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PubMed2005

Research on screening and identification of proteins interacting with ataxin-3.

OBJECTIVE: This study sought to isolate and identify the proteins that interact with ataxin-3, to confirm the interacted domain, and to provide new clues for exploring the function of ataxin-3 and the pathogenesis of spinocerebellar ataxia type 3 and Machado-Joseph disease (SCA3/MJD). METHODS: Yeast two-hybrid screen (MATCHMAKER GAL4 Two-Hybrid System 3) and regular molecular biologic techniques were undertaken to screen human brain cDNA library with mutant ataxin-3 bait. Two baits from both normal and mutant C-terminus of ataxin-3 were created by subcloned methods to determine which domain of ataxin-3 interacts with the putative associated proteins and to find out optimal candidate proteins that interact with C-terminus of ataxin-3. Confocal microscope was used to observe whether ataxin-3 co-localized with the obtained interacting proteins in mammalian cells. RESULTS: Five novel ataxin-3 interacting proteins were obtained, among which were three known proteins, namely human rhodopsin guanosine diphosphate dissociation inhibitor alpha, small ubiquitin-like modifier 1, and human neuronal amiloride-sensitive cation channel 2; the other two were unknown. Interacting domain analysis revealed that an unknown protein interacted with the C-terminus near the polyglutamine tract of ataxin-3, the other four all interacted with the N-terminus. In the nucleus of SH-SY5Y cell, small ubiquitin-like modifier 1 co-localized with the wild-type ataxin-3 and with the intranuclear aggregates formed by the mutant ataxin-3. CONCLUSION: An unknown protein probably interacting with C-terminus of ataxin-3 is firstly discovered, and the initiative findings suggest first that the interaction of small ubiquitin-like modifier 1 with N-terminus of ataxin-3 and the relevant sumoylation probably participate in the post-translation modifying of ataxin-3 and in the pathogenesis of SCA3/MJD.

Acid Sensing Ion Channels↗
PubMed2007

No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis. Results of a meta-analysis of published studies and a large case-only study.

Homocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C, it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies, but not in others. We performed a metaanalysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls. We also investigated the interaction effect of factor V Leiden and hyperhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis. The meta-analysis yielded no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) -1.77 (95%CI -8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)]. The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction; RERI 0.13 (95%CI -3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.

Factor V↗
PubMed1987

Direct receptor:receptor interactions between T and B lymphocytes: idiotypic restriction in the antibody response to a cloned helper T cell receptor.

The concept of an immunological network includes the possibility of interactions between receptors on T and B lymphocytes, and such interactions, should they occur, might be expected to influence the repertoire of receptors in each set of cells. Indeed, B cell idiotype specific helper T cells, both MHC-restricted and MHC-unrestricted, have been reported and have been shown to influence the expression of the B cell repertoire. Likewise, it has been reported that B cells may influence the specificity of both regulatory and MHC-restricted T cells. However, interactions between receptors on cloned, MHC-restricted helper T cells and B cells have been difficult to document. Recently, we have taken advantage of an unusual cloned helper T cell line to demonstrate that anti-T cell receptor antibody is produced by direct receptor:receptor interactions between T and B lymphocytes, and that these interactions are not MHC restricted. However, these earlier studies did not address the question of whether such interactions led to activation of B cells expressing multiple distinct antibodies, or whether direct T cell receptor:B cell receptor interactions would lead to an idiotypically restricted B cell response. To address this question, we have now examined both monoclonal and polyclonal responses to the receptor of a conventional, MHC-restricted cloned T cell line, and have shown that these responses are of limited idiotype heterogeneity. Indeed, about 60% of antibodies produced to the receptor of this cloned line share idiotypic determinants, and appear to recognize a single epitope on the receptor. Idiotypically unrelated anti-receptor antibodies, although still specific for the cloned line, recognize what appears to be a distinct epitope on the receptor. These data suggest several conclusions. First, they demonstrate further that direct receptor:receptor interactions between helper T cells and B cells can occur, and can be mutually stimulatory for the two cell types. Second, as shown previously, such interactions are not MHC restricted. Third, such interactions can lead to an idiotypically restricted B cell response. Finally, it is interesting to compared these results with those of other investigators studying idiotype-specific helper T cells. As the cloned line used in this study is a conventional, MHC-restricted, antigen specific helper T cell bearing an alpha:beta heterodimeric receptor complex, and as its interaction with B cells is MHC unrestricted and leads to idiotypically restricted antibody responses, one might propose that such cells are candidates for a clone of an idiotype-specific helper.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Intercellular interactions as a basis for the expedient behaviour of multicellular systems.

Functional and structural aspects of intercellular interactions are considered. Chemical substances are universal mediators of intercellular interactions. Electrical and mechanical interactions are also involved in cell-cell cooperation. Functional peculiarities of the two principal types of intercellular interactions-ligand-receptor interactions and interactions based on permeable contacts-are compared. Examples of basic tissue processes are given (such as the mechanisms of embryonic induction and differentiation, regulation of cell proliferation, temporal and spatial regulation of the activity of differentiated cells, interactions between excitable cells) to illustrate the notion that the types of intercellular interactions are mutually complementary and fulfill different functions. Ligand-receptor interactions predominantly provide signal functions and ensure intertissue interactions, while the interactions based on permeable contacts mainly fulfill intratissue coordination relying on positional information and the exchange of energy and matter.

Cell Communication↗
PubMed2025

Immune-mediated indirect interaction between gut microbiota and bacterial pathogens.

BACKGROUND: In many animals, survival during infection depends on the ability to coordinate interactions between the host immune system and gut microbiota. These tripartite interactions, in turn, potentially shape pathogen virulence evolution. A key regulator of the immune system and, hence, bipartite interactions in insects is the immune deficiency (Imd) pathway, which modulates gut microbiota and pathogens by synthesizing antimicrobial peptides (AMPs) through the NF-κB transcription factor Relish. However, whether Imd-dependent AMPs mediate indirect interactions between gut microbiota and pathogens in a tripartite context remains unclear. Using RNAi-mediated knockdown of Tenebrio molitor Relish (TmRelish), we hypothesized that Imd-dependent AMPs influence indirect interaction between Providencia burhodogranariea_B (P. b_B) infection and the gut microbiota. RESULTS: TmRelish knockdown altered bipartite interactions by disrupting gut microbiota load and composition, increasing pathogen load, and ultimately leading to higher host mortality during infection. However, we did not find support for our tripartite hypothesis that Imd-dependent AMPs mediate indirect interactions between the gut microbiota and P. b_B infection, suggesting the involvement of alternative regulatory pathways or Imd-independent mechanisms. Nevertheless, our investigations of tripartite interactions showed a positive effect of P. b_B infection on gut microbiota load, which in turn stimulated the expression of a subset of AMPs. However, this upregulation of AMPs did not result in reduced P. b_B load. Notably, the gut microbiota did not affect pathogen load but promoted host survival during P. b_B infection, indicating a role in increasing host tolerance rather than resistance. CONCLUSIONS: These findings suggest that while Imd-dependent AMPs may not mediate tripartite interactions in our system, microbiota-host interactions, such as microbiota-mediated immune priming and changes in microbiota load, can shape infection outcomes. These effects on infection outcomes almost certainly exert important selective pressures on the evolution of bacterial virulence.

Animals↗
PubMed2004

Food-drug interactions via human cytochrome P450 3A (CYP3A).

Food-drug interactions have been reported to occur in various systems in the body. The causes of these interactions are mainly divided into pharmacodynamic and pharmacokinetic processes. Among these processes, drug metabolism plays a crucial role in drug interactions. Metabolic food-drug interactions occur when a certain food alters the activity of a drug-metabolizing enzyme, leading to a modulation of the pharmacokinetics of drugs metabolized by the enzyme. A variety of interactions have been documented so far. Foods consisting of complex chemical mixtures, such as fruits, alcoholic beverages, teas, and herbs, possess the ability to inhibit or induce the activity of drug-metabolizing enzymes. According to results obtained thus far, cytochrome P450 3A4 (CYP3A4) appears to be a key enzyme in food-drug interactions. For example, interactions of grapefruit juice with felodipine and cyclosporine, red wine with cyclosporine, and St John's wort with various medicines including cyclosporine, have been demonstrated. The results indicate the requirement of dosage adjustment to maintain drug concentrations within their therapeutic windows. The CYP3A4-related interaction by food components may be related to the high level of expression of CYP3A4 in the small intestine, as well as its broad substrate specificity, as CYP3A4 is responsible for the metabolism of more than 50% of clinical pharmaceuticals. This review article summarizes the findings obtained to date concerning food-drug interactions and their clinical implications. It seems likely that more information regarding such interactions will accumulate in the future, and awareness is necessary for achieving optimal drug therapy.

Beverages↗
PubMed2005

Systematic overview of warfarin and its drug and food interactions.

BACKGROUND: Warfarin is a highly efficacious oral anticoagulant, but its use is limited by a well-founded fear of bleeding. Drug and food interactions are frequently cited as causes of adverse events with warfarin. We provide an updated systematic overview of the quality, clinical effect, and importance of these reported interactions. DATA SOURCES: MEDLINE, TOXLINE, IPA, and EMBASE databases from October 1993 to March 2004. Database searches combined the keyword warfarin with drug interactions, herbal medicines, Chinese herbal drugs, and food-drug interactions. STUDY SELECTION: Eligible articles contained original reports of warfarin drug or food interactions in human subjects. Non-English articles were included if sufficient information could be abstracted. DATA EXTRACTION: Reports were rated independently by 2 investigators for interaction direction, clinical severity, and quality of evidence. Quality of evidence was based on previously validated causation criteria and study design. DATA SYNTHESIS: Of 642 citations retrieved, 181 eligible articles contained original reports on 120 drugs or foods. Inter-rater agreement was excellent, with weighted kappa values of 0.84 to 1.00. Of all reports, 72% described a potentiation of warfarin's effect and 84% were of poor quality, 86% of which were single case reports. The 31 incidents of clinically significant bleeding were all single case reports. Newly reported interactions included celecoxib, rofecoxib, and herbal substances, such as green tea and danshen. CONCLUSIONS: The number of drugs reported to interact with warfarin continues to expand. While most reports are of poor quality and present potentially misleading conclusions, the consistency of reports of interactions with azole antibiotics, macrolides, quinolones, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, lipid-lowering agents, amiodarone, and fluorouracil, suggests that coadministration with warfarin should be avoided or closely monitored. More systematic study of warfarin drug interactions in patients is urgently needed.

Anticoagulants↗
PubMed2006

Use of an online surveillance system for screening drug interactions in prescriptions in community pharmacies.

OBJECTIVE: Computerised surveillance systems have become available for screening potential adverse drug interactions during drug prescribing and dispensing. The purpose of this study was to analyse the frequency and profile of alerts given by one such system in two community pharmacies in Finland. METHODS: In a prospective study, all interaction alerts given by the surveillance system were collated during September-November 2004 in two community pharmacies in Southern Finland. The alerts were categorised into four classes (A-D) according to their clinical significance. RESULTS: During the 3-month study period, a total of 39,539 prescriptions were dispensed. The system flagged 3,861 prescriptions as having potential interactions (9.8% of all prescriptions). Since one prescription could be the source of several interaction alerts, a total of 5,647 alerts were given. The clinically most significant interactions (class D) represented 0.4% of prescriptions (3.0% of all interactions). Class C alerts were most prevalent (9.4% of all prescriptions, 65.9% of all interactions). The most commonly encountered interaction in class D was between warfarin and non-steroidal anti-inflammatory drugs. CONCLUSIONS: Although the incidence of potentially most hazardous interactions in prescriptions is rather low in this study (0.4%), the overall incidence is relatively high (9.8%). Implementation of the interaction surveillance system in the participating pharmacies makes it possible to study in the future in quantitative terms whether the quality of drug dispensing is improved.

Community Pharmacy Services↗
PubMed2005

Potential for drug interactions in hospitalized cancer patients.

OBJECTIVES: To quantify the frequency of potential drug interactions unrelated to chemotherapy in cancer patients admitted to our institution, and to define risk factors for such interactions. METHODS: Charts of 100 consecutive hospitalized cancer patients were reviewed. Patients receiving chemotherapy and/or hormone therapy were excluded, as were patients admitted for intensive care. Drug-drug interactions were screened with Drug Interaction Facts software, and manually by the authors. Potential interactions were graded by levels of severity (severe, moderate, minor) and significance (one to five, with one representing the highest level of evidence). RESULTS: The median age of the patients was 67 years, and the length of hospital stay and the number of drugs per patient were 6 days and eight drugs, respectively. In 63 patients 180 potential interactions were detected. Of the potential interactions, 18.3% were severe, 56.7% were moderate, and 25% were minor. Approximately 7%, 18% and 13% of potential interactions were graded as level 1, 2 and 3, respectively. In multivariate analysis, prescriptions with eight or more drugs (P=0.0004) and six or more days of hospital stay (P=0.014) were independent risk factors for potential interactions. CONCLUSION: Potential drug interactions are common among hospitalized cancer patients. Length of hospital stay and number of prescribed drugs are risk factors.

Adult↗
PubMed1987

Drug interactions in surgical patients.

Drug interactions, defined as when the administration of a single substance (drug, nutrient, or tobacco) modifies the response to a drug, occur relatively frequently in surgical patients and may result in increased morbidity and lengthened hospital stay. Drug interactions also account for some instances of drug ineffectiveness or exaggerated pharmacologic response. There are many types of drug interactions. However, most of them are related to altered drug pharmacokinetic properties, where there are alterations in drug absorption, distribution, metabolism, or elimination; or altered drug pharmacodynamic actions, where two agents may have synergistic, additive, or antagonistic pharmacologic effects. The term, drug interaction, usually refers to pairs of drug substances administered concurrently, but more than two agents may be involved. When patients are taking a large number of different medications, there may be multiple drug interactions with additive or antagonistic effects, the overall effects of which are difficult to predict. There are hundreds of reported drug interactions, and some may be of important clinical consequence. In surgical patients, the majority of drug interactions involve histamine-2 blockers (particularly cimetidine), digoxin, warfarin, or a variety of agents that may be administered during anesthesia. Recognition of the potential for adverse drug interactions is of primary importance in minimizing their effects. Usually, potentially interacting drugs may be administered concurrently as long as appropriate patient or laboratory assessments are performed. For some agents, such as digoxin or theophylline, serum drug concentrations may aid in the avoidance of adverse drug interactions.

Anesthesia↗
PubMed2003

Isobolographic and subthreshold methods in the detection of interactions between oxcarbazepine and conventional antiepileptics--a comparative study.

Until now, a character of interactions among the antiepileptic drugs (AEDs), in some experimental models of epilepsy, has been determined alternatively with subthreshold and isobolographic methods. In order to elicit the precise and adequate method for evaluating two drug interactions, the comparative study was performed in the maximal electroshock-induced seizure test in mice. In this experimental model, the exact types of interactions among oxcarbazepine (OXC) and conventional AEDs (diphenylhydantoin, phenobarbital, valproate, carbamazepine, and clonazepam) were determined with both methods. Results from the subthreshold method showed a considerable reduction of ED(50) values of clonazepam, diphenylhydantoin and valproate (after administration of OXC at the highest subthreshold dose of 2.5 mg/kg), whilst ED(50)s of carbamazepine or phenobarbital were almost unchanged when OXC (2.5 mg/kg) was co-administered with these AEDs. Results from the 2-dimensional (2-D) isobolographic analysis of interactions for a 50% anticonvulsant effect, for three fixed drug dose ratio combinations of 1:2, 1:1, and 2:1, indicate antagonism between OXC and diphenylhydantoin as regards their anticonvulsant (protective) activity. Furthermore, the interactions between OXC and clonazepam occurred either antagonistic (for the fixed-ratios of 1:4 and 1:3) or synergistic (for the fixed-ratio combinations of 1:1 and 2:1) depending on the proportions of used drugs. Remaining interactions between OXC and carbamazepine, OXC and valproate, or OXC and phenobarbital (for the fixed-ratios of 1:3, 1:1, and 3:1) were isobolographically additive for a 50% anticonvulsant effect tested. The 3-dimensional (3-D) isobolographic analysis of interactions between OXC and CZP revealed that the dual character of interactions (antagonistic and synergistic) observed for a 50% anticonvulsant effect (ED(50)) was also present for additional drug-dose effects tested, i.e. ED(16) and ED(84). The 3-D isobologram for the combination of OXC with CZP clearly visualized either synergy or antagonism between the drugs in combinations.Distinct differences resulting from two experimental methods prove evidently the superiority of isobolographic analysis over the subthreshold method. The former clearly and adequately detects the exact types of interactions between two AEDs, becoming a potent and powerful paradigm for further studies evaluating the character of interactions among AEDs.

Animals↗
PubMed2006

Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor.

The NKX3.1 transcription factor is an NK family homeodomain protein and a tumor suppressor gene that is haploinsufficient and down-regulated in the early phases of prostate cancer. Like its cardiac homolog, NKX2.5, NKX3.1 acts synergistically with serum response factor (SRF) to activate expression from the smooth muscle gamma-actin (SMGA) gene promoter. Using NMR spectroscopy, three conserved motifs in a construct containing the N-terminal region and homeodomain of NKX3.1 were observed to interact with the MADS box domain of SRF. These motifs interacted both in the absence of DNA and when both proteins were bound to a SMGA promoter DNA sequence. No significant interaction was seen between the homeodomain and SRF MADS box. One of the SRF-interacting regions was the tinman (TN) or engrailed homology-1 motif (EH-1), residues 29-35 (FLIQDIL), which for other NK proteins is the site of interaction with the repressor protein Groucho. A second hydrophobic interacting region was designated the SRF-interacting (SI) motif and included residues 99-105 (LGSYLLD). A third interacting motif was the acidic region adjacent to the SI motif including residues 88-96 (ETLAETEPE). The acidic domain (AD) motif signals also showed strengthening upon the NKX3.1 homeodomain binding to DNA in the absence of SRF, consistent with the acidic region weakly interacting with the homeodomain in the unbound state. The importance of these linear motifs in the transcriptional interaction of NKX3.1 and SRF was demonstrated by targeted mutagenesis of an NKX3.1 expression vector in a SMGA reporter assay. The results implicate the NKX3.1 N-terminal region in regulation of transcriptional activity of this tumor suppressor.

Amino Acid Motifs↗
PubMed2006

Biological units and their effect upon the properties and prediction of protein-protein interactions.

Structural data as collated in the Protein Data Bank (PDB) have been widely applied in the study and prediction of protein-protein interactions. However, since the basic PDB Entries contain only the contents of the asymmetric unit rather than the biological unit, some key interactions may be missed by analysing only the PDB Entry. A total of 69,054 SCOP (Structural Classification of Proteins) domains were examined systematically to identify the number of additional novel interacting domain pairs and interfaces found by considering the biological unit as stored in the PQS (Protein Quaternary Structure) database. The PQS data adds 25,965 interacting domain pairs to those seen in the PDB Entries to give a total of 61,783 redundant interacting domain pairs. Redundancy filtering at the level of the SCOP family shows PQS to increase the number of novel interacting domain-family pairs by 302 (13.3%) from 2277, but only 16/302 (1.4%) of the interacting domain pairs have the two domains in different SCOP families. This suggests the biological units add little to the elucidation of novel biological interaction networks. However, when the orientation of the domain pairs is considered, the PQS data increases the number of novel domain-domain interfaces observed by 1455 (34.5%) to give 5677 non-redundant domain-domain interfaces. In all, 162/1455 novel domain-domain interfaces are between domains from different families, an increase of 8.9% over the PDB Entries. Overall, the PQS biological units provide a rich source of novel domain-domain interfaces that are not seen in the studied PDB Entries, and so PQS domain-domain interaction data should be exploited wherever possible in the analysis and prediction of protein-protein interactions.

Database Management Systems↗
PubMed2003

Higher-order interhelical spatial interactions in membrane proteins.

Higher-order interactions are important for protein folding and assembly. We introduce the concept of interhelical three-body interactions as derived from Delaunay triangulation and alpha shapes of protein structures. In addition to glycophorin A, where triplets are strongly correlated with protein stability, we found that tight interhelical triplet interactions exist extensively in other membrane proteins, where many types of triplets occur far more frequently than in soluble proteins. We developed a probabilistic model for estimating the value of membrane helical interaction triplet (MHIT) propensity. Because the number of known structures of membrane proteins is limited, we developed a bootstrap method for determining the 95% confidence intervals of estimated MHIT values. We identified triplets that have high propensity for interhelical interactions and are unique to membrane proteins, e.g. AGF, AGG, GLL, GFF and others. A significant fraction (32%) of triplet types contains triplets that may be involved in interhelical hydrogen bond interactions, suggesting the prevalent and important roles of H-bond in the assembly of TM helices. There are several well-defined spatial conformations for triplet interactions on helices with similar parallel or antiparallel orientations and with similar right-handed or left-handed crossing angles. Often, they contain small residues and correspond to the regions of the closest contact between helices. Sequence motifs such as GG4 and AG4 can be part of the three-body interactions that have similar conformations, which in turn can be part of a higher-order cooperative four residue spatial motif observed in helical pairs from different proteins. In many cases, spatial motifs such as serine zipper and polar clamp are part of triplet interactions. On the basis of the analysis of the archaeal rhodopsin family of proteins, tightly packed triplet interactions can be achieved with several different choices of amino acid residues.

Amino Acid Motifs↗
PubMed2002

An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase inhibitors on health care utilization: a Canadian population-based study.

BACKGROUND: Cytochrome P450-related drug interactions can lead to adverse effects that may affect health care resource utilization. OBJECTIVE: The purpose of this study was to quantify the impact of drug interactions involving hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) on health care resource utilization. METHODS: Using the Manitoba Health Research database, we identified patients who had used statins between January 1, 1995, and March 31, 1998. New statin users (NSUs) were those who received a first prescription for a statin after April 30, 1995; old statin users (OSUs) were those who had a statin prescription before January 1, 1995. The number of hospitalizations, physician visits, and prescriptions, and their associated costs to the Manitoba health care system were calculated. Statin interacters were defined as users with >1 prescription for an interacting drug while receiving a statin. Interacting drugs were classified into 2 groups: group A included drugs whose levels increased as a result of the statin prescription; drugs in group B increased statin levels. The Wilcoxon rank-sum test was used to analyze differences by statin on health care resource use. RESULTS: A total of 28,705 statin users (18, 181 NSUs and 10,524 OSUs) were identified. During the study period, 24,496 (85.3%) individuals took 1 statin, 3751 (13.1%) took 2 statins, and 458 (1.6%) took 3 to 5 statins. The most common coadministered group A interacting drugs were diclofenac (5.8%), amitriptyline (4.9%), warfarin (4.5%), and ibuprofen (1.8%). The most common group B interacting drugs were erythromycin (8.2%), omeprazole (5.5%), cimetidine (3.6%), and clarithromycin (3.5%). Statin interacters consumed significantly more health care resources than did noninteracters for both incident and prevalent analyses (P < 0.001). In the prevalent analysis (NSUs + OSUs), pravastatin users taking interacting drugs had significantly fewer hospitalizations (mean, 1.3), fewer physician visits (mean, 24.2), and lower health care costs (mean, 5,526 dollars) compared with prevalent users of lovastatin (1.7, 28.0, and 6,925 dollars, respectively) and fewer physician visits than simvastatin users (25.6, P < 0.001). In the incident analysis, pravastatin users had significantly less physician visits (20.8 vs 23.5, P < 0.001) and lower health care costs (4,739 dollars vs 6,323 dollars, P < 0.001) than lovastatin users. CONCLUSION: Pravastatin was associated with fewer hospitalizations, physician visits, and overall health care resource utilization in prevalent users than lovastatin, possibly due to a lack of drug interaction effects.

Anticholesteremic Agents↗
PubMed2003

Effects of retinoid ligands on RIP140: molecular interaction with retinoid receptors and biological activity.

Receptor interacting protein 140 (RIP140) interacts with retinoic acid receptor (RAR) and retinoid X receptor (RXR) constitutively, but hormone binding enhances this interaction. The ligand-independent interaction is mediated by the amino and central regions of RIP140 which contain a total of nine copies of the LXXLL motif, whereas the agonist-induced interaction is mediated by its carboxyl terminus which contains a novel motif (1063-1076, LTKTNPILYYMLQK). The ligand-independent interaction could be enhanced slightly by agonists, whereas the ligand-dependent interaction was strictly agonist dependent for both RAR and RXR. In the context of heterodimers, ligand occupancy of RXR played a more dominant role for both molecular interaction and biological activity of RIP140. Competition and mutation studies demonstrated an essential role for (1067)Asn and (1073)Met for a ligand-dependent interaction. A model was proposed to address the constitutive and agonist-dependent interaction of RIP140 with RAR/RXR.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Interactions of dendrimers with selected amino acids and proteins studied by continuous wave EPR and Fourier transform EPR.

Interactions of polyamidoamine dendrimers, termed Gn, where n indicates the generation (=number of amidoamine layers), at different protonation levels with selected amino acids and proteins have been investigated by means of continuous wave electron paramagnetic resonance (cw-EPR) and pulsed-EPR (electron spin-echo = ESE) analyses. A low-generation dendrimer (G2) and a high-generation one (G6) were labeled with nitroxides for the EPR measurements. Gly, Glu, Arg, and Leu were selected as representative of neutral(zwitterionic)-polar, acidic, basic, and low-polar amino acids, respectively. The water-soluble proteins alpha-chymotrypsin and albumin were selected on the basis of a basic and an acidic isoelectric point, respectively. The cw-EPR spectra were analyzed by computing the line shapes to extract information about the dendrimer-biomolecule interactions. In general, dendrimers at a high protonation level interact stronger with amino acids than those at a low level of protonation. However, even for highly protonated dendrimers, a synergistic effect between hydrophilic and hydrophobic interactions promoted the formation of stable Gn-amino acid adducts, as demonstrated by the enhanced interactions with Leu. As expected from acid-base interactions, stable adducts were formed between Arg and highly protonated dendrimers and between Glu and low level protonated dendrimers. The relatively strong dendrimer interactions with the protein chymotrypsin and the poor interactions of dendrimers with albumin demonstrated that the protonated amino groups of the dendrimers are predominantly involved in the interactions with these proteins and indicated a significant role in the interactions with the dendrimers of the hydrophobic external residues of chymotrypsin. Computer-aided analysis of the ESE experiments was consistent with the cw-EPR results and supported the conclusion of a partial complexation of the nitroxides of the dendrimer with Leu and alpha-chymotrypsin.

Albumins↗
PubMed2003

A summary of Food and Drug Administration-reported adverse events and drug interactions occurring during therapy with omeprazole, lansoprazole and pantoprazole.

BACKGROUND: Pantoprazole is claimed to have a lower potential for drug interaction than other proton pump inhibitors. AIM: To estimate the frequency of adverse events and drug interactions reported to the Food and Drug Administration in patients receiving omeprazole, lansoprazole or pantoprazole. METHODS: The study involved a search of the Food and Drug Administration's database for adverse events and drug interactions with omeprazole, lansoprazole or pantoprazole as primary or secondary suspect drug. An estimate of the amount of drug dispensed during the adverse event collection period (from US drug launch) was obtained from the International Medical Statistics health database. RESULTS: Of the suspected drug interactions recorded, vitamin K antagonist interactions, although rare, were the most common. The frequency of vitamin K antagonist interactions was 0.09 per million packages for omeprazole and 0.11 per million packages for lansoprazole and pantoprazole. Interactions with benzodiazepines or phenytoin were even rarer, being reported in less than 10 patients on each proton pump inhibitor. CONCLUSION: The frequency of reported drug interactions was low for omeprazole, lansoprazole and pantoprazole and vitamin K antagonist interactions were by far the most common. These potentially important drug interactions, although rare, were no less frequent on pantoprazole than on omeprazole or lansoprazole, suggesting a class effect.

2-Pyridinylmethylsulfinylbenzimidazoles↗