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Abstract

N.H. Rietbrock

Clinical Pharmacological Research Institute, Bad Nauheim, Germany

Abstract

C. Morgenstern and E. Biermann

Allgemeines Krankenhaus St. Georg, Hamburg
Objective: The objective of the present study in 60 patients with chronic tinnitus aurium was to confirm the efficacy of oral treatment with 2 × 80 mg Ginkgo special extract EGb 761 per day subsequent to 10-day EGb 761 infusion treatment. Methods: Patients with chronic tinnitus aurium underwent 10 days of in-patient infusion treatment with 200 mg/day EGb 761, after which they were randomized to double-blind, oral out-patient treatment with either 2 × 80 mg/day EGb 761 or placebo, given over a scheduled treatment period of 12 weeks. The primary outcome measure was the change in tinnitus volume in the more severely affected ear during randomized treatment. Results: Fifty-two of 60 patients (89.7%) completed the infusion treatment; complete sets of data were available for 40 (66.7%), 30 (50.0%) and 22 (36.7%) patients after 4, 8 and 12 weeks of randomized treatment, respectively. For the primary outcome measure, significant superiority of EGb 761 over placebo was demonstrated in the intention-to-treat analysis data set after 4, 8 and 12 weeks of out-patient treatment (p < 0.05, 1-tailed), although the absolute treatment group difference was moderate. The results were supported by the secondary outcome measures for efficacy (e.g. decreased hearing loss, improved self-assessment of subjective impairment). During out-patient treatment, there were no attributable adverse events under EGb 761. Conclusions: A combination of infusion therapy followed by oral administration of Ginkgo special extract EGb 761 appears to be effective and safe in alleviating the symptoms associated with tinnitus aurium.Correspondence to:
Prof. Dr. C. Morgenstern; Allgemeines Krankenhaus St. Georg, Lohmühlenstraße 5, D-20099 Hamburg, Germany

Abstract

S. Persiani¹, M. D’Amato¹, F. Makovec¹, I.A. Tavares², P.M. Bishai² and L.C. Rovati¹

¹Rotta Research Laboratorium, Monza, Italy, and ²Academic Department of Surgery, The Rayne Institute, School of Medicine, King’s College, London, United Kingdom
Objective: To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. Subjects and methods: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard non-compartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. Results: After a single oral administration, dexloxiglumide was rapidly bioavailable with mean tmax ranging from 0.9 – 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7 ± 0.6, 5.4 ± 1.7, and 11.9 ± 4.7 mg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4 ± 3.3, 8.6 ± 3.6, and 18.3 ± 5.9 mg×h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8 ± 13.9, 27.2 ± 10.6, and 21.1 ± 8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 – 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 – 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4 ± 0.4, 0.4 ± 0.2, and 0.3 ± 0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 – 1.6 h after drug administration and averaged 2.4 ± 1.3, 7.1 ± 2.9, and 15.3 ± 2.7 mg/ml for the 3 doses, respectively. The AUC values averaged 5.9 ± 3.0, 16.0 ± 8.8, and 50.8 ± 38.1 mg×h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6 ± 1.6, 11.3 ± 3.6, and 28.4 ± 8.2 mg×h/ml, whereas CL/F averaged 20.3 ± 8.3, 16.3 ± 9.0, and 10.3 ± 5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification of the terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4 ± 0.4, 0.3 ± 0.3, and 0.3 ± 0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 – 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 – 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 – 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 – 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. Conclusions: The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 – 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.Correspondence to:
Dr. S. Persiani; Pharmacokinetics and Metabolism, Rotta Research Laboratorium, S.p.A., Via Valosa di Sopra, 7-9, I-20052 Monza (MI), Italy
Email: stefano.persiani@rotta.com

Abstract

C. De Santi¹, A. Pietrabissa², F. Mosca² and G.M. Pacifici¹

¹Department of Neurosciences, Section of Pharmacology, Medical School, and ²Department of Oncology, Section of Surgery, Cisanello Hospital at University of Pisa, Cisanello, Pisa, Italy
The aim of this investigation was to study the methylation of quercetin and fisetin, 2 chemically related flavonoids, in human liver and to this purpose, an assay was set-up to measure the rates of quercetin and fisetin methylation in human liver. The methylation rates (pmol/min/mg) of quercetin and fisetin were measured in 10 liver samples and the mean ± SD and the median were 170 ± 30 and 177 (quercetin) and 183 ± 15 and 178 (fisetin). The rates of quercetin and fisetin methylation were not different (p = 0.283). The fold of variation among samples was 2 (quercetin) and 1.3 (fisetin). Methyltransferase towards quercetin and fisetin followed Michaelis-Menten kinetics, and the Km values were 2.6 ± 0.3 (quercetin) and 8.6 ± 0.7 mM (fisetin, p = 0.009) and the Vmax values were 187 ± 20 (quercetin) and 276 ± 33 pmol/min/mg (fisetin, p = 0.009). Two, 4 and 8 ml of red Chianti wine added to the incubation mixture reduced the rate of quercetin methylation to 75 ± 4%, 65 ± 9% and 59 ± 9%, respectively, and that of fisetin methylation to 62 ± 3%, 51 ± 3% and 44 ± 4%, respectively. In conclusion, quercetin and fisetin are methylated in human liver and their rates of methylation have a limited variation among subjects.Correspondence to:
Prof. Dr. G.M. Pacifici; Department of Neurosciences, Section of Pharmacology, Medical School, Via Roma 55, I-56126 Pisa, Italy
Email: pacifici@biomed.unipi.it

Abstract

A. Stockis, A.-M. Allemon, S. De Bruyn and C. Gengler

SGS Biopharma S.A., Wavre, Belgium
Objectives: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating species metabolites after oral administration of N. Bioavailability is substantially increased by food. The objectives of this phase IA study were to assess the tolerability and to determine the pharmacokinetic linearity of T and TG after single oral administration of increasing doses of N with and without food in healthy volunteer subjects. Methods: Thirty-two healthy male volunteers were randomly assigned to 1 of 4 treatment groups. In each successive group, 2 subjects received a placebo and 6 received a single oral dose of 1 g, 2 g, 3 g, or 4 g of N, first under fasted conditions and a week later with a standardized breakfast. Blood samples were collected during 24 h for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded. Results: Tolerability was good up to the maximum dose of 4 g. Mild, mostly gastrointestinal side effects were observed and their frequency increased significantly with the dose level. No significant changes were noted in the ECGs, vital signs and laboratory tests. Plasma concentrations increased linearly with the dose from 1 – 4 g, although a trend to increased bioavailability was observed at 4 g. Food approximately doubled the concentrations of T and TG irrespective of dose. Peak times and apparent half-lives increased in proportion to the dose. The apparent body clearance for total T (T+TG) at the highest dose was only half that at the low dose. TG was eliminated more slowly than T. Conclusion: Nitazoxanide can be safely administered up to 4 g single oral doses, with or without food. The slow elimination of TG and the overproportional concentrations at the highest dose can be accounted for by solubility- or transport-limited elimination mechanisms becoming apparent at the upper dose level.Correspondence to:
Dr. A. Stockis; UCB Pharma, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium
Email: armel.stockis@ucb-group.com

Abstract

A. Stockis, S. De Bruyn, C. Gengler and D. Rosillon

SGS Biopharma S.A., Wavre, Belgium
Objectives: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating metabolites after oral administration of N. The objectives of this phase IB study were to assess the tolerability and to determine the pharmacokinetics of T and TG after 7 days of 0.5 g and 1 g b.i.d. dosing of N in healthy volunteer subjects. Methods: Sixteen healthy male volunteers were randomly assigned to 1 of 2 treatment groups. In each group, 2 subjects received a placebo and 6 received a single oral dose of 0.5 or 1 g of N followed by 7 days of b.i.d. dosing. Blood samples were collected during the first and last dosing intervals for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded before and during treatment days. Results: The 0.5 g b.i.d. dose was well-tolerated with only mild adverse events not differing significantly from the placebo. The 1 g b.i.d. dose was associated with an increased frequency of gastrointestinal side effects, primarily diarrhea and abdominal discomfort. No significant changes were noted in the ECGs, vital signs and laboratory tests. At the 0.5 g b.i.d. dose, the bioavailability of T and TG was only slightly influenced by repeated administration. At the 1 g b.i.d. dose regimen, the extent of bioavailability of both T and TG was increased by 50 – 70%, indicating significant accumulation. Tmax was not significantly modified. Conclusion: Oral administration of 0.5 g of nitazoxanide b.i.d. for 7 days with food in healthy volunteers is well-tolerated and is not associated with any significant accumulation of T or TG. A higher 1 g dose results in an increased frequency of gastrointestinal discomfort and is associated with significant accumulation of T and TG.Correspondence to:
Dr. A. Stockis UCB Pharma, Chemin du Foriest, B-1420, Braine-l’Alleud Belgium
Email: armel.stockis@ucb-group.com

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Volume 40, No. 5/2002(May)