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Biomedical subjects

F Hasler

Publications and source records attributed to F Hasler.

At least 19 recordsLinked to original sources
PubMed1997

Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man.

In order to investigate the pharmacokinetic properties of psilocybin (PY), the main psychoactive compound of Psilocybe mushrooms, high performance liquid chromatographic procedures with column-switching coupled with electrochemical detection (HPLC-ECD) for reliable quantitative determination of the PY metabolites psilocin (PI) and 4-hydroxyindole-3-acetic acid (4HIAA) in human plasma were established. Sample work-up includes protection of the highly unstable phenolic analytes with ascorbic acid, freeze-drying and in-vitro microdialysis. The data of two controlled clinical studies with healthy volunteers are presented. The subjects (N = 6 for both studies) received single oral PY doses of 0.224 +/- 0.02 mg/kg b.wt. (10-20 mg) and intravenous doses of 1 mg PY, respectively. Peak plasma levels of PI after oral administration of PY were measured after 105 +/- 37 min showing an average concentration of 8.2 +/- 2.8 ng PI/ml plasma. 4HIAA peak concentrations of 150 +/- 61 ng/ml plasma were found 113 +/- 41 min after ingestion of PY. After intravenous administration, a mean PI maximum plasma concentration of 12.9 +/- 5.6 ng/ml plasma was found 1.9 +/- 1.0 min after injection. The maximum plasma levels appearing within a very short period indicate a rapid dephosphorylation of PY also when administered systemically. 4HIAA was not detected after 1 mg of intravenous PY. Estimates for the absolute bioavailability of PI after oral administration of PY were 52.7 +/- 20% (N = 3).

Administration, Oral↗
PubMed1994

Analysis and pharmacokinetics of glycyrrhizic acid and glycyrrhetinic acid in humans and experimental animals.

Glycyrrhizic acid (GZA) and glycyrrhetinic acid (GRA) can be determined rapidly and precisely by high-performance liquid chromatography (HPLC) in biological fluids and tissues from experimental animals and humans. From plasma and tissues, GZA and GRA are extracted by organic solvents and the extracts can directly be used for HPLC. From bile or urine, extraction and determination of GZA and GRA are more difficult due to interfering endogenous compounds and conjugation of GRA with glucuronides or sulfates. Extraction of GZA and GRA from urine or bile can be performed by ion-pairing followed by extraction with organic solvents or by solid phase extraction. GRA conjugates can be determined by chromatographic separation or by pretreatment with beta-glucuronidase. The pharmacokinetics of GRA and GZA can be described by a biphasic elimination from the central compartment with a dose-dependent second elimination phase. Depending on the dose, the second elimination phase in humans has a half-life of 3.5 hours for GZA and between 10-30 hours for GRA. The major part of both GRA or GZA is eliminated by the bile. While GZA can be eliminated unmetabolized and undergoes enterohepatic cycling, GRA is conjugated to GRA glucuronide or sulfate prior to biliary excretion. Orally administered GZA is almost completely hydrolyzed by intestinal bacteria and reaches the systemic circulation as GRA.

Animals↗
PubMed1994

Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans.

18 beta-Glycyrrhetinic acid (GRA) represents a major metabolite of glycyrrhizic acid (glycyrrhizin), an important constituent of licorice and licorice root, and is a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta OHSD). Different oral doses of GRA (500, 1000, or 1500 mg) were administered to healthy volunteers in order to study its kinetics and dynamics. In agreement with the lipophilic nature of GRA, with a biphasic decay of the plasma concentration-time curve at doses greater than 500 mg. The mean (+/-SEM) half-life of the second elimination phase was 11.5 +/- 1.2 h after 1000 mg GRA and 38.7 +/- 10.5 h after 1500 mg GRA (P < 0.05). The peak plasma concentration and the area under the plasma concentration-time curve (AUC) increased with increasing GRA doses. Urinary elimination of GRA and GRA glucuronides over 24 h was less than 1% of the dose administered. The dynamics of GRA were assessed by measuring the activity of the 11 beta OHSD in vivo, as reflected by the cortisol and cortisone concentrations in plasma. With increasing doses of GRA, the cortisone concentration declined, and the cortisol/cortisone ratio increased. Both peak plasma concentration and AUCs of GRA correlated with changes in the AUC values of cortisone. Based on the single dose kinetics, the kinetic/dynamic analysis of the data revealed that after multiple doses of 1.5. g GRA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Determination of 18 beta-glycyrrhetinic acid in biological fluids from humans and rats by solid-phase extraction and high-performance liquid chromatography.

Methods have been developed and characterized allowing rapid isolation and quantification of 18 beta-glycyrrhetinic acid (GRA) in biological fluids from both humans and rats. Sample preparation includes extraction with urea-methanol for plasma samples, and solid-phase extraction (SPE) for urine and bile samples. Hydrolysis of GRA glucuronides in urine and bile was performed by treatment with beta-glucuronidase. MGRA, the 3-O-methyl derivative of GRA was synthesized as an internal standard resistant to hydrolysis. High-performance liquid chromatography (HPLC) was performed with an isocratic system using methanol-water-acetic acid (83:16.8:0.2, v/v/v) as solvent on a Lichrocart RP-18 column at 30 degrees C with ultraviolet detection. The methods allowed base line separation of GRA and MGRA from all biological fluids tested, with a detection limit of 0.15 mg/l. Validation of the methods included determination of recovery, accuracy and precision in plasma, bile and urine from humans and rats. The methods were further evaluated by investigating the pharmacokinetics of GRA in normal rats and in rats with a bile fistula. Following an intravenous dose of 10 mg/kg, the plasma concentration-time curve of GRA could be fitted to a one compartment model both in control and bile fistula rats. The elimination half life averaged 15.0 +/- 2.2 versus 16.8 +/- 2.4 min in control and bile fistula rats (difference not significant). Within 90 min following administration of GRA, urinary elimination of GRA and GRA glucuronides was less than 1% in both groups whereas biliary elimination averaged 51.3 +/- 3.1%. The results show that the methods developed allow pharmacokinetic studies of GRA in humans and rats.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

[If I had chronic polyarthritis--current ideas on basic therapy].

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of largely unknown etiology and complex multifactorial pathogenesis. To date, the medical management has been less than optimal and has consisted primarily of drugs that modulate the acute inflammatory process. Over the years a treatment program referred to as the classical therapeutic pyramid has evolved. A new concept and a controversial one in therapy of RA is that already at the time of definitive diagnosis, a more concerted effort towards vigorous treatment using second-line drugs such as methotrexate, should be made. It is very likely that over the next 5 years interventions such as monoclonal antibodies directed against predetermined T-cell subpopulations and anti-cytokines such as TNF-alpha binding proteins will evolve as new concepts in therapy of RA.

Anti-Inflammatory Agents↗
PubMed1993

Soluble tumor necrosis factor receptors in human inflammatory synovial fluids.

OBJECTIVE: To test synovial fluid (SF) for the presence of soluble fragments originating from distinct tumor necrosis factor receptors (TNF-sR55 and TNF-sR75) which bind to TNF and inhibit its biologic activity. METHODS: TNF-sR55 and TNF-sR75 were measured in 62 SF samples by specific immunoassays using monoclonal antibodies. RESULTS: Both TNF-sR were present in all of the SF tested. Their concentrations were higher in SF from patients with seropositive rheumatoid arthritis than in patients with other inflammatory arthritides. The relative amount of TNF-sR75, as compared with TNF-sR55, was higher in seropositive RA SF than in other SF. CONCLUSION: The balance between TNF and its specific inhibitors may be critical to the biologic outcome mediated by this cytokine.

Humans↗
PubMed1992

Diffuse idiopathic skeletal hyperostosis (DISH) of the elbow: a cause of elbow pain? A controlled study.

Elbow pain is a common complaint and elbow hyperostosis a frequent radiological condition. However, little is known about the association between the clinical and radiological findings. To evaluate the relationship between spinal and extraspinal hyperostotic features and the clinical relevance of elbow hyperostosis we have performed the first controlled, double-blinded study of 85 hospitalized probands, 33 with and 52 without thoracospinal hyperostosis on lateral chest X-ray. Elbow and shoulder hyperostosis were graded on bilateral standard radiographs. Elbow pain was assessed by an interviewer using a standardized questionnaire and extraskeletal causes of elbow pain were recorded. The prevalence of elbow hyperostosis was increased in cases with thoracospinal hyperostosis compared to controls (82% versus 58%, chi 2 = 5.32, P less than 0.025, n = 85, olds ratio (OR) 3.30 (95% CI 1.16-9.35)). Similarly, the prevalence of elbow hyperostosis was increased in cases with shoulder hyperostosis compared to controls (83% versus 60%, chi 2 = 4.51, P less than 0.05, n = 84, OR = 3.20 (95% CI 1.06-9.66)), emphasizing the multifocal nature of hyperostotic features. Elbow pain was only slightly more prevalent in cases with elbow hyperostosis compared to controls (21% versus 13%, chi 2 = 0.75, NS, OR = 1.84 (95% CI 0.46-7.44)). We conclude that elbow hyperostosis is a radiological finding of doubtful clinical relevance.

Aged↗
PubMed1988

Diminished IL-2-induced gamma-interferon production by unstimulated peripheral-blood lymphocytes in rheumatoid arthritis.

A diminished gamma-interferon (IFN-gamma) production by T cells from patients with rheumatoid arthritis (RA) in response to autologous stimulation coincides with a defective regulation of Epstein-Barr virus (EBV) transformation and is in part due to monocyte-produced interleukin-1 (IL-1) inhibitor and prostaglandins. Since IL-2 can act directly on unstimulated T-cells to induce IFN-gamma production we have now examined the effect of recombinant IL-2 (rIL-2) on purified resting T lymphocytes from RA patients. Treatment with rIL-2(25 U/ml) of lymphocytes from 15 controls led to an increased production of 72-h supernatant EBV-inhibitory activity (19 +/- 4% SE without; 48 +/- 7% with rIL-2), but had only minimal or no effect on gamma-interferon production by E-rosetting lymphocytes from 15 patients with active RA. This defect could not be corrected by adding indomethacin to RA cultures.

Adult↗
PubMed1984

[Recent aspects of Epstein-Barr virus infections].

Epstein-Barr virus (EBV) is regularly associated with Burkitt's lymphoma (nasopharyngeal carcinoma) and has been extensively documented as causal in infectious mononucleosis. Recently it has become evident that this virus is associated or handled differently in patients with a variety of immunological disorders. If the mechanisms that normally limit the effects of EBV infection are blunted, as in rheumatoid arthritis, antibody responses to EBV induced cellular antigens are significantly higher than in healthy individuals. In the host with more profound immunosuppression a polyclonal B cell lymphoproliferation takes place which may progress to the monoclonal proliferation of true lymphoma.

Arthritis, Rheumatoid↗
PubMed1984

Vasculitis: immunological aspects.

The laboratory approach to patients with a vasculitic syndrome is of limited help in defining the diagnosis but may provide clues as to the pathogenesis (immune complex-mediated or cell-mediated reaction). Serial determinations of immune complexes or complement levels can also serve as the basis for assessment of disease activity and therapeutic interventions in some patients. In addition to angiographic findings there is only one way of establishing a tentative diagnosis of vasculitis: by histological demonstration.

Antigen-Antibody Complex↗
PubMed1983

Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation.

T cells of patients with rheumatoid arthritis (RA) do not control the rate of B lymphoblast transformation induced by Epstein-Barr virus (EBV) as efficiently as T cells from healthy individuals; thus, lymphoblast cell lines are established more readily in RA lymphocytes in vitro after EBV infection. In the present experiments, we have asked whether this T cell regulation can be reproduced by lymphocytes. We found that normal T cells, activated in allogeneic or autologous mixed leukocyte reactions (MLR), produce lymphokines that inhibit in vitro EBV-induced B cell proliferation. Allogeneic MLR supernatants inhibited EBV-induced DNA synthesis 62 +/- 4% (mean +/- SE) at 10 d post-infection, whereas autologous MLR supernatants suppressed it 50 +/- 3%. RA T cell supernatants produced in an allogeneic MLR suppressed as well as normal T cell supernatants (64 +/- 5% inhibition). In contrast, supernatants from RA autologous MLR had little inhibitory activity. EBV-induced DNA synthesis at 10 d was reduced only 8 +/- 3%, compared with the 50 +/- 3% suppressive activity of normal autologous MLR supernatants. The magnitude of the proliferative responses in the autologous MLR regenerating the lymphokines was similar in the normal and RA populations. After depletion of adherent cells from the RA auto-MLR stimulators, supernatant inhibitory activities increased to normal levels (from 11 +/- 6 [SE] to 52 +/- 6% [SE]). The inhibitory factor involved in the regulation of in vitro EBV infection is a protein with a molecular weight of approximately 50,000. Its activity is eliminated by hearing at 56 degrees C and by exposure to acid at pH 2. The inhibitory activity is blocked by mixing the MLR supernatants with a polyvalent antisera or monoclonal antibodies specific for human gamma interferon. Gamma interferon produced by activating T cells in allo- or auto-MLR can reproduce T cell-mediated regulation of EBV-induced B cell proliferation, and the failure of RA auto-MLR to generate that lymphokine parallels the defective T cell regulation of EBV-induced B cell proliferation characteristic of RA lymphoid cells.

Arthritis, Rheumatoid↗
PubMed1983

Analysis of the defects responsible for the impaired regulation of EBV-induced B cell proliferation by rheumatoid arthritis lymphocytes. II. Role of monocytes and the increased sensitivity of rheumatoid arthritis lymphocytes to prostaglandin E.

Diminished regulation of EBV-induced B cell proliferation by T cells from patients with rheumatoid arthritis (RA) is paralleled by diminished production of gamma-interferon in response to autologous but not allogeneic stimulation. We have shown that the adherent cell subpopulation within the autologous RA stimulators plays a major role in the RA defect. In analyzing the mechanisms responsible for the adherent cell effect in RA, we examined the contribution of prostaglandin production. Indomethacin treatment (1 microgram/ml) of the RA auto-MLR led to increased production of supernatant inhibitory activity (8% +/- 4 without, 57% +/- 4 with indomethacin), but had no significant effect on the inhibition of EBV-induced B cell proliferation by normal auto-MLR supernatants. Adding excess autologous adherent cells to the normal auto-MLR, however, led to an indomethacin-reversible decline in the production of the inhibitory factor without suppressing the auto-MLR proliferative response. The adherent cell effect could be reproduced by adding PGE1 or PGE2 (10(-8) to 10(-6) M) to the normal auto-MLR. PGE2 levels in 72-hr auto-MLR supernatants were similar in RA (4.2 +/- 1 ng) and normal control (3.6 +/- 0.5 ng/ml) supernatants. Because we could not detect differences in PGE production, we assessed the sensitivity of adherent cell-depleted normal and RA auto-MLR to exogenous PGE. Concentrations of 10(-7) to 10(-6) M PGE were needed to block production of the inhibitory factor by to normal cells, whereas only 10(-13) to 10(-12) M PGE1 completely blocked it in RA cell cultures. Thus, the defective production of gamma-interferon in the RA auto-MLR is, at least in part, due to enhanced sensitivity of the RA lymphocytes to adherent cell-produced prostaglandins.

Arthritis, Rheumatoid↗