Biomedical subjects

M Wagener

Publications and source records attributed to M Wagener.

At least 19 recordsLinked to original sources

PubMed2000

Potential drugs and nondrugs: prediction and identification of important structural features

Using decision trees, a model to discriminate between potential drugs and nondrugs has been developed. Compounds from the Available Chemical Directory and the World Drug Index databases were used as training set; the molecular structures were represented using extended atom types. The error rate on an independent validation data set is 17.4%. The number of false negatives can be reduced by penalizing the misclassification of drugs so that 92 out of 100 potential drugs are correctly recognized. At the same time, 34 out of 100 nondrugs are classified as potential drugs. The predictions of the model can be used to guide the purchase or selection of compounds for biological screening or the design of combinatorial libraries. The visualization of the generated models in the form of colored trees allowed us to identify a few, surprisingly simple features that explain the most significant differences between drugs and nondrugs in the training set: Just by testing the presence of hydroxyl, tertiary or secondary amino, carboxyl, phenol, or enol groups, already three quarters of all drugs could be correctly recognized. The nondrugs, on the other hand, are characterized by their aromatic nature with a low content of functional groups besides halogens. The general applicability of the model is shown by the predictions made for several Organon databases.

Journal Article↗

PubMed1999

Efficacy and selectivity in flexible database docking.

Flexible database docking with DOCK 4.0 has been evaluated for its ability to retrieve biologically active molecules from a database of approximately 1,000 compounds with known activities against thrombin and the progesterone receptor. The retrieval of known actives and chemically similar but inactive molecules was monitored as a function of conformational and orientational sampling. The largest enrichment of actives among the 10% highest ranking molecules is obtained when only five conformations are used to seed the next round of ligand reconstruction and limited sampling is applied to place the base fragment in the binding site. The performance of energy and chemical scoring, as implemented in DOCK 4.0, was found to depend on the protein used for docking. For the progesterone receptor, energy scoring yields the largest enrichments (64%) in terms of actives retrieved among the 10% top scoring molecules, while chemical scoring performs best for thrombin (94%). With the exception of the application of energy scoring to the progesterone receptor, both energy-based scoring schemes applied in this study do not discriminate well between true actives and chemically similar but inactive compounds. In conclusion, flexible docking is able to effectively prioritize high-throughput screening databases, using less conformational sampling than normally required for appropriate reconstruction of protein-ligand complexes. The more subtle discrimination between chemically similar classes of active and inactive compounds remains, however, problematic.

Algorithms↗

PubMed1999

The role of the common cytokine receptor gamma-chain in regulating IL-2-dependent, activation-induced CD8+ T cell death.

IL-2-dependent, activation-induced T cell death (AICD) plays an important role in peripheral tolerance. Using CD8+ TCR-transgenic lymphocytes (2C), we investigated the mechanisms by which IL-2 prepares CD8+ T cells for AICD. We found that both Fas and TNFR death pathways mediate the AICD of 2C cells. Neutralizing IL-2, IL-2R alpha, or IL-2R beta inhibited AICD. In contrast, blocking the common cytokine receptor gamma-chain (gamma c) prevented Bcl-2 induction and augmented AICD. IL-2 up-regulated Fas ligand (FasL) and down-regulated gamma c expression on activated 2C cells in vitro and in vivo. Adult IL-2 gene-knockout mice displayed exaggerated gamma c expression on their CD8+, but not on their CD4+, T cells. IL-4, IL-7, and IL-15, which do not promote AICD, did not influence FasL or gamma c expression. These data provide evidence that IL-2 prepares CD8+ T lymphocytes for AICD by at least two mechanisms: 1) by up-regulating a pro-apoptotic molecule, FasL, and 2) by down-regulating a survival molecule, gamma c.

Animals↗

PubMed1999

Feedback to nursing staff as an intervention to reduce catheter-associated urinary tract infections.

Because of high incidence of catheter-related urinary tract infections (UTIs) in our Veterans Affairs medical center, we began providing nursing staff with unit-specific UTI rates. In our preintervention period, the first quarter of 1995, 38 infections occurred in 1186 catheter-patient-days or 32/1000 catheter-patient-days (95% CI, 22.9-43.7). Thereafter, nursing staff members were provided with a quarterly report with catheter-related UTI rates depicted graphically by unit. In the 18 months after this intervention, the mean UTI rate decreased to 17.4/1000 catheter-patient-days (95% CI, 14.6-20.6, P =.002). We estimated a cost savings of $403,000. We conclude that unit-specific feedback of nosocomial UTI rates to nursing staff is a highly effective method of reducing infection rates and reducing costs associated with nosocomial UTI.

Cross Infection↗

PubMed1999

Fever in liver transplant recipients in the intensive care unit.

Whether febrile illnesses in the intensive care unit (ICU) have unique spectrum, etiologies, and outcome has not been determined in liver transplant recipients. We studied 78 consecutive febrile patients over a 4-yr period; 49% (38/78) were in the ICU and 51% (40/78) were in the non-ICU setting. Of febrile patients in the ICU, 87% (33/38) had infection and 13% had non-infectious etiology for fever. Seventy-nine percent (26/33) of the infections associated with fever in the ICU were bacterial, 9% (3/33) were viral, and 9% (3/33) were fungal in etiology. Pneumonia (30%), catheter-related bacteremia (15%), and biliary tree (9%) were the predominant sources of infections associated with fever in the ICU. Bacteremia was documented in 45% of the patients with fever in the ICU. Fifty-three percent (20/38) of the febrile episodes in the ICU occurred during the initial post-transplant stay, and 47% (18/ 38) during a subsequent readmission. Pneumonia accounted for 41% of all febrile infections during the first 7 d of ICU stay, but only 14% of those after 7 d. Febrile patients in the ICU had higher APACHE II scores (p = 0.001), higher APS scores (p = 0.0001), higher bilirubin (p = 0.001), lower cholesterol (p = 0.019), higher prothrombin time (p = 0.001), were more tachycardiac (p = 0.002), and were more likely to have abnormal blood pressure (p = 0.001) than those in the non-ICU setting. Twenty-three percent of all infections in the ICU were unaccompanied by fever and 9% were accompanied by hypothermia. Mortality at 14 d (24 versus 0%, p = 0.001) and at 30 d (34 versus 5%, p = 0.001) was significantly higher in febrile patients in the ICU, as compared to the patients in the non-ICU setting. These data have implications for diagnostic evaluation and management of critically ill febrile liver transplant recipients.

Adult↗

PubMed1999

[Serological diagnosis of celiac disease: anti-gliadin peptide antibodies and tissue anti-transglutaminase].

Serological markers currently used for the diagnosis of celiac disease are anti-gliadin (AG) and anti-endomysium (AE) antibodies. Recently tissue transglutaminase (tTG) was identified as the specific autoantigen for endomysial antibodies. The aim of this work was to determine sensitivity and specificity of ELISA tests developed by using defined molecular structures as capture antigen for AG and AE antibodies. Three synthetic peptides, from the amino terminal region of alpha gliadin, were used as immobilized antigens for AG, and the transglutaminase from guinea pig liver for AE. A total of 80 sera from celiac patients, non celiac disease controls and healthy controls were examined. Age range was 7 months to 14 years. A sensitivity of 97% and a specificity of 86% was obtained for IgG determined by using as antigen one of the three synthetic peptides (corresponding to residues 31-55 of alpha gliadin). Therefore, this peptide appears as a highly sensitive antigen and more specific than gliadin. The best result, showing 100% of sensitivity and specificity, was obtained for IgA anti-tTG, thus pointing out the relevance of these antibodies as serological markers for celiac disease.

Adolescent↗

PubMed1998

Orthotopic liver transplantation in high-risk patients: risk factors associated with mortality and infectious morbidity.

BACKGROUND: One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression. METHODS: Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years). RESULTS: Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07). CONCLUSIONS: Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.

Adult↗

PubMed1998

[New developments in asthma therapy: how do individual leukotriene antagonists work?].

Today it is generally acknowledged that bronchial asthma is a chronic inflammatory airway disease which is marked by recurrent bronchial obstructions and hyperreactivity of the airways. The best anti-inflammatory characteristics are shown by corticosteroids. However these can have considerable side-effects in long-term, systemic use. The search for alternative forms of therapy has for some time concentrated on the development and testing of leukotriene antagonists. These can limit the effect of leukotrienes via receptor antagonism or synthesis inhibition. The leukotrienes B4, C4, and D4 count as important key mediators in bronchial asthma. They are released by numerous inflammatory cells, have a bronchoconstricting effect and chemotactic characteristics, promote vessel permeability and increase mucous secretion. In addition, they probably increase bronchial hyperreactivity. Among biosynthesis restrictors, the 5-lipoxygenase restrictors have shown an anti-inflammatory effect in both experimental asthma models and in clinical use. In mild to moderate asthma, lung function improved and the use of a concomitant beta-agonist medication was reduced. While the older leukotriene receptor antagonists were rather disappointing, the newer substances display a significantly improved effect, are generally well tolerated and can also be given orally. In experimental asthma models, receptor antagonists, after antigen provocation, led to a marked reduction in bronchoconstriction and a decrease in the number of inflammatory cells (lymphocytes and eosinophils) in bronchial alveolar fluid. In clinical studies, this new class of drugs showed a reduction in clinical symptoms and an improvement in lung function in mild to moderate asthma. In addition, a bronchodilatatory effect was shown. The option of oral administration and good tolerance should improve compliance. The potential and long-term efficacy in severe asthma remains unclear. Further studies are required to elucidate the scope of their role and define their place in the treatment of asthma.

Anti-Asthmatic Agents↗

PubMed1997

Hepatitis C virus genotypes in liver transplant recipients: impact on posttransplant recurrence, infections, response to interferon-alpha therapy and outcome.

BACKGROUND: End-stage liver disease due to hepatitis C virus (HCV) is the most common indication for liver transplantation in U.S. veterans. We investigated the influence of HCV genotypes on the incidence and timing of recurrent HCV hepatitis, survival, infectious morbidity, and response to interferon-alpha therapy in this unique patient population. METHODS: HCV genotype was determined by direct sequencing of the NS5 region of HCV with type-specific primers. RESULTS: Genotype 1a (66%, 32/47) was the predominant genotype. Type 1b was found in 25% (12/47) of patients and type 2b was found in 9% (4/47). Histopathologically recurrent HCV hepatitis developed in 53% (25/47) of the patients after transplantation. This group included 45% (14/31) of the patients with type 1a, 67% (8/12) of the patients with type 1b, and 25% (1/4) of the patients with type 2b (P>0.5). The time to recurrence and the severity of HCV recurrence as defined by aminotransferase levels or Knodell scores were not different among the three genotypes. There was a trend toward a higher incidence of major infections in patients with type 1b (75%) versus type 1a (48%) and type 2b (50%) (P=0.11). The response to interferon-a therapy did not differ significantly among the genotypes. Mortality at 5 years was 16% (5/31) in patients with genotype 1a, 42% (5/12) in patients with genotype 1b, and 50% (2/4) in patients with genotype 2b (P=0.06). CONCLUSIONS: The incidence, time to recurrence, and response to interferon-alpha therapy did not differ between the various genotypes in our liver transplant recipients. However, there was a trend toward higher infectious morbidity and overall mortality in patients with genotype 1b after transplantation.

Adult↗

PubMed1997

Isolation and characterization of the complete mouse emerin gene.

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked recessive disorder associated with muscle wasting, contractures, and cardiomyopathy. The responsible emerin gene has recently been identified and found to encode a serine-rich protein similar to lamina-associated protein 2 (LAP2), although the disease mechanism remains obscure. In order to pursue the pathophysiology of this disorder, we report here the isolation and characterization of the complete mouse emerin gene. The emerin cDNA was isolated from murine strain BALB/c, and the emerin gene was isolated from strain 129. The 2.9-kb mouse emerin gene was completely sequenced and found to be composed of 6 exons and encode a protein 73% identical to that of the human protein. Key similarities with LAP2 were found to be conserved, including critical LAP2 phosphorylation sites. Examination of the murine promoter revealed three previously unrecognized cAMP response elements (CRE) conserved between human and mouse. While Northern analysis shows emerin to be widely expressed in the mouse, as it is in humans, these promoter elements may indicate cAMP responsiveness. These data provide the necessary elements to further investigate EMD in a murine system.

Amino Acid Sequence↗

PubMed1996

Pneumonia in a long-term care facility. A prospective study of outcome.

BACKGROUND: Pneumonia is a major cause of morbidity and mortality among patients in long-term care facilities. OBJECTIVES: To conduct a prospective study of 108 consecutive patients who acquired pneumonia in a Veterans Affairs facility from January through December 1993, and to identify (1) the short- and long-term outcome of pneumonia, (2) the determinants of outcome, and (3) the frequency of recurrent episodes. METHODS: Patient characteristics, including scores from the Activities of Daily Living (ADL) Index of Katz et al and the Comorbidity Index of Charlson et al, were recorded End points were survival at 14 days and 12 and 24 months, recurrent episodes of pneumonia, and hospitalization for nonpneumonic illness. RESULTS: Fourteen-day mortality was 19%; outcome was significantly related to the ADL score. There was no relationship between short-term outcome and age or the Comorbidity Index score. Mortalities at 12 and 24 months were 59% and 75%, respectively. Long-term survival also correlated with the ADL score. For the least debilitated patients (ie, those with an ADL score < or = 10), mortalities were 33% and 48% at 12 and 24 months, respectively; for those with ADL scores of 11 to 15, the corresponding mortalities were 60% and 75%; and for those with ADL scores of 16 or greater, the mortalities were 65% and 77% (P = .02). Within 12 months, 43% of the survivors had additional episodes, and 37% required transfer to an acute care facility for other diagnoses. Functional status did not change among the most dependent patients. CONCLUSIONS: Functional status is the major determinant of survival following pneumonia. Pneumonia in a debilitated patient in a long-term care facility predicts recurrent pneumonia and death within 1 to 2 years.

Activities of Daily Living↗

PubMed1996

Pulmonary infections in liver transplant recipients receiving tacrolimus. Changing pattern of microbial etiologies.

Pulmonary infections are a significant cause of morbidity after liver transplantation; Gram-negative bacilli, cytomegalovirus, and Pneumocystis carinii were the usual pulmonary pathogens in the earlier studies in liver transplant recipients receiving cyclosporine. We prospectively assessed the impact of pulmonary infection in 101 consecutive liver transplant recipients receiving the new immunosuppressive agent tacrolimus (FK506). Fifteen percent (15/101) of the patients had 19 episodes of pneumonia; 58% (11/19) of the pneumonias were bacterial, 37% (7/19) were fungal, and 5% (1/19) were protozoal (Toxoplasma gondii). Twenty-seven percent of the bacterial pneumonias were due to Legionella. None of the patients had cytomegalovirus or P carinii pneumonia. Seven percent (7/10) of the study patients had fungal pneumonitis; 4% had invasive aspergillosis and 3% had cryptococcosis. Mortality was significantly higher (53%, 8/15) for patients with pneumonia than for patients without pneumonia (10%, 9/86, P = 0.0004). Only fungal pneumonias were the direct cause of death; 63% (5/8) of the deaths were in patients with fungal pneumonitis. Our data suggest a changing pattern of microbial etiologies of pneumonitis in the era of modern immunosuppressive agents. We show that P carinii pneumonia and cytomegalovirus can be effectively curtailed with appropriate prophylaxis. Fungal infections, on the contrary, not only constituted a major proportion of the pneumonia, but also carried the highest pneumonia-associated mortality. Legionella infections can be overlooked unless specialized laboratory methodology (cultured on selective media, urinary antigen) are applied routinely on all cases of pneumonia. We recommend routine culture on the water supply for Legionella in all transplant centers.

Adult↗

PubMed1996

A high incidence of native portal vein thrombosis in veterans undergoing liver transplantation.

The incidence of native portal vein thrombosis (PVT) in liver transplant recipients has been reported to range from 2.1 to 13.8%. We have identified an inordinately high incidence of PVT in a consecutive series of U.S. veterans receiving liver transplants. Between October 1989 and February 1994, 88 consecutive U.S. veterans received 99 orthotopic liver transplants under primary Tacrolimus (Prograf, formerly FK506) based immunosuppression. A number of clinical features were examined in an effort to identify risk factors for PVT and outcome was compared to patients without PVT. Native PVT was present in 23/88 (26%) patients. All of these patients were male U.S. veterans with a mean age of 47 years. When compared to the 65 patients without PVT, we found no significant difference with respect to underlying liver disease, age, Childs-Pugh score (mean = 12), UNOS status as defined prior to April 1995 (95% UNOS 3 or 4), previous abdominal surgery, or liver volume. Median blood loss for patients with PVT (21 units of packed red blood cells) was greater than for those without PVT (14 units, P = 0.04). Portal thrombectomy was performed in 11 patients, 11 patients required mesoportal jump grafts, and 1 patient had an interposition graft. Standard veno-venous bypass was used in 10 patients with single bypass utilized for the remainder. Actuarial patient survival for all patients at 1, 2, and 4 years was 88, 85, and 79%, respectively. There was no significant difference in patients with or without PVT. Patients with PVT had poorer graft survival than patients without PVT (86% vs 65%, 1 year; 81% vs 65%, 2 years; 81% vs 61%, 4 years; P = 0.03); however, this was not related to technical problems with the portal venous inflow. PVT occurred in 26% of U.S. veterans undergoing liver transplantation. These patients had significantly higher operative blood loss and poorer graft survival. The high incidence of postnecrotic cirrhosis in a predominantly male group of patients with advanced disease, as is evident by the high mean Childs-Pugh score and UNOS status, perhaps accounts for our observations.

Female↗

PubMed1996

Determinants of nontraditional therapy use in patients with HIV infection. A prospective study.

BACKGROUND: The popularity and use of nontraditional therapies among patients with human immunodeficiency virus (HIV) infection has grown enormously. DESIGN: A prospective, longitudinal cohort study of 56 patients aged 23 through 68 years with HIV infection followed up at the HIV clinic at a university-affiliated Veterans Affairs Medical Center. OBJECTIVE: To assess the demographic and psychologic characteristics of patients who seek nontraditional remedies, and their impact on disease progression and mortality from HIV. METHODS: A standardized, self-administered questionnaire to assess the incidence and type of nontraditional therapies used by patients with HIV. Data on demographics, medical status, physical functioning (Karnofsky performance score), CD4 lymphocyte counts, depression (Beck Depression Inventory), coping (inventory of coping with illness scale), psychological and/or emotional stress (Profile of Mood States scores), and compliance with prescribed therapy were prospectively assessed on all patients at baseline and every 6 months. RESULTS: Thirty percent of patients reported using nontraditional therapies. Nontraditional therapy users were significantly older than patients who did not use such therapies (44 vs 38 years, P = .03); with 94% of patients who used nontraditional therapy being older than 35 years compared with 56% of conventional therapy users (P = .005). Alternative therapy use did not correlate with race, education, HIV-risk group affiliation, duration of HIV seropositivity, stage of HIV disease, CD4 cell count, or Karnofsky performance scores. Nontraditional therapy users reported greater community-based acquired immunodeficiency syndrome group support (P = .06), greater perceived social support (P = .08), and significantly higher recreational or "street drugs" use (P = .02). Depression, adaptive coping, and emotional stress were not different between nontraditional and conventional therapy users; however, nontraditional therapy users were significantly more assertive (P = .04). On follow-up, CD4 cell count, HIV disease progression, physical functioning, or mortality were similar between the two groups. CONCLUSIONS: Recourse to nontraditional therapy is common among patients with HIV. Because of the possibility of untoward effects and potential adverse drug interactions associated with nontraditional therapy, HIV care givers should be aware of its use in their patients and take a history of nontraditional therapy first. Patients who choose nontraditional remedies do so not because they are depressed or emotionally disturbed, but rather because they seek greater control of the outcome of their disease. However, no beneficial effect on disease progression, CD4 cell count, or mortality was observed in these patients when compared with patients receiving only conventional medical therapy.

Adaptation, Psychological↗

PubMed1996

Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter.

The presence of a proton-coupled electrogenic high-affinity peptide transporter in the apical membrane of tubular cells has been demonstrated by microperfusion studies and by use of brush border membrane vesicles. The transporter mediates tubular uptake of filtered di- and tripeptides and aminocephalosporin antibiotics. We have used expression cloning in Xenopus laevis oocytes for identification and characterization of the renal high-affinity peptide transporter. Injection of poly(A)+ RNA isolated from rabbit kidney cortex into oocytes resulted in expression of a pH-dependent transport activity for the aminocephalosporin antibiotic cefadroxil. After size fractionation of poly(A)+ RNA the transport activity was identified in the 3.0- to 5.0-kb fractions, which were used for construction of a cDNA library. The library was screened for expression of cefadroxil transport after injection of complementary RNA synthesized in vitro from different pools of clones. A single clone (rPepT2) was isolated that stimulated cefadroxil uptake into oocytes approximately 70-fold at a pH of 6.0. Kinetic analysis of cefadroxil uptake expressed by the transporter's complementary RNA showed a single saturable high-affinity transport system shared by dipeptides, tripeptides, and selected amino-beta-lactam antibiotics. Electrophysiological studies established that the transport activity is electrogenic and affected by membrane potential. Sequencing of the cDNA predicts a protein of 729 amino acids with 12 membrane-spanning domains. Although there is a significant amino acid sequence identity (47%) to the recently cloned peptide transporters from rabbit and human small intestine, the renal transporter shows distinct structural and functional differences.

Amino Acid Sequence↗

PubMed1996

The peptide-based thrombin inhibitor CRC 220 is a new substrate of the basolateral rat liver organic anion-transporting polypeptide.

The peptidomimetic thrombin inhibitor CRC 220, 4-methoxy-2,3,6-trimethylphenylsulfonyl-L-aspartyl-D-4-amidinop henylalanyl- piperidide, is taken up into isolated rat hepatocytes through active, carrier-mediated transport. This uptake is inhibited by bile acids. Functional expression in Xenopus laevis oocytes was performed to identify the transport system responsible for the hepatocellular CRC 220 uptake. Injection of poly(A)+RNA in X. laevis oocytes resulted in a two- to three-times higher uptake of CRC 220, compared with uninjected or water-injected control oocytes. Taurocholate (200 mumol/L) inhibited this uptake completely. No uptake of the peptidomimetic thrombin inhibitor was observed, when X. laevis oocytes were injected with complementary RNA (cRNA) encoding either the cloned rat liver Na(+)-dependent taurocholate transporter Ntcp, the renal oligopeptide carrier rhaPT or the intestinal oligopeptide transporter PepT1. However, after injection of cRNA of the cloned rat liver Na(+)-independent organic anion transporting polypeptide oatp, a specific and saturable CRC 220 uptake was observed (Michaelis-Menten constant 29.5 mumol/L). Cis-inhibition with known oatp-substrates, e.g., 20 mumol/L Bromsulphalein (BSP), 2007 mumol/L taurocholate and 2007 mumol/L cholate, occurred in oatp-expressing X. laevis oocytes, whereas substrates of the two peptide carriers as well as dipeptide- and single-amino acid constituents of the thrombin inhibitor itself lacked any significant inhibitory effects. These data show that the modified dipeptide CRC 220 is a highly selective substrate of the organic anion transporting polypeptide oatp in the basolateral plasma membrane of rat hepatocytes.

Animals↗

PubMed1996

The comparison of geometric and electronic properties of molecular surfaces by neural networks: application to the analysis of corticosteroid-binding globulin activity of steroids.

It is shown how a self-organizing neural network such as the one introduced by Kohonen can be used to analyze features of molecular surfaces, such as shape and the molecular electrostatic potential. On the one hand, two-dimensional maps of molecular surface properties can be generated and used for the comparison of a set of molecules. On the other hand, the surface geometry of one molecule can be stored in a network and this network can be used as a template for the analysis of the shape of various other molecules. The application of these techniques to a series of steroids exhibiting a range of binding activities to the corticosteroid-binding globulin receptor allows one to pinpoint the essential features necessary for biological activity.

Drug Design↗

PubMed1996

Comparison of structurally different allosteric modulators of muscarinic receptors by self-organizing neural networks.

Similarities in the molecular structure and surface properties of the allosteric modulators of muscarinic receptors, alcuronium, gallamine, tubocurarine, and the hexamethonium compound W84, a well-known pharmacological tool, are explored. The analysis of the molecular electrostatic potential (MEP) as well as of the shape of the molecular surface is performed by self-organizing neural networks. A distorted sandwich conformation of W84 is suggested to be the active form. The importance of the MEP for binding of these compounds could be established.

Alcuronium↗