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PubMed2004

The interactional management of patients' physical incompetence: a conversation analytic study of physiotherapy interactions.

Patients' physical incompetence is a feature of many clinical interactions; the challenges it presents are not only technical but also interactional. This paper examines how interpretations and interactional consequences of physical incompetence are dealt with during stroke physiotherapy. A conversation analytic approach was used to examine video-recorded treatment sessions. Analysis demonstrated that managing physical incompetence forms an important element of the organisation of these interactions. Through their conduct, patients and therapists limit and counter its various negative implications, including those which attribute it to failure of a patient's efforts, co-operation and personal competence, and failure of therapy. Understanding orientations to incompetence and their influence upon interactions provides some explanations, or 'good reasons', for certain features of clinical interactions that have attracted criticism. Analysis also shows how management of incompetence is grounded in the clinician's authority and contributes to its maintenance. In the face of failures of physical competence, participants collaboratively and continually work to portray patients as deserving of treatment rather than sanction, and to convey that despite evident difficulties, the therapeutic process is a co-operative and successful endeavour. The paper examines how these meanings are addressed and accomplished through interaction.

Aged↗
PubMed1986

The effects of consequences on patterns of social interaction: a quasi-experimental approach to reinforcement in natural interaction.

Research on social interaction has consistently documented the existence of mutual interdependencies between the behavior of 1 person and reactions to that behavior by others in the social environment. The concept of social reinforcement, although often used to explain acquisition and change in interaction patterns defined by such interdependencies, is difficult to apply to interaction observed in natural settings. On the basis of extended observation of the interaction of 2 mother-child dyads, the procedures needed to assess the effects of naturally occurring consequences on interactional patterns are detailed in this study. Reliable mother action-child reaction patterns were first identified, and the effect of maternal consequences for those patterns on the probability of their subsequent occurrence was assessed. Positive consequences were associated with increases, and negative consequences with decreases, in the probability of a child reacting to the next occurrence of the maternal action when compared to the base-rate probability of that action-reaction pattern. Thus consequences affect momentary shifts around the baseline probability of interactional patterns. Positive consequences were also associated with short-term increases, and negative consequences with short-term decreases, in the base-rate probability of interactional patterns.

Adult↗
PubMed1987

Infants' interactions with mother, sibling, and peer: contrasts and relations between interaction systems.

The role of the mother in structuring interactions with the infant during free play was examined at 6 and 9 months. Maternal scaffolding of turn-taking exchanges was then contrasted to the forms of turn-taking apparent in sibling-infant and peer-infant observations. Infants spent more time in turn-taking exchanges with their mothers than with their siblings or peers. These exchanges most often took the form of mothers creating sequences by responding to infants' social and nonsocial acts and by eliciting social and nonsocial responses from the infants. Infants' exchanges with older siblings were briefer and more typically involved the older children eliciting nonsocial responses from the infants but not responding contingently to the infants' interests and actions. Infant peers spent less time in turn-taking exchanges, and their interactions showed less evidence of scaffolding. At the same time, the proportion of strictly social interactions was greatest with peers. Relations were apparent between infants' turn-taking experiences with their mothers and the infants' subsequent interactions with their siblings and with their peers. Relations were also found between infants' interaction experiences with their older siblings and subsequent peer interaction. Those infants with more extensive turn-taking experience with more skilled social partners were subsequently observed to engage in more extensive turn-taking interactions with a peer. These results are discussed in terms of studies on mother-infant attachment and peer competence, maternal scaffolding, and Vygotsky's zone of proximal development.

Child Development↗
PubMed1995

Receptor-receptor interactions and their relevance for receptor diversity. Focus on neuropeptide/dopamine interactions.

Receptor diversity in combination with receptor-receptor subtype specific interactions, which can be antagonistic or synergistic in character, markedly increase plasticity in WT and VT in the nervous system. In this way switching among transmission lines for the various DA receptor subtypes becomes possible. Some of these aspects are supported by our work on selective modulation of D2 receptors by CCK and NT. Selective regulation of D2 receptors via CCK-8 receptor subtypes and NT receptors may underlie CCK/DA interactions and NT/DA interactions in the basal ganglia. These studies underline the importance of receptor-receptor interactions exerted at the membrane level between neuropeptide receptors and D2 receptors, which are determined at least in part by the ongoing activity at D1 receptors. In the case of both CCK/D2 and NT/D2 receptor interactions, it has been possible, by means of intrastriatal and intraaccumbens microdialysis, to obtain a functional correlate to the receptor interactions found in the membrane preparations from the striatum. Schizophrenia may be in part related to reduced release of CCK and/or NT peptides or to alterations in their receptor interactions with the D2 receptor. This view may lead to new therapeutic approaches.

Animals↗
PubMed1997

Two classes of human papillomavirus type 16 E1 mutants suggest pleiotropic conformational constraints affecting E1 multimerization, E2 interaction, and interaction with cellular proteins.

Random mutagenesis of human papillomavirus type 16 (HPV16) E1 was used to generate E1 missense mutants defective for interaction with either hUBC9 or 16E1-BP, two cDNAs encoding proteins that have been identified by their ability to interact with HPV16 E1 in two-hybrid assays. hUBC9, the human counterpart of Saccharomyces cerevisiae UBC9, is a ubiquitin-conjugating enzyme known to be involved in cell cycle progression. 16E1-BP encodes a protein of no known function but does contain an ATPase signature motif. Eight hUBC9 or 16E1-BP interaction-defective HPV16 E1 missense mutants were identified and characterized for origin-dependent transient DNA replication, ATPase activity, and various protein-protein interaction phenotypes. Six of these mutant E1 proteins were significantly impaired for replication. Among these, two classes of replication-defective HPV16 E1 missense mutants were observed. One class, represented by the S330R replication-defective mutant (containing an S-to-R change at position 330), remained competent for all protein-protein interactions tested, with the exception of hUBC9 association. Furthermore, this mutant, unlike the other replication-defective HPV16 E1 missense mutants, had a strong dominant negative replication phenotype in transient-replication assays. The other class, represented by five of the missense mutants, was defective for multiple protein-protein interactions, usually including, but not limited to, the interaction defect for which each mutant was originally selected. In many cases, a single missense mutation in one region of HPV16 E1 had pleiotropic effects, even upon activities thought to be associated with other domains of HPV16 E1. This suggests that E1 proteins are not modular but may instead be composed of multiple structurally and/or functionally interdependent domains.

Adenosine Triphosphatases↗
PubMed2002

NRC-interacting factor 1 is a novel cotransducer that interacts with and regulates the activity of the nuclear hormone receptor coactivator NRC.

We previously reported the cloning and characterization of a novel nuclear hormone receptor transcriptional coactivator, which we refer to as NRC. NRC is a 2,063-amino-acid nuclear protein which contains a potent N-terminal activation domain and several C-terminal modules which interact with CBP and ligand-bound nuclear hormone receptors as well as c-Fos and c-Jun. In this study we sought to clone and identify novel factors that interact with NRC to modulate its transcriptional activity. Here we describe the cloning and characterization of a novel protein we refer to as NIF-1 (NRC-interacting factor 1). NIF-1 was cloned from rat pituitary and human cell lines and was found to interact in vivo and in vitro with NRC. NIF-1 is a 1,342-amino-acid nuclear protein containing a number of conserved domains, including six Cys-2/His-2 zinc fingers, an N-terminal stretch of acidic amino acids, and a C-terminal leucine zipper-like motif. Zinc fingers 1 to 3 are potential DNA-binding BED finger domains recently proposed to play a role in altering local chromatin architecture. We mapped the interaction domains of NRC and NIF-1. Although NIF-1 does not directly interact with nuclear receptors, it markedly enhances ligand-dependent transcriptional activation by nuclear hormone receptors in vivo as well as activation by c-Fos and c-Jun. These results, and the finding that NIF-1 interacts with NRC in vivo, suggest that NIF-1 functions to regulate transcriptional activation through NRC. We suggest that NIF-1, and factors which associate with coactivators but not receptors, be referred to as cotransducers, which act in vivo either as part of a coactivator complex or downstream of a coactivator complex to modulate transcriptional activity. Our findings suggest that NIF-1 may be a functional component of an NRC complex and acts as a regulator or cotransducer of NRC function.

Amino Acid Motifs↗
PubMed2006

Estimation of medium effects on equilibrium constants in moderate and high ionic strength solutions at elevated temperatures by using specific interaction theory (SIT): interaction coefficients involving Cl, OH- and Ac- up to 200 degrees C and 400 bars.

In this study, a series of interaction coefficients of the Brønsted-Guggenheim-Scatchard specific interaction theory (SIT) have been estimated up to 200 degrees C and 400 bars. The interaction coefficients involving Cl- estimated include epsilon(H+, Cl-), epsilon(Na+, Cl-), epsilon(Ag+, Cl-), epsilon(Na+, AgCl2 -), epsilon(Mg2+, Cl-), epsilon(Ca2+, Cl-), epsilon(Sr2+, Cl-), epsilon(Ba2+, Cl-), epsilon(Sm3+, Cl-), epsilon(Eu3+, Cl-), epsilon(Gd3+, Cl-), and epsilon(GdAc2+, Cl-). The interaction coefficients involving OH- estimated include epsilon(Li+, OH-), epsilon(K+, OH-), epsilon(Na+, OH-), epsilon(Cs+, OH-), epsilon(Sr2+, OH-), and epsilon(Ba2+, OH-). In addition, the interaction coefficients of epsilon(Na+, Ac-) and epsilon(Ca2+, Ac-) have also been estimated. The bulk of interaction coefficients presented in this study has been evaluated from the mean activity coefficients. A few of them have been estimated from the potentiometric and solubility studies. The above interaction coefficients are tested against both experimental mean activity coefficients and equilibrium quotients. Predicted mean activity coefficients are in satisfactory agreement with experimental data. Predicted equilibrium quotients are in very good agreement with experimental values. Based upon its relatively rapid attainment of equilibrium and the ease of determining magnesium concentrations, this study also proposes that the solubility of brucite can be used as a pH (pcH) buffer/sensor for experimental systems in NaCl solutions up to 200 degrees C by employing the predicted solubility quotients of brucite in conjunction with the dissociation quotients of water and the first hydrolysis quotients of Mg2+, all in NaCl solutions.

Journal Article↗
PubMed1999

INTERACT: an object oriented protein-protein interaction database.

MOTIVATION: Protein-protein interactions provide vital information concerning the function of proteins, complexes and networks. Currently there is no widely accepted repository of this interaction information. Our aim is to provide a single database with the necessary architecture to fully store, query and analyse interaction data. RESULTS: An object oriented database has been created which provides scientists with a resource for examining existing protein-protein interactions and inferring possible interactions from the data stored. It also provides a basis for examining networks of interacting proteins, via analysis of the data stored. The database contains over a thousand interactions. CONTACT: k.eilbeck@stud.man.ac.uk

Computational Biology↗
PubMedDate not supplied

[Statistical and frequency-amplitude characteristics of ultra-weak emissions of loach eggs and embryos under normal conditions and on their optic interactions. II. Changes in characteristics of ultra-weak emissions upon optic interaction of groups of embryos of different ages. ].

We compared the characteristics of ultraweak emissions from groups of loach embryos of different ages in the presence or absence of optic interaction. The percentage of zero values of emission gradually increased during the first hour of optic interaction. The number and height of rare big pulses estimated by the value of kurtosis increased in parallel. In addition, the correlation between the Fourier spectra of optically interacting samples decreased at a higher rate than in the absence of optical contact. Just after the 1-hour optic interaction was terminated, the number of high pulses decreased in a younger interacting group and increased in the older one and the farther away the partner groups were in developmental stages, the more pronounced these differences were. Measurements of the Fourier spectra after long-term (12-22-hour) optic interactions have shown that an "exchange" of autocorrelation characteristics of the spectra took place among the samples: the sums of autocorrelation coefficients were inverted in the vast majority of cases, often with an "overshoot" or, at least, were smoothed over with reference to the control samples. We conclude that the previously described effects of optic interactions between groups of loach embryos of different ages could be due to changes in the frequency spectra of their ultraweak emissions.

Animals↗
PubMedDate not supplied

[Interaction of deacylated phenylalanyl tRNA from yeasts with Escherichia coli ribosomes. The role of the modified nucleotide in codon-anticodon interaction].

The method of anticodon loop replacement has been used to make derivatives of yeast tRNA(Phe)GmAAY with the substitution at the 37 position (tRNA(Phe)GAAA), and at both the anticodon (tRNA(Phe)GCAG) and the 37 position. A quantitative study of the interaction of various types of yeast deacylated tRNA: tRNA(Phe)GmAAY, tRNA(Phe)GAAA, tRNA(Phe)GCAG, and tRNA(Phe)-Y with the P site of the 70S ribosome.poly(U) complex was carried out at different Mg2+ concentrations and temperatures. The replacement of the Y base on the nonmodified adenosine decreases the interaction enthalpy from 39 to 24 kcal/mole, whereas the complete removal of the Y base reduces the interaction enthalpy to 16 kcal/mole. The replacement of the second letter of the anticodon (A) with cytosine leads to a drop in the enthalpy to 6 kcal/mole, which is typical of tRNA interaction with the P site in the absence of poly(U). In the absence of poly(U) the affinity of tRNA(Phe)-Y for the P site of the 70S ribosome is 5 times lower than the affinity of tRNA(Phe)GmAAY and tRNA(Phe)GCAG. Thus, in the ribosome the modified nucleotide not only stabilizes the codon-anticodon interaction owing to the stacking interaction with the stack of codon-anticodon bases, but also lowers the free energy of binding as a result of the interaction of the modified nucleotide itself with the hydrophobic center of the P site on the ribosome.

Acylation↗
PubMed2006

ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions.

Receptor interacting protein-2 (RIP2) is a caspase recruitment domain (CARD)-containing kinase that interacts with caspase-1 and plays an important role in NF-kappaB activation. Apoptosis-associated speck-like protein containing a CARD (ASC) is a PYRIN and CARD-containing molecule, important in the induction of apoptosis and caspase-1 activation. Although RIP2 has also been linked to caspase-1 activation, RIP2 knockout animals fail to show a defect in caspase-1-mediated processing of proIL-1beta to its active form. Therefore, RIP2 function in binding to caspase-1 remains poorly understood. We hypothesized that caspase-1 may serve as a scaffolding molecule that promotes RIP2 interaction with IkappaB kinase-gamma thus inducing NF-kappaB activation. We further hypothesized that ASC, which also interacts with caspase-1 via its CARD, may interfere with the caspase-1 RIP2 interaction. In HEK293 cells, ASC induced prominent activation of caspase-1 and proIL-1beta processing. RIP2 transient transfection induced transcription of an NF-kappaB reporter gene. This RIP2-induced NF-kappaB activity and caspase-1 binding was inhibited in a dose-dependent fashion by ASC. Consistent with a role for caspase-1 as a scaffold for RIP2, caspase-1 knockout macrophages were suppressed in their ability to activate NF-kappaB, and septic caspase-1 knockout animals produced less IL-6, a functional marker of NF-kappaB activity. Lastly, THP-1 cells treated with small interfering RNA for ASC decreased their caspase-1 activity while enhancing their NF-kappaB signal. These data suggest that ASC may direct caspase-1 away from RIP2-mediated NF-kappaB activation, toward caspase-1-mediated processing of proIL-1beta by interfering with the RIP2 caspase-1 interaction.

Animals↗
PubMed2005

Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions.

Currently, 3 phosphodiesterase 5 (PDE5) inhibitor agents are available worldwide for the treatment of erectile dysfunction (ED): sildenafil, vardenafil, and tadalafil. Each of these agents is effective across a broad range of etiologies, including vasculogenic ED in men. Because PDE5 enzyme is found within the vascular smooth muscle cells in the walls of systemic arteries and veins, PDE5 inhibitors are mild vasodilators associated with small (and in general, clinically insignificant) decreases in blood pressure. However, because of the synergistic decrease in blood pressure (both systolic and diastolic) in the presence of organic nitrates, these 3 agents are contraindicated in patients receiving organic nitrates. The duration of interaction between a PDE5 inhibitor and nitrate administration depends on the specific drug being studied. The interaction between sildenafil or vardenafil and nitroglycerin is no longer observed by 24 hours. A preliminary study with sildenafil and sublingual nitroglycerin suggested the interaction is no longer observable by 4 hours. The interaction between tadalafil and nitroglycerin has dissipated by 48 hours after tadalafil administration. This is consistent with the longer elimination half-life of the drug. When PDE5 inhibitors are administered to patients with hypertension who are taking most antihypertensive agents (eg, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium antagonists, diuretics), there are usually small additive decreases in blood pressure without a significant increase of adverse events. Some patients develop orthostatic hypotension when PDE5 inhibitors are used in conjunction with an alpha-blocker (typically for hypertension or for urologic conditions, such as benign prostatic hypertrophy). Precautions are necessary for all 3 of the PDE5 inhibitors regarding this potential interaction. Some studies suggest that the interaction is less relevant clinically if the patient has been undergoing long-term alpha-blocker therapy. Several analyses have suggested that PDE5 inhibitors do not increase myocardial infarction rates or death rates compared with placebo controls or expected rates from age-matched populations. In contrast, recent studies have shown that PDE5 inhibitors may have therapeutic potential for a host of cardiovascular diseases. In general, these agents, when used appropriately, are highly safe and effective.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs.

There are two types of interactions between drugs, pharmacokinetic and pharmacodynamic. For antiepileptic drugs (AEDs), pharmacokinetic interactions are the most notable type, but pharmacodynamic interactions involving reciprocal potentiation of pharmacological effects at the site of action are also important. By far the most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism. Among old generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone induce the activity of several enzymes involved in drug metabolism, leading to decreased plasma concentration and reduced pharmacological effect of drugs, which are substrates of the same enzymes (eg, tiagabine, valproic acid, lamotrigine, and topiramate). In contrast, the new AEDs gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other AEDs. Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid. Among AEDs, the least potential interaction is associated with gabapentin and levetiracetam.

Anticonvulsants↗
PubMedDate not supplied

Measuring protein interactions by microchip self-interaction chromatography.

The self-interaction of proteins is of paramount importance in aggregation and crystallization phenomena. Solution conditions leading to a change in the state of aggregation of a protein, whether amorphous or crystalline, have mainly been discovered by the use of trial and error screening of large numbers of solutions. Self-interaction chromatography has the potential to provide a quantitative method for determination of protein self-interactions amenable to high-throughput screening. This paper describes the construction and characterization of a microchip separation system for low-pressure self-interaction chromatography using lysozyme as a model protein. The retention time was analyzed as a function of mobile-phase composition, amount of protein injected, flow rate, and stationary-phase modification. The capacity factors (k') as a function of crystallizing agent concentration are compared with previously published values for the osmotic second virial coefficient (B(22)) obtained by static light scattering, showing the ability of the chip to accurately determine protein-protein interactions. A 500-fold reduction in protein consumption and the possibility of using conventional instrumentation and automation are some of the advantages over currently used methodologies for evaluating protein-protein interactions.

Chromatography↗
PubMed2004

The inhibitor ABIN-2 disrupts the interaction of receptor-interacting protein with the kinase subunit IKKgamma to block activation of the transcription factor NF-kappaB and potentiate apoptosis.

NF-kappaB (nuclear factor kappaB) proteins are key transcription factors that regulate gene expression in response to various extracellular stimuli. The pathway leading to the activation of NF-kappaB involves a complicated network that includes a number of signalling molecules. The recent identification of a wide range of negative regulators of NF-kappaB has given another layer of complexity in NF-kappaB activation. We and others have previously identified the protein ABIN-2 (A20 binding inhibitor of NF-kappaB 2) as an inhibitor of NF-kappaB activation. In the present paper, we demonstrate that ABIN-2 exerts its inhibitory function by blocking the interaction of RIP (receptor-interacting protein) with the downstream effector IKKgamma, a non-kinase component of the IkappaB (inhibitory kappaB) kinase complex. When overexpressed in cells, ABIN-2 bound to IKKgamma and prevented the association of IKKgamma with RIP. By a deletion mapping, a stretch of 50 amino acids on ABIN-2 is found to be essential for its interaction with IKKgamma. The ABIN-2 mutant that lacked these 50 amino acids did not interact with IKKgamma and, consequently, failed to inhibit NF-kappaB activation. Strikingly, a portion of RIP, which is similar to this 50-residue domain of ABIN-2, is also essential for RIP interaction with IKKgamma. The RIP mutant with deletion of this similar region did not associate with IKKgamma and had substantial reduction of its ability to mediate NF-kappaB activation. Taken together, these conserved 50 residues of ABIN-2 and RIP define a novel structural domain in mediating a key step in the NF-kappaB signalling pathway through the interaction with IKKgamma. Finally, the signalling pathway of NF-kappaB activation is known to promote survival in many cellular events. The mechanism for decision between cell death and survival is under fine regulation. In the present paper, we demonstrated further that the expression of ABIN-2 could promote the RIP-mediated apoptosis by presumably suppressing the anti-apoptotic effect of NF-kappaB.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A literature search on pharmacokinetic drug interactions of statins and analysis of how such interactions are reflected in package inserts in Japan.

BACKGROUND AND OBJECTIVES: Statins (HMG-CoA reductase inhibitors) are one of the most widely prescribed classes of drugs throughout the world, because of their excellent cholesterol-lowering effect and overall safety profile except for rare but fatal rhabdomyolysis arising either directly or indirectly by pharmacokinetic interactions with certain other drugs. As package inserts in pharmaceuticals are the primary source of information for health care providers, we carried out a literature search to examine how crucial information was provided in package inserts of five statins approved in Japan (simvastatin, atorvastatin, fluvastatin, pravastatin and pitavastatin). METHODS: A MEDLINE search from 1996 to June 2004 was carried out to identify studies on clinical pharmacokinetic drug interactions for the five statins. We mainly collected information on area under plasma concentration (AUC) following co-administration of statins with other drugs. The current package inserts used in Japan were obtained from the website of the Pharmaceutical and Medical Device Agency whereas USA package inserts were obtained from the Food and Drug Administration website. RESULTS: The majority of package inserts listed the drugs that interacted with statins with most describing the risk of rhabdomyolysis because of the possibility of increases in blood concentration. However, quantitative information such as change in AUC was provided in only a few cases. Instructions for dosage adjustment are seldom provided in the Japanese package inserts. USA package inserts list almost identical drug interactions as the Japanese package inserts, although they contain more quantitative data, especially for typical cytochrome P450 (CYP) inhibitors. CONCLUSION: All pharmacokinetic drug interactions including relevant quantitative data for potential effectors and details on mechanisms of interaction need to be given in package inserts as soon as the information becomes available, to ensure safe and proper use of the drugs concerned. Including such information in the package insert will be an extremely valuable aid for health care providers.

Area Under Curve↗
PubMed2004

In vitro interactions between amphotericin B, itraconazole, and flucytosine against 21 clinical Aspergillus isolates determined by two drug interaction models.

Combination therapy of flucytosine (5FC) with other antifungal agents could be of use for the treatment of invasive aspergillosis. However, interpretation of the results of in vitro interactions is problematic. The fractional inhibitory concentration (FIC) index is the most commonly used method, but it has several major drawbacks in characterizing antifungal drug interaction. Alternatively, a response surface approach using the concentration-effect relationship over the whole concentration range instead of just the MIC can be used. We determined the in vitro interactions between amphotericin B (AMB), itraconazole, and 5FC against 21 Aspergillus isolates with a broth microdilution checkerboard method that employs the dye MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. FIC indices based on three different MIC endpoints (MIC-0, MIC-1, and MIC-2) and the interaction coefficient alpha were determined, the latter by estimation from the response surface approach described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995). The value obtained for the FIC index was found to be dependent on the MIC endpoint used and could be either synergistic, indifferent, or antagonistic. The response surface approach gave more consistent results. Of the three combinations tested, the AMB-5FC combination was the most potent in vitro against Aspergillus spp. We conclude that the use of the response surface approach for the interpretation of in vitro interaction studies of antifungals may be helpful in order to predict the nature and intensity of the drug interaction. However, the correlation of these results with clinical outcome remains difficult and needs to be further investigated.

Algorithms↗
PubMedDate not supplied

[Drug-drug interactions: predictive in vitro models of in vivo interactions. Round table no. 6.XV].

Liver drug metabolism is a major source of drug interactions. Three major human in vitro models are employed to detect drug interactions in the preclinical phases of drug development: recombinant enzymes, human liver microsomes and primary human hepatocyte cell cultures. Results obtained from these models may vary during the different phases of drug development. Identification of the metabolic pathways, enzymes involved in drug metabolism (mainly cytochrome P450s), enzyme induction or inhibition allow us to detect the major pharmacokinetic drug interactions which can occur in man and to identify specific populations at risk for such interactions. In vitro models are essential to decide if and which future drug interaction studies should be performed in man. However, the clinical relevance of the potential pharmacokinetic drug interactions detected by these in vitro models remains to be determined and confirmed by human studies.

Animals↗