Biomedical subjects

H Blume

Publications and source records attributed to H Blume.

At least 19 recordsLinked to original sources

PubMed2006

Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union.

The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.

Adult↗

PubMed2005

[New guidelines for the assessment of bioavailability and bioequivalence].

Bioavailability and bioequivalence studies are essential in the clinical development of medicinal products and the optimization of pharmaceutical forms. Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action. In practice, drug concentration-time courses are measured in the systemic circulation, and the area under the curve (AUC) as well as the observed maximum concentration (C(max)) are determined. Products are considered bioequivalent if their bioavailabilities after administration of the same molar doses are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same and thus, there are no relevant differences in terms of AUC and C(max). In 2002 a revised version of the 'Note for Guidance on the Investigation of Bioavailability and Bioequivalence' came into effect (CPMP/EWP/QWP/1401/98). Relevant changes in comparison to the previous version are: request for GLP-compliant bioanalytical measurements; for long half-life drugs a truncated AUC is acceptable; acceptance criteria for bioequivalence assessment and requirements for a waiver of bioequivalence studies were further specified. In this context the Biopharmaceutics Classification System (BCS) seems appropriate to decide whether in special cases of rapidly dissolving solid oral dosage forms a biowaiver may be granted or not. Products not considered critical in this matter are medicinal products for which the formulation does not affect the rate and extent of absorption, i. e. bioavailability, of the active moiety. Highly soluble (and highly permeable) drugs (BCS class I) are such candidates. Comprehensive state-of-the-art guidance on the design, conduct and analysis of bioavailability and bioequivalence studies is given in the current European guideline.

Administration, Oral↗

PubMed2002

Automated mounting, centering and screening of crystals for high-throughput protein crystallography.

A fully automated system for screening protein crystals for X-ray diffraction analysis has been designed and is being installed on the beamline BW6 at DORIS in Hamburg, Germany. The system includes robotic mounting of flash-frozen crystals from a storage dewar, centering and alignment of the sample both by optical and X-ray (scattering and fluorescence) techniques, assessment of the diffraction quality of the sample, and SAD/MAD or non-conventional diffraction data acquisition with high-throughput data rates. The system covers all experimental steps required for protein x-ray structure analysis and provides a powerful means for structural genomics projects.

Crystallography, X-Ray↗

PubMed2001

Simultaneous determination of flupirtine and its major active metabolite in human plasma by liquid chromatography-tandem mass spectrometry.

A rapid, selective and sensitive HPLC-tandem mass spectrometry method was developed and validated for simultaneous determination of flupirtine and its active metabolite D-13223 in human plasma. The analytes and internal standard diphenhydramine were extracted from plasma samples by liquid-liquid extraction, and chromatographed on a C18 column. The mobile phase consisted of acetonitrile-water-formic acid (60:40:1, v/v/v), at a flow rate of 0.5 ml/min. Detection was performed on a triple quadrupole tandem mass spectrometer by selected reaction monitoring (SRM) mode via atmospheric pressure chemical ionization (APCI). The method has a limit of quantitation of 10 ng/ml for flupirtine and 2 ng/ml for D-13223, using 0.5-ml plasma sample. The linear calibration curves were obtained in the concentration range of 10.0-1500.0 ng/ml for flupirtine and 2.0-300.0 ng/ml for D-13223. The intra- and inter-run precision (RSD), calculated from quality control (QC) samples was less than 7.2% for flupirtine and D-13223. The accuracy as determined from QC samples was less than 5% for the analytes. The overall extraction recoveries of flupirtine and D-13223 were determined to be about 66% and 78% on average, respectively. The method was applied for the evaluation of the pharmacokinetics of flupirtine and active metabolite D-13223 in volunteers following peroral administration.

Aminopyridines↗

PubMed2001

A validated high-performance liquid chromatographic assay for the simultaneous determination of denaverine and its N-monodemethyl metabolite in human plasma.

An isocratic reversed-phase high-performance liquid chromatographic method for the simultaneous determination of denaverine and its N-monodemethyl metabolite (MD 6) in human plasma is described. The assay involves the extraction with an n-heptane-2-propanol mixture (9:1, v/v) followed by back extraction into 12.5% (w/w) phosphoric acid. The analytes of interest and the internal standard were separated on a Superspher RP8 column using a mobile phase of acetonitrile-0.12 M NH4H2PO4-tetrahydrofuran (24:17.2:1, v/v), adjusted to pH 3 with 85% (w/w) phosphoric acid. Ultraviolet detection was used at an operational wavelength of 220 nm. The retention times of MD 6, denaverine and the internal standard were 5.1, 6.3 and 10.2 min, respectively. The assay was validated according to international requirements and was found to be specific, accurate and precise with a linear range of 2.5-150 ng/ml for denaverine and MD 6. Extraction recoveries for denaverine and MD 6 ranged from 44 to 49% and from 42 to 47%, respectively. The stability of denaverine and MD 6 in plasma was demonstrated after 24 h storage at room temperature, after three freeze-thaw cycles and after 7 months frozen storage below -20 degrees C. The stability of processed samples in the autosampler at room temperature was confirmed after 24 h storage. The analytical method has been applied to analyses of plasma samples from a pharmacokinetic study in man.

Benzilates↗

PubMed2001

Experimental tests of EEG source localization accuracy in spherical head models.

OBJECTIVES: The locations of electrical sources in the brain can be calculated using EEG data. However, the accuracy of these calculations is not well known because it is usually not possible to compare calculated source locations with actual locations since little accurate location information is available about most sources in the brain. METHODS: In this study, sources at known locations are created by injecting current into electrodes implanted in the brains of human subjects. The locations of the implanted and scalp EEG electrodes are determined from CTs. The EEG signals produced by these dipolar sources are used to calculate source locations in spherical head models containing brain, skull, and scalp layers. The brain and scalp layers have the same electrical conductivity while 3 different skull conductivity ratios of 1/80th, 1/40th, and 1/20th of brain and scalp conductivity are used. Localization errors have been determined for 177 sources in 13 subjects. RESULTS: An average localization error of 10.6 (SD=5.5) mm for all 177 source was obtained for a skull conductivity ratio of 1/40. The average errors for the other ratios are only a few millimeters larger. The average localization error for 108 sources at superior locations in the brain is 9.2 (4.4) mm. The average error for 69 inferior location sources is 12.8 (6.2) mm. There are no significant differences in localization accuracy for deep and superficial sources. CONCLUSIONS: These results indicate that the best average localization that can be achieved using a spherical head model is approximately 10 mm. More realistic head models will be required for greater localization accuracy.

Algorithms↗

PubMed2001

Experimental tests of EEG source localization accuracy in realistically shaped head models.

OBJECTIVES: To determine the accuracy with which electrical sources in the human brain can be located using realistically shaped boundary element models of the head and to compare this accuracy with that using spherical head models. METHODS: In a previous study, electroencephalographs (EEGs) produced by sources at known locations in the brains of human subjects were recorded. The sources were created by injecting current into implanted depth electrodes. The locations of the implanted depth and scalp EEG electrodes and head shape were determined from computerized tomography images. The EEGs were used to calculate source locations in spherical head models and localization accuracy was determined by comparing the calculated and actual locations. In this study, these same EEGs are used to determine localization accuracy in realistically shaped head models. RESULTS: An average localization error of 10.5 (SD=5.4) mm was obtained in the realistically shaped models for all 176 sources in 13 subjects. This compares with 10.6 (5.5) mm in the spherical models. The average localization error for 105 sources at superior locations in the brain is 9.1 (4.2) mm. The average error for 71 inferior location sources is 12.4 (6.4) mm. The corresponding values for the spherical models are 9.2 (4.4) and 12.8 (6.2) mm. CONCLUSIONS: The realistically shaped head boundary element models used in this study produced very nearly the same localization accuracy as spherical models.

Brain↗

PubMed2000

Determination of clonixin in plasma and urine by reversed-phase high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method that enables the determination of clonixin in human plasma and urine samples is described. Recovery of the drug was over 87.6 and 80.7% for plasma and urine, respectively. The limit of quantitation of the method was established as 10 ng/ml in plasma and 20 ng/ml in urine samples, with RSDs of less than 11.1%. The applicability of the method was further assessed by determining the plasma concentrations time course of clonixin in six healthy volunteers after single oral dose administration of 150 and 300 mg of clonixin and Clonix.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Stereoselective pharmacokinetics of propafenone and its major metabolites in healthy Chinese volunteers.

The stereoselective pharmacokinetics of propafenone (PPF) and its active metabolite 5-hydroxypropafenone (5-OHP) as well as their glucuronide and sulfate conjugates have been investigated, in order to clarify the relationship between metabolism and stereoselective disposition of PPF in humans. After oral administration of 300 mg racemic PPF hydrochloride to 10 healthy Chinese subjects, the areas under the plasma concentration-time curves (AUCs) for (S)-PPF were significantly higher (S/R ratio, 1.50+/-0.17) and the apparent oral clearance significantly lower (S/R ratio, 0.68+/-0.07) than those parameters for (R)-PPF. In contrast, the AUCs of PPF glucuronide (PPF-G) were lower for (S)-PPF-G than for the (R)-enantiomer (S/R ratio, 0.83+/-0.12). The partial clearance of (S)-PPF by glucuronidation pathway was lower than that of (R)-PPF and the enantiomeric ratio was 0.62+/-0.04. The t(max) values of PPF glucuronide diastereoisomers showed no statistically significant differences between each other, but were much shorter than the corresponding values of the parent drug, implying that glucuronidation may be the 'first-choice' pathway in presystemic metabolism of PPF. Glucuronidation of 5-OHP favored the (S)-enantiomer, whereas the sulfation showed a large preference for the (R)-enantiomer. After beta-glucuronidase hydrolysis, no significant differences were observed in AUCs between 5-OHP enantiomers (including unconjugated and conjugated 5-OHP). The results suggest that the significant difference in disposition between PPF enantiomers may be, at least in part attributed to stereoselective metabolism in the glucuronidation pathway.

Adult↗

PubMed1999

Determination of clindamycin in human plasma by high-performance liquid chromatography using coupled columns.

A rapid automated method has been developed for the determination of clindamycin, a lincosamide antibiotic, in human plasma. Coupled column HPLC was used after precipitation of plasma proteins with a saturated ammonium sulfate solution. As a first step, the drug and internal standard were trapped on a precolumn of LiChrospher 60RP-select B. A reversed-phase Nucleosil 100 C18 HD column then separated drug and internal standard from each other and from remaining plasma components. The assay was validated in the range 0.2-10.0 micrograms ml-1 plasma. The results obtained for accuracy, intra- and inter-day precision complied very well with the generally accepted criteria for bioanalytical assays.

Anti-Bacterial Agents↗

PubMed1999

Image processing strategies in picture archiving and communication systems.

An image processing strategy is presented that assures very similar soft-copy presentation on diagnostic workstations of a picture archiving and communication system (PACS) over the lifetime of an image file and simultaneously provides efficient work-flow. The strategy is based on rigid partitioning of image processing into application- and display-device-specific processing. Application-specific processing is optimized for a reference display system. A description of this system is attached to the file header of the application-specifically processed image which is stored in the PACS. Every diagnostic display system automatically reproduces the image quality for which the application-specific processing was optimized by adjusting its properties by display-system-specific processing so that the system becomes effectively equal to the reference display system.

Computer Systems↗

PubMed1999

Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor metrifonate in patients with renal impairment.

The aim of this study was to assess the influence of renal function on the pharmacokinetics, pharmacodynamics, safety, and tolerability of the acetylcholinesterase inhibitor metrifonate. Four groups of six age- and gender-matched subjects with varying degrees of renal function (creatinine clearances more than 90, 60-90, 30-60, and less than 30 mL/min/ 1.73 m2, respectively) were administered a single 50-mg oral dose of metrifonate. Blood and urine samples were collected for 24 hours and concentrations of metrifonate and its metabolites dichlorvos, dichloroacetic acid, and M3 were determined. Inhibition of acetylcholinesterase activity in erythrocytes and butyrylcholinesterase in plasma were also measured. Metrifonate was well tolerated in all treatment groups. The urinary excretion of metrifonate and dichlorvos decreased with decreasing renal function but accounted for less than 2% of the elimination. There were no statistically significant differences in primary pharmacokinetic parameters--Cmax, t(max), area under the concentration-time curve (AUC), and t1/2--of metrifonate and dichlorvos among the different groups. The excretion of dichloroacetic acid and M3 was not influenced by renal impairment. Acetylcholinesterase was not inhibited, whereas butyrylcholinesterase was inhibited markedly but independently of renal function. No metrifonate dose adjustments are needed when treating subjects with renal impairment.

Aged↗

PubMed1998

Validated high-performance liquid chromatographic assay for the determination of promazine in human plasma. Application to pharmacokinetic studies.

A high-performance liquid chromatographic method for the determination of promazine in human plasma is described. The assay involves a single-step liquid-liquid extraction using pentane-2-propanol (98:2, v/v). The analyte of interest and the internal standard chlorpromazine were separated on a Spherisorb CN column using a mobile phase of acetonitrile-50 mM ammonium acetate (9:1, v/v). Electrochemical detection was achieved using an applied potential of +750 mV. The assay was validated according to international requirements prior to application to a pharmacokinetic study and was found to be specific, accurate and precise with a linear range of 0.25-25 ng ml(-1).

Antipsychotic Agents↗

PubMed1998

When are bioavailability studies required? A German proposal.

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their "Guidelines on interchangeability of multisource pharmaceutical products." This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.

Biological Availability↗

PubMed1998

Grapefruit juice increases oral nimodipine bioavailability.

The bioavailability of dihydropyridine calcium channel blockers following oral administration was shown to be increased by concomitant intake of grapefruit juice for all drugs of this class tested up to now. Here we report a randomized crossover interaction study on the effects of grapefruit juice on the pharmacokinetics of nimodipine and its metabolites. Eight healthy young men (4 smokers/4 nonsmokers) were included. Nimodipine was given as a single 30 mg tablet (Nimotop) with either 250 ml of water or 250 ml of grapefruit juice (751 mg naringin/l). Drug concentrations in plasma withdrawn up to 24 hours postdose were measured by GC-ECD, and model-independent pharmacokinetic parameters were estimated. The study was handled as an equivalence problem. Point estimators and ANOVA based 90% confidence intervals (CI) were calculated for the test (= grapefruit juice period) to reference (= water period) ratios using dose-normalized concentrations. The absence of a relevant interaction was assumed if the CIs were within the 0.67-1.50 range. Cmax for nimodipine reached 124% of the reference period (90% CI 0.76-2.01), AUC was increased to 151% (90% CI 114%-200%), respectively. The null hypothesis "relevant interaction" thus could not be rejected for the primary pharmacokinetic parameters AUC and Cmax. The ratios of metabolite AUC to parent drug AUC were slightly reduced with grapefruit juice intake. Additionally, there was evidence for a more pronounced hemodynamic response in the grapefruit juice period. To avoid the interaction, nimodipine should not be taken with grapefruit juice.

Administration, Oral↗

PubMed1998

Bioavailability study of two carbamazepine containing sustained release formulations after multiple oral dose administration.

Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatment of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil retard) was compared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose administration. During a run-in phase of 6 days the daily dose was gradually increased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparation for a further 7 days of treatment (days 16 to 22). On the pharmacokinetic profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for determination of carbamazepine and carbamazepine-10,11-epoxide trough values. Plasma concentrations of carbamazepine and its metabolite carbamazepine-10,11-epoxide were determined using a specific and sensitive HPLC method with UV detection. The results showed that autoinduction of carbamazepine metabolism under the chosen dosage regimen was complete within 14 days after start of treatment and that the criteria for bioequivalence were met. The 90% confidence intervals of all ratios were included by a range of 80-125% (AUC0-12: 103-120; AUC12-24: 105-119; Cmax0-12: 104-118; Cmax12-24: 104-118). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver enzyme activity in serum during the course of the study, one subject was excluded from further study participation. There were no serious adverse events. It was concluded that the test formulation is bioequivalent to the reference formulation with respect to rate and extent of absorption.

Adult↗

PubMed1997

Evidence for rapid face recognition from human scalp and intracranial electrodes.

It is still generally believed that complex visual analysis is not carried out within the first 100 ms. Here we show that intra- and extracranial visual evoked potentials (VEPs) differentiate previously seen faces from novel faces as early as 50 ms after stimulus onset. EEG was recorded from scalp electrodes in 12 male healthy volunteers (group I) and intracranially from implanted depth electrodes in the temporal and frontal cortex of seven epilepsy patients (group II). Both groups were engaged in a face recognition task. All subjects showed significant differential responses which occurred very early (50-90 ms) and later (190-600 ms). In group II, the early responses were recorded more frequently in the right hemisphere, whereas the late differential VEPs were found in both hemispheres. Both types of VEPs were more frequent in the temporal neocortex, underlining its role as a major contributor to these fast recognition processes.

Adult↗

PubMed1997

Body composition, resting metabolic rate, and energy requirements of short- and normal-stature, low-income Guatemalan children.

We examined body composition using bioelectrical impedance analysis and isotope dilution (18O and 2H), resting metabolic rate (RMR) by indirect calorimetry, and total energy expenditure (TEE) by doubly labeled water in 15 short-stature (height-for-age < or = -1.5 SD) and 15 normal-stature (height-for-age > -1.5 SD) Guatemalan children aged 4-6 y. Although, in absolute terms significant group differences were found in fat-free mass (FFM), fat mass, and total body water (TBW), there were no significant differences in fat mass and TBW after adjustment for FFM. RMR of the short-stature children (3791 +/- 376 kJ/d) was not significantly different from that of normal-stature children (4038 +/- 531 kJ/d), and the regression between RMR and FFM was also not significantly different between groups. TEE was not significantly different in short-stature (4753 +/- 761 kJ/d) compared with normal-stature children (5304 +/- 1020 kJ/d); the regression between TEE and FFM was not significantly different between the two groups. There were no significant group differences in RMR and TEE after adjustment for FFM. FFM was the strongest predictor of TEE, but could only explain 29% of the variance. We conclude that 1) the lower TBW and fat mass in the short-stature group is proportional to their lower FFM, 2) there is no significant difference in either RMR or TEE between short- and normal-stature children, and 3) TEE is highly variable among these children and cannot be explained by differences in body size alone.

Adipose Tissue↗