A moderate, but statistically significant interaction between emedastine and ketoconazole was observed. Pharmacodynamic data indicate no increase in the QTc interval during concomitant therapy. This result is consistent with the multiple emedastine metabolic pathways shown in man which supplement the metabolism by different enzymatic isoforms of CYP450. Concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals can therefore, be undertaken without special precautions.

An uncommon indication for tracheal resection.

In well selected cases, in which preoperative investigations allow us to plan a tracheal resection-anastomosis, surgery is the best current treatment also for secondary tumours involving the trachea. We report a case of a patient suffering from severe dyspnoea for tracheal stenosis due to recurrence of an epidermoid cancer of the tongue. Surgical treatment allowed us to obtain very good palliation.

Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation.

AIMS: The aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (MMX) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability. METHODS: Two phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of (153)Sm-labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco-scintigraphy. The effect of food was tested by comparing plasma pharmacokinetics after intake of a high fat and high calorie breakfast with fasting controls. RESULTS: (153)Sm-labelled tablets reached the ascending colon after a mean +/- SD 9.8 +/- 6.9 h. Initial tablet disintegration was observed in the ileum in 42% and the ascending and transverse colon in 33% of subjects. Ninety-six per cent of the dose was absorbed into the systemic circulation during passage through the whole colon including the sigmoid. Food significantly decreased C(max) values from 1429 +/- 1014 to 1040 +/- 601 pg mL(-1) (P = 0.028) and AUC values from 14 814 +/- 11 254 to 13 486 +/- 9369 pg h(-1) mL(-1) (P = 0.008). Mean residence time and t(max) increased by 12-29%. There was no drug accumulation after 1 week of once daily oral administration of budesomide. CONCLUSIONS: MMX-budesonide tablets appear suitable for targeted colonic drug delivery. Transit parameters and low systemic bioavailability warrant further studies with the new formulation.

[Acute treatment of arterial hypertension using calcium antagonists: comparison between diltiazem and nifedipine]. / Akute Behandlung der arteriellen Hypertonie mit Calcium-antagonisten: Diltiazem im Vergleich zu Nifedipin.

Calcium antagonists have been used for the acute treatment of hypertension. Among these compounds, diltiazem induces the least tachycardia in response to acute administration. The effects of this agent, in a dose of 0.3 mg/kg given intravenously, on arterial pressure, heart rate and plasma renin activity were assessed in 10 patients with benign moderate to severe essential hypertension; nifedipine (10 mg sublingually) in 10 patients or 5% glucose (placebo) in 4 patients was used as a control. As compared with the 5% glucose group, diltiazem caused a persistent fall in diastolic pressure during 60 minutes, but only a transient decrease in systolic arterial pressure and heart rate; plasma renin activity was unchanged. Nifedipine caused a persistent fall in both systolic and diastolic pressure and a slight but significant increase in plasma renin activity, but did not modify heart rate. The diltiazem-induced decrease in systolic pressure was significantly smaller than the pressure changes caused by nifedipine. Variations in plasma renin activity between the two calcium antagonists were not significant. These findings suggest that in patients with hypertension diltiazem exerts a less marked acute antihypertensive effect than nifedipine.