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PubMed1985

Acetylcholine and histamine interact supra-additively on bronchomotor tone in guinea-pigs in vivo: a possible consequence of the relationship between airways resistance and calibre.

Histamine and acetylcholine administered simultaneously to anaesthetized guinea-pigs result in a bronchoconstriction greater than that of the sum of the individual bronchoconstrictor effects of histamine and acetylcholine administered separately, i.e., a supra-additive interaction. In contrast, a supra-additive effect of acetylcholine and histamine on the isolated tracheal strip did not occur. At a pretreatment concentration of acetylcholine of 5 microM, histamine concentration-response curves were shifted rightwards, i.e., a less than additive interaction, suggesting that, at higher concentrations, histamine and acetylcholine do not act as independent agonists on guinea-pig tracheal smooth muscle. There was no supra-additive interaction between histamine and acetylcholine on tracheal segment tension when measured in situ. These observations suggest that there is no direct interaction between histamine and acetylcholine on the airways smooth muscle cell capable of explaining the supra-additive interaction in vivo. Hexamethonium pretreatment did not alter the magnitude of this supra-additive interaction indicating that an indirect interaction involving autonomic control of airways calibre does not contribute to this phenomenon. The selectivity of the supra-additive interaction for changes in airways resistance rather than compliance, together with the negative evidence for either a direct or an indirect pharmacological interaction between histamine and acetylcholine, suggest that the interaction may result from the physical relationship between airways resistance and airways calibre.

Acetylcholine↗
PubMed1984

[Molecular interactions of membrane proteins and erythrocyte deformability].

The structural and functional properties of the erythrocytic membrane constitute one of the essential elements of the red cell deformability. They intervene not only in the flexibility of the membrane, but also in the surface/volume relation and, through transmembrane exchanges, in the internal viscosity of the red cells. These properties depend essentially on the molecular composition of the elements which constitute the membrane, and on their interactions. The shape of the red cell and the flexibility of its membrane depend, to a great extent, on the membrane skeleton, whose main components are spectrin, actin, and protein 4.1. The spectrin basic molecule is a heterodimer, but there occur interactions between dimers in vitro as well as in vivo, which lead to the formation of tetrameric and oligomeric structures of higher complexity. Disturbances of these interactions, such as have been observed in pathological cases, lead to an instability of the membrane, a loss of membrane fragments, and a decrease in the surface/volume relation, with, as a consequence, a reduced deformability. The stability of the membrane skeleton also depends on the interactions between spectrin and protein 4.1. These interactions occur through a binding site on the beta chain of spectrin apparently close to actin and calmodulin binding sites. Other interactions occur between the hydrophobic segment of spectrin and membrane lipids. The cytoskeleton is bound to the transmembrane proteins: by ankyrin to the internal segment of protein band 3, and by protein 4.1 to a glycoprotein named glycoconnectin. There seems to exist other, more direct, lower affinity bindings between the cytoskeleton on the one hand, and band 3 and glycophorin transmembrane proteins on the other hand, whose lateral mobilities are modified when the structure of the skeleton is perturbed. The membrane proteins, which are in contact with the cytosol, interact with the cytosolic proteins, in particular with certain enzymes involved in anaerobic glycolysis and with hemoglobin. The Hb-membrane interactions are complex and involve different binding types with various affinities, as through band 3 protein, phospholipids, and glycophorin. These bindings are particularly important in the case of certain abnormal hemoglobins such as S and C. If the existence of molecular interactions inside the membrane and their sites are fairly well known, the mechanisms which control or influence such interactions remain unknown.(ABSTRACT TRUNCATED AT 400 WORDS)

Actins↗
PubMed1993

Interactions between physicians and the pharmaceutical industry: what does the literature say?

OBJECTIVE: To determine the effect of three types of interaction between physicians and the pharmaceutical industry--company-funded clinical trials, company-sponsored continuing medical education (CME) and information for physicians supplied by pharmaceutical detailers--on orientation and quality of clinical trials, content of CME courses and physicians' prescribing behaviour. DATA SOURCES: MEDLINE and HEALTH searches for English-language articles published from 1978 to 1993, supplemented by material from the author's personal collection. STUDY SELECTION: A total of 227 papers from the MEDLINE and HEALTH searches and about 2000 items from the author's library were initially reviewed. The following selection criteria were used: studies conducted in Australia, Canada, New Zealand, Britain and the United States; studies conducted after 1977; quantitative surveys containing details of the survey methods; studies on the orientation and quality of company-funded clinical trials and on the content of CME courses giving explicit criteria used in the evaluation; and reports on the outcome of interactions stating how the outcomes were assessed. Thirty-six studies met these criteria. DATA EXTRACTION: Information was extracted on five topics: physicians' attitudes toward drug industry interactions, frequency with which physicians participate in the interactions, orientation and quality of company-funded clinical trials, content of company-sponsored CME courses and changes in physicians' prescribing behaviour as a result of an interaction. DATA SYNTHESIS: Although most physicians participate only occasionally in company-sponsored clinical trials, most see detailers and attend company-sponsored CME courses. However, physicians do not have a very high opinion of the information from detailers or of company-sponsored CME events. Many doctors regard pharmaceutical companies as an important source of funding for clinical trials, but they also have concerns about accepting money from this source. Company funding of clinical trials may affect the quality of the trials and the types of research that physicians undertake. Company-sponsored CME courses may have a commercial bias even if conducted under guidelines designed to ensure the independence of the event. All three types of interactions affect physicians' prescribing behaviour and, in the case of obtaining information from detailers, physicians' prescribing practices are less appropriate as a result of the interaction. CONCLUSIONS: Physicians are affected by their interactions with the pharmaceutical industry. Further research needs to be done in most cases to determine whether such interactions lead to more or less appropriate prescribing practices. The CMA's guidelines on this topic should be evaluated to see whether they are effective in controlling physician-industry interactions. Further measures may be necessary if the guidelines fail to prevent negative effects on prescribing practices.

Attitude of Health Personnel↗
PubMed1996

[Interpersonal interactions between demented elderly and family caregivers in their home].

The objective of this study was to clarify the actual status of interactions performed at home between demented elders and their family caregivers. An inductive qualitative study was conducted by using a grounded theory approach. Subjects were 25 elderly individuals with dementia of Alzheimer type, and 28 caregivers in their family. The study was performed using the participant observation and interviews in their homes. Based on a constant comparative analysis, results revealed the levels of "certainty" and "maintenance of self" of the elders as core variables in interactions between the elders and the caregivers. Characteristic interactions were found to fall into three categories. The interactions in Category 1 showed caregiver's persistence in potential "certainty" of the demented elders. Category 2 was the interactions when the uncertainty of demented elders was unquestionable, and category 3 was interactions when certainty of demented elders was clear: In the category 1, subcategories named "looking for the holes", "digging the holes" and "filling in the holes" were found. In the category 2, phenomena named "protection", "friction", "harmony" and "resistance" were observed. And the category 3 contained "equality." The researcher examined and clarified behavioral characteristics, the backgrounds, topics and the results of the interactions as components of each subcategory. The triggers the transition of categories of the interactions were examined. This study also treated the differences produced according the levels of dementia and role relations of the caregivers for each category. This study revealed a part of actual interactions between the demented elders and their caregivers, and a part of the world which demented elders may experience in interaction with their caregivers.

Adult↗
PubMed1998

Human signaling protein 14-3-3zeta interacts with platelet glycoprotein Ib subunits Ibalpha and Ibbeta.

The initiation of primary hemostasis is mediated by interaction of the platelet glycoprotein Ib (GPIb) surface receptor and its arterial subendothelial von Willebrand factor (vWF) ligand. The intracellular signaling immediately following GPIb receptor occupancy connecting the adhesive event to platelet activation and aggregation has not been well characterized. The 14-3-3 proteins are a 27- to 30-kD ubiquitous protein family with diverse biologic roles, including functional modulation of several prominent signaling proteins. We used the yeast two-hybrid system and confocal microscopy to characterize the recently described interaction between GPIb and platelet 14-3-3zeta, and provide evidence for the potential signaling role of this protein. Two-hybrid interactions suggest that platelet 14-3-3zeta associates with the cytoplasmic domain of GPIb subunits Ibalpha and Ibbeta in transformed yeast cells. The 14-3-3 interaction with GPIbbeta may be partly mediated through the latter's phosphorylated serine 166 residue as its mutagenesis results in 20% to 40% reduced interaction. There was 51% to 59% reduced interaction between GPIb and three 14-3-3zeta deletion mutants compared with full-length 14-3-3zeta, suggesting that either the N-terminal dimerization or membrane-binding domains or more than one noncontiguous 14-3-3zeta element may be required for optimal GPIb interaction. Confocal studies of platelets and a megakaryocyte cell line provided additional evidence for interaction of 14-3-3zeta with GPIbalpha and GPIbbeta. We also found that, similar to the signaling mediators phosphatidylinositol 3-kinase and Src, platelet cytoskeletal 14-3-3zeta content is increased following vWF and ristocetin stimulation. We suggest that platelet 14-3-3zeta interacts with GPIbalpha and Ibbeta, that this interaction may be partly mediated through phosphoserine recognition, and that 14-3-3zeta cytoskeletal translocation may serve as a GPIb post-receptor occupancy signaling event.

14-3-3 Proteins↗
PubMed2005

Natural health product interactions with medication.

Natural health products (or dietary supplements) refer to those products found in oral dosage forms, containing 1 or more active ingredients considered to be a nutrient, an herbal product, or any other nonnutrient/nonherbal substance. Their use continues to increase in the general population and in patients seen by nutrition support clinicians. Aside from an appraisal of product safety and effectiveness, attention should be paid to the potential for these product ingredients to interact with medication. Estimates are that at least 15 million adults in the United States are at risk for supplement-drug interactions. These can occur through both pharmacokinetic and pharmacodynamic mechanisms. This review describes the influence of dietary supplements on both the disposition and the effect of medication and provides numerous examples. Patients at greatest risk for interactions are those with chronic disease, who use multiple medications-particularly those with a narrow therapeutic range-have genetic variants in drug metabolism, impaired organ function, and are at either end of the age spectrum. Knowledge of the specific effects on drug absorption, metabolism, and effect is still incomplete. Relative to the large number of possible interactions between supplements and medication, only a small number of combinations have been examined or reported. The greatest limiting factor remains the quality or reliability of the existing evidence, as many widely accepted interactions are only theoretical based either on in vitro data or known pharmacology. A distinction needs to be clearly drawn between "documented" interactions and "potential" interactions. Although drug-drug interactions have been widely recognized, supplement-drug interactions may be as important to recognize, report, and manage.

Dietary Supplements↗
PubMed2002

Interaction of the Yersinia pestis type III regulatory proteins LcrG and LcrV occurs at a hydrophobic interface.

BACKGROUND: Secretion of anti-host proteins by Yersinia pestis via a type III mechanism is not constitutive. The process is tightly regulated and secretion occurs only after an appropriate signal is received. The interaction of LcrG and LcrV has been demonstrated to play a pivotal role in secretion control. Previous work has shown that when LcrG is incapable of interacting with LcrV, secretion of anti-host proteins is prevented. Therefore, an understanding of how LcrG interacts with LcrV is required to evaluate how this interaction regulates the type III secretion system of Y. pestis. Additionally, information about structure-function relationships within LcrG is necessary to fully understand the role of this key regulatory protein. RESULTS: In this study we demonstrate that the N-terminus of LcrG is required for interaction with LcrV. The interaction likely occurs within a predicted amphipathic coiled-coil domain within LcrG. Our results demonstrate that the hydrophobic face of the putative helix is required for LcrV interaction. Additionally, we demonstrate that the LcrG homolog, PcrG, is incapable of blocking type III secretion in Y. pestis. A genetic selection was utilized to obtain a PcrG variant capable of blocking secretion. This PcrG variant allowed us to locate a region of LcrG involved in secretion blocking. CONCLUSION: Our results demonstrate that LcrG interacts with LcrV via hydrophobic interactions located in the N-terminus of LcrG within a predicted coiled-coil motif. We also obtained preliminary evidence that the secretion blocking activity of LcrG is located between amino acids 39 and 53.

Alanine↗
PubMed1994

Interactions of warfarin with drugs and food.

PURPOSE: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance. DATA SOURCES: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only. STUDY SELECTION: All articles reporting original data on drug and food interactions with warfarin. DATA EXTRACTION: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred. Inter-rater agreement was assessed using a weighted kappa statistic. RESULTS: Of 793 retrieved citations, 120 contained original reports on 186 interactions. The weighted kappa statistic was 0.67, representing substantial agreement. Of 86 different drugs and foods appraised, 43 had level 1 evidence. Of these, 26 drugs and foods did interact with warfarin. Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole. Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado. CONCLUSIONS: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications. Many of these drug interactions increase warfarin's anticoagulant effect.

Animals↗
PubMed2006

An evaluation of in vitro protein-protein interaction techniques: assessing contaminating background proteins.

Determination of protein-protein interactions is an important component in assigning function and discerning the biological relevance of proteins within a broader cellular context. In vitro protein-protein interaction methodologies, including affinity chromatography, coimmunoprecipitation, and newer approaches such as protein chip arrays, hold much promise in the detection of protein interactions, particularly in well-characterized organisms with sequenced genomes. However, each of these approaches attracts certain background proteins that can thwart detection and identification of true interactors. In addition, recombinant proteins expressed in Escherichia coli are also extensively used to assess protein-protein interactions, and background proteins in these isolates can thus contaminate interaction studies. Rigorous validation of a true interaction thus requires not only that an interaction be found by alternate techniques, but more importantly that researchers be aware of and control for matrix/support dependence. Here, we evaluate these methods for proteins interacting with DmsD (an E. coli redox enzyme maturation protein chaperone), in vitro, using E. coli subcellular fractions as prey sources. We compare and contrast the various in vitro interaction methods to identify some of the background proteins and protein profiles that are inherent to each of the methods in an E. coli system.

Blotting, Far-Western↗
PubMed2005

Protein-nucleic acid recognition: statistical analysis of atomic interactions and influence of DNA structure.

We analyzed structural features of 11,038 direct atomic contacts (either electrostatic, H-bonds, hydrophobic, or other van der Waals interactions) extracted from 139 protein-DNA and 49 protein-RNA nonhomologous complexes from the Protein Data Bank (PDB). Globally, H-bonds are the most frequent interactions (approximately 50%), followed by van der Waals, hydrophobic, and electrostatic interactions. From the protein viewpoint, hydrophilic amino acids are over-represented in the interaction databases: Positively charged amino acids mainly contact nucleic acid phosphate groups but can also interact with base edges. From the nucleotide point of view, DNA and RNA behave differently: Most protein-DNA interactions involve phosphate atoms, while protein-RNA interactions involve more frequently base edge and ribose atoms. The increased participation of DNA phosphate involves H-bonds rather than salt bridges. A statistical analysis was performed to find the occurrence of amino acid-nucleotide pairs most different from chance. These pairs were analyzed individually. Finally, we studied the conformation of DNA in the interaction sites. Despite the prevalence of B-DNA in the database, our results suggest that A-DNA is favored in the interaction sites.

Amino Acids↗
PubMed2001

Defining the molecular basis of Arf and Hdm2 interactions.

Understanding the interaction of Arf and Hdm2 has recently become a central issue in cancer biology. In response to hyperproliferative signals, p14(Arf) stabilizes p53 by binding to Hdm2 and inhibits the ubiquitination and subsequent proteosome-dependent degradation of p53. The medical importance of the Arf-Hdm2-p53 regulatory system is highlighted by the finding that either p53 or p14(Arf) are lost or modified in virtually all human cancers. Isolated Arf and Hdm2 domains are dynamically disordered in solution, yet they retain the ability to interact in vitro and in cellular assays. Upon binding, domains of both Arf and Hdm2 undergo a dramatic transition from disordered conformations to extended structures comprised of beta-strands. The presence of domains from both proteins are necessary and sufficient for the formation of the highly stable extended beta structures. We have mapped sites within Arf and Hdm2 that interact at a resolution of five amino acid residues using surface plasmon resonance. Surface plasmon resonance and circular dichroism spectropolarimetry confirm the presence of multiple interaction domains within each protein. Both p14(Arf) (human) and p19(Arf) (mouse) interact with Hdm2 through two short motifs present in their N termini. The Arf interacting region of Hdm2 is also composed of two short sequences located in the central acidic domain, between residues 235-264 and 270-289. The binding-induced structural transition is also induced by short peptides, 15 amino acids in length, that contain the binding motifs. Micro-injection and live cell imaging of proteins tagged with fluorescent labels was used to confirm the in vivo function of the interaction domains. Arf and Hdm2 thus appear to interact through a novel mechanism that exerts control over the cell division cycle. The novel molecular mechanism of interaction and the limited size of the protein domains involved provide opportunities for the development of anticancer therapeutics.

3T3 Cells↗
PubMed1999

Physiological modeling of the toxicokinetic interactions in a quaternary mixture of aromatic hydrocarbons.

The available data on binary interactions are yet to be considered within the context of mixture risk assessments because of our inability to predict the effect of a third or fourth chemical in the mixture on the interacting binary pairs. Physiologically based toxicokinetic (PBTK) models represent a framework that can be potentially used for predicting the impact of multiple interactions on component kinetics at any level of complexity. The objective of this study was to develop and validate an interaction-based PBTK model for simulating the toxicokinetics of the components of a quaternary mixture of aromatic hydrocarbons [benzene (B), toluene (T), ethylbenzene (E), m-xylene (X)] in the rat. The methodology consisted of: (1) obtaining and refining the validated individual chemical PBTK models from the literature, (2) interconnecting all individual chemical PBTK models at the level of liver on the basis of the mechanism of binary chemical interactions (e.g., competitive, noncompetitive, or uncompetitive metabolic inhibition), and (3) comparing the a priori predictions of the interaction-based model to corresponding experimental data on venous blood concentrations of B, T, E, and X during mixture exposures. The analysis of blood kinetics data from inhalation exposures (4 h, 50-200 ppm each) of rats to all binary combinations of B, T, E, and X was suggestive of competitive metabolic inhibition as the plausible interaction mechanism. The metabolic inhibition constant (K(i)) for each binary combination was quantified and incorporated within the mixture PBTK model. The binary interaction-based PBTK model predicted adequately the inhalation toxicokinetics of all four components in rats following exposure to mixtures of BTEX (50 ppm each of B, T, E, and X, 4 h; 100 ppm each of B, T, E and X, 4 h; 100 ppm B + 50 ppm each of T, E, and X, 4 h). The results of the present study suggest that data on interactions at the binary level alone are required and sufficient for predicting the kinetics of components in complex mixtures.

Administration, Inhalation↗
PubMed2004

Requirements for a successful implementation of drug interaction information systems in general practice: results of a questionnaire survey in Germany.

OBJECTIVE: To determine drug interaction information requirements in general practice with respect to both content and mode of presentation. METHODS: In a mail survey among 2,000 general practitioners in south-west Germany, we collected information on risk evaluation of drug interactions and combinations of concern, usage of and satisfaction with the current information sources, desirable content and mode of future presentation and demographic variables. Categorical variables were compared using chi2 test. Trends were analysed with Cochran-Armitage test and determinants of literature usage with logistic regression. RESULTS: Response rate was 60.8%. The majority of general practitioners considered drug interactions a risk factor in prescribing (88.6%). For 18.2% of the drug combinations most frequently indicated as interacting, there was no published evidence of a clinically relevant interaction. More than half of the participants were dissatisfied with the information on severity, mechanism, and dose adjustment currently available in their sources. In particular, non-interacting alternatives were thought to be lacking (86.9%). Users of drug interaction software more frequently retrieved drug interaction information than non-users [odds ratio (OR) 1.95; 95% confidence intervals (CI) 1.50, 2.52], but only 28.6% of general practitioners had access to such systems. There was a significant trend towards electronic sources among younger physicians, but at present, 41.7% of general practitioners favour printed sources, and 8.8% would refuse to use electronic sources. CONCLUSION: General practitioners wish for more informative support on drug interactions, especially concerning management. Despite a trend towards electronic information sources, printed documents are presently still required to reach all prescribers.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK).

OBJECTIVE: Ca antagonists are one of the most popular classes of drugs used to treat hypertension and angina. These drugs may interact with either CYP3A4 or MDR-1 substrates, with the degree of interaction differing with each drug. We carried out a literature search to examine and compare the extent to which crucial pharmacokinetic (PK) information is included in package inserts (PIs) in Japan, USA and the UK. METHODS: A MEDLINE search from 1966 to November 2004 was undertaken with the aim of identifying studies on clinical PK drug interactions between seven Ca antagonists that are available in three countries and three CYP3A4 inhibitors (erythromycin, itraconazole and cimetidine), a CYP3A4 inhibitory food, grapefruit juice (GFJ) and the MDR-1 substrate, digoxin. The current PIs for Ca antagonists were obtained from the website of the regulatory authorities or the electronic Medicines Compendium. RESULTS: Of all possible combinations of seven Ca antagonists with three CYP3A4 inhibitor drugs, drug interaction information was available in the literature on nine combinations: Seven of these were listed in the USA PIs, two in the UK PIs, and none in the Japanese PIs. Interaction studies with GFJ were reported for every Ca antagonist; PIs in the USA provided quantitative data for four of these interactions, whereas UK PIs provided quantitative data for only one of the interactions and Japanese PIs provided no quantitative information. The PK data of co-medication of digoxin with Ca antagonists have been reported for every Ca antagonists. The USA PIs provided quantitative data for five Ca antagonists, whereas the UK PIs provided quantitative data for three Ca antagonists and Japanese PIs provided no quantitative data. CONCLUSION: The literature search revealed that PIs in the USA provided a great deal of quantitative information on PK interactions between Ca antagonists and other drugs or GFJ. In contrast, PIs in the UK and Japan did not provide sufficient information. We conclude that crucial quantitative information on these drug interactions should be incorporated in PIs, especially in Japan and the UK, as a means of assisting healthcare providers.

Calcium Channel Blockers↗
PubMed2005

Drug-drug interactions among recently hospitalised patients--frequent but mostly clinically insignificant.

OBJECTIVE: Patients use and store considerable amounts of drugs. The aim of the present study was to identify potential drug-drug interactions between drugs used by patients recently discharged from the hospital and, subsequently, to estimate the clinical implications of these interactions. METHODS: Patients were visited within 1 week following their discharge from hospital and interviewed about their drug use. Stored products were inspected. We used a bibliography (Hansten and Horn; Wolters Kluwer Health, St. Louis, Mo., 2004) to identify and classify potential drug-drug interactions. RESULTS: In total, 83 surgical and 117 medical patients (n = 200) were included in the survey, of which 139 (70%) were women. The median age was 75 years (range: 24-100 years). Patients stored 2119 medications at home (median: nine per patient; range: 2-44) and used 1622 medications daily or on demand (median: eight per patient; range: 1-24). With respect to those drugs used daily or on demand, 476 potential interactions were identified (126 patients); none were class 1 (always avoid drug combination) and 25 were class 2 (usually avoid combination; 24 patients). Eleven of the potential class 2 interactions involved over-the-counter products (aspirin and ginkgo biloba). Of the 52 drugs involved in potential class 2 interactions, 50 had been used for more than 1 month. According to the hospital case notes, none of the potential class 2 interactions had actually caused adverse effects. CONCLUSION: Although potential drug-drug interactions are highly prevalent, serious and clinically significant interactions are rare among recently hospitalised patients.

Adolescent↗
PubMed2006

Detection of potential drug interactions - a model for a national pharmacy register.

OBJECTIVE: The widespread use of pharmaceuticals prescribed by different physicians has caused the Swedish government to propose a new legislation with registration of all prescriptions dispensed at the Swedish pharmacies. In the present study, we wanted to examine the frequency, distribution and determinants of potential drug interactions. METHODS: The prescriptions from all individuals (n=8,214) with two or more prescriptions during October 2003 to December 2004 were collected from the ongoing Jämtland cohort study of a total of about 11,000 individuals. Potential drug-drug interactions were detected with a computerized interaction detection system and classified according to clinical relevance (types A-D). RESULTS: On average each individual filled 14.6 (men 14.3, women 14.8) prescriptions during the study period. 3.6% of the individuals used more than 15 different drugs. The number of detected potential drug interactions type A-D was 4,941 (men 1,949, women 2,992). The risk of receiving a potential interaction type A-D was estimated as the cumulative incidence 0.26 (2,116/8,214) overall, 0.22 (748/3,467) for men and 0.29 (1,368/4,747) for women during the 15-month study period. The age adjusted risk, RR(adj), for women was estimated as 1.30. Excluding sex hormones and modulators of the genital system, the RR(adj) was 0.96, with no elevated risk for women. For potential interactions type D, that might have serious clinical consequences, 167 (cumulative incidence 0.0203) individuals (72 men, cumulative incidence 0.0208, 95 women cumulative incidence 0.0200) were detected. The risk of receiving a combination of potentially interacting drugs was positively correlated to age and polypharmacy. The cumulative incidence for elderly was estimated as 0.36 (65-84 years) and 0.39 (85 years and above). The relative risk for individuals with 15 drugs or more was estimated as 3.67 (95% CI 3.46-3.90). CONCLUSION: In a general population there were relatively few severe potential drug interactions. The new Swedish national pharmacy register will provide health care professionals with a powerful tool to systematically review all prescriptions. An alert system should focus on the more potential drug interactions, type C-D, with close monitoring of elderly and patients with polypharmacy.

Adult↗
PubMed2000

Frequency of daily over-the-counter drug use and potential clinically significant over-the-counter-prescription drug interactions in the Finnish adult population.

OBJECTIVE: To explore the frequency of continuous use of over-the-counter (OTC) drugs among the Finnish adult population and the potential for harmful interactions between OTC drugs and prescribed (Rx) drugs. METHODS: Data were extracted from a 1995-1996 population-based interview survey on health care (n = 10,477, response rate 86%). The drug interaction classification system from the Swedish Drug Compendium FASS 1997 was used to identify OTC drugs likely to have clinically significant interactions with prescription drugs. Logistic regression was used to study factors related to continuous use and risks for interactions. RESULTS: Seventeen percent of the population had used OTC drugs and 15% had used OTC vitamins during the 2 days prior to the interview. Daily use of OTC drugs and of vitamins was reported by 7% and 9%, respectively. Continuous use of OTC drugs was related to older age, female gender, higher education, poor health status, long-term morbidity, psychosomatic symptoms (fatigue) and use of prescription drugs, but not to poor lifestyle. Four percent of the OTC drug users had taken drug combinations with potential for clinically significant interactions. Interactions were most common for ketoprofen (15% of ketoprofen users), ibuprofen (10%), and acetylsalicylic acid (ASA) (6%). The number of prescription drugs, long-term illness and lower education best explained the risk for interactions. CONCLUSION: Continuous use and potentially harmful Rx/ OTC drug interactions occur among OTC drug users. Further studies should be done to investigate whether potential combinations will actually lead to clinical problems. The possible interactions of non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with prescription drugs should especially be taken into account in drug information.

Adolescent↗
PubMed1999

Drug-drug interactions of new active substances: mibefradil example.

INTRODUCTION: Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound. RESULTS AND CONCLUSION: The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed.

Calcium Channel Blockers↗