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Biomedical subjects

L Schmid

Publications and source records attributed to L Schmid.

At least 37 records · Page 2Linked to original sources
PubMed1997

In vivo modulation of benzodiazepine receptor function after inhibition of endogenous gamma-aminobutyyric acid synthesis.

The influence of decreased endogenous gamma-aminobutyric acid (GABA) concentration on benzodiazepine receptor function was studied in the brain of living baboons. Positron emission tomography and the radiotracer [11C]flumazenil combined with electroencephalography were used to determine the pharmacological properties of two bezodiazepine receptors agonists, diazepam and bretazenil, in baboons pre-treated or not with DL-allylglycine (an inhibitor of GABA synthesis). Our results show that, in vivo, DL-allylglycine reduces the affinity of benzodiazepine receptors for their agonists without altering the intrinsic capability of agonists to allosterically modulate GABAergic transmission.

Allylglycine↗
PubMed1997

Post-remission therapy of adult acute myeloid leukaemia: one cycle of high-dose versus standard-dose cytarabine. Leukaemia Project Group of the Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Intensification of post-remission therapy improves the cure rate of acute myeloid leukemia (AML) but is often accompanied by unacceptable toxicity. From 1985 to 1992 the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III trial to evaluate the effectiveness of one single postremission course of high-dose cytarabine (HDAC) in terms of leukaemia-free and overall survival in adults with de novo AML. PATIENTS AND METHODS: Adult (15-65 years) AML patients in remission after two induction courses were randomly assigned to one consolidation course either with standard (SDAC: 100 mg/sqm 24 hours infusion over seven days) or with high-dose cytarabine (HDAC: 3000 mg/sqm every 12 hours as one-hour-infusion for six days). In addition, both arms included daunorubicin (45 mg/sqm daily on days 1 to 3). Thereafter, patients were observed without maintenance until relapse. RESULTS: After two induction courses 208/276 eligible patients achieved remission (CR: 169, 61%, PR: 39, 14%), 41 were resistant (15%) and 20 died early (7%). Seventy-one patients in remission were not randomized. One hundred thirty-seven were randomized in CR/PR (67 SDAC, 70 HDAC). 4/70 patients randomized to HDAC did not receive it. Treatment-related mortality in HDAC was 1.4% (1/66). WHO grade 3-4 toxicities occurred in 14/67 SDAC and in 38/66 HDAC patients (P < 0.0001). The median event free survival was 10.8 (SDAC) vs. 12.2 months (HDAC; P = 0.18). The median overall survival was 24.6 (SDAC) vs. 32.6 months (HDAC; P = 0.07). Although statistically uncertain, HDAC reduced the hazard of progression (hazard ratio: 0.69, P = 0.08) and of death (hazard ratio: 0.70, P = 0.13). For 112 patients stratified as CR the estimated four-year disease-free survival was 25% (+/-6%) with SDAC and 37% (+/-6%) with HDAC (P = 0.09). The overall survival rates at four years were 38% (+7%) and 48% (+7%), respectively (P = 0.10). In multivariate analysis HDAC significantly reduced the hazard of relapse by 39% compared to SDAC (hazard ratio = 0.61, 95% CI: 0.37-0.99; P = 0.049). CONCLUSIONS: We conclude that early consolidation of adult AML in CR with a single course of HDAC is superior in terms of outcome to one cycle of SDAC. The results of our intensive, single course HDAC group compare favourably with less intensive, repetitive HDAC cycles, suggesting that Ara-C dose intensity may be more important than total dosage. In addition, our treatment strategy is much less toxic and less expensive.

Acute Disease↗
PubMed1997

Intermittent exposure to doxorubicin in vitro selects for multifactorial non-P-glycoprotein-associated multidrug resistance in RPMI 8226 human myeloma cells.

The purpose of the present study was to evaluate whether intermittent exposure to a constant dose of doxorubicin selects for multidrug resistance (MDR) in RPMI 8226 human myeloma cells and, if so, to determine the molecular mechanism. In an attempt to approximate clinical doxorubicin treatment in vitro, cells were exposed to a fixed dose of doxorubicin for 4 d alternating with growth in drug-free medium for 17 d. An MDR subline emerged, termed 8226/DOXint5, which was 3-4-fold resistant to doxorubicin, etoposide and m-AMSA, and 1.6-fold resistant to vincristine. Sensitivity to docetaxel, melphalan and cisplatin was normal. Verapamil normalized vincristine sensitivity but had little effect on resistance to the other agents. Cellular uptake and retention of daunorubicin and vincristine were reduced by approximately 10%. The 8226/DOXint5 cells showed diminished DNA topoisomerase IIalpha expression and increased expression of the multidrug resistance protein MRP. Expression of MDR1/P-glycoprotein was not detected. Immunostaining showed 70% of the cells to over-express the lung-resistance protein LRP. This new MDR myeloma cell line may prove to be a useful model for the development of strategies to overcome low-level, multifactorial MDR, which might be a common phenomenon in clinical myeloma treated with doxorubicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation.

BACKGROUND: Thrombotic complications are common in patients with endstage renal disease and contribute substantially to the morbidity and mortality in this population. The aim of the present study was to: i) determine the prevalence and the extent of hypercoagulability in patients undergoing dialysis treatment by measuring parameters that directly reflect thrombin concentrations; ii) assess changes in coagulation status during haemodialysis (HD); iii) quantify the relative impact of heparin, dialysis and their combined effects on coagulation status and iv) detect factors that modify coagulation haemostasis in dialysis patients. METHODS: A total of 39 patients (HD: n = 29, CAPD: n = 10) was analysed for procoagulatory and fibrinolytic activity determined by measurements of partial thromboplastin time, prothrombin fragments F1 + 2, thrombin-antithrombin complexes and D-dimer concentrations. HD patients were investigated prior to and during dialysis. A subgroup of patients was infused heparin alone without dialysis or was dialysed without heparin administration. Furthermore, subgroup and correlation analyses were performed for the type of dialysis (HD vs CAPD), dialyzer and shunt, Kt/V, underlying disease and treatment with recombinant erythropoietin (rhEPO). RESULTS: Baseline levels of all parameters-procoagulatory and fibrinolytic--were substantially elevated in all patients, but to a higher degree among those on CAPD. Moreover, haemodialysis treatment increased procoagulatory markers even further, suggesting stimulated coagulation and/or insufficient anticoagulation during dialysis. However, after 3 h of dialysis thrombin concentrations, determined by quantification of prothrombin fragments, were inversely correlated with Kt/V. Selective heparin infusion diminished procoagulatory activity only slightly and incompletely, whereas HD without heparin resulted in excess thrombin accumulation. Finally, subgroup analyses revealed more pronounced thrombin formation among patients treated with polysulfon dialyzers, whereas erythropoietin dosage was positively related with lower procoagulatory activity. CONCLUSION: A majority of patients on dialysis are in a hypercoagulable state, which is further aggravated by the haemodialysis procedure itself and may not be sufficiently controlled with current anticoagulation regimens. Intensified heparin treatment and the use of rhEPO are likely to improve coagulation haemostasis, whereas the type of dialyzer should be considered as a relevant procoagulatory factor.

Adult↗
PubMed1996

[Chondrocalcinosis and Bartter syndrome].

A patient presenting with acute left-knee arthritis was diagnosed as having articular chondrocalcinosis. Routine laboratory tests motivated by a history of muscular cramps and weakness revealed hypokalemia and hypomagnesemia. Further investigations showed Bartter's syndrome. The characteristics of Bartter's syndrome and chondrocalcinosis and the relationship between the two diseases are developed.

Adult↗
PubMed1996

Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor: 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)- 1,3,4-oxadiazol-[11C]-2(3H)-one.

We report the radiochemical synthesis of a specific MAO B inhibitor, namely 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-[11C]-2(3 H)-one (2b) (in vitro IC50=4nM and selectivity over 71000 for MAO B), by cyclization of its hydrazide precursor 1 with [11C]phosgene. The reaction occurred within 2 min. The product obtained after HPLC purification, 2b, had a high specific activity (11.1-22.2 GBq/micromol), allowing its use in experiments as a radiotracer in vivo. Biodistribution of 2b in the CNS and in the peripheral organs of the rat, and positron emission tomography (PET) studies in the living baboon brain, pretreated or not with L-deprenyl (1mg/kg, 1h), an irreversible MAO B-specific inhibitor, were undertaken. The results showed a good uptake of 2b in all organs of the rat, with a rapid clearance from the blood (10 min). Metabolite analyses in plasma and in the diencephalon of the rat showed that 2b was the only radioactive compound in brain structure whereas in plasma three other radioactive products appeared. PET experiments show that in the L-deprenyl-pretreated baboon brain, specific binding of 2b represents around 70% of total radioactivity, whereas in the blood and plasma the radioactivity cleared rapidly (15 min).

Animals↗
PubMed1996

Pharmacological characterization and positron emission tomography evaluation of 4-[76Br]bromodexetimide and 4-[76Br]bromolevetimide for investigations of central muscarinic cholinergic receptors.

4-[76Br]bromodexetimide and its inactive enantiomer 4-[76Br]bromolevetimide were prepared via electrophilic bromodesilylation using chloramine-T and no-carrier-added (NCA) [76Br]NH4. In vitro, Bmax measured on rat cortex membranes were 3.7 +/- 0.2 and < 0.07 pmol/mg protein for 4-[76Br]bromodexetimide and 4-[76Br]bromolevetimide, respectively. The kD of 4-[76Br]bromodexetimide was 1.9 +/- 0.3 nM. In vivo studies in rats showed specific uptake of 4-[76Br]bromodexetimide in cortex, striatum, thalamus and hippocampus. No specific uptake was observed with 4-[76Br]bromolevetimide. With [76Br]bromodexetimide, positron emission tomography (PET) studies in primates demonstrated a preferential accumulation of the radioactivity in the cortex and striatum which was displaced to the level of cerebellum by dexetimide. With 4-[76Br]bromolevetimide, the radioactivity concentrations in the cortex and striatum were similar to that of cerebellum.

Animals↗
PubMed1996

Vigabatrin modulates benzodiazepine receptor activity in vivo: a positron emission tomography study in baboon.

The influence of increased endogenous gamma-aminobutyric acid (GABA) concentrations on benzodiazepine receptor (BZR) function was studied in the living baboon brain. By using positron emission tomography and the radiotracer [11C] flumazenil combined with electroencephalography, the anticonvulsant/proconvulsant activity and the potency of the BZR agonist diazepam and the inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM), a beta-carboline, were determined in baboons pretreated or not with 500mg/kg of vigabatrin (irreversible inhibitor of the GABA-aminotransferase which increases GABA concentrations in vivo). Pretreatment with vigabatrin increased the threshold of paroxysmal pentylenetetrazol-induced seizure. In both vigabatrin-treated and -untreated animals, the threshold dose of pentylenetetrazol increased with increasing doses of diazepam; it decreased with increasing doses of beta-CCM. The proconvulsant activity of beta-CCM was at all doses reduced in vigabatrin-treated animals compared to untreated animals, whereas, surprisingly, the anticonvulsant activity of high doses of diazepam was reduced after vigabatrin. The potency of diazepam in displacing [11C] flumazenil was enhanced in vigabatrin-pretreated animals, contrasting with the reduced anticonvulsant effects of diazepam in those animals. We determined the linear relationship between the fractional receptor occupancy and the anticonvulsant/proconvulsant effect. The slope, an estimate of the intrinsic efficacy of a BZR ligand, was reduced markedly for diazepam after vigabatrin pretreatment, whereas that for beta-CCM was unmodified. This indicates that increasing GABA levels in vivo reduce the anticonvulsant activity of the BZR agonist diazepam by decreasing its intrinsic efficacy, whereas the intrinsic efficacy of the inverse agonist beta-CCM remains essentially unaltered.

Animals↗
PubMed1995

[Is the assessment of prothrombin fragment F1+2 for monitoring of heparin therapy in patients with deep vein thrombosis useful?].

Prothrombin fragments (F1+2) can be used to monitor oral anticoagulation; their generation is also suppressed by heparin. We studied the course of F1+2, aPTT, heparin doses administered and heparin concentrations, as well as prothrombin time, during the first 7 days of heparin therapy (target aPTT 70 s) and overlapping oral anticoagulation (target INR 2-3) in 26 patients routinely treated for deep venous thrombosis (deep venous thrombosis +/- pulmonary embolism, 23 patients) or pulmonary embolism with a history of recurring deep venous thrombosis (3 patients). Although we found significant suppression of F1+2 between all pre- and post-treatment values, a transient, significant increase was seen on days 2-4. The amount of heparin given was stable from day 1-5; the fact of a transient increase in F1+2 might thus indicate that heparin doses routinely used are too low for the treatment of hypercoagulability in deep venous thrombosis in patients. We also found a decrease in heparin concentration on day 2, which may be explicable by changed pharmacokinetics of heparin in individuals with deep venous thrombosis. In conclusion, F1+2 may be useful for monitoring heparin treatment and oral anticoagulation in deep venous thrombosis patients from a laboratory point of view. However, larger studies are necessary to confirm these results. It remains to be clarified whether monitoring of anticoagulation by molecular markers might improve therapy of deep venous thrombosis. Such studies are in progress.

Heparin↗
PubMed1995

Zolpidem displays heterogeneity in its binding to the nonhuman primate benzodiazepine receptor in vivo.

The distinctive pharmacological activity of zolpidem in rats compared with classical benzodiazepines has been related to its differential affinity for benzodiazepine receptor (BZR) subtypes. By contrast, in nonhuman primates the pharmacological activity of zolpidem was found to be quite similar to that of classical BZR agonists. In an attempt to explain this discrepancy, we examined the ability of zolpidem to differentiate BZR subtypes in vivo in primate brain using positron emission tomography. The BZRs were specifically labeled with [11C]flumazenil. Radiotracer displacement by zolpidem was monophasic in cerebellum and neocortex, with in vivo Hill coefficients close to 1. Conversely, displacement of [11C]flumazenil was biphasic in hippocampus, amygdala, septum, insula, striatum, and pons, with Hill coefficients significantly smaller than 1, suggesting two different binding sites for zolpidem. In these cerebral regions, the half-maximal inhibitory doses for the high-affinity binding site were similar to those found in cerebellum and neocortex and approximately 100-fold higher for the low-affinity binding site. The low-affinity binding site accounted for < 32% of the specific [11C]-flumazenil binding. Such zolpidem binding characteristics contrast with those reported for rodents, where three different binding sites were found. Species differences in binding characteristics may explain why zolpidem has a distinctive pharmacological activity in rodents, whereas its pharmacological activity in primates is quite similar to that of classical BZR agonists, except for the absence of severe effects on memory functions, which may be due to the lack of substantial zolpidem affinity for a distinct BZR subtype in cerebral structures belonging to the limbic system.

Animals↗
PubMed1994

Assessing intervention effects in the Minnesota Heart Health Program.

The Minnesota Heart Health Program is a 13-year research and demonstration project to reduce morbidity and mortality from coronary heart disease in whole communities in the upper Midwest. Six communities were selected for the study: three intervention and three comparison sites, matched to increase baseline comparability. After 2-4 years of baseline observations, a 5- to 6-year program of intensive intervention was introduced in the three intervention communities. Periodic cross-sectional and cohort surveys provided data on risk factors and related behaviors. Regression adjustments within and between communities reduced the confounding influences of important covariates and the variance inflation associated with the nesting of individuals within communities and surveys. Post hoc stratification allowed exploration of the main and strata-specific effects of the intervention program. Finally, the intervention effect was modeled as a departure from the trend line fit to the nonintervention city-year means. Together, these procedures explicitly acknowledged the component of variance associated with communities, and so avoided a major source of bias created in the usual analysis when that variation is ignored. They also increased the interpretability of the analyses and reduced the mean square errors used to assess the treatment effects.

Cohort Studies↗
PubMed1994

Coincidence of familial platelet glycoprotein Ib/IX deficiency (Bernard-Soulier syndrome), idiopathic autoantibody against platelet glycoprotein Ib/IX, familial appearance of antiphospholipid antibodies, and familial factor XII deficiency.

The case of an 8-year-old boy with apparently homozygous Bernard-Soulier syndrome (platelet GP Ib/IX complex deficiency) and a transient idiopathic autoantibody against GP Ib/IX is described. He had been diagnosed with chronic autoimmune thrombocytopenia (due to the detection of antiplatelet autoantibodies) before Bernard-Soulier syndrome was proven. Both parents and his brother displayed intermediate deficiency of GP Ib/IX, thus indicating a heterozygote state for Bernard-Soulier syndrome. Alloimmunization as an explanation for the appearance of GP Ib/IX antiplatelet antibodies in the propositus can be excluded. A so-called pseudo Bernard-Soulier syndrome due to selective antibodies was also excluded. Flow cytometric analysis revealed residual expression of 2% GP Ib and 13% GP IX on the propositus' platelets. It seems that the propositus showed an idiopathic autoantibody against a platelet glycoprotein in which he is genetically deficient (but which is not completely lacking). Thus, in patients with untypical behavior upon therapy of "autoimmune thrombocytopenia", other differential diagnoses should also be considered even if antiplatelet antibodies are detected. In addition, all family members displayed elevated concentrations of antiphospholipid antibodies. These findings raise the question of a genetic predisposition for the development of autoantibodies. Moreover, an F. XII deficiency was found in all family members except the mother.

Adult↗
PubMed1994

In vivo high intrinsic efficacy of triazolam: a positron emission tomography study in nonhuman primates.

The triazolobenzodiazepine triazolam is a central-type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of gamma-aminobutyric acid-mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [11C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist 1C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half-life of 202 min). Triazolam is very potent in displacing [11C]flumazenil (ID50 = 28 +/- 6 micrograms/kg). Hill analysis of the displacement curve does not show obvious binding-site heterogeneity. Triazolam is 20 times more potent in displacing [11C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol-induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam-positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.

Animals↗
PubMed1994

Childhood stroke at three years of age with transient protein C deficiency, familial antiphospholipid antibodies and F. XII deficiency--a family study.

The unusual case of a boy with a stroke occurring at three years of age, transient reduction in protein C activity and high concentrations of antiphospholipid antibodies (APA) is described. APA or Lupus Anticoagulant (LA) were found in 7 of 11 relatives studied out of three different generations. In addition, antigenic Factor (F) XII deficiencies or borderline values were found in the propositus and 2 relatives. Evidence for F. XII inhibitors was found in the propositus, one of his brothers and both of his parents. Whether F. XII inhibitors in patients with APA and/or LA are pathophysiologically relevant in vivo or if they are only an in vitro phenomenon remains to be elucidated. It is reasonable to believe that the main laboratory pathology (APA and/or LA activity) in antiphospholipid syndrome is related to the clinical picture of a hypercoagulable state. There is evidence from the literature that deficiency or inhibition of F. XII might contribute to a prothrombotic state through impairment of the fibrinolytic system. There is also evidence that APA are able to reduce protein C activation. From a clinical point of view, it seems that hypercoagulability in our patient was controlled by low-dose aspirin therapy (75 mg/d). In conclusion, this case seems to support the idea of a genetic predisposition for the development of APA and/or LA. The related disturbances of the coagulatory, anticoagulatory and fibrinolytic systems might contribute in different ways to the prothrombotic state seen in patients with "antiphospholipid syndrome", eventually resulting in possible venous thrombosis or arterial thrombosis with corresponding ischaemic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Antiphospholipid↗
PubMed1994

Unstable distal radius fractures treated by modified Kirschner wire pinning: anatomic considerations, technique, and results.

A modified technique of percutaneous Kirschner-wire pinning for unstable distal radius fractures is presented. Three to four pins are placed from the radial styloid process toward and through the dorsal, volar, and ulnar cortices of the proximal fracture fragment, respectively. Rotational stability is achieved by bending and counterblowing of the wire ends in the styloid process. Anatomic studies of cadaver wrists revealed possible lesions of the superficial radial nerve, the cephalic vein, and the tendons of the brachioradialis muscle or the thumb and wrist extensors, respectively. Nevertheless, in a follow-up of 80 patients after 1 year, no tendinous lesions nor any other serious complications were seen. Using the criteria of Green and O'Brien, the results were excellent in 66.25%, good in 20%, and fair in 8.75%.

Arthritis↗