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Biomedical subjects

K Jaschonek

Publications and source records attributed to K Jaschonek.

At least 19 recordsLinked to original sources
PubMed2003

Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.

BACKGROUND: Antiplatelet agents such as acetylsalicylic acid (aspirin) reduce the relative risk for cerebrovascular events in patients with cardiovascular or cerebrovascular disorders by approximately 23 %. Recent observations raise the possibility that aspirin resistance may contribute to the failure of aspirin treatment in a significant proportion of patients (aspirin non-responders). To evaluate the clinical relevance of aspirin non-responder status, we analysed platelet functions in symptomatic and asymptomatic patients treated with aspirin for secondary prevention of cardiovascular and cerebrovascular events. METHODS: A total of 53 patients on 100 mg aspirin daily for secondary prevention (mean treatment duration > 60 months) were included. Patients were categorized as asymptomatic if they were free of cerebrovascular incidents for at least 24 months (n = 18). Symptomatic patients had suffered ischemic strokes or transient ischemic attacks within the previous 3 days (n = 35). Platelet function was assessed using the PFA-100 system that allows for quantitative assessment of platelet function, reporting platelet aggregatability as the time required to close a small aperture in a biologically active membrane. RESULTS: Collagen/epinephrine closure times were significantly shorter in symptomatic patients than in asymptomatic patients (p < 0.01). Individual closing times were normal in 12 of 35 symptomatic patients (34 % non-responders) whereas all asymptomatic patients had prolonged closure times. CONCLUSIONS: Aspirin non-responder status may contribute to failure of aspirin therapy in the secondary prevention of cerebrovascular incidents in as much as 30-40 % of patients. Quantitative assessment of platelet functions may provide a means to predict aspirin treatment failure in individual patients and to re-direct therapeutic strategies.

Aged↗
PubMed1993

Fish oil preparations rich in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists.

The effects of daily dietary supplementation for 6 weeks with either 4.5 g eicosapentaenoic acid (EPA) and 3.35 g docosahexaenoic acid (DHA) (group I, EPA/DHA = 1.33) or 3.5 g EPA and 6.4 g DHA (group II, EPA/DHA = 0.54) on platelet responsiveness to the stable prostaglandin (PG)-endoperoxide analogue 9,11-dideoxy,9 alpha-11 alpha-methanoepoxy-PGF2 alpha (U 46619) were studied in healthy volunteers. Dose-response curves (DRC) of U 46619-induced platelet aggregation were analysed by computerized non-linear curve fitting. In group I, the concentration of U 46619 required for half-maximum platelet aggregation (EC50) remained unchanged, whereas the Hill coefficient decreased from 6.2 to 3.3 (P < 0.02). In group II, characterized by a high intake of DHA, a considerable increase of EC50 from 0.3 to 1.4 microM was found (P < 0.02). These results suggest different effects of EPA and DHA on the platelet thromboxane/endoperoxide-amplifying system. The considerable shift of the DRC in group II suggests a direct effect of DHA on the presentation of the endoperoxide receptor and/or post-receptoral events.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Platelets from patients with liver cirrhosis exhibit a defect in the von Willebrand factor-binding domain.

In this study, we examined the platelet von Willebrand factor (vWF)-binding domain in patients with liver cirrhosis. Direct binding studies were performed with the monoclonal antibody (mab) AN51 with specificity for the glycoprotein (GP) lb alpha. Specific binding of AN51 to intact washed platelets was monitored by an enzyme-linked immunoassay (ELISA). Half-maximum binding to intact washed platelets occurred at concentrations as low as 94 +/- 24 ng/ml; N = 12). Binding saturation analysis of with AN51 revealed a more than fifty percent reduction of AN51-binding sites (p < 0.001) in cirrhosis (N = 13) as compared to sex- and age-matched healthy controls (N = 12). These data demonstrate an impairment of the platelet surface vWF-binding domain in patients with liver cirrhosis. The resulting defect in primary haemostasis, i.e. the vWF-mediated attachment of platelets to the exposed subendothelium, is expected to contribute to the increased risk of haemorrhagic complications in these patients.

Antibodies, Monoclonal↗
PubMed1992

Intracellular cytosine arabinoside accumulation and cytosine arabinoside triphosphate formation in leukemic blast cells is inhibited by etoposide and teniposide.

Cytosine arabinoside (ara-C) is one of the most active compounds in the treatment of acute leukemias. In the majority of current protocols ara-C is combined with other cytotoxic agents in an attempt to increase antileukemic activity. The present study investigated the impact of etoposide, teniposide, amsacrine, mitoxantrone, anthracyclines, and asparaginase on the cellular accumulation of ara-C and its intracellular metabolism in order to provide a better rationale for combination therapy. Intracellular accumulation and phosphorylation of ara-C were determined in peripheral blast cells from twenty patients with acute leukemias after exposure to 1 and 10 mumol/l ara-C alone and after preincubation with 1 and 10 micrograms/ml etoposide, 10 and 100 micrograms/ml teniposide, 10 mumol/l amsacrine, 500 ng/ml mitoxantrone (or daunorubicin or doxorubicin) or 10 mumol/l asparaginase. Ara-C accumulation at 10 mumol/l was decreased by 1 microgram/ml etoposide (67 +/- 18% of control), 10 micrograms/ml etoposide (30 +/- 22%), 10 micrograms/ml teniposide (12 +/- 23%), 100 micrograms/ml teniposide (10 +/- 18%), and amsacrine (51 +/- 21%). Intracellular ara-CTP formation was determined at an extracellular concentration of 10 mumol/l and preincubation with these drugs. The intracellular formation of ara-CTP was decreased by 1 microgram/ml etoposide (77 +/- 15% of control), 10 micrograms/ml etoposide (32 +/- 22%), 10 micrograms/ml teniposide (10 +/- 9%), 100 micrograms/ml teniposide (0 +/- 0%), but not by amsacrine. These data indicate that prior exposure to etoposide and teniposide influence ara-C metabolism and possibly cytotoxicity, and thus should not immediately precede ara-C administration in clinical trials.

Acute Disease↗
PubMed1991

The anti-fungal agent itraconazole exerts immunosuppressive effects on alloreactivity but not on natural immunity in vitro.

The anti-fungal azole drug itraconazole was compared with fluconazole regarding immunosuppressive effects in a model of human alloreactivity in vitro (the mixed lymphocyte culture, MLC) and in assays of non-adaptive immunity (natural killing, NK, and lymphokine activated killing, LAK). Itraconazole, but not fluconazole, strongly inhibited lymphocyte proliferation and the generation of allospecific cytolytic activity, but had no effect on the development of major histocompatibility complex (MHC)-unrestricted ("natural killer-like") cytotoxicity or of alloindifferent suppressive activity in MLC. Neither drug blocked LAK cell induction, nor the effector phase of either NK or LAK activity. These results suggest that itraconazole might represent a new class of immunosuppressive agent which specifically blocks alloreactivity without affecting natural immunity.

Antifungal Agents↗
PubMed1991

Comparison of the immunosuppressive activities of the antimycotic agents itraconazole, fluconazole, ketoconazole and miconazole on human T-cells.

Four antifungal agents have been screened in vitro for their immunosuppressive effects on proliferative responses in human mixed lymphocyte cultures (MLC). A hierarchy of inhibitory activity was observed, where itraconazole was greater than ketoconazole greater than miconazole greater than fluconazole, with itraconazole as suppressive as cyclosporin A, and fluconazole completely without suppressive activity. The mechanism of inhibition did not involve blockade of T-cell growth factor production and, consistent with this, interleukin-2-dependent T-cell clone proliferation was blocked by these agents in the same order of decreasing activity as in MLC. The secretion of cytokines without known T-cell growth factor activity (interferon-gamma, tumour necrosis factor-alpha) was also not significantly blocked by these agents. These results therefore demonstrate that antifungal azole drugs may be variably strongly immunosuppressive for human T-lymphocyte proliferation in vitro, but none appear to be so via a mechanism involving inhibition of cytokine secretion.

Antifungal Agents↗
PubMed1991

Platelet endoperoxide/thromboxane A2 (PGH2/TXA2) receptors in patients with myeloproliferative disorders.

In patients with myeloproliferative disorders (MPD) an altered sensitivity of platelets to antiaggregatory prostaglandins and to the endoperoxide analogue U 46619 has been found. In this study we examined U 46619-induced platelet aggregation and binding of the endoperoxide/thromboxane A2 (TXA2) receptor antagonist SQ 29548 in 11 patients with MPD and 11 healthy controls. Although platelet responsiveness to U 46619 was significantly enhanced (p less than 0.05) in MPD, binding affinity and binding capacity of the corresponding endoperoxide/TXA2 receptor were not altered (Bmax 0.67 +/- 0.20 vs. 0.58 +/- 0.14 pmol/10(9) platelets, Kd 0.41 +/- 0.11 vs. 0.55 +/- 0.09 nM). These data exclude the possibility that changes in the presentation of endoperoxide/TXA2 receptors are responsible for the enhanced platelet sensitivity to endoperoxides found in MPD.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

[Rocky Mountain spotted fever].

After returning from a holiday in the USA a 24-year-old man fell ill with diarrhoea, high fever and marked rash including the palms of the hands and soles of the feet. When a history of a tick bite in the USA was elicited, a rickettsial infection was suspected. Treatment with doxycycline, 100 mg twice daily, was instituted finally and the fever slowly resolved. The patient became completely well again within four weeks. Serological tests confirmed the diagnosis of Rocky Mountain spotted fever.

Adult↗
PubMed1990

Effects of novel antifungal azole derivatives on the 5-lipoxygenase and cyclooxygenase pathway.

5-Lipoxygenase and cyclooxygenase catalyze the first steps of the conversion of arachidonic acid into leukotrienes and prostanoids, respectively. Leukotrienes are important mediators of inflammation and thromboxanes are mainly involved in platelet functions. The effects of the new antimycotic drugs, itraconazole and fluconazole, on the 5-lipoxygenase pathway in human polymorphonuclear leukocytes (PMNL), on the eicosanoid metabolism in platelets, platelet aggregation and on cyclooxygenase activity were investigated and compared with miconazole and ketoconazole. Itraconazole inhibited the formation of 5-lipoxygenase metabolites in human PMNL (IC50 = 2 x 10(-6) mol/l), while it had no effect on cyclooxygenase and platelet aggregation at concentrations up to 10(-4) mol/l and 10(-5) mol/l, respectively. Fluconazole was ineffective in all assays. Miconazole inhibited thromboxane synthase (IC50 = 1 x 10(-5) mol/l) and platelet aggregation (IC50 = 3 x 10(-5) mol/l). Ketoconazole was less active in this respect (IC50 for platelet aggregation = 2 x 10(-4) mol/l). All compounds did not affect cyclooxygenase activity in concentrations up to 10(-4) mol/l in the pure enzyme assay. These results indicate that among the tested azoles two compounds show remarkable effects. Miconazole inhibits thromboxane synthesis and itraconazole is a potent inhibitor of leukotriene formation which has only minor effects on the cyclooxygenase pathway. This finding is of considerable interest regarding the application of itraconazole during immunosuppressive therapy and suggests further studies of its potential antiphlogistic properties.

Antifungal Agents↗