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Biomedical subjects

D Hauschke

Publications and source records attributed to D Hauschke.

At least 19 recordsLinked to original sources
PubMed2001

Dose linearity and steady state pharmacokinetics of the new antiparkinson agent budipine after oral administration.

The dose-dependency of budipine pharmacokinetic characteristics was studied. Eighteen healthy male subjects were given 10, 20 and 30 mg oral single doses according to a randomized, open, 3-period crossover design. Additionally, the steady state conditions were investigated after repeated intake of 10 mg t.i.d for 10 days and compared to the 10 mg single dose. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with ascending doses of orally given budipine. Time to maximum serum concentration (tmax) and terminal half-life (t1/2) were independent of the administered dose. As compared to the 10 mg single dose pharmacokinetics, the repeated oral administration of budipine 10 mg t.i.d. resulted in an increase in AUC of 11% and 93% for budipine and its metabolite p-OH-budipine, respectively. In clinical practice, a predictable response in proportion to the dose is to be expected.

Administration, Oral↗
PubMed2000

The U.S. draft guidance regarding population and individual bioequivalence approaches: comments by a research-based pharmaceutical company.

Generally, the motivation for switching from average bioequivalence to population and/or individual bio-equivalence is well recognized in the light of certain limitations of the concept of average bioequivalence. However, this switch still results in unresolved issues which should be addressed before the regulatory guidance is finalized.

Chemistry, Pharmaceutical↗
PubMed2000

Identifying the maximum safe dose: a multiple testing approach.

Identifying the maximum safe dose (MAXSD) is an objective of both randomized clinical dose-finding studies for the safety endpoint and toxicological studies. MAXSD is defined as the highest experimental dose with no significant increased safety effect relative to the placebo or control group. In safety assessment, the primary control of the false-negative error rate is more important than that of the false-positive rate. Therefore, we propose a multiple testing procedure for equivalence in the many-to-one design with a priori ordered contrasts (shifted control vs. dose), where the acceptable risk delta is defined in advance. Tests for shifted and ratio hypotheses are presented and discussed.

Animals↗
PubMed1999

Sample size determination for proving equivalence based on the ratio of two means for normally distributed data.

Equivalence trials aim to demonstrate that two treatments do not differ by more than a prespecified clinically irrelevant amount. We consider the problem when equivalence is defined in terms of the ratio of population means and the original (untransformed) data are normally distributed. Application of the intersection-union principle to the test proposed by Sasabuchi results in a two one-sided tests procedure of size alpha. We give the associated 100 (1-2 alpha) per cent confidence interval and derive the exact methods for calculation of power and sample sizes for the parallel group design and the two-period cross-over. We present tables and figures of required sample sizes and achieved power.

Administration, Inhalation↗
PubMed1999

Effects of early treatment with rSP-C surfactant on oxygenation and histology in rats with acute lung injury.

Surfactant treatment in patients with acute respiratory distress syndrome (ARDS) may be a promising treatment strategy. The aim of this study was to investigate whether addition of a recombinant surfactant protein C (rSP-C) to a plain phospholipid (PL) surfactant (PL surfactant) can result in activity comparable to commercially available surfactant preparations (Alveofact and bLES) which contain surfactant protein B and C. In this investigation dose-response comparisons of four surfactants were performed in an animal model of ARDS induced by total lung lavage. The surfactants were given shortly (;10 min) after the last lavage. The effects of surfactant treatment were compared with respect to improve oxygenation and to prevent histopathological changes, such as hyaline membrane formation. The surfactants were compared to lavaged, untreated controls. The surfactants were administered at doses of 25, 50 and 100 mg total amount of phospholipids/kg body weight. At 120 min after early treatment, all three doses of rSP-C surfactant showed statistically significant higher improvements in oxygenation than PL surfactant. This improvement was comparable to bLES and superior to Alveofact. The rSP-C surfactant showed the most prominent effect on preventing hyaline membrane formation. It was again superior to PL surfactant and comparable to bLES. It is concluded that addition of rSP-C enhances the activity of a pure PL surfactant. The rSP-C surfactant showed comparable or even superior activity to bovine-derived surfactant preparations containing both, SP-B and SP-C.

Acute Disease↗
PubMed1999

Characterisation of the rat lung lavage model as biological assay for testing the activity of surfactant preparations.

The present report describes how pharmacological assays may be validated and sets a basis for a discussion on the validation of biological test systems. The note for guidance on the validation of analytical procedures published by the European agency for the evaluation of medicinal products was adapted to the validation of a pharmacological test system. The presently described rat lung lavage test (RLL-test) is an animal model that has great similarities to the pathophysiology of the acute respiratory distress syndrome of humans. In this RLL-test, the activity of surfactants can be tested in a standardised fashion. The usefulness of the point estimator and the corresponding confidence intervals (CI) as a statistical test procedure for equivalence was demonstrated. A validation can be based on the above mentioned guidance but should be adjusted to pharmacological needs. Based on the presented experiences, it can be concluded that a specific guideline for validation of pharmacological or biological tests is desirable.

Anesthesia↗
PubMed1999

Intratracheally applied rSP-C surfactant exhibits no anaphylactic shock reactions in a guinea pig model of acute lung hypersensitivity.

The effect of the intratracheal administration of the recombinant SP-C surfactant apoprotein (rSP-C) with phospholipids (PL) in comparison to an ovalbumin induced anaphylactic shock reaction was studied in guinea pigs lungs. Narcotized guinea pigs were challenged by intratracheal administration on test day 24/25 once with a suspension of rSP-C/PL (reconstituted suspension). These animals were priorily sensitized on test day 1, 3 and 5 intraperitoneally with rSP-C/PL suspension or with Ovalbumin (OV) respectively. The following groups were used to assess the anaphylactic lung shock symptoms: group 1: positive control, 1 mg/kg OV protein, 2 ml/kg application volume, (Appl. vol.), N: 5 animals; group 2: 1 mg rSP-C/50 mg PL/0.5 ml/kg Appl. vol., N: 10; group 3: 2 mg rSP-C/100 mg PL/1.0 ml/kg Appl. vol., N: 10; group 4: 4 mg rSP-C/200 mg PL/2.0 ml/kg Appl. vol., N: 10. Clinical signs, mortality, lung weights and histopathological changes were evaluated. Additionally the lungs were investigated immunohistologically with polyclonal antibodies against rSP-C to determine the pulmonary distribution of the intratracheal applied rSP-C. In the OV-treated positive control group, all animals died within 4 minutes after intratracheal challenge, while only 1 animal of group 4 died probably due to an narcosis related respiratory arrest. In the rSP-C/PL treated groups, the lung weights showed a dose-related increase, but nevertheless all these rSP-C-treated groups showed a significant lower lung weight in comparison to the OV treated positive control group. The histopathology assessment of the lungs in the OV-treated animals revealed a severe generalised bronchoconstriction and a hyperemia in connection with a slight interstitial edema in all five animals. The rSP-C/PL-treated animals, which were sacrificed after 3 days, showed no bronchoconstriction but a slight increase in the severity of bronchus-associated infiltration with eosinophilic granulocytes and in the formation of peripheral emphysema, but with no dose-dependency. A slight dose-dependent increase in the deposition of peribronchiolar eosinophilic foreign material was evident. In contrast to this, the number of lipid-laden alveolar macrophages seemed to decrease with increasing doses of rSP-C/PL. The immunohistological investigation with a polyclonal antibody against rSP-C showed an intraalveolar distribution of the intratracheally applied rSP-C which is mainly located in the peribronchiolar alveolar parenchyma. A rSP-C-positive staining was visible within the cytoplasm of alveolar histiocytes, type II pneumocytes and also as an extracellularly rim along the alveolar walls. The polyclonal antibody showed no cross reaction with natural occuring SP-C-protein of the guinea pigs. We conclude that the intratracheal application of the rSP-C surfactant containing phospholipids (PL) exhibits no significant risk of an anaphylactic shock reaction in this guinea pig lung hypersensitivity model. The immunohistological investigation with polyclonal antibodies against rSP-C demonstrated clearly the distribution of intratracheal applied material in this toxicological animal model.

Anaphylaxis↗
PubMed1999

Approximate sample sizes for testing hypotheses about the ratio and difference of two means.

This article deals with a unifying approach to approximate sample size determination for different types of hypotheses formulated in terms of two means of normally distributed data. A simple approximation is given to the sample size required for testing hypotheses about the ratio of the means. The formula includes the situations of testing noninferiority, superiority, or equivalence. We present a more general formula that also covers hypotheses formulated in terms of the difference of means. We show that over a wide range of parameter values the approximation provides reliable sample sizes.

Controlled Clinical Trials as Topic↗
PubMed1998

Comparison of rSP-C surfactant with natural and synthetic surfactants after late treatment in a rat model of the acute respiratory distress syndrome.

1. In a previous paper we showed that an SP-C containing surfactant preparation has similar activity as bovine-derived surfactants in a rat lung lavage model of the adult respiratory distress syndrome. In this study surfactant was given ten minutes after the last lavage (early treatment). In the present investigation we were interested how different surfactant preparations behave when they are administered 1 h after the last lavage (late treatment). 2. Four protein containing surfactants (rSP-C surfactant, bLES, Infasurf and Survanta) were compared with three protein-free surfactants (ALEC, Exosurf and the phospholipid (PL) mixture of the rSP-C surfactant termed PL surfactant) with respect to their ability to improve gas exchange in this more stringent model when surfactant is given one hour after the last lavage. For better comparison of the surfactants the doses were related to phospholipids. The surfactants were given at doses of 25, 50 and 100 mg kg(-1) body weight. The surfactants were compared to an untreated control group that was only ventilated for the whole experimental period. 3. Tracheotomized rats (8-12 per dose and surfactant) were pressure-controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths min(-1), inspiration expiration ratio of 1:2, peak inspiratory pressure of 28 cmH2O at positive endexpiratory pressure (PEEP) of 8 cmH2O. Animals were ventilated for one hour after the last lavage and thereafter the surfactants were intratracheally instilled. During the whole experimental period the ventilation was not changed. 4. Partial arterial oxygen pressures (PaO2, mmHg) at 30 min and 120 min after treatment were used for statistical comparison. All protein containing surfactants caused a dose-dependent increase of the reduced PaO2 values at 30 min after treatment. The protein-free surfactants showed only weak dose-dependent increase in PaO2 values at this time. This difference between the protein-containing and the protein-free surfactants was even more pronounced when comparing the PaO2 values at 120 min after treatment. Only rSP-C surfactant, bLES and Infasurf showed a dose-dependent increase in PaO2 at this time. 5. With this animal model of late treatment it is possible even to differentiate between bovine derived surfactants. The differences between protein-containing and protein-free surfactants become even more pronounced. From the comparison of rSP-C surfactant with bovine-derived surfactants and the PL surfactant without rSP-C, it can be concluded that addition of rSP-C is sufficient to achieve the same activity as that of natural surfactants.

Acute Disease↗
PubMed1998

Effects of rSP-C surfactant on oxygenation and histology in a rat-lung-lavage model of acute lung injury.

We have tested two surfactant preparations with the same phospholipid (PL) composition, containing recombinant surfactant protein-C (rSP-C surfactant) and without SP-C (plain PL surfactant). The effects of rSP-C surfactant were compared with the bovine-derived surfactant preparations Alveofact, bLES, and Infasurf in a lung lavage model, with surfactant given 1 h after the last lavage. The effects of surfactant treatment on histopathologic changes (e.g., hyaline-membrane formation) and improvement of oxygenation were compared with changes in untreated controls. The surfactants were given in doses of 25, 50, and 100 mg PL/kg body weight. At 120 min after treatment, only the protein-containing surfactants showed a statistically significant increasing dose dependence with respect to improving oxygenation. The values were 318 +/- 120 mm Hg, 443 +/- 58 mm Hg, and 480 +/- 43 mm Hg (mean +/- SD) for the three doses of rSP-C surfactant and 105 +/- 81 mm Hg, 100 +/- 69 mm Hg, and 131 +/- 108 mm Hg for the three doses of PL surfactant. The respective values for Alveofact were 104 +/- 81 mm Hg, 105 +/- 93 mm Hg, and 260 +/- 143 mm Hg; for bLES 373 +/- 138 mm Hg, 441 +/- 88 mm Hg, and 467 +/- 43 mm Hg; and for Infasurf 146 +/- 96 mm Hg, 284 +/- 178 mm Hg, and 436 +/- 70 mm Hg. The oxygen values of controls remained low, at 74 +/- 46 mm Hg. Only the protein-containing surfactants dose-dependently inhibited the formation of hyaline membranes. We conclude that rSP-C surfactant is at least as effective as bovine-derived surfactants. Furthermore, the data imply that the difference between plain PL surfactant preparations and bovine-derived surfactant preparations containing both SP-B and SP-C can be overcome by addition of SP-C.

Animals↗
PubMed1997

Individual bioequivalence--a European perspective.

Regulatory requirements for average bioequivalence have been internationally harmonized, which is by no means the case for the more recent concept of individual bioequivalence. The main reason for introducing more complex replicate designs and bioequivalence criteria are the highly variable drugs, for which the setting of suitable bioequivalence ranges poses a major problem and scaling of the bioequivalence criteria by the intrasubject variability has been suggested. The shortcoming of the present two-treatment, two-period (2 x 2) crossover design to detect subject-by-formulation interaction provides a second argument in favor of the more complex replicate designs. A unified approach of proposed statistical procedures for the replicate design has been given by Schall. However, the availability of these methods and understanding of them seems to be limited to a small working group, so a broader international awareness of the problems and potentional solutions is desirable.

Europe↗
PubMed1997

Choice of student's t- or Wilcoxon-based confidence intervals for assessment of average bioequivalence.

An open question in the analysis of average bioequivalence is whether the nonparametric (Wilcoxon) or parametric (t) approaches to two one-sided tests is preferable. Previous work has made particular distributional assumptions as to the distribution of AUC and C(max). Instead, we simulate data according to a pharmacokinetic model for an immediate-release formulation. We find that both approaches have estimated level consistent with the nominal 5%. The only concern is a possible anticonservativeness of the parametric approach for C(max). Further, the nonparametric approach is consistently less powerful than the parametric for the cases studied.

Area Under Curve↗
PubMed1995

Reference tables for the intrasubject coefficient of variation in bioequivalence studies.

Bioequivalence studies are usually performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. However, this information is usually not accessible in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. It is the purpose of the present communication to provide reference values of the intrasubject coefficient of variation for various previously investigated drugs. The presentation includes pertinent pharmacokinetic characteristics for immediate- and extended-release formulations in single- and multiple-dose crossover studies.

Administration, Oral↗
PubMed1994

Effects of lung surfactant factor (LSF) treatment on gas exchange and histopathological changes in an animal model of adult respiratory distress syndrome (ARDS): comparison of recombinant LSF with bovine LSF.

Repetitive lung lavage of adult rats leads to lung injury similar to ARDS resulting in poor gas exchange, protein leakage and infiltration of polymorphonuclear neutrophils (PMN) into the alveolar spaces (J Appl Physiol 1983; 55: 131-138). In a previous dose response comparison we have demonstrated that poor gas exchange could be improved by lung surfactant factor (LSF) instillation soon after lavage. Since Surfacten (Tokyo Tanabe Co. Ltd., Tokyo, Japan) was described in vitro to inhibit PMN activity, we compared this preparation with a Recombinant LSF preparation (Byk Gulden, Konstanz, Germany; phospholipids plus human identical surfactant protein C) at doses of 25, 50 and 100 mg/kg body weight. Their efficacy was compared with an untreated control group with respect to improving gas exchange, inhibition of hyaline membrane formation and inhibition of the inflammatory response after multiple lavage. Tracheotomized rats were pressure-controlled ventilated (Siemens Servo Ventilator 900C, Sweden) with 100% oxygen at a respiratory rate of 30 breaths/min, inspiration:expiration ratio of 1:2, peak inspiratory pressure (PIP) of 28 cmH2O at positive end-expiratory pressure (PEEP) of 8 cmH2O. Two hours after LSF administration PEEP was reduced from 8 to 6 cmH2O (first PEEP-reduction), from 6 to 3 (second reduction) and from 3 to 0 cmH2O (third reduction) and finally raised to 8 cmH2O. Results for the averaged partial arterial oxygen pressure [PaO2 (mmHg)] of the 2 h period [PaO2(5'-120')] and for the PaO2 during the second PEEP reduction [PaO2(PEEP23/3] were calculated. Both LSF preparations caused a dose-dependent increase of the PaO2 (5'-120') and the PaO2(PEEP23/3). Similarly, the formation of hyaline membranes was inhibited by both LSF preparations in a dose-dependent manner. Inhibition of the inflammatory response (infiltration of PMN) was not effected by either of the LSF preparations at any dose level. The described variations in ventilator settings are useful to evaluate the deflation stability and re-expansion potential of different LSF preparations. The reported results give evidence that prevention of atelectasis by LSF treatment improves gas exchange and inhibits formation of hyaline membranes, leading to the conclusion that LSF treatment may be a promising therapy in ARDS patients.

Animals↗
PubMed1994

Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations.

For immediate release drug formulations the maximum concentration (Cmax), the time to the maximum concentration (tmax), and the ratio Cmax/AUC have been suggested as absorption rate characteristics. Although tmax is easier to interpret as absorption rate characteristic than Cmax and Cmax/AUC, the latter are generally preferred in practice because these characteristics can be observed with higher precision, and are easier to handle statistically than tmax. In this paper we propose a strategy for setting appropriate bioequivalence ranges for tmax and Cmax/AUC, and for choosing the best characteristic for the comparison of absorption rates when planning a bioequivalence study. This involves motivating the bioequivalence range on that scale which is most convenient for that purpose, namely in terms of differences in tmax. Exploiting the pharmacokinetic relationship between tmax and Cmax/AUC this bioequivalence range is then translated into the corresponding bioequivalence range for Cmax/AUC. The characteristic that gives the greatest power to show bioequivalence can then be specified as the primary absorption rate characteristic. For drugs with short elimination half-lives, or short fastest disposition half-lives if the drug concentrations follow a higher compartmental model, Cmax/AUC is the best characteristic, but for drugs with long elimination or fastest disposition half-lives tmax can be superior to Cmax/AUC.

Absorption↗