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Biomedical subjects

E Weber

Publications and source records attributed to E Weber.

At least 181 records · Page 10Linked to original sources
PubMed1994

[Status of 3 years of hyperthyroidism treatment with iodine 131].

We analysed retrospectively the results obtained during 3 years in the treatment of thyrotoxicosis with 131-iodine. A group of 32 patients, including 21 Graves' diseases, 10 multinodular toxic goitres and 1 toxic adenoma has been collected. The therapeutic efficacy of one dose of radioiodine, assessed after 6 months was 100% in toxic multinodular goitres and 57% in Graves' diseases. No acute complications were observed. The best radiosensitivity of toxic multinodular goitres compared with diffuse goitres is probably due to the mechanisms themselves of thyrotoxicosis in these diseases. Results also suggest that multinodular toxic goitres in our country should be systematically treated with antithyroid drugs before radioiodine. In Graves' disease, no predictive factor of the early response to therapy could be definitely evidenced. Finally, clinicians should be aware of the advantages of such a treatment of thyrotoxicosis which is not very aggressive and at least definitive.

Adult↗
PubMed1993

Primary structure analysis of a duplicated region in the amplifiable AUD6 locus of Streptomyces ambofaciens DSM40697.

In Streptomyces ambofaciens, an amplifiable unit of DNA (AUD6) contains two homologous sequences, one located on the right extremity of the AUD (S1R), the other being internal (IHS). This paper presents the molecular analysis of this duplication. The nucleotide sequences are almost identical (95%) and each contains an ORF of about 330 codons, the two ORFs being nearly identical. The two hypothetical proteins, deduced from these sequences, show about 30% identity with different bacterial repressors. They also show a particularly strong similarity (90% identity between the full-length sequences) with hypothetical proteins of Streptomyces lividans 66 encoded by sequences also present on an amplifiable DNA region (AUD1).

Amino Acid Sequence↗
PubMed1993

Blockade of morphine-induced analgesia and tolerance in mice by MK-801.

The effect of MK-801 on morphine-induced analgesia, tolerance and opioid binding sites was examined in mice. In analgesia studies, mice received either naloxone or MK-801. Controls were injected with saline. Mice were then injected with morphine 10 or 30 min following naloxone or MK-801, respectively, and tested for analgesia (tail flick assay) 45 min later. Pretreatment with naloxone or MK-801 blocked morphine-induced analgesia. In tolerance studies, mice were pretreated with either saline or MK-801. Thirty minutes later, mice were injected with either saline or morphine (acutely or chronically) and tested for analgesia 24 h later. Pretreatment with MK-801 partially or completely blocked the development of acute and chronic tolerance, respectively. In binding studies, MK-801 displaced [3H]naloxone poorly compared to naloxone or morphine. Together, these data suggest a role for NMDA receptors in morphine-induced analgesia and tolerance. The poor inhibition of the [3H]naloxone binding sites by MK-801 supports the possibility that MK-801 might not act directly on the opioid receptors, but rather, inhibits morphine-induced analgesia and tolerance by some other mechanisms.

Analgesia↗
PubMed1993

10,5-(Iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and derivatives. Potent PCP receptor ligands.

IDDC (3, 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene++ +) and a series of substituted derivatives were synthesized and evaluated in vitro for their ability to displace tritiated MK-801 ([3H]-2) from its specific binding site in guinea pig brain homogenate. Substitution at the 3-position of 3 with bromine, chlorine, and fluorine led to increased binding affinity. In contrast, substitution of donor groups at the 3-position gave decreased binding affinities, as did all substitutions at the 7-position and on nitrogen. Where racemic mixtures were resolved, the (+)-optical antipodes were more active than their enantiomers or racemates. The most active ligand found in this study was (+)-13e (IC50 = 15.5 +/- 4.5 nM). The affinity of (+)-13e for the PCP receptor makes it among the most potent ligands known. In vitro neuroprotection was demonstrated by 3, (+)-3, and (+)-6 (N-Me-IDDC) against glutamate-induced cell death in rat hippocampal cells.

Animals↗
PubMed1993

NMDA receptor antagonists, MK-801 and ACEA-1011, prevent the development of tonic pain following subcutaneous formalin.

Subcutaneous injection of formalin produces a biphasic pain response: an early, transient phase followed by a late tonic phase. The present study examined the involvement of the N-methyl-D-aspartic acid (NMDA) receptor in the development of the late pain produced following subcutaneous injection of formalin into the hind paw in mice. Blockade of the NMDA receptor by its non-competitive antagonist, MK-801, prior to formalin injection, but not after, reduced pain during the late phase. Similarly, blockade of the NMDA receptor allosteric site by the novel glycine site antagonist, ACEA-1011, also reduced the pain response in the late phase. These results suggest that the development of the late phase of formalin pain is due to NMDA-mediated activity during the early phase.

Analgesics↗
PubMed1993

Monoclonal antibody SEN7 recognizes a new epitope on the neural cell adhesion molecule present on small cell lung cancer but not on lymphocytes.

In our continuing attempt to select monoclonal antibodies for immunotargeting of small cell lung carcinoma (SCLC) we have developed the IgG1 murine antibody SEN7 which by immunofluorescence stained all SCLC cell lines tested. On frozen tumor section six of seven SCLCs were positively stained. The reactivity of this antibody in a series of lung tumors and on normal tissues has some similarities with cluster 1 antibodies and cluster w4 antibodies, as defined by the First and Second International Workshop on Lung Cancer Antigens [P.C.L. Beverley, Y. Olabrian, J.A. Ledermann, L.G. Bobrow, and R.L. Souhami, Br. J. Cancer, 63 (Suppl): 10-19, 1991], particularly with regard to staining of neuroendocrine tissues. The similarities in staining of neuroendocrine tissues between antibody SEN7 and cluster 1 and cluster w4 antibodies prompted us to examine the binding of SEN7 with transfectants expressing the respective antigens. On the murine lymphoma cells B-9, stably transfected with a complementary DNA clone coding for an M(r) 140,000 isoform of human SCLC neural cell adhesion molecule (NCAM), antibody SEN7 reacted positively whereas the cluster w4 antibody was negative. The reaction of antibody SEN7 with the NCAM transfected murine lymphoma cells was unexpected in view of its lack of binding to peripheral blood mononuclear cells which regularly stain positive with NCAM antibodies. Western blotting of a renatured SCLC extract revealed a strong band around M(r) 180,000 in contrast to other cluster 1 antibodies which recognized a broad polydisperse band with a molecular weight of 140,000 to 210,000. Antibody binding was sensitive to tunicamycin treatment, suggesting the epitope to reside on an N-linked carbohydrate structure. No significant competition for SEN7 binding on SCLC cells was seen with other NCAM antibodies against the three distinct epitopes described on SCLC. This finding together with the lack of staining of peripheral blood mononuclear cells and the selected reactivity with the M(r) 180,000 band of NCAM indicate the antibody SEN7 recognizes an epitope on NCAM which has not been described previously. Biodistribution studies with radiolabeled SEN7 in nude mice bearing s.c. SCLC xenografts demonstrated the selective localization of more than 30% of the total injected dose per g tissue at day 4 following i.v. injection. The homogeneous binding to SCLC, the lack of binding to peripheral blood mononuclear cells, and the favorable tumor localization in a xenograft model indicates that SEN7 is a good antibody for immunotargeting of SCLC.

Animals↗
PubMed1993

Compliance and adverse drug reactions: a prospective study with ethinylestradiol using continuous compliance monitoring.

This study examined the relationship between adverse reactions and patient compliance with ethinylestradiol at 40 micrograms twice daily versus 20 micrograms four times daily. In a randomized study 61 female patients with primary infertility were prescribed the drug twice daily (n = 31) or four times daily (n = 30). Ethinylestradiol was administered for 7 days before the sperm cervical mucus penetration-test was performed for hormonal standardization of the cervical mucus quality. Drug compliance was measured by continuous monitoring using the Medication Event Monitoring System. Two parameters were evaluated: percentage of prescribed doses taken (administration compliance) and adherence to the prescribed dose schedule (regimen compliance, number of days with two or four dosing events recorded). Adverse drug reactions were assessed using a standardized questionnaire. Fourty-four women experienced side effects, of which 81% were rated by patients as being mild. Patient compliance was higher with the twice daily than with the four times daily regimen: 85% versus 65% prescribed doses taken (P < 0.05). There was no significant difference in compliance comparing patients with and without adverse reactions (82% versus 72%, respectively), but compliance was lower and more irregular with at least 3 versus one or two adverse reactions reported: 54% versus 84% in administration compliance and 31% versus 58% in regimen compliance (P < 0.05). Compliance was also lower in patients with nausea and vomiting than in those without these symptoms, 59% versus 91% and 34% versus 66% (P < 0.005), respectively, and lower with moderate or severe compared to mild side effects; 48% versus 85% and 25% versus 59% (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Bioequivalence of allopurinol preparations: to be assessed by the parent drug or the active metabolite?

Allopurinol is converted almost completely into a single active metabolite, oxipurinol, which has the same therapeutic pattern but a much longer elimination half-life than the parent compound. Therefore both allopurinol and oxipurinol were evaluated in our bioequivalence study in healthy volunteers comparing two allopurinol brands. Bioequivalence determination was based on the 90% confidence intervals (CI) of the area under the plasma concentration time curve from time zero to infinity (AUC0-infinity), of the area from time zero to the last measurable plasma concentration (AUC0-t (last)), and Cmax. Because of the lack of compound-specific criteria we used conventional limits for the bioequivalence range. Under these conditions the brand chosen as test preparation was judged to be bioequivalent to the reference form with respect to the extent of bioavailability, AUC0-infinity, and AUC0-t (last) of the parent drug. The CI of Cmax of allopurinol slightly exceeded the upper limit of 130%, so that bioequivalence was not confirmed with regard to the rate of bioavailability of the parent compound. The CI values of both AUC and Cmax of the active metabolite were tighter than those of allopurinol. In addition, the CI values of Cmax of oxipurinol were smaller than those of the corresponding AUC. As a consequence the test drug can clearly be accepted as bioequivalent, based on metabolite data. Since the active metabolite is of greater therapeutic significance than the parent drug, assessment of the bioequivalence of allopurinol preparations needs to be based on oxipurinol rather than allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Benzbromarone hydroxylation in man: defective formation of the 6-hydroxybenzbromarone metabolite.

To determine the elimination phenotype of the uricosuric agent benzbromarone 100 mg of the drug was administered as a single oral dose to 11 volunteers on a formula diet; plasma concentration-time profiles of the parent drug and the main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxy-benzbromarone) were measured by high-performance liquid chromatography for 168 h. Of the 11 subjects 2 showed higher plasma concentrations and delayed elimination of benzbromarone and metabolite M1 but reduced formation of metabolite M2 compared to the other 9 subjects. However, the plasma concentration-time profiles of the metabolites in these two slow eliminators, termed type 2, differed from those of a poor eliminator characterized during a previous study; the latter, termed type 1, eliminated benzbromarone as well as both metabolites M1 and M2 slowly. The differences in the elimination of benzbromarone and its metabolites are probably caused by differences in the activities of the cytochrome P450 mono-oxygenase isozymes. The results show that determination of the phenotype solely by measurement of the 24-h benzbromarone plasma concentration does not unequivocally characterize slow benzbromarone eliminators; additional plasma concentration-time profiles of the parent drug and metabolites are necessary. Metabolite M2 is characterized as 6-hydroxybenzbromarone; the formation and elimination of the chiral metabolite M1 is enantioselective.

Administration, Oral↗
PubMed1993

Actual versus prescribed timing of lovastatin doses assessed by electronic compliance monitoring.

The objective of the study was to compare compliance with and the hypocholesterolaemic effect of lovastatin given once daily as a morning or an evening dose. Twenty-four out-patients with familial hypercholesterolaemia were randomly assigned to receive placebo first, then lovastatin 20 mg, to be taken once daily for 4 weeks, either with the breakfast or evening meal, in a single-blind fashion. Drug compliance was assessed by pill counts and continuous electronic monitoring. Two compliance parameters were evaluated, consumption, defined as percentage of prescribed doses taken, and time compliance, the percentage of total dosing events recorded within defined intervals (6.00-10.00 h, and 17.00-21.00 h), for the morning and evening regimes. Both regimes satisfactorily reduced the total and LDL-cholesterol concentrations, and there was no significant difference in the extent of the reductions. Pill counts overestimated compliance, as revealed by the monitoring method. The times of actual consumption of doses by the patients often differed from that prescribed, predominantly in patients who were told to take the evening dose. Partial time compliance may have confounded the efficacy of the drugs. Electronic compliance monitoring appears to be particularly useful in chronopharmacological studies.

Adult↗
PubMed1993

Antibodies to the protein core of the small cell lung cancer workshop antigen cluster-w4 and to the leucocyte workshop antigen CD24 recognize the same short protein sequence leucine-alanine-proline.

We recently described the identity of the small cell lung cancer (SCLC) cluster-w4 antigen and the human B cell differentiation marker CD24, a glycosylphosphatidylinositol (GPI)-anchored, highly glycosylated surface molecule of only 31-35 amino acids [15]. The specificities of three anti-cluster-w4 and of eleven anti-CD24 MoAbs have been investigated with respect to their binding capacity to the protein core of cluster-w4/CD24 antigen. Four overlapping peptides spanning this protein core were synthesized. MoAbs shown to bind to two overlapping peptides by antibody binding inhibition using the cluster-w4/CD24-positive SCLC cell line SW2 and by direct peptide binding detected in an ELISA were investigated in more detail. To determine the exact epitopes recognized by these MoAbs, an epitope mapping assay using peptides synthesized onto polyethylene pins was established. The three anti-cluster-w4 MoAbs SWA11, SWA21 and SWA22 and the anti-CD24 MoAbs OKB2 and ALB9 recognized the same short leucine-alanine-proline (LAP) sequence in an area without potential glycosylation sites close to the GPI anchor of the protein core of the cluster-w4/CD24 antigen.

Amino Acid Sequence↗
PubMed1993

Recirculating, retrograde heart perfusion according to the Langendorff method for evaluation of MTG--methyl-2-tetradecylglycidate, McNeil 3716--cardiomyopathy.

Recirculating, retrograde heart perfusion according to the Langendorff method was used in an attempt to further elucidate the cardiotoxicity of methyl-2-tetradecylglycidate (McNeil 3716, MTG) and the eccentric hypertrophy elicited by the compound. In subchronic experiments female rats were exposed to MTG 2 x 10 mg/kg and 2 x 25 mg/kg per day for 4 weeks. At various times hearts were perfused ex vivo for up to 2 hr with either 5 mmolar glucose or 0.5 mmolar palmitate as substrate. Substrate uptake (glucose or palmitate) and enzyme release (LDH-lactic dehydrogenase or CPK-creatine-phosphate kinase) were assessed during perfusion. Biochemical analysis (ATP, ADP, AMP, c-AMP, CP, creatine, pyruvate, lactate, glucose-6-phosphate, glycogen, phospholipids, triglycerides and non-esterified fatty acids) were done in hearts before (drug effect) and after perfusion (stress of perfusion). Besides changes in energy metabolism and high-energy phosphate production, as observed in previous experiments (Bachmann et al. 1984) massive changes were seen in energy reserves in heart tissue (ATP, CP, glycogen, phospholipids and triglycerides). As expected, MTG led to significant increases also in non-esterified fatty acids content in hearts.

Adenine Nucleotides↗
PubMed1993

Comparative plasma disposition and anticoagulant activities of racemic phenprocoumon and its metabolites in rats.

The anticoagulant phenprocoumon (PH) and its metabolites 6-hydroxy-, 7-hydroxy- and 4'hydroxy-phenprocoumon (6-OH-PH, 7-OH-PH and 4'-OH-PH, respectively) were separately administered intravenously as racemates to rats in order to measure the potential effects of the major metabolites of PH on coagulation. Plasma samples were assayed for total concentrations of the administered compounds and the corresponding prothrombin times; kinetic parameters and anticoagulant activities were estimated using a pharmacodynamic model based on the rate of synthesis of clotting factors. The relative potencies were in the order PH > 4'-OH-PH > 6-OH-PH > 7-OH-PH the latter showing no activity. Patients on PH therapy showed lower plasma concentrations of metabolites than of PH; in humans the metabolites of PH will not contribute significantly to the overall anticoagulant activity of the drug.

Animals↗
PubMed1993

[Early results of surgical revascularization of the subclavian artery].

In the last 14 years (1978 to 1991) in the Clinic of Cardiovascular Surgery, University Hospital Zurich, 72 patients were operated due to obstruction of the subclavian artery. The left side was affected in 46/72 (63.9%), the right side in 21/72 (29.2%), both sides in 5/72 (6.9%) patients. Only thrombendarterectomy has been done in 48/72 (66.7%), followed by carotis-subclavian-bypass (9/72, 12.5%). Furthermore the following techniques were applied: endarterectomy and patch in 6/72 (8.3%), aorta-subclavian-bypass in 5/72 (6.9%), bypass between proximal and distal subclavian artery in 2/72 (2.8%), resection and graft-interposition in 1/72 (1.4%) cases. As well as operation-related reactions of soft tissues (hematoma, swelling) the following complications have been recognized: re-stenosis with embolus or intima-flap in 8/72 (11.1%) cases, 3-times persistent, paralysis of the vocal cord in 3/72 (4.2%) cases, phrenic nerve paralysis in 2/72 (2.8%), in two separate cases Horner's syndrome and pneumothorax. The oldest patient (81 years) died 10 days after operation due to hemorrhage, in spite of 3 re-thoracotomies. Additional complications arose independently of the subclavian operation (atrial flatter, heart-infarction, lungoedema, exitus following extensive heart-operation with valve-replacement and aorto-coronary bypass).

Adult↗
PubMed1992

CD24, a signal-transducing molecule expressed on human B cells, is a major surface antigen on small cell lung carcinomas.

Cell lines derived from human small cell carcinoma of the lung express high levels of a surface polypeptide termed the cluster-w4 antigen, which was previously identified as a potential target for toxin-based immunotherapy of lung cancer. We have cloned a complementary DNA encoding the cluster-w4 antigen from COS-1 fibroblasts transfected with a SW2 small cell carcinoma library, by panning with a mixture of the cluster-w4-specific monoclonal antibodies SWA11, SWA21, and SWA22. The sequence of the cluster-w4 complementary DNA encodes an unusually short (80-amino acid) protein identical to that recently reported for the leukocyte activation molecule CD24 except for a single valine-alanine substitution due to a single-base polymorphism within the region of the gene coding for the extracellular domain. Biochemical analyses of the cloned cluster-w4 antigen confirmed both the presence of the phosphatidylinositol tail and the extensive glycosylation reported for the CD24 molecule. Furthermore, the cloned cluster-w4 antigen expressed on COS cells was shown to react with a comprehensive panel of CD24-specific monoclonal antibodies, as assessed by indirect immunofluorescence staining. Northern blot hybridization indicated the presence of several transcript sizes for the cluster-w4 antigen that were greatly overexpressed in small cell carcinoma cell lines, compared with normal hemopoietic cells and CD24-positive cell lines. Southern blot hybridization of restriction digests of genomic DNA identified a complex pattern of bands consistent with either a complex gene structure containing many exons or the presence of a family of closely related genes.

Alanine↗
PubMed1992

Dose dependent suppression of mineralocorticoid metabolism by different heparin fractions.

One neglected side effect of heparin therapy is the inhibition of adrenal aldosterone production leading to occasionally life-threatening hyperkalaemia. This is only reported with (therapeutic) high doses (greater than or equal to 20.000 IU). The complex interplay of mineralocorticoid metabolites was studied in 29 subjects with unfractionated (UFH) and low molecular weight heparin (LMWH). Both heparins altered mineralocorticoid metabolism in a dose dependent manner. Whereas no effect was observed with UFH 2 x 5000 IU sc/day or LMWH 2500 a FXa U sc/day, higher doses significantly suppressed aldosterone and 18-hydroxycorticosterone production in plasma and urine. Three out of seven patients receiving UFH 3 x 7500 IU sc/day developed hyperkalaemia. This study shows the threshold dosage of UFH leading to suppression of mineralocorticoid metabolism in man and provides information that LMWH as well as UFH can suppress mineralocorticoid production. With respect to therapeutic implications it is important that LMWH at 2500 a FXa U sc/d had no effect on mineralocorticoid metabolism in contrast to UFH at a dosage currently used for prevention of thromboembolism (3 x 5000 IU sc/d).

Adult↗
PubMed1992

Lack of accumulation of midazolam in plasma and lipoprotein fractions during intravenous lipid infusions in patients on artificial respiration.

Severely ill patients often require total parenteral nutrition including intravenous lipid emulsions concurrently administered with lipophilic drugs. Therefore we investigated whether therapeutic application of a mixed medium chain/long chain triglyceride infusion affects the disposition of midazolam necessary for sedation in patients on artificial respiration. The concentrations of midazolam were measured in unfractionated plasma, and in lipoprotein fractions isolated from ex vivo blood samples, including determination of triglycerides and cholesterol; the albumin level was also analysed. Midazolam in the VLDL fraction was only 0.246 microgram.ml-1, whereas the total plasma concentration averaged 1.101 micrograms.ml-1, and the midazolam content of the LDL plus HDL fractions amounted to 1.771 micrograms.ml-1. Albumin in these lipoprotein fractions was just as unequally distributed. A lipid infusion resulted in a significant elevation of total triglycerides from 157 to 221 mg.dl-1 and VLDL-triglycerides from 77 to 155 mg.dl-1. The triglyceride content of the LDL plus HDL fraction rose from 102 to 139 mg.dl-1. At the same time the midazolam concentration in unfractionated plasma and in the VLDL and the LDL + HDL fractions decreased to 0.899 microgram.ml-1, 0.130 micrograms.ml-1, and 1.265 micrograms.ml-1, respectively. Cholesterol and albumin concentrations were not affected. The data show for the first time that a significant increase in plasma triglycerides during an intravenous lipid infusion does not result in accumulation of midazolam in lipoproteins, probably because albumin binding of the drug is very strong. The lack of midazolam trapping is important with respect to the safety of concurrent use of lipophilic drugs and intravenous lipid infusions.

Adult↗