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Biomedical subjects

H G Eichler

Publications and source records attributed to H G Eichler.

At least 19 recordsLinked to original sources
PubMed2002

Mucosal tolerance as therapy of type I allergy: intranasal application of recombinant Bet v 1, the major birch pollen allergen, leads to the suppression of allergic immune responses and airway inflammation in sensitized mice.

BACKGROUND: Several studies have demonstrated that mucosal administration of soluble antigens can prevent the onset or reduce the severity of certain autoimmune diseases or allergies. Few studies exist showing the efficacy of mucosal tolerance for therapy of such diseases. OBJECTIVE: The aim of the present study was to modulate an allergic immune response by intranasal antigen administration in an already sensitized organism. METHODS: A murine model of allergic asthma to birch pollen (BP) and its major allergen Bet v 1 was utilized. Sensitized mice were intranasally treated with recombinant (r)Bet v 1 in different concentrations and at different intervals. On the day the mice were killed, blood and bronchoalveolar lavage fluids were taken and immediate type I skin tests were performed. T cell proliferation and cytokine production (interleukin (IL)-5, interferon (IFN)-gamma) were measured in spleen and lung cell cultures. RESULTS: Mucosal treatment with rBet v 1 (3 x 50 microg in 4 day intervals) led to a reduction of type I skin reactions, suppressed immunoglobulin (Ig)G1/IgE antibody levels and markedly decreased IL-5 and IFN-gamma production in vitro in spleen and lung cell cultures. Moreover, lung inflammation (i.e. eosinophilia and IL-5 levels in bronchoalveolar lavage fluids) was significantly suppressed by the treatment. CONCLUSION: Our results demonstrate that intranasal treatment with rBet v 1 reduced systemic allergic immune responses as well as airway inflammation in BP-sensitized mice. We therefore suggest that mucosal tolerance induction with recombinant allergens could be a promising concept for the therapy of allergic diseases.

Administration, Intranasal↗
PubMed2001

Application of the minimal trauma tissue biopsy to transdermal clinical pharmacokinetic studies.

Although the transdermal administration of drugs has gained considerable importance, reliable methods for the quantitative assessment of transdermal drug penetration are scarce. The aim of the present study was therefore to evaluate the scopes and limits of the minimal trauma tissue biopsy (MTTB) technique for the in vivo characterization of the transdermal penetration process and the assessment of dermal drug kinetics in humans following topical drug application. Nicotine TTS (21 mg/24 h) was administered transdermally to 13 healthy volunteers. Repeated minimally invasive dermal and subdermal tissue biopsies were obtained at defined time points from defined skin layers directly underlying the TTS. The position of the biopsy needle and depth of biopsate were determined by 2D ultrasound scanning. The biopsy procedure was well tolerated by all volunteers and up to six biopsies within a period of 10 h were easily accepted. Dermal pharmacokinetic profiles for nicotine were obtained in all experiments and corresponded well to the values measured in previous studies on transdermal nicotine penetration. Mean area under the nicotine concentration time curve (AUC) in subepidermal layers underneath the application site of the TTS was 70.0+/-55.1 microg/g per h. There was a correlation between the depth of biopsy sampling and dermal nicotine concentrations at steady state (r=0.7). The MTTB is a suitable, well tolerated technique for the detection of transdermally applied compounds in defined subepidermal tissue layers and could therefore become a valuable tool in the development and assessment of transdermal dosage forms.

Administration, Cutaneous↗
PubMed2001

Ocular hemodynamics during isometric exercise.

The autoregulatory capacity of the human retina is well documented, but the pressure-flow relationship of the human choroid is still a matter of controversy. Recent data, using laser Doppler flowmetry to measure choroidal blood flow, indicate that the choroid has some autoregulatory potential, whereas most data using other techniques for the assessment of choroidal hemodynamics indicate that the choroidal pressure-flow curve is linear. We used a new laser interferometric technique to characterize choroidal blood flow during isometric exercise. Twenty healthy subjects performed squatting for 6 min during normocapnia and during inhalation of 5% CO2 and 95% air. Ocular fundus pulsation amplitude, flow velocities in the ophthalmic artery, intraocular pressure, and systemic hemodynamics were measured in 2-min intervals. To gain information on choroidal blood flow fundus pulsation amplitude was corrected for changes in flow pulsatility using data from the ophthalmic artery and for changes in pulse rate. Ocular perfusion pressure was calculated from mean arterial pressure and intraocular pressure. The ocular pressure-flow relationship was calculated by sorting data according to ascending ocular perfusion pressure values. In a pilot study in 6 healthy subjects comparable ocular pressure flow relationships were obtained when choroidal blood flow was assessed with the method described above and with laser Doppler flowmetry. In the main study isometric exercise caused a significant increase in mean arterial pressure (56%, P < 0.001), pulse rate (84%, P < 0.001), and intraocular pressure (37%, P 0.004), but decreased fundus pulsation amplitude (-36%, P < 0.001). Significant deviations from baseline choroidal blood flow were observed only at ocular perfusion pressures >69% during normocapnia and 70% during hypercapnia. Our data indicate that during isometric exercise the choroid has a high capacity to keep blood flow constant despite changes in perfusion pressure and that this pressure-flow relationship is not altered by moderate changes in arterial carbon dioxide levels.

Adult↗
PubMed2001

Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model.

We used Bcl-2 antisense oligonucleotides (G3139) to chemosensitize human gastric cancer by downregulation of Bcl-2 expression in vivo. Oligonucleotides and cisplatin were administered systemically in a human gastric cancer SCID mouse model, and Bcl-2 expression, apoptosis, tumor size, and survival were assessed. Used alone, G3139 treatment led to downregulation of Bcl-2 and moderate tumor reduction compared to saline control. G3139 combined with cisplatin treatment markedly enhanced the antitumor effect of cisplatin (70% tumor size reduction vs. cisplatin alone), associated with increased apoptosis measured in tumor biopsy specimens. Combined treatment with G3139 and cisplatin prolonged survival of the tumor-bearing SCID mice by more than 50% without adding significant drug-related toxicity. Treatment with Bcl-2 antisense oligonucleotides is thus a promising novel approach to enhance antitumor activity of cisplatin or other drugs used in gastric cancer therapy and warrants further evaluation in clinical trials.

Animals↗
PubMed2001

Pharmacokinetics of emedastine difumarate, a new anti-histaminic agent in patients with renal impairment.

OBJECTIVE: Emedastine difumarate is a new H1 receptor antagonist with well defined pharmacokinetic and pharmacodynamic profiles in healthy volunteers. However, to date it is not known whether impaired renal function in patients with chronic renal insufficiency affects its pharmacokinetics and probably also its tolerability. Therefore, we here set out to compare the pharmacokinetics of emedastine difumarate in patients suffering from different degrees of renal failure with a control group of healthy volunteers. METHODS AND RESULTS: For this purpose we conducted an open, single-centre, comparative parallel group study in patients and healthy volunteers. Emedastine difumarate 2 mg was administered orally to the study population in single and seven repetitive doses twice daily (b.i.d.). Pharmacokinetics differed markedly between volunteers (n = 6) and patients (n = 17). The maximum serum concentration of emedastine (Cmax), area under the serum concentration-time curve, mean residence time and terminal disposition half-life were significantly higher in patients (P < 0.05), while time to reach Cmax and apparent volume of disposition were not statistically different after single and repeated (steady-state) oral administrations. Blood pressure and heart rate were also not affected by the study medication. CONCLUSION: The present study shows that impaired renal function alters the pharmacokinetics of emedastine in plasma. Thus, dose adjustment of emedastine difumarate is advisable in patients with impaired renal function.

Administration, Oral↗
PubMed2001

Retinal blood flow and systemic blood pressure in healthy young subjects.

BACKGROUND: The aim of the present study was to investigate the association between systemic blood pressure and retinal blood flow in healthy young subjects. METHODS: Three independent study cohorts were included. A cross-sectional study was performed in 420 young male subjects with systolic blood pressure < 160 mmHg and diastolic blood pressure <100 mmHg. Retinal white blood cell flux (n=210) and blood velocity in the central retinal artery (n=210) were measured. In addition, a longitudinal study was performed in 40 young male subjects in whom retinal and systemic haemodynamic parameters were measured thrice within 6 weeks. Retinal white blood cell flux was measured with the blue-field entoptic technique. Blood flow velocity in the central retinal artery was measured by means of colour Doppler imaging. RESULTS: Retinal white blood cell flux (r=0.262; P<0.001) and mean flow velocity in the central retinal artery (r=0.174, P=0.010) were significantly associated with mean arterial pressure in the cross-sectional study. In the longitudinal study retinal white blood cell flux and mean flow velocity in the central retinal artery were also correlated with systemic blood pressure. CONCLUSIONS: Our data indicate a slight but significant increase in retinal blood flow with blood pressure. Whether this is of clinical relevance in eye diseases with altered retinal perfusion, such as diabetic retinopathy, remains to be established.

Adult↗
PubMed2001

Effects of heparin and aspirin on circulating P-selectin, E-selectin and von Willebrand Factor levels in healthy men.

As thrombin stimulates P-selectin expression on platelets and its release into plasma, we hypothesized that enhancing antithrombin activity by unfractionated heparin (UFH) could decrease plasma levels of circulating (c)P-selectin, (c)E-selectin, and von Willebrand Factor (vWF). Hence the effect of UFH and aspirin were examined on these activation markers in healthy volunteers. UFH decreased cP-selectin levels by -10% (CI: -16 - (-4%); P = 0.005) at 24 h, but did not change levels of vWF-Ag. In contrast, aspirin did not affect cP-selectin levels but decreased vWF-Ag levels by -12% (CI: -18 - (-7%); P = 0.005) at 24 h. Neither drug affected cE-selectin levels. Thus, UFH decreases cP-selectin levels, which may reflect decreased platelet activation in vivo. An increase in cP-selectin under UFH therapy should alert the clinician to look for platelet destruction.

Adult↗
PubMed2001

Comparison of the effects of ketamine and memantine on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial.

N-methyl D-aspartate (NMDA)-antagonists decrease neurotoxicity by inhibiting Ca2+ influx which is of interest for the treatment of acute cerebrovascular insults and chronic neurodegenerative disorders. Currently, there is no surrogate marker for quantification of NMDA-receptor-mediated drug effects, which hampers dose-finding clinical studies. As prolactin and cortisol liberation is in part influenced through NMDA-receptors we investigated whether the elevation of prolactin or cortisol plasma levels is a class effect of NMDA-antagonists and might be an appropriate marker for studying NMDA-antagonistic potency. Fifteen healthy male volunteers participated in this placebo-controlled, randomized, three-way crossover trial. Ketamine (0.5mg/kg), memantine (0.16 mg/kg; i.e., a well tolerated standard dose) or placebo were infused over 60 min. Ketamine increased serum prolactin and cortisol levels (p < 0.001), whereas memantine and placebo did not affect hormone levels. Further studies are needed to define whether higher doses of memantine or other NMDA antagonists can induce hormone release.

Adult↗
PubMed2001

A double masked placebo controlled study on the effect of nifedipine on optic nerve blood flow and visual field function in patients with open angle glaucoma.

AIMS: To investigate whether nifedipine affects ocular perfusion or visual fields in open angle glaucoma patients. METHODS: In a parallel group study nifedipine or placebo was administered for 3 months (n = 30). Ocular fundus pulsation amplitude (FPA), cup blood flow (Flowcup) and visual field mean deviation (MD) were measured. RESULTS: Five patients receiving nifedipine discontinued due to adverse events. Nifedipine did not affect FPA [difference: 0.3 microm (95% CI -0.3,0.9); P = 0.70], Flowcup: [difference: -9 rel.units (95% CI -133,114); P = 0.99], or MD [difference: 0.2dB (95% CI -2.2,2.7); P = 0.51] vs placebo. CONCLUSIONS: Systemic nifedipine is not well tolerated in glaucoma patients and exerts no effect on visual fields or ocular perfusion.

Administration, Oral↗
PubMed2001

Effects of anticoagulation on thrombopoietin release during endotoxemia.

Several lines of evidence suggest that coagulation may induce the release of thrombopoietin (TPO) into plasma and that TPO levels are higher in disseminated intravascular coagulation. Therefore we set out to illuminate the mechanism of TPO release in the setting of experimental endotoxemia, which induces activation of coagulation and platelets. Endotoxin (lipopolysachharide [LPS], 2 ng/kg) was infused into a total of 54 healthy men in two subsequent studies. Volunteers received infusions of unfractionated heparin, low-molecular-weight heparin, lepirudin, or placebo in a randomized, placebo-controlled fashion after bolus injection of LPS. TPO levels increased on average by 27% to 38% in all groups at 6 hours (P <.05 vs baseline), although all active drugs effectively blocked coagulation. Platelet counts dropped by about 15% at 1 hour after LPS infusion, recovered after 2 days, and exceeded baseline values by 8% to 18% after 7 days (P <.001 vs baseline for all groups). Yet lepirudin blunted the LPS-induced increase in circulating P-selectin by one half (P <.005 vs placebo), whereas both heparins did not diminish the increase in this platelet or endothelial activation marker as compared with placebo. Endotoxemia enhances TPO plasma levels independent of the degree of coagulation induction, which eventually results in increased platelet numbers. Of potential clinical interest is the observation that the direct thrombin inhibitor lepirudin, in contrast to heparins, mitigated LPS-induced platelet activation.

Adult↗
PubMed2001

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

OBJECTIVE: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DESIGN: Prospective comparative study of two groups. SETTING: The intensive care unit and research ward of an university hospital. SUBJECTS: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. INTERVENTIONS: To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. CONCLUSION: The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Adipose Tissue↗
PubMed2001

Differential expression levels of Par-4 in melanoma.

The pro-apoptotic prostate apoptosis response-4 gene product Par-4 sensitizes prostate cells to the induction of programmed cell death. In this study we examined Par-4 expression in human melanoma cell lines and melanoma metastases. The heterogeneous expression detected prompted us to investigate the biological relevance of Par-4 in a human melanoma xenotransplantation model. Overexpression of Par-4 by transfection decreased tumour development in xenotransplanted A375-C6 melanoma cells in SCID mice and correlated to an increase in tumour cell apoptosis. These data suggest that high expression of the pro-apoptotic protein Par-4 could qualify as a prognostic marker in human melanoma.

Animals↗
PubMed2001

Elevated procaspase levels in human melanoma.

In this study procaspase expression levels were investigated by Western blotting in a panel of established melanoma cell lines, transformed melanocytic cell lines and normal primary melanocytes. Upstream caspases such as procaspase-8 that contain a death effector domain were found to be overexpressed in transformed melanocytes and melanoma cell lines compared with melanocytes. Heterogeneous levels of procaspase-8 were seen in melanoma cells, including one cell line that completely lacked procaspase-8 expression. Procaspase-10 is generally overexpressed in transformed melanocytes and melanoma cell lines. Expression of the downstream procaspases-3 and -7 was increased in melanoma cells compared with normal melanocytes. Procaspases containing caspase recruitment domains such as procaspase-2 were expressed at similar levels in nearly all the cell lines investigated. Reduced levels of procaspase-1 compared with normal melanocytes were detected in transformed melanocytes and melanoma cell lines. These data indicate that procaspase levels in general increase during the malignant transformation of melanocytic cells.

Blotting, Western↗
PubMed2000

Validation of urea as an endogenous reference compound for the in vivo calibration of microdialysis probes.

Microdialysis is a widely used experimental technique, which offers the opportunity to measure drug and metabolite concentrations in the interstitial space fluid in animals and humans. However, microdialysis probes need to be calibrated in vivo to obtain a recovery factor, which describes the relative drug transfer across the membrane. Recently, novel time-saving calibration techniques, based on the use of reference compounds, have been developed. In particular, the use of endogenous urea levels has been advocated. In the present study we set out to validate the use of the urea reference technique for microdialysis probe calibration in healthy volunteers, employing glucose and paracetamol as model analytes. Urea calibration was compared with the results of two standard calibration techniques, i.e. the no net flux technique and the retrodialysis technique. For glucose, recovery values, calculated by the urea reference technique differed significantly from those values, which were assessed by the no net flux technique (p < 0.05), whereas for paracetamol recovery values did not differ significantly, albeit a high intramethod variability was observed (CV=66%). As a conclusion, we could not confirm the hypothesis that recovery values calculated by the urea reference technique provide equivalent results compared with standard calibration techniques.

Acetaminophen↗
PubMed2000

Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.

During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.

Adult↗
PubMed2000

Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans.

A recent study in dogs suggested that erythropoietin (EPO) not only promotes the synthesis of increased numbers of reticulated platelets but that these newly produced platelets are hyperreactive compared with controls. Because of the increasing use of EPO in the perioperative setting, we characterized the effects of EPO on platelet reactivity in healthy human volunteers. In a randomized, controlled trial, we studied the effects of EPO on platelet reactivity, thrombopoiesis, and endothelial activation in circumstances similar to those of autologous blood donation. Thirty healthy male volunteers received placebo or EPO (100 or 500 U/kg of body weight given intravenously) three times a week for 2 weeks and underwent phlebotomy on days 8 and 15. Thrombin receptor-activating peptide induced expression of P-selectin, and CD63 increased 2- to 3-fold during EPO treatment. The enhanced platelet reactivity was also reflected by a 50% increase in soluble P-selectin in plasma. Plasma E-selectin levels increased in a dose-dependent fashion by more than 100% during EPO treatment, indicating substantial activation of endothelial cells. A 10% to 20% increase in platelet counts was observed in both EPO groups on day 5. In the placebo group, platelets increased only several days after the first phlebotomy. The increase in platelet counts was not reflected by changes in the amounts of reticulated platelets or circulating progenitor cells. In summary, we found that EPO markedly enhances endothelial activation and platelet reactivity, which may adversely affect patients at cardiovascular risk. However, the increased platelet reactivity could be exploited in patients with platelet dysfunction. (Blood. 2000;95:2983-2989)

Adult↗
PubMed2000

Lepirudin blunts endotoxin-induced coagulation activation.

During sepsis, lipopolysaccharide (LPS) triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney and decreased mortality in LPS-induced DIC. Accordingly, the effects of recombinant hirudin (lepirudin) was compared with those caused by placebo on LPS-induced coagulation in humans. Twenty-four healthy male subjects participated in this randomized, double-blind, placebo-controlled, parallel group study. Volunteers received 2 ng/kg LPS intravenously, followed by a bolus-primed continuous infusion of placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h for 5 hours) to achieve a 2-fold prolongation of the activated partial thromboplastin time (aPTT). LPS infusion enhanced thrombin activity as evidenced by a 20-fold increase of thrombin-antithrombin complexes (TAT), a 6-fold increase of polymerized soluble fibrin, termed thrombus precursor protein (TpP), and a 4-fold increase in D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP increased by only 50%, and D-dimer only slightly exceeded baseline values (P <.01 versus placebo). Concomitantly, lepirudin also blunted thrombin generation evidenced by an attenuated rise in prothrombin fragment levels (F(1 + 2), P <. 01 versus placebo) and blunted the expression of tissue factor on circulating monocytes. This experimental model proved the anticoagulatory potency of lepirudin in LPS-induced coagulation activation. Results from this trial provide a rationale for a randomized clinical trial on the efficacy of lepirudin in DIC. (Blood. 2000;95:1729-1734)

Adult↗