Biomedical subjects

G Hochhaus

Publications and source records attributed to G Hochhaus.

At least 19 recordsLinked to original sources

PubMed2006

Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids.

Due to the high affinity of new inhaled corticosteroids (ICS) towards the glucocorticoid receptor (GR), and because of the similarities between the binding domains of the GR and the progesterone receptor (PR), the present study focused on assessing the relative binding affinities (RBA) of glucocorticoids (systemic and ICS) to PR (RBAPR). By comparison with the affinities towards the GR (RBAGR) the binding selectivities were also assessed. In general, the selectivity of the investigated glucocorticoids showed a decreasing trend with increasing lipophilicity. When orally administered, less lipophilic glucocorticoids showed the highest selectivity, with RBAGR/RBAPR ratios of 1,375, 760 and 476 for betamethasone, beclomethasone and dexamethasone, respectively. For ICS, mometasone furoate, the most lipophilic steroid, was the least selective (1.1), followed by beclomethasone monopropionate (9), fluticasone propionate (12), triamcinolone acetonide (18), mometasone (25) and budesonide (44), which shows the highest selectivity among inhaled glucocorticoids. In conclusion, the present study revealed that there are differences in selectivity among commercially available glucocorticoids. Future clinical studies are needed to investigate whether the high affinity of some of the investigated glucocorticoids to the progesterone receptor is of clinical relevance.

Administration, Inhalation↗

PubMed2006

Do intensive care patients need an individualized dosing regimen for levofloxacin?

OBJECTIVE: In general, the pharmacokinetics (PK) of antibiotics in intensive care unit (ICU) patients are known to differ from healthy subjects. These differences can pose challenges in developing appropriate dosing guidelines. The primary objective of this report was to characterize the disposition of levofloxacin in critically ill patients and to assess any relationships between patient covariates and the PK parameters. METHODS: 20 patients in the ICU were given levofloxacin, 500 mg, as an i.v. infusion for a half hour. Plasma samples were taken until 24 hours and assayed using HPLC. The concentration-time data were analyzed using population analysis with NONMEM. RESULTS: The data were described using a 2-compartment model. Creatinine clearance was determined to be a statistically significant predictor of variability in total levofloxacin clearance. For patients with higher levofloxacin clearance, the resulting efficacy for different strains of bacteria (expressed as free AUC/MIC ratios) suggested that for less sensitive pathogens, a dosage adjustment may be needed. CONCLUSION: A model describing the pharmacokinetics of levofloxacin in critically ill patients was developed. It was determined that creatinine clearance has a significant role in the disposition of levofloxacin. This may have significant implications in the clinical setting for identifying optimal dosage regimens for ICU patients.

Anti-Bacterial Agents↗

PubMed2006

Influence of the N-acetylation polymorphism on the metabolism of talampanel: an investigation in fasted and fed subjects genotyped for NAT2 variants.

Talampanel is a 2,3-benzodiazepine-type allosteric (noncompetitive) AMPA-antagonist currently being developed as an orally active, broad-spectrum anticonvulsant. Here, a detailed study of its N-acetylation in humans is presented using plasma concentration data of both TLP and its N-acetyl metabolite obtained from healthy volunteers (n = 28) genotyped for N-acetyltansferase NAT2 isozymes. Plasma samples were obtained for up to 48 h after a single oral dose of 75 mg TLP both in fasted and in fed subjects. A perfect correspondence could be established between the phenotype inferred before the study from genotyping and that determined after the study by using plasma metabolite-to-parent molar ratios confirming that this route of metabolism is indeed mediated by NAT2. Analysis of the data has been performed using both noncompartmental analysis and a custom-built, unified parent-metabolite PK model, which incorporates three different acetylation rates according to the genotype-based classification of each subject as slow, intermediate, or fast acetylator to simultaneously fit plasma levels for both TLP and its metabolite. This suggest that for TLP in humans, (i) N-acetylation represents only a relatively small fraction of its total elimination (about one-fourth in fast acetylators and much less in slow acetylators), (ii) acetylation is about eight-twelve times faster in fast and three-six times faster in intermediate acetylators than in slow acetylators, and (iii) the N-acetyl metabolite is eliminated faster than the parent TLP.

Acetylation↗

PubMed2006

Pharmacological effects of some newly developed soft anticholinergics and a receptor-binding QSAR study.

Receptor-binding studies using cloned human muscarinic receptors (M1-M4 subtypes) were performed on newly synthesized soft anticholinergics (F-828, F-838, SGM, SGE, SA-A) that are isosteric/ isoelectronic analogs of glycopyrrolate. The receptor binding pK(i) values of the new soft drugs were in the 5.5-9.5 range; with the majority being in the 7.0-8.5 range. As previously observed for similar structures, the pK(i) values tended to decrease with increasing molecular size, and with the introduction of three structural indicator variables, a QSAR equation accounting for close to 75% of the variability could be established. Confirming the known stereospecificity of these receptors, pure 2R isomers were found more active than the corresponding isomeric mixtures. In agreement with soft drug design principles, acid metabolites (SA-A) were found considerably less active than their parent esters. The more active, 2R isomer of SA-A showed some muscarinic subtype selectivity (M3/M2), which was not observed for the parent compounds of this zwitterionic metabolite. Guinea pig ileum assay pA2 values have also been determined, and they were found to be in good agreement with the pK(i), values obtained from the binding study (r2 = 0.72). SGM and SGE caused pupil-dilation in rabbit eyes, but their mydriatic effects lasted considerably shorter than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that they are locally active and safe, with a low potential to cause systemic side effects.

Algorithms↗

PubMed2005

Metabolism of mometasone furoate and biological activity of the metabolites.

To better evaluate the pharmacokinetic and pharmacodynamic properties of the new inhaled glucocorticoid mometasone furoate (MF), the metabolism of MF was evaluated in rat and human tissues and in rat after i.v. administration. Metabolic studies with 3H-MF in human and rat plasma and S9 fractions of human and rat lung showed relatively high stability and a degradation pattern similar to that seen in buffer systems. MF was efficiently metabolized into at least five metabolites in S9 fractions of both rat and human liver. There were, however, quantitative differences in the metabolites between the two species. The apparent half-life of MF in the S9 fraction of human liver was found to be 3 times greater compared with that in rat. MET1, the most polar metabolite, was the major metabolite in rat liver fractions, whereas both MET1 and MET2 were formed to an equal extent in human liver. Metabolism and distribution studies in rats after intravenous and intratracheal administration of [1,2-(3)H]MF revealed that most of the radioactivity (approximately 90%) was present in the stomach, intestines, and intestinal contents, suggesting biliary excretion of MF and its metabolites. Radiochromatography showed that most radioactivity was associated with MET1, MET2, and MET 3. Fractionation of the high-performance liquid chromatography eluate (MET1-5) revealed that only MF [relative binding affinity (RBA) 2900] and MET2 (RBA 700) had appreciable glucocorticoid receptor binding affinity. These results suggest that MF undergoes distinct extrahepatic metabolism but generates active metabolites that might be in part responsible for the systemic side effects of MF.

Animals↗

PubMed2005

Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling.

OBJECTIVE: Reports characterizing the pharmacokinetics of inhaled fluticasone propionate (FP) using compartmental approaches have suggested that the absorption of FP into the systemic circulation is rapid with a half-life of approximately 10 min. We believe that this is a classical case of misassignment of the pharmacokinetic parameter estimates, a problem often encountered while modeling pharmacokinetic data. The objective of this study was to illustrate and analyze this problem using actual blood level data of FP obtained in 14 healthy subjects. MATERIALS AND METHODS: Serum concentration-time data of FP were obtained from a double-blind, randomized study involving single and multiple twice-daily inhalations of 500 microg via a dry powder device, Diskus. The profiles were fitted using one- and two-compartment pharmacokinetic models with first order absorption. Various permutations of the resulting exponential rate constants were analyzed to determine the combination that was most consistent with the underlying physical process. RESULTS: The two-compartment body model with first order absorption gave excellent fits for the observed FP concentrations after both single and multiple dosing. Even though peak levels were reached relatively early (30 - 90 min) after inhalation, the combination that most appropriately described the underlying process was alpha > Ka > beta, i.e. slow absorption, rapid distribution and slower elimination kinetics. The absorption, distribution and elimination half-lives resulted to be 3.8 h, 9.9 min and 13.6 h, respectively, consistent with the high lipophilicity and sustained dissolution characteristics observed in vitro. CONCLUSIONS: Analysis of FP pharmacokinetics after inhalation represents a classical case of potential misassignment of the exponential rate constants, which if ignored, could lead to erroneous interpretations regarding the underlying process. The study also elucidates the pitfall of using t(max) to calculate absorption rate.

Absorption↗

PubMed2004

Age effects on the pharmacokinetics of tityustoxin from Tityus serrulatus scorpion venom in rats.

The pharmacokinetics of scorpion venom and its toxins has been investigated in experimental models using adult animals, although, severe scorpion accidents are associated more frequently with children. We compared the effect of age on the pharmacokinetics of tityustoxin, one of the most active principles of Tityus serrulatus venom, in young male/female rats (21-22 days old, N=5-8) and in adult male rats (150-160 days old, N=5-8). Tityustoxin (6 microg) labeled with 99mTechnetium was administered subcutaneously to young and adult rats. The plasma concentration vs time data were subjected to non-compartmental pharmacokinetic analysis to obtain estimates of various pharmacokinetic parameters such as total body clearance (CL/F), distribution volume (Vd/F), area under the curve (AUC), and mean residence time. The data were analyzed with and without considering body weight. The data without correction for body weight showed a higher Cmax (62.30 +/- 7.07 vs 12.71 +/- 2.11 ng/ml, P<0.05) and AUC (296.49 +/- 21.09 vs 55.96 +/- 5.41 ng h(-1) ml(-1), P<0.05) and lower Tmax (0.64 +/- 0.19 vs 2.44 +/- 0.49 h, P<0.05) in young rats. Furthermore, Vd/F (0.15 vs 0.42 l/kg) and CL/F (0.02 +/- 0.001 vs 0.11 +/- 0.01 l h(-1) kg(-1), P<0.05) were lower in young rats. However, when the data were reanalyzed taking body weight into consideration, the Cmax (40.43 +/- 3.25 vs 78.21 +/- 11.23 ng kg(-1) ml(-1), P<0.05) and AUC (182.27 +/- 11.74 vs 344.62 +/- 32.11 ng h(-1) ml(-1), P<0.05) were lower in young rats. The clearance (0.03 +/- 0.002 vs 0.02 +/- 0.002 l h(-1) kg(-1), P<0.05) and Vd/F (0.210 vs 0.067 l/kg) were higher in young rats. The raw data (not adjusted for body weight) strongly suggest that age plays a pivotal role in the disposition of tityustoxin. Furthermore, our results also indicate that the differences in the severity of symptoms observed in children and adults after scorpion envenomation can be explained in part by differences in the pharmacokinetics of the toxin.

Age Factors↗

PubMed2004

Drugs used in the treatment of opioid tolerance and physical dependence: a review.

Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependence, which becomes apparent particularly in heroin withdrawal. Our knowledge about the mechanisms underlying tolerance has increased dramatically in recent years, but a final picture of the importance of each particular mechanism under in vivo conditions has not yet emerged. Recent studies suggest that the so-called receptor down-regulation is not the main mechanism in vivo. A desensitization on the basis of receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated. However, a functional antagonism of the opioid effects seems to be clinically most important, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase and nitric oxide synthase. Drugs blocking these mechanisms are the most promising option in the treatment of tolerance. Namely, alpha2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan have been used to minimize tolerance development during opioid treatment. Moreover, clinical strategies such as opioid rotation and multimodal analgesia, i.e. the simultaneous application of several analgetics of different type, have proven to be successful approaches.

Adenylyl Cyclases↗

PubMed2004

Metabolism of dynorphin A(1-13).

Dynorphin A(1-13), a tridecapeptide of the endogenous opioid peptides, has modest effects in reducing mild opiate withdrawal in humans. Previous studies revealed that dynorphin also potentiates the analgesic effect of morphine in morphine-tolerant rats and mice. The therapeutic potential of dynorphin A(1-13) is limited due to extensive metabolism by human metabolic enzymes resulting in an in vivo half-life of less than one minute. Chemical modifications of dynorphin A(1-13), such as N-methylation of Tyr1 and amidation of the C-terminus have been shown to be effective in protecting against the proteolytic enzymes in human plasma. This article is a general review of the metabolism of dynorphin A(1-13) in human plasma and CSF.

Animals↗

PubMed2004

Characterization of degradation products of mometasone furoate.

Mometasone furoate (MF) is a synthetic glucocorticoid with anti-inflammatory activity, which is used for the treatment of topical skin disorders, allergic rhinitis and treatment of mild to moderate persistent asthma. The focus of this study is to examine the stability of MF in simulated lung fluid (SLF) and to clearly identify the structure of the degradation products of MF by MS and NMR analysis. Mometasone furoate degradation leads to the formation of two products, D1 and D2 with significant pH dependence. The half-lives for the conversion of MF to D1 and subsequent conversion of D1 to D2 at 37 degrees C in SLF were 1.3 and 4.8 h respectively. LC-MS and NMR analysis confirmed that D1 is 9,11-epoxide mometasone furoate while D2 represents a new chemical structure that shows cyclization within the C17-C21 region. The biological activity of these degradation products was assessed in rat lung glucocorticoid receptor binding studies. D1 showed 4 fold greater receptor affinity to glucocorticoid receptors compared to dexamethasone. However, the receptor affinity for D2 was a log order lower than that for dexamethasone. The instability of MF in SLF resulted in two degradation products, one of the degradation products showing glucocorticoid receptor activity, the other representing a new cyclized structure whose pharmacological properties have not been described. The biological significance of these degradation products is unknown.

Animals↗

PubMed2004

Possibilities in improvement of glucocorticoid treatments in asthma with special reference to loteprednol etabonate.

Allergic conditions contribute significantly to the burden of chronic disease in the industrialized world. The increasing prevalence has lead research into the discovery and development of various new therapeutic strategies. Despite considerable efforts of the pharmaceutical industry, the leukotriene antagonists were the only new class of asthma treatments to be licensed in the past 30 years. Topical glucocorticoids (GCs) are the most potent and effective therapy for treating allergic diseases. However, their use is limited by diverse undesired effects. Changes in pharmacokinetic parameters of GCs may be an interesting and promising approach to improve efficacy and safety of inhaled GCs. Loteprednol etabonate has been developed on the basis of the retrometabolic drug design. In animal studies, it has been demonstrated to have long-lasting anti-allergic (anti-asthmatic) effects without influencing the hypothalamic-pituitary axis (HPA). This soft steroid is now in phase III of the clinical development. Recently, loteprednol has been proven to be effective in the management of allergic rhinitis (400 microg once daily). No suppression of HPA was observed at clinically effective and higher doses. In conclusion, loteprednol as the first representative of soft steroids elicits marked anti-inflammatory effects, but has no impact on endocrine responses. It may represent a promising new therapy in the treatment of allergic rhinitis and asthma.

Anaphylaxis↗

PubMed2003

SPE/RIA vs LC/MS for measurement of low levels of budesonide in plasma.

A radioimmunoassay is described that measures budesonide in plasma after solid-phase extraction (SPE/RIA) of the analyte. The performance of the assay was compared with that of a selective LC/MS method. The limit of quantitation of budesonide determined for the LC/MS and SPE/RIA assay was 50 pg/mL and 120 pg/mL, respectively. Based on quality control samples, a higher variability was observed for the SPE/RIA (CV between 4.5 and 23.0%) than for the LC/MS method (CV between 7.5 and 12.5%). Plasma samples obtained from healthy volunteers after administration of budesonide rectal foam were assayed by both methods. In a subset of samples, these results were compared with those measured by direct RIA to evaluate the selectivity of two assays. About two times higher budesonide levels were measured with the direct RIA (lacking the extraction step), presumably because of cross-reactivity with budesonide metabolites, indicating that the extraction step in SPE/RIA is necessary for selectivity. Both SPE/RIA and LC/MS methods were found to be selective, sensitive and suitable for pharmacokinetic studies. Results obtained from the two methods were compared with a number of statistical methods. Ratios of results obtained for the clinical samples were close to 1 (ratio LC-MS/ SPE/RIA = 0.98 +/- 0.27). Linear regression indicated a slope of 1.17 +/- 0.0378. The concordance correlation (r = 0.91) indicated that the agreement between both methods was fair while the Bland-Altman plot indicated that the agreement was less pronounced at higher concentrations (1-3 ng/mL). In summary, the results confirm that the SPE/RIA is an alternative to HPLC/MS and that among the statistical methods tested the concordance correlation analysis was judged to be the most informative test to assess the comparability of two methods.

Bronchodilator Agents↗

PubMed2003

Population pharmacokinetics and pharmacodynamics of ciclesonide.

Ciclesonide is a novel glucocorticoid that is converted into ciclesonide--active principle (CIC-AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC-AP using nonlinear mixed-effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD) parameters, and investigate the effects of CIC-AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400-3600 micrograms) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC-AP population PK analysis. Various models examined inter- and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% co-efficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC-AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC-AP can be described using mixed-effect modeling. The estimated EC50 is similar to mean Cmax from an 800-micrograms dose, further suggesting CIC-AP has little effect on cortisol suppression.

Administration, Inhalation↗

PubMed2001

Current concepts in pharmacokinetics and their implications for clinical medicine.

The history of medicine provides ample evidence of the physicians' struggle with the subject of appropriate drug dosing. Recent studies indicate that drug-related mortality due to inadequate dosing principles still is a leading cause of death, only surpassed by cardiovascular diseases, cancer and stroke. In an effort to rationalize drug therapy, pharmacokinetic (PK) principles were introduced in medical practice in the early 1970s, mainly in the field of therapeutic drug monitoring (TDM). This measure was shown to reduce mortality. Several limitations in traditional PK, however, have led to the belief among many physicians that clinical PK is an unnecessary assignment of limited clinical relevance. Despite the perceived limitations of traditional PK research, remarkable developments have taken place in recent years and have made clinical PK a "physiological-mechanism based endeavor" with important implications for clinical medicine. Notably, the introduction of (1) PK-PD (pharmacokinetic-pharmacodynamic) modeling (2) target site PK (3) population PK and (4) pharmacogenomics has permitted better integration of PK principles into clinical drug therapy. The aim of the present article is to provide an overview of these developments and to discuss their impact on our understanding of clinical drug therapy.

Biological Availability↗

PubMed2001

Methods used to assess pulmonary deposition and absorption of drugs.

The assessment of pulmonary drug absorption and deposition is becoming increasingly important in drug development. Absorption information can be used to maximize pulmonary selectivity, to screen drug candidates and to help evaluate the bioequivalence of generic inhalation products. Several methods are available to investigate pulmonary drug absorption and deposition, ranging from in vitro experiments to in vivo pharmacokinetic and pharmacodynamic analyses. In combination, these methods can indicate the fate of an inhaled drug.

Journal Article↗

PubMed2001

Pharmacokinetics of plasmid DNA in the rat.

PURPOSE: The pharmacokinetics of plasmid DNA after IV bolus administration in the rat by following supercoiled (SC), open circular (OC), and linear (L) pDNA forms of the plasmid. METHODS: SC, OC, and L pDNA were injected at 2,500, 500, 333, and 250 microg doses. The concentrations in the bloodstream of OC and L pDNA were monitored. RESULTS: SC pDNA was detectable in the bloodstream only after a 2,500 microg dose, and had a clearance of 390(+/-50) ml/min and Vd of 81(+/-8) ml. The pharmacokinetics of OC pDNA exhibited non-linear characteristics with clearance ranging from 8.3(+/-0.8) to 1.3(+/-0.2) ml/min and a Vd of 39(+/-19) ml. L pDNA was cleared at 7.6(+/-2.3) ml/min and had a Vd of 37(+/-17) ml. AUC analysis revealed that 60(+/-10) % of the SC was converted to the OC form, and nearly complete conversion of the OC pDNA to L pDNA. Clearance of SC pDNA was decreased after liposome complexation to 87(+/-30) ml/min. However the clearance of OC and L pDNA was increased relative to naked pDNA at an equivalent dose to 37(+/-9) ml/min and 95(+/-37) ml/min respectively. CONCLUSIONS: SC pDNA is rapidly metabolized and cleared from the circulation. OC pDNA displays non-linear pharmacokinetics. Linear pDNA exhibits first order kinetics. Liposome complexation protects the SC topoform, but the complexes are more rapidly cleared than the naked pDNA.

Animals↗

PubMed2001

Evaluation of pulmonary absorption using pharmacokinetic methods.

When assessing inhaled drug absorption, standard pharmacokinetic analyses cannot differentiate drug that reaches the systemic circulation from the lungs from that of the gut. Pulmonary absorption kinetics can be assessed for drugs with negligible gastrointestinal absorption or for drugs that are eliminated via first-pass metabolism. For other drugs, pulmonary absorption kinetics can be studied by blocking gastrointestinal absorption with charcoal, or by studying absorption during the first 30 minutes post inhalation before appreciable oral absorption has occurred. Pharmacokinetic data generally agree well with pulmonary deposition data derived by measuring inhaled radiotracer-labelled drug using gamma-scintigraphy. Monitoring pulmonary and oral absorption also provides information on total systemic exposure and therefore safety. Furthermore, the duration of action of different inhaled drugs and the degree of pulmonary targeting can be obtained by determining the corticosteroid occupancy of lung and systemic glucocorticoid receptors. Pharmacokinetic data from healthy volunteers cannot be extrapolated to patients with asthma, as systemic exposure to inhaled drugs can be markedly less in patients than in healthy volunteers. This correlates with the observed differences in side effects in these two groups. Although pharmacokinetic methods do not provide information on regional deposition, they do generate data on systemic and pulmonary exposure, and so play a role in the development of delivery systems.

Administration, Inhalation↗

PubMed2001

Pharmacokinetics and pharmacodynamics of dexamethasone sodium-m-sulfobenzoate (DS) after intravenous and intramuscular administration: a comparison with dexamethasone phosphate (DP).

The pharmacokinetics (PK) and pharmacodynamics (effects on blood lymphocytes) of dexamethasone (D) after intravenous (i.v.) administration of dexamethasone phosphate (DP, 10 mg, equivalent to 8.3 mg of dexamethasone) and after intravenous and intramuscular (i.m.) administration of dexamethasone sulfobenzoate sodium (DS, 9.15 mg, equivalent to 6 mg of dexamethasone) were assessed. Only 25% of DS was converted into dexamethasone with a half-life for DS of 5.4 hours and 7.4 hours after i.v. and i.m. administration, respectively. Consequently, the mean residence time of D after both i.m. and i.v. administration of DS (10.4-11.6 h) was longer than that after DP administration (6.1 h). The smaller lymphocyte suppression induced by DS (50% of that after DP administration) was shown to be related to differences in the pharmacokinetics. This study revealed significant differences in the pharmacokinetics of D after administration of DS and DP and stresses the importance of the prodrug for the pharmacological response. Because of the slow and incomplete conversion of DS into dexamethasone, its use in emergency medicine situations should be critically evaluated.

Adult↗