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Abstract

T.J. Cleophas¹ and R.B. Kalmansohn²

¹European Interuniversity College of Pharmaceutical Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands, and ²Departments of Medicine and Cardiology, University of California UCLA, Los Angeles, USA
Background: We recently demonstrated that in self-controlled clinical trials using t-statistic the correlation level between treatment responses is an important determinant of the sensitivity of testing. Methods: The current study uses hypothetical examples and real data to study whether this phenomenon also affects other parametric statistical procedures. Results: With negative correlations between treatment responses, not only paired t-test, but also repeated measures analysis of variance (ANOVA), Bonferroni adjustments for ANOVA, and therapeutic equivalence testing, lack sensitivity to demonstrate significant results. Conclusions: Negative correlations are increasingly encountered in clinical pharmacological research, and standard parametric statistical methods are increasingly inefficient to compare between treatment responses with decreasing correlation. Proposals for handling this problem include: increase the sample sizes in the trial; replace intraindividual comparison by parallel-group assessment; find the reason for the negative correlation, and reanalyze the data, for example by subgroup analysis; if the distribution of paired differences is skewed, use a non-parametric test.Correspondence to:
Dr. T.J. Cleophas; Department of Medicine, Albert Schweitzer Hospital, P.O. Box 306, NL-3300 AH Dordrecht, Netherlands

Abstract

A.O. Mueck, H. Seeger, C. Lippert and D. Wallwiener

Section of Clinical Pharmacology, Department of Obstetrics and Gynecology, University of Tübingen, Germany
Objective: The effect of estradiol on the renal excretion of vasoactive substances was studied in postmenopausal women. The following markers surrogating an estrogenic effect on the cardiovascular system were measured: prostacyclin and thromboxane, cGMP, which reflects systemic nitric monoxide production, serotonin and relaxin. Methods: The effect of estradiol was compared using two clinical forms of administration, transdermal and oral, in two groups of 20 postmenopausal women each. The treatment was carried out for two and four weeks, respectively. Nocturnal urine was collected over 8 hours before and after estradiol treatment. The quantity of markers excreted during the experiment was determined. Results: Excretion of prostacyclin and thromboxane, calculated as prostacyclin/ thromboxane ratio, was increased using both forms of administration. Both forms of treatment brought about only slight non-significant changes in renal cGMP excretion compared with values before treatment. The production of serotonin and relaxin was only increased using transdermal treatment. Conclusion: The resulting data show that estradiol replacement in postmenopausal women is able to increase renal excretion of various vasoactive substances implying a vasodilative effect of estrogen. This was seen, both in transdermal and oral administration, transdermal application having a more pronounced effect on the markers than oral administration.Correspondence to:
PD Dr. Dr. A.O. Mueck; Sektion Klinische Pharmakologie, Universitäts-Frauenklinik, Schleichstraße 4, D-72076 Tübingen, Germany

Abstract

J. Broekhuysen¹, A. Stockis¹, R.L. Lins¹, J. De Graeve² and J.F. Rossignol³

¹SGS Biopharma S.A., Wavre, ²Institute of Pathology, University of Liège, Sart Tilman (Liège), Belgium, and ³Romark Laboratories l.c., Tampa, Florida, USA
Objectives: Nitazoxanide (N), a new broad-spectrum parasiticidal agent, is rapidly deacetylated to tizoxanide (T). The objective of the study was to determine if metabolites other than T are present in the plasma and excreted after single dose oral administration of radiocarbon-labelled N in healthy subjects. Methods: Six healthy volunteers received a single 500 mg oral dose of N labelled with 2.92 MBq radiocarbon. The radioactivity in blood, plasma, urine, feces and expired air was monitored at scheduled intervals for up to 10 days. Selected samples were assayed by HPLC for T and submitted to metabolite identification by mass spectrometry. In vitro experiments were also conducted (incubation with animal and human microsomes, deacetylation kinetics). Plasma and bile samples obtained in a patient treated with N for sporozoal infection were also assayed for T. Results: Elimination of radiocarbon occurred both in the urine (31.5% of the dose on average) and in the feces (66.2% on average). T and T-glucuronide contributed 15% of total urine radioactivity. N was found to deacetylate extremely rapidly to T in plasma (half-life of about 6 minutes at 37° C) as well as in presence of liver microsomes. T was the only species obtained by incubation with human microsomes while rat microsomes yielded hydroxylated T in addition. The main species identified in human plasma, urine and bile was T-glucuronide, the identification of which was confirmed by comparison with an authentic sample. No species other than T was detected in feces, indicating intensive intestinal deconjugation, while radioactivity and absorbance detectors showed largely unresolved clusters.Correspondence to:
Dr. A. Stockis; SGS Biopharma S.A., 10 Vieux Chemin du Poète, B-1301 Wavre, Belgium

Abstract

M. Wangemann¹, A. Retzow¹, D. Mazur² and B. Vens-Cappell²

¹Desitin Arzneimittel GmbH Hamburg, and ²Phoenix International Mc Knight Hamburg, Germany
Objective: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. Subjects and methods: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. Results: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 mg/ml, 6.8 mg/ml and 12.8 mg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-¥ as well as Cmax related to each other approximately according to the expected ratios of 0.33 : 0.5 : 1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-¥, Cmax) were included by the acceptance range of 80 – 125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. Conclusion: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.Correspondence to:
Dr. M. Wangemann; Desitin Arzneimittel GmbH, Weg beim Jäger 214, D-22335 Hamburg, Germany

Abstract

G. Titti¹, A. Lizzio², C. Termini³, P. Negri⁴, S. Fazzio⁵ and C. Mancini⁶

¹Paediatric Hospital, Rome, ²Vittorio Emanuele Hospital, Catania, ³Civil Hospital, Vittoria, ⁴Civil Hospital, Frascati, ⁵Civil Hospital, Anzio, and ⁶Edmond Pharma, Milano, Italy
Introduction: Erdosteine is an original drug which has been suggested as secretolytic compound and promoter of respiratory ventilation in the treatment of acute and chronic respiratory diseases. Moreover, the drug possesses also scavenging, anti-oxidant, and bacterial anti-adhesivity properties. From a clinical point of view the best results have been obtained by combined treatment with an antibiotic agent of useful spectrum activity. Aim of the present study was to evaluate the improvement induced in the risk/benefit ratio by erdosteine on the broad-spectrum antibiotic (ampicillin) in the treatment of acute lower respiratory tract diseases in the pediatric field. Material and methods: A controlled multicenter double-blind parallel group trial was planned comparing erdosteine, supplied as syrup 3.5% or as sachets 225 mg, versus the relevant placebo. The tested compounds were administered in association with ampicillin. Two-hundred (n = 200) subjects entered the trial, randomly selected among patients monitored by the different centers, and were assigned to one of the treatments under evaluation, i.e. active compound or placebo with the aim to constitute two comparative homogeneous groups of 100 subjects each. Subsequently each group was again divided according to age in two equivalent subgroups of 50 patients each and treated with the syrup 3.5% (age from 2 to 4 years) or the sachet form (age from 5 to 10 years). The treatments administered in the two comparison groups were erdosteine (syrup 3.5% and 225 mg sachets) or the relevant placebo. The erdosteine posologies were adapted according to age. The lower dosage of the 5 – 10 years range in comparison with the 2 – 4 years range was established on the base of bioavailability characteristics of the two pharmaceutical forms. In all groups ampicillin was administered at the dosage of 100 mg/kg/day, according to a b.i.d. time schedule. The primary efficacy criterion was the cough score evaluated in a subjective way and expressed with the following scores: 1 = absent; 2 = mild; 3 = moderate; 4 = severe. The secondary efficacy end-points were: body temperature (expressed in ° C); the polypnea, ronchi and rales estimation with a rating scale similar to that previously mentioned. These parameters were determined before starting of the treatment (V0); at the 3rd ± 1 (V1) and at the 7th ± 2 (V2) day of treatment. The body temperature was measured orally in the morning at awakening time with a mercury thermometer. Obtained data expressed in Celsius degrees are recorded by the investigator in the patient file during control visits.The safety of adopted treatments was evaluated with two different approaches. The clinical part was determined with the adverse drug reactions (ADRs) estimate. The biological safety was estimated at admission day (day 0) and at the final visit by means of a sophisticated statistical approach. Results: The final results were the following: Erdosteine syrup 3.5%: concerning cough (primary end-point) in the group of patients (n = 50) treated with erdosteine it has been possible to point out a reduction of 23.8% at V1, i.e. after 3 ± 1 days, and of 59.8% at V2, i.e. after 7 ± 2 days. In the group of patients treated with placebo (n = 50) the reduction has been of 20.1% at V1 and of 36.6% at V2. The statistical analysis evidenced p values < 0.01 for times, treatments, time × treatments. The relevant results are summarized in Table 2. Erdosteine sachets 225 mg: concerning cough (primary end-point) in the group of patients (n = 50) treated with erdosteine it has been possible to point out a reduction of 17.6% at V1, i.e. after 3 ± 1 days, and of 56.8% at V2, i.e. after 7 ± 2 days. In the group of patients treated with placebo (n = 50) the reduction has been of 15.6% at V1 and of 31.8% at V2. The statistical analysis evidenced p values < 0.01 for times, treatments, time × treatments. Conclusions: In general terms, it could be concluded that erdosteine, administered in association with an antibiotic in pediatric febrile lower respiratory tract infections is quite useful, allowing a more rapid and definite amelioration of the clinical evidence, with reduction of the relevant symptomatology (cough, body temperature, rhonchi, rales). The safety and tolerability of the treatment has been proved to be as good as already known from the existing documentation on the product.Correspondence to:
Dr. C. Mancini; Edmond Pharma, via Gadames 58, I-20151 Milano, Italy

Abstract

D.H. Bremerich¹, V. Lischke¹, F. Asskali², H. Förster² and M. Behne¹

¹Department of Anesthesiology and Resuscitation, and ²Department of Experimental Anesthesiology, Johann-Wolfgang-Goethe-Universitätsklinikum, Frankfurt, Germany
Objective: Acetyl starch (ACS) is a new synthetic colloid solution for plasma volume expansion and is now undergoing phase II clinical trials. We compared the pharmacodynamics and tolerability of ACS with those of hydroxyethyl starch (HES) in 32 patients (American Society of Anesthesiologists physical status I and II) undergoing elective surgery. Subjects, material and methods: In this prospective, randomized, double-blind trial patients received either 15 ml/kg ACS 6% (average molecular weight (Mw) 200,000/ molar substitution (MS) 0.5) or HES 6% (Mw 200,000/ MS 0.5) i.v. up to a maximum dose of 1000 ml. Hemodynamic parameters, rheologic parameters, volume effect, acid-base status as well as effects on hemostasis were studied. Results: After infusion of ACS and HES there was a similar increase in central venous pressure and mean arterial pressure in both groups. Acid-base status was not significantly altered after the end of the colloid infusions. After ACS infusion, plasma acetate concentration increased from 0.13 ± 0.16 mg/dl to 2.87 ± 1.13 mg/dl, however, after 24 h there was no significant difference in plasma acetate concentration compared to HES. The volume effect ranged from 104 – 116% (ACS) and from 88 – 118% (HES) of the colloid dose administered. These differences were not statistically significant. Partial thromboplastin time (aPTT) was only slightly increased after ACS infusion (from 38.6 ± 5.7 sec to 41.4 ± 5.1 sec), but was significantly increased after HES infusion (from 38.7 ± 5.7 sec to 46.1 ± 7.0 sec). Conclusion: ACS and HES are equally effective plasma volume expanders; ACS might be a new, alternative colloid solution with fewer coagulation side-effects than HES.Correspondence to:
Dr. D.H. Bremerich; Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Zentrum der Anästhesiologie und Wiederbelebung, Klinikum der Johann-Wolfgang-Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany

Abstract

S. Savu¹, M. Mitrea², L. Silvestro¹ and C. Mancini³

¹Pharmacokinetic Laboratory, ICCF, Bucharest ²⁶th Department of Pneumology, Hospital Filaret, Bucharest and ³Edmond Pharma, Milano, Italy
A newer technique, HPLC with mass spectrometry (MS) detection has been used to evaluate the pharmacokinetics of a new mucoactive compound, erdosteine and its metabolites (N-thioglycolilhomocysteine and homocysteine). To this aim a population of 12 patients of both genders with mean age 52.1 ± 6.34 years was enrolled in a trial after protocol approval from Ethics Committee and informed consent obtainment. The patients were treated with erdosteine for 7 days and blood samples were obtained at baseline and on 8th day for analytical purposes. The obtained results are discussed in correlation with those of two previous existing trials on the same product.Correspondence to:
C. Mancini; Edmond Pharma, via Gadames 58, I-20151 Milano, Italy

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Volume 38, No. 8/2000(August)