Search PubMed⌕ Search

Biomedical subjects

P Koch

Publications and source records attributed to P Koch.

At least 91 records · Page 5Linked to original sources
PubMed1996

Metabolism of the new immunosuppressor cyclosporin G by human liver cytochromes P450.

Cyclosporin G is a new immunosuppressor structurally similar to cyclosporin A. Although this drug is pharmacologically as active as cyclosporin A, it is less toxic, in particular at the kidney level. The aim of this work was to identify the enzyme system(s) involved in the oxidative metabolism of cyclosporin G in man: (1) in a bank of human liver microsomes (n = 22), cyclosporin G oxidase activity correlated significantly with cyclosporin A oxidase activity (P < 0.0001) and with the level of CYP3A4 (P < 0.002), determined by immunoblot; (2) specific inhibitors of CYP3A4, troleandomycin, and ketoconazole, inhibited cyclosporin G oxidase activity by more than 80%; (3) antiCYP3A4 antibodies specifically inhibited this activity by nearly 90%; (4) cyclosporin A was a competitive inhibitor of cyclosporin G oxidase and vice versa; (5). Among a battery of cDNA-expressed CYPs, only CYP3A4 was able to generate detectable amounts of metabolites of cyclosporin G and cyclosporin A with a turnover number close to that calculated from experiments with liver microsomes; (6) in human hepatocytes in culture, pretreatment of cells with rifampicin and phenobarbital, 2 inducers of CYP3A4, produced a great increase in cyclosporin G oxidase activity, while beta-naphthoflavone, an inducer of CYP1As, did not. We conclude that CYP3A4 is the major enzyme involved in the oxidative metabolism of cyclosporin G in human liver.

Adult↗
PubMed1996

Improved outcome in adult B-cell acute lymphoblastic leukemia.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

Adolescent↗
PubMed1996

Contact stomatitis due to palladium and platinum in dental alloys.

We report a patient with contact stomatitis due to combined sensitization to palladium and platinum. Patch testing showed strong and persistent allergic patch test reactions to palladium chloride (1% pet.), ammonium tetrachloroplatinate (0.25% pet.), and a palladium metal plate. A platinum metal plate showed a weaker reaction. Histological examination of a biopsy from the test site of palladium chloride (1% pet.) at D3 showed both eczematous and lichenoid changes.

Adult↗
PubMed1996

Occupational allergic contact dermatitis and airborne contact dermatitis from 5 fungicides in a vineyard worker. Cross-reactions between fungicides of the dithiocarbamate group?

We report a patient with occupational contact dermatitis due to sensitization to mancozeb and perhaps metiram used in a vineyard. Patch testing showed strong allergic patch test reactions to 2 of the commercially available preparations used (Dithane Ultra and Polyram WG). Further patch tests showed allergic patch test reactions to mancozeb (0.5 and 1% pet.), a weak reaction to metiram (1% pet.) as well as to 4 other fungicides of the dithiocarbamate group (maneb, nabam, propineb and zineb), which had never been used in the vineyard.

Adult↗
PubMed1996

Allergic contact dermatitis and mercury exanthem due to mercury chloride in plastic boots.

We report a 5-year-old child with previous skin intolerance from Mercurochrome (merbromin), who developed a severe allergic contact dermatitis of both feet when wearing new polyvinyl chloride (PVC) boots. Within a few days, he developed a mercury exanthem involving both legs, groins and lateral parts of the trunk. Patch tests showed strong reactions to organic and inorganic mercury compounds, in particular to mercury chloride (mercury chloride; HgCl2), 0.01% pet., which was identified by atomic absorption spectrometry and polarography in the boots worn. New hidden sources of mercury in consumer goods may represent a potential source of danger for the future, if its use is not more strictly regulated.

Anti-Infective Agents, Local↗
PubMed1996

Glycemic effect of a single high oral dose of the novel sweetener sucralose in patients with diabetes.

OBJECTIVE: To examine the effect of a single high oral dose of the novel noncaloric sweetener sucralose on short-term glucose homeostasis in patients with IDDM or NIDDM. RESEARCH DESIGN AND METHODS: A total of 13 IDDM and 13 NIDDM patients with glycosylated hemoglobin levels < 10% completed this double-blind cross-over study. After an overnight fast, patients were administered opaque capsules containing either 1,000 mg sucralose or cellulose placebo, followed by a standardized 360-kcal liquid breakfast. Plasma glucose and serum C-peptide levels were measured over the next 4 h. RESULTS: Regardless of the type of diabetes, areas under the curves for changes of plasma glucose and serum C-peptide levels after sucralose administration were not significantly different from those after placebo. During test meals with sucralose, one episode of symptomatic hypoglycemia occurred in each of three IDDM patients, but these episodes were not considered the result of sucralose administration. CONCLUSIONS: The present results support the conclusion that sucralose consumption does not adversely affect short-term blood glucose control in patients with diabetes.

Administration, Oral↗
PubMed1996

Wave theory of large-scale organization of cortical activity.

Large neural systems are conveniently analyzed through a continuum model in which the differential element contains many cells and consequently near-neighbor synaptic connections can be neglected. At this level of detail, the constituent neurons can be replaced by figurative cells that are purely excitatory or inhibitory. The simplest continuum configuration that approximates the mammalian cortex consists of two layers each containing both species of cell, with a time delay in the interlayer synapses. If it is variable, the delay acts like a control, determining the wavelengths and frequencies of waves that preferentially grow out of a small disturbance in neural activity level. The amplified mode structure becomes more complex as delay increases and is always characterized by wavelengths significantly larger than typical synaptic connection ranges. As the favored modes grow and propagate they associate, through simultaneous activation, mutually distant continuum elements. The activation patterns are reproducible in wavelength spectrum, but, especially at large delays, their spatiotemporal forms are partly functions of the initial random noise. Since the individual continuum elements contain enough neurons to be capable of storing as much information as artificial neural networks, it can be argued that the delay-controlled waves provide a mechanism by which "memories" can be reproducibly recalled, and "creative thoughts" generated and developed.

Cerebral Cortex↗
PubMed1996

Quantitative comparison of direct antibody labeling and tumor pretargeting in uveal melanoma.

UNLABELLED: SPECT radioimmunoscintigraphy with 99mTc-labeled anti-melanoma monoclonal antibodies (MAbs) 225.28S is being used to detect uveal melanoma. Recently, pretargeting methods have been described to reduce background activity and perform imaging in a shorter time interval. METHODS: We compared the three-step pretargeting method with conventional radioimmunoscintigraphy in 15 patients with a clinical and laboratory diagnosis of uveal lesion. High-resolution SPECT radioimmunoscintigraphy was performed in all patients with directly labeled MAbs and, 1 wk later, with the three-step pretargeting technique. Eleven patients underwent eye enucleation and specimens of uveal melanoma were available for histology, whereas four patients underwent conservative therapy. The percent injected dose (%ID) delivered to the tumor and the tumor-to-background ratio were calculated. RESULTS: In all three-step radioimmunoscintigraphy studies, there was a reduction of nonspecific nasopharyngeal background. The three-step radioimmunoscintigraphy tumor-to-nontumor ratio was 3.1 +/- 1.3 versus 1.5 +/- 0.5 of conventional radioimmunoscintigraphy, while the percent injected dose on the tumor was similar for the two methods (4.4 +/- 3.0 versus 3.8 +/- 2.8) x 10(-3). CONCLUSION: Improved SPECT imaging with the three-step radioimmunoscintigraphy results from reduced background and from higher counting statistics due to reduction of time interval between radiotracer administration and imaging, whereas the absolute amount of tracer delivered to the tumor by the two methods is comparable.

Antibodies, Monoclonal↗
PubMed1996

[Surgical procedure in non-Hodgkin's lymphomas of the digestive system--a status quo analysis].

A total of 329 patients were registered in the Münster multicenter study, "Gastrointestinal Lymphomas", including 118 different centers since October 1992. Primary surgical intervention was performed in 135 cases. In contradiction to the prospective results of other oncological centers, the preoperative diagnosis of non-Hodgkin lymphoma was only known in 44.4% of cases. R0 resection was achieved in only 62 of the 135 patients (46%). This study reveals the realistic situation of operative treatment of non-Hodgkin lymphomas in everyday practice.

Gastrointestinal Neoplasms↗
PubMed1996

[Skin burns, necrosis and ulcers caused by wet cement, ready-mixed concrete and lime. 8 cases].

INTRODUCTION: Skin burns and caustic ulcers caused by wet cement, due to calcium hydroxyde, are rarely reported in the literature. They occur mostly among amateur cement users. OBSERVATIONS: We report seven cases of skin burns, necrosis and ulcerations after use of wet cement and ready-mixed concrete, and one case of caustic ulcers induced by wet lime. CONCLUSION: Even short skin contacts to wet cement or concrete may induce extensive lesions in some cases. However, we were not able to incriminate with certainty any special concrete additives which could increase skin penetration of calcium hydroxyde. Warning notices about the danger of skin contact should be prominent on sacked cement. When ready-mixed concrete is delivered, the purchaser should be handed a note explaining the risk of kneeling in wet concrete and the importance of protective measures. This may probably contribute to reduce the frequency of those accidents.

Accidents, Home↗
PubMed1995

Baculovirus expression of human P450 2E1 and cytochrome b5: spectral and catalytic properties and effect of b5 on the stoichiometry of P450 2E1-catalyzed reactions.

The baculovirus (BV)-insect cell expression system has been successfully used to express high levels of mammalian proteins. Here we report the baculovirus-mediated expression of human P450 2E1 and cytochrome b5 in Sf9 insect cells. The BglI-EcoRI fragment of the human P450 2E1 cDNA (Umeno et al., Biochemistry 27, 1988) was used for the expression of P450 2E1. Human cytochrome b5 cDNA was obtained by the polymerase chain reaction using human liver cDNA as template. Infection of Sf9 insect cells with a recombinant 2E1-BV resulted in the expression of a protein which comigrated with human liver P450 2E1 on SDS gels and cross-reacted with a polyclonal antibody against rat liver P450 2E1. Inclusion of hemin in the cell growth medium greatly enhanced the spectral activity of expressed 2E1. Expression levels of 1.5 nmol/mg cell lysate were obtained after 7 days of infection. However, maximal turnover numbers (min-1) were observed after 48 h of infection. The lambdamax of the CO:reduced CO difference spectrum of human P450 2E1 was found to be 451.1 nm. In the presence of exogenous hemin, BV-expressed human b5 showed a typical reduced-oxidized difference spectrum with lambdamax and lambdamin of 425 and 409 nm, respectively. With saturating levels of purified rat liver NADPH:P450 oxidoreductase and rat liver cytochrome b5 included in the incubations, expressed human P450 2E1 showed high catalytic activity for the metabolism of p-nitrophenol (PNP), ethoxycoumarin, N-nitrosodiethylamine, and N-nitrosodimethylamine (NDMA). The presence of b5 in the incubations increased the activities several-fold. The Km and kcat values for the N-demethylation of NDMA to HCHO in the presence of rat b5 by expressed 2E1 were 36.0 microM and 8.3 min-1, respectively. In the absence of extra added b5, the Km was increased sixfold and the kcat decreased fourfold. In the presence of extra added b5 expressed 2E1 showed a Km for PNP metabolism of 86 microM and a kcat of 7.8 min-1. Simultaneous infection of Sf9 insect cells with both 2E1 and human bE recombinant BV resulted in membrane fraction (2E1:b5) containing both proteins at a ratio of b5 to P450 of approximately 1.8:1. The Km and kcat values for NDMA demethylase activity by the 2E1:b5 membrane fraction were similar to those with exogenously added b5.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Gemcitabine: clinical and economic impact in inoperable non-small cell lung cancer.

This study assesses retrospectively the clinical and economic impact of gemcitabine monotherapy on the management of inoperable stage III/IV non-small cell lung cancer in Germany. Based on current methods of clinical practice and using the best outcome data available, the costs and benefits of gemcitabine were compared to a dual therapy (ifosfamide/etoposide). While the two treatments showed broadly equivalent efficacy in terms of tumour response rate and survival, a cost analysis showed the potential for savings with gemcitabine. These largely related to hospital hotelling costs, due to the fact that gemcitabine may be given as an out-patient therapy. Further savings were found in investigative procedures and the management of treatment toxicity. Excluding the cost of the chemotherapy, gemcitabine was associated with potential savings of DM3,026 over two cycles of therapy, which included a 40% decrease in hospitalization costs and a 54% decrease in the cost of managing adverse events. We conclude that gemcitabine monotherapy could offer considerable cost savings while offering the potential for improved quality of palliative treatment compared to existing in-patient treatments, and it may have a place in shifting care from an in-patient to an out-patient setting in line with recent health care reforms.

Antimetabolites, Antineoplastic↗