No description available.

Multidrug resistance (MDR), a phenomenon in which tumors that were initially sensitive, recur and start showing resistance not only to the initial chemotherapeutic agent but also to various anticancer drugs that are structurally and functionally different from the initial drug, constitutes one of the main reasons for the failure of chemotherapy. An important mechanism of MDR is the enhanced cellular efflux of anticancer agents due to an overexpression of ATP-binding cassette (ABC) transporters (i.e. efflux transporters), especially P-glycoprotein (Pgp), Multidrug Resistance-associated Protein 1 (MRP1) and Breast Cancer Resistance Protein (BCRP), in cancer cells. In order to reverse this resistance, there has been a lot of emphasis on the development of Pgp, MRP1 and BCRP inhibitors. Although this search has been ongoing for three decades, there are still no clinically available efflux transporter modulators. Tyrosine kinase inhibitors (TKIs) are a novel, rapidly growing class of anticancer agents that have a target-based mechanism of action, and their use transformed cancer chemotherapy due to higher specificity and enhanced safety profiles compared to conventional chemotherapeutic agents. Despite their tremendous success in treating various types of tumors, patients develop resistance to TKIs over time. Most of the FDA- approved TKIs are substrates of Pgp and/or BCRP, and as a result, these efflux transporters are also an important cause of conferred resistance against TKIs in cancer cells. Additionally, none of the 31 approved TKIs have an indication for use in brain tumors and interestingly, this may also due to the presence of Pgp and BCRP at the blood-brain barrier (BBB) and in the tumor cells, which prevent the TKI from crossing the BBB and reaching its target tumor site. Since Pgp- and BCRP- mediated TKI efflux has been shown to be involved in TKI resistance, the inhibition of these transporters could represent a potential TKI resistance reversal strategy. Over the last three decades, a large number of Pgp and/or BCRP inhibitors have been identified, but none of them have successfully made it to the clinic. It was observed that most drugs identified as inhibitors were either unable to achieve Pgp and BCRP inhibitory concentrations in-vivo without imparting severe toxicity, or did not possess adequate bioavailability and tissue distribution profiles in order to reach the tumor site. From these identified candidate inhibitors, after much thought and consideration, we chose to investigate TKIs and methylated flavones as modulators of efflux transporter-mediated TKI resistance. The overall goal of this project was to investigate the promising chemosensitizing potential of TKIs and methylated flavones in efflux transporter-mediated TKI resistance, both in-vitro and in-vivo. To identify potent efflux transporter inhibitor TKIs, we evaluated the effect of various TKIs on the accumulation of afatinib, the model TKI substrate, in Pgp- and BCRP- overexpressing cell lines. Afatinib was chosen as the model TKI substrate for our study because it undergoes very minimal metabolism in several species. Afatinib is a substrate of both Pgp and BCRP, but is not a substrate of uptake transporters. Therefore, it was anticipated that an in-vivo efflux transporter-mediated interaction with afatinib would most likely not be confounded or masked by other factors influencing its disposition. From the in-vitro cell uptake studies, we found that nilotinib is a potent inhibitor of both Pgp and BCRP, and it reversed Pgp- and BCRP- mediated afatinib efflux. Subsequently, an in-vivo study was carried out in mice to investigate the interaction between afatinib and nilotinib; and also the impact of nilotinib on the pharmacokinetics and tissue distribution of afatinib. Afatinib exposure in the plasma and in most tissues, namely liver, lung, kidney, heart, muscle, fat, and skin, was found to be significantly increased when nilotinib was coadministered with afatinib. Further, the nilotinib concentrations in most mice tissues was above that needed for Pgp and BCRP inhibition. These results showed that nilotinib could be a potent chemosensitizing agent for Pgp- and BCRP- mediated TKI resistance. Additionally, a significant increase in afatinib brain exposure was observed in the mice which were administered afatinib in combination with nilotinib. This is an interesting and important finding that could potentially be very useful in the treatment of primary and metastasized brain tumors. We also developed a physiologically based pharmacokinetic model of afatinib to characterize its tissue disposition in mice organs, and this model was then scaled up to humans. The developed model accurately predicted afatinib plasma exposure in healthy volunteers and patients with solid malignant tumors, renal impairment, and hepatic impairment. To investigate the chemosensitizing potential of methylated flavones in efflux transporter-mediated TKI resistance, the Bcrp1 inhibitory effect of 5,7-DMF and its effect on sorafenib accumulation was evaluated in-vitro. 5,7- DMF was found to be a potent inhibitor of Bcrp1 and consequently, its impact on the pharmacokinetics and tissue distribution of sorafenib was evaluated in mice. Results showed that co-administration with 5,7-DMF led to significantly greater sorafenib exposure in plasma and in most tissues collected. This indicated that 5,7-DMF may represent a promising chemosensitizing agent for Bcrp1-mediated TKI resistance due to its low toxicity and potent Bcrp1 inhibition. Our results may have important clinical implications as TKIs are currently the most widely used anticancer agents. 5,7-DMF may show great potential in reversing MDR in tumors expressing BCRP. On the other hand, TKI-TKI combination therapy, especially with nilotinib as the perpetrator, is an attractive strategy to combat both Pgp- and BCRP-mediated TKI resistance. Additionally, since nilotinib has a wide volume of distribution and can reach various tissues at concentrations sufficient enough to inhibit Pgp and BCRP; it could potentially be used as a chemosensitizer in the treatment of numerous types of cancers. Furthermore, its chemosensitizing potential could particularly be useful in the treatment of primary and metastatic brain tumors. Further studies are warranted to assess the chemosensitizing effect of nilotinib in tumor xenograft models.

OBJECTIVES: (1) To assess prescribers' ability to recognize clinically significant DDIs, (2) to examine demographic and practice factors that may be associated with prescribers' DDI knowledge, and (3) to evaluate prescribers' perceived usefulness of various DDI information sources.METHODS: This study used a mailed questionnaire sent to a national sample of prescribers based on their past history of DDI prescribing which was determined using data from a pharmacy benefit manager covering over 50 million lives. The survey questionnaire included 14 drug-drug pairs that tested prescribers' ability to recognize clinically important DDIs and five 5-point Likert scale-type questions that assessed prescribers' perceived usefulness of DDI information provided by various sources. Demographic and practice characteristics were collected as well. Rasch analysis was used to evaluate the knowledge and usefulness questions.RESULTS: Completed questionnaires were obtained from 950 prescribers (overall response rate: 7.9%). The number of drug pairs correctly classified by the prescribers ranged from zero to thirteen, with a mean of 6 pairs (42.7%). The percentage of prescribers who correctly classified specific drug pairs ranged from 18.2% for warfarin-cimetidine to 81.2% for acetaminophen with codeine-amoxicillin. Half of the drug pair questions were answered "not sure" by over one-third of the respondents; among which, two were contraindicated. Rasch analysis of knowledge and usefulness questions revealed satisfactory model-data fit and person reliability of 0.72 and 0.61, respectively. A multiple regression analysis revealed that specialists were less likely to correctly identify interactions as compared to prescribers who were generalists. Other important predictors of DDI knowledge included the experience of seeing a harm caused by DDIs and the extent to which the risk of DDIs affected the prescribers' drug selection. ANOVA with the post-hoc Scheffe test indicated that prescribers considered DDI information provided by "other" sources to be more useful than that provided by computerized alert system. CONCLUSIONS: This study suggests that prescribers' DDI knowledge may be inadequate. The study found that for the drug interactions evaluated, generalists performed better than specialists. In addition, this study presents an application of IRT analysis to knowledge and attitude measurement in health science research.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

A anticoagulação inadequada pode ocasionar eventos tromboembólicos e hemorrágicos, representando um desafio para a medicina. A varfarina, anticoagulante oral de amplo uso, está associada a reações adversas graves, frequentes nos pacientes em tratamento com múltiplos fármacos. Objetivo: Este estudo pretende avaliar as potenciais interações medicamentosas com a varfarina, descrever e quantificar as intervenções farmacêuticas para minimizá-las, verificar o grau de aceitação da equipe médica em relação às intervenções e a repercussão no resultado do RNI. Método: Estudo de coorte, realizado entre os meses de agosto de 2009 a janeiro de 2010, envolvendo pacientes internados que iniciaram o tratamento com varfarina em duas unidades de clínica médica em um hospital universitário localizado no sul do Brasil. As potenciais interações medicamentosas com a varfarina (graves e moderadas) foram identificadas no sistema Drug-Reax, Micromedex Healthcare. Outras informações foram obtidas diretamente no prontuário. As intervenções com a equipe médica ocorreram por meio de registro em prontuário ou por informação verbal. O valor do RNI (Relação Normatizada Internacional) foi constantemente monitorado e serviu como medida do resultado da intervenção. Resultados: Foram acompanhados 202 pacientes. O total de medicamentos prescritos foi de 2071, com média de 10 (DP=3,6) por paciente. Todos pacientes apresentaram pelo menos uma interação medicamentosa potencial grave ou moderada com a varfarina, sendo a média de 3,6 (DP=1,6) por paciente. Pacientes com mais de 4 interações medicamentosas potenciais apresentaram maior risco para eventos hemorrágicos (RNI > 5 - RR = 2,57; IC95% 1,37–4,80). Foram identificadas 737 potenciais interações; 675 (91,5%) com possibilidade de potencializar o efeito anticoagulante e 29 (3,9%) de reduzir este efeito. Os medicamentos mais envolvidos em interações de potencialização foram enoxaparina (32,2%), sinvastatina (27,6%), omeprazol (22,5%) e tramadol (21,5%). Das intervenções realizadas com a equipe médica, 116 (57,4%) se deram através de registros em prontuário e 86 (42,6%) de forma verbal. Para 32 pacientes (15,8%) as intervenções não foram aceitas e estes apresentaram maior risco (RR = 2,17; IC95% 1,10 –4,27) para exame alterado (RNI > 5). Análise multivariada mostrou que idade, tempo de internação, apresentar 4 ou mais interações potenciais graves ou moderadas e não aceitar a intervenção farmacêutica contribuem significativamente para o paciente apresentar resultado de RNI > 5, o que implica em risco para eventos hemorrágicos. Conclusão: Interações medicamentosas graves e moderadas envolvendo a varfarina são muito comuns nos pacientes internados e estão associadas à maior risco do paciente apresentar RNI fora da faixa terapêutica desejada. A participação do farmacêutico no manejo das interações através de informações e orientações aos prescritores mostrou ter boa aceitação em nosso meio e parece contribuir para a segurança do paciente. / Introduction: Inadequate anticoagulation may cause bleeding and thromboembolic events, representing a challenge for medicine. Warfarin, an oral anticoagulant in wide use, has severe adverse reactions, common in patients taking multiple drugs. Objectives: This study aims to evaluate potential drug interactions with warfarin; to describe and quantify pharmaceutical interventions in order to minimize them; to assess the degree of acceptability by the medical team in relation to interventions as well as the impact on the outcome of the INR. Method: A Cohort study, done between August 2009 and January 2010 involving hospitalized patients who started warfarin therapy in two internal medicine units in a university hospital located in southern Brazil. Potential pDDIs with warfarin with warfarin (major and moderate) were identified in the online system Drug-Reax, Micromedex Healthcare. Additional information was obtained directly from medical records. Interventions with medical team were through medical record notes or verbal information. The value of the INR (international normalized ratio) was continuously monitored and served as a measure of the outcome of the intervention. Results: Two hundred and two inpatients were followed. The total number of prescribed drugs was 2071, with mean of 10 (SD = 3.6) per patient. All inpatients had at least one potential moderate or severe pDDIs with warfarin, the mean was 3.6 (SD = 1.6) per patient. Patients with more than four potential drug interactions showed a higher risk for hemorrhagic problems (INR> 5 - RR = 3.00, 95% CI 1.59-5.70). For 737 pDDIs identified, 675 (91.5%) may result in increased anticoagulation activity and 29 (3.9%) may reduce this effect. The drugs most commonly involved in these pDDIs were enoxaparin (32.2%), simvastatin (27.6%), omeprazole (22.5%) and tramadol (21.5%). The medical team’s intervention were 116 (57.4%) through medical records and 86 (42.6%) were orally. For 32 patients (15.8%), interventions were not accepted and they had higher risk (RR = 2.17; 95% CI 1.10 – 4.27) for amended exam (INR > 5). Multivariate analysis showed that age, length of hospital stay, having four or more major or moderate potential interactions and unwillingness to accept pharmaceutical intervention contribute significantly to the patient current values of INR> 5, which implies a risk of bleeding. Conclusion: Major and moderate drug interactions involving warfarin are very common in hospitalized patients and are associated with patient’s high risk of having an INR outside the target range. The collaboration of pharmacists in the management of interactions with information and guidance to physicians showed a good acceptance and seems to contribute to patient safety.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Alice Mlčochová Supervisor: PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: In vitro transport of abacavir across the monolayer of Caco-2 cells; interaction with etravirine and rilpivirine. Abacavir belongs among nucleoside reverse transciptase inhibitors (NRTIs) representing a basic component of combined antiretroviral therapy used in treatment of HIV-positive patients [1]. Etravirine and rilpivirine are newer non-nucleoside reverse transcriptase inhibitors (NNRTIs) combined in cART together with NRTI. ATP-dependent transporters, so called ABC transporters, are able to affect pharmacokinetic properties of drugs, thus they are important site of drug-drug interactions affecting absorption, distribution and excretion level. P-glycoprotein (Pgp, ABCB1) and BCRP (ABCG2) belong among the most clinically important ABC transporters able to cause drug-drug interactions. The aim of this thesis was to introduce and optimize the method for evaluation of drug absorption using monolayers of Caco-2human intestine cell lines, whose integrity was verified by evaluating TEER (transepithelial electrical resistance). This model was also used for abacavir transport studies. Significant...

Counselling centres are facilities that provide services especially to problematic drug users. To achieve the highest possible effectiveness it is necessary to include also social surroundings (parents, partners or school) of the problematic drug user into the overall treatment. The fundamental prerequisite of existence of these centres is their accessibility without booking in advance and without waiting times for everyone who needs to deal with his or her emergency situation immediately. That is why these centres are called mentally and socially barrier-free, so called low-threshold facilities. I have chosen the qualitative method to conduct the research. As a technique for data gathering I selected secondary data analysis and semi-structured interviews with drug users who visit counselling centres. For the research I used data from annual reports from counselling centres in Písek and České Budějovice. The results of my research could be useful for workers in helping professions, for workers dealing with the issue of illegal drug abuse, to improve the effectiveness of services in the counselling centres or as groundwork for further research or training.

A anticoagulação inadequada pode ocasionar eventos tromboembólicos e hemorrágicos, representando um desafio para a medicina. A varfarina, anticoagulante oral de amplo uso, está associada a reações adversas graves, frequentes nos pacientes em tratamento com múltiplos fármacos. Objetivo: Este estudo pretende avaliar as potenciais interações medicamentosas com a varfarina, descrever e quantificar as intervenções farmacêuticas para minimizá-las, verificar o grau de aceitação da equipe médica em relação às intervenções e a repercussão no resultado do RNI. Método: Estudo de coorte, realizado entre os meses de agosto de 2009 a janeiro de 2010, envolvendo pacientes internados que iniciaram o tratamento com varfarina em duas unidades de clínica médica em um hospital universitário localizado no sul do Brasil. As potenciais interações medicamentosas com a varfarina (graves e moderadas) foram identificadas no sistema Drug-Reax, Micromedex Healthcare. Outras informações foram obtidas diretamente no prontuário. As intervenções com a equipe médica ocorreram por meio de registro em prontuário ou por informação verbal. O valor do RNI (Relação Normatizada Internacional) foi constantemente monitorado e serviu como medida do resultado da intervenção. Resultados: Foram acompanhados 202 pacientes. O total de medicamentos prescritos foi de 2071, com média de 10 (DP=3,6) por paciente. Todos pacientes apresentaram pelo menos uma interação medicamentosa potencial grave ou moderada com a varfarina, sendo a média de 3,6 (DP=1,6) por paciente. Pacientes com mais de 4 interações medicamentosas potenciais apresentaram maior risco para eventos hemorrágicos (RNI > 5 - RR = 2,57; IC95% 1,37–4,80). Foram identificadas 737 potenciais interações; 675 (91,5%) com possibilidade de potencializar o efeito anticoagulante e 29 (3,9%) de reduzir este efeito. Os medicamentos mais envolvidos em interações de potencialização foram enoxaparina (32,2%), sinvastatina (27,6%), omeprazol (22,5%) e tramadol (21,5%). Das intervenções realizadas com a equipe médica, 116 (57,4%) se deram através de registros em prontuário e 86 (42,6%) de forma verbal. Para 32 pacientes (15,8%) as intervenções não foram aceitas e estes apresentaram maior risco (RR = 2,17; IC95% 1,10 –4,27) para exame alterado (RNI > 5). Análise multivariada mostrou que idade, tempo de internação, apresentar 4 ou mais interações potenciais graves ou moderadas e não aceitar a intervenção farmacêutica contribuem significativamente para o paciente apresentar resultado de RNI > 5, o que implica em risco para eventos hemorrágicos. Conclusão: Interações medicamentosas graves e moderadas envolvendo a varfarina são muito comuns nos pacientes internados e estão associadas à maior risco do paciente apresentar RNI fora da faixa terapêutica desejada. A participação do farmacêutico no manejo das interações através de informações e orientações aos prescritores mostrou ter boa aceitação em nosso meio e parece contribuir para a segurança do paciente. / Introduction: Inadequate anticoagulation may cause bleeding and thromboembolic events, representing a challenge for medicine. Warfarin, an oral anticoagulant in wide use, has severe adverse reactions, common in patients taking multiple drugs. Objectives: This study aims to evaluate potential drug interactions with warfarin; to describe and quantify pharmaceutical interventions in order to minimize them; to assess the degree of acceptability by the medical team in relation to interventions as well as the impact on the outcome of the INR. Method: A Cohort study, done between August 2009 and January 2010 involving hospitalized patients who started warfarin therapy in two internal medicine units in a university hospital located in southern Brazil. Potential pDDIs with warfarin with warfarin (major and moderate) were identified in the online system Drug-Reax, Micromedex Healthcare. Additional information was obtained directly from medical records. Interventions with medical team were through medical record notes or verbal information. The value of the INR (international normalized ratio) was continuously monitored and served as a measure of the outcome of the intervention. Results: Two hundred and two inpatients were followed. The total number of prescribed drugs was 2071, with mean of 10 (SD = 3.6) per patient. All inpatients had at least one potential moderate or severe pDDIs with warfarin, the mean was 3.6 (SD = 1.6) per patient. Patients with more than four potential drug interactions showed a higher risk for hemorrhagic problems (INR> 5 - RR = 3.00, 95% CI 1.59-5.70). For 737 pDDIs identified, 675 (91.5%) may result in increased anticoagulation activity and 29 (3.9%) may reduce this effect. The drugs most commonly involved in these pDDIs were enoxaparin (32.2%), simvastatin (27.6%), omeprazole (22.5%) and tramadol (21.5%). The medical team’s intervention were 116 (57.4%) through medical records and 86 (42.6%) were orally. For 32 patients (15.8%), interventions were not accepted and they had higher risk (RR = 2.17; 95% CI 1.10 – 4.27) for amended exam (INR > 5). Multivariate analysis showed that age, length of hospital stay, having four or more major or moderate potential interactions and unwillingness to accept pharmaceutical intervention contribute significantly to the patient current values of INR> 5, which implies a risk of bleeding. Conclusion: Major and moderate drug interactions involving warfarin are very common in hospitalized patients and are associated with patient’s high risk of having an INR outside the target range. The collaboration of pharmacists in the management of interactions with information and guidance to physicians showed a good acceptance and seems to contribute to patient safety.

A anticoagulação inadequada pode ocasionar eventos tromboembólicos e hemorrágicos, representando um desafio para a medicina. A varfarina, anticoagulante oral de amplo uso, está associada a reações adversas graves, frequentes nos pacientes em tratamento com múltiplos fármacos. Objetivo: Este estudo pretende avaliar as potenciais interações medicamentosas com a varfarina, descrever e quantificar as intervenções farmacêuticas para minimizá-las, verificar o grau de aceitação da equipe médica em relação às intervenções e a repercussão no resultado do RNI. Método: Estudo de coorte, realizado entre os meses de agosto de 2009 a janeiro de 2010, envolvendo pacientes internados que iniciaram o tratamento com varfarina em duas unidades de clínica médica em um hospital universitário localizado no sul do Brasil. As potenciais interações medicamentosas com a varfarina (graves e moderadas) foram identificadas no sistema Drug-Reax, Micromedex Healthcare. Outras informações foram obtidas diretamente no prontuário. As intervenções com a equipe médica ocorreram por meio de registro em prontuário ou por informação verbal. O valor do RNI (Relação Normatizada Internacional) foi constantemente monitorado e serviu como medida do resultado da intervenção. Resultados: Foram acompanhados 202 pacientes. O total de medicamentos prescritos foi de 2071, com média de 10 (DP=3,6) por paciente. Todos pacientes apresentaram pelo menos uma interação medicamentosa potencial grave ou moderada com a varfarina, sendo a média de 3,6 (DP=1,6) por paciente. Pacientes com mais de 4 interações medicamentosas potenciais apresentaram maior risco para eventos hemorrágicos (RNI > 5 - RR = 2,57; IC95% 1,37–4,80). Foram identificadas 737 potenciais interações; 675 (91,5%) com possibilidade de potencializar o efeito anticoagulante e 29 (3,9%) de reduzir este efeito. Os medicamentos mais envolvidos em interações de potencialização foram enoxaparina (32,2%), sinvastatina (27,6%), omeprazol (22,5%) e tramadol (21,5%). Das intervenções realizadas com a equipe médica, 116 (57,4%) se deram através de registros em prontuário e 86 (42,6%) de forma verbal. Para 32 pacientes (15,8%) as intervenções não foram aceitas e estes apresentaram maior risco (RR = 2,17; IC95% 1,10 –4,27) para exame alterado (RNI > 5). Análise multivariada mostrou que idade, tempo de internação, apresentar 4 ou mais interações potenciais graves ou moderadas e não aceitar a intervenção farmacêutica contribuem significativamente para o paciente apresentar resultado de RNI > 5, o que implica em risco para eventos hemorrágicos. Conclusão: Interações medicamentosas graves e moderadas envolvendo a varfarina são muito comuns nos pacientes internados e estão associadas à maior risco do paciente apresentar RNI fora da faixa terapêutica desejada. A participação do farmacêutico no manejo das interações através de informações e orientações aos prescritores mostrou ter boa aceitação em nosso meio e parece contribuir para a segurança do paciente. / Introduction: Inadequate anticoagulation may cause bleeding and thromboembolic events, representing a challenge for medicine. Warfarin, an oral anticoagulant in wide use, has severe adverse reactions, common in patients taking multiple drugs. Objectives: This study aims to evaluate potential drug interactions with warfarin; to describe and quantify pharmaceutical interventions in order to minimize them; to assess the degree of acceptability by the medical team in relation to interventions as well as the impact on the outcome of the INR. Method: A Cohort study, done between August 2009 and January 2010 involving hospitalized patients who started warfarin therapy in two internal medicine units in a university hospital located in southern Brazil. Potential pDDIs with warfarin with warfarin (major and moderate) were identified in the online system Drug-Reax, Micromedex Healthcare. Additional information was obtained directly from medical records. Interventions with medical team were through medical record notes or verbal information. The value of the INR (international normalized ratio) was continuously monitored and served as a measure of the outcome of the intervention. Results: Two hundred and two inpatients were followed. The total number of prescribed drugs was 2071, with mean of 10 (SD = 3.6) per patient. All inpatients had at least one potential moderate or severe pDDIs with warfarin, the mean was 3.6 (SD = 1.6) per patient. Patients with more than four potential drug interactions showed a higher risk for hemorrhagic problems (INR> 5 - RR = 3.00, 95% CI 1.59-5.70). For 737 pDDIs identified, 675 (91.5%) may result in increased anticoagulation activity and 29 (3.9%) may reduce this effect. The drugs most commonly involved in these pDDIs were enoxaparin (32.2%), simvastatin (27.6%), omeprazole (22.5%) and tramadol (21.5%). The medical team’s intervention were 116 (57.4%) through medical records and 86 (42.6%) were orally. For 32 patients (15.8%), interventions were not accepted and they had higher risk (RR = 2.17; 95% CI 1.10 – 4.27) for amended exam (INR > 5). Multivariate analysis showed that age, length of hospital stay, having four or more major or moderate potential interactions and unwillingness to accept pharmaceutical intervention contribute significantly to the patient current values of INR> 5, which implies a risk of bleeding. Conclusion: Major and moderate drug interactions involving warfarin are very common in hospitalized patients and are associated with patient’s high risk of having an INR outside the target range. The collaboration of pharmacists in the management of interactions with information and guidance to physicians showed a good acceptance and seems to contribute to patient safety.