Future Perspectives of Pulmonary Arterial Hypertension: A Review of Novel Pipeline Treatments and Indications.

Pulmonary arterial hypertension is characterized by elevated blood pressure and pathological changes in the pulmonary arterioles, leading to the development of right-heart failure and potentially fatal outcomes if left untreated. This review aims to provide an overview of novel drugs or formulations and new drug indications for pulmonary arterial hypertension that are currently in phases II-III of randomized controlled trials, and describe the rationale for the use of these targeted therapies, as well as their efficacy, safety profile, and impact on quality of life and survival. The literature research was conducted using data from ClinicalTrials.gov for the period between 1 January 2016 up to 31 December 2022. The population of interest includes individuals aged ≥ 18 years who have been diagnosed with pulmonary arterial hypertension. The review selection criteria included trials with recruiting, enrolling by invitation, active, terminated or completed status in 2022 and 2023. A total of 24 studies were selected for evaluation based on the inclusion and exclusion criteria. This review summarizes the updated information from randomized clinical trials involving novel therapies for pulmonary arterial hypertension. However, larger clinical trials are required to validate their clinical safety and effects. In the future, clinicians should choose therapies based on the patient's individual situation and requirements when developing treatment strategies.

Tacrolimus-Induced Neurotoxicity After Transplant: A Literature Review.

Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used globally to prevent rejection after organ transplantation. Although it significantly improves outcomes for solid organ transplant patients, it is associated with various side effects such as nephrotoxicity and neurotoxicity. Tacrolimus-induced neurotoxicity is frequently encountered in clinical practice and can present with a variety of symptoms that may occur even at therapeutic levels. Although tacrolimus-induced neurotoxicity is well documented, there is limited literature available on pharmacologic management. Twenty-eight case reports of tacrolimus-induced neurotoxicity were identified and analyzed in addition to other literature including reviews, retrospective studies, and animal model studies. The severity of cases of tacrolimus-induced neurotoxicity reported ranged from mild symptoms that could be managed with symptomatic treatment to conditions such as posterior reversible encephalopathy syndrome and chronic inflammatory demyelinating polyradiculoneuropathy that may require more immediate intervention. This information was utilized in addition to clinical experience to compile potential management options for prevention and treatment of neurotoxic adverse events. This review is limited by the utilization of primarily retrospective studies and case reports. The available literature on the subject is largely narrative and there are no guidelines on treatment of tacrolimus-induced neurotoxicity at the time of this research. This comprehensive review may guide further studies to investigate the pathophysiology of tacrolimus-induced neurotoxicity and to define patient-specific strategies for mitigation or minimization of neurotoxicity. This is especially important given that management of tacrolimus-induced neurotoxicity can include changes to immunosuppression that can result in an increased risk of rejection.

Telemedicine in Patients Affected by Chronic Liver Disease: A Scoping Review of Clinical Outcomes and the Devices Evaluated.

For patients with chronic liver disease (CLD), telemedicine is emerging as a useful tool to prevent liver decompensation or hospitalization, allowing access to and the decentralization of care, even for patients with limited resources. However, research and attendant evidence are still lacking; thus, this review aims to systematically explore the topic of telemonitoring for CLD to describe the currently used tools and clinical outcomes. The review was conducted by using key terms on PubMed/EMBASE and searching for observational studies or clinical trials (according to PRISMA recommendations) that were published between 6 April 2013 and 6 April 2023 to keep the technological framework limited to the last 10 years. The studies were described and grouped according to the aim of telemonitoring, the underlying disease, and the tools adopted to achieve remote monitoring. A total of 32 articles met the inclusion criteria. Of these, 11 articles report the successful use of a telehealth program to support and improve access to care in the management of HCV-related cirrhosis, eight articles examine the efficacy of telemedicine for remote monitoring interventions to prevent or decrease the risk of decompensation in high-risk patients, and five articles examine improvements in the physical performance and quality of life of cirrhotic patients through telehealth rehabilitation programs. Four studies were completed during the recent COVID-19 pandemic. Telehealth has the potential to provide and expand treatment access and reduce barriers to care for the most disadvantaged patients and might be able to reduce the need for hospital readmission for CLD, though most practice to test feasibility is still in the pilot stage.

Role of the hospital pharmacist in an Italian antimicrobial stewardship programme.

The inappropriate use of antimicrobial agents is contributing to an increasing phenomenon of bacterial resistance. For this reason, there is a growing interest in 'antimicrobial stewardship', a series of coordinated and multidisciplinary interventions aimed to promote the safe and appropriate use of antimicrobials in which the pharmacist's contribution is necessary for the optimal choice of drug, dose, duration of therapy and the implementation of cost containment strategies. AIM OF THE STUDY: We wanted to create a reference model and a specific training manual on antibiotic stewardship to introduce the role of the department pharmacist with specific infection disease skills in the Italian health system hospitals. METHODS: This study was conducted in six Italian hospitals for 24 months. It was divided into three phases: definition of indicators (as defined daily doses/100 days of hospitalisation, switches from intravenous (IV) to oral and from empirical to targeted therapies, etc) elaboration of research protocol; sharing, application and detection of the indicators and selection of centres involved; analysis and sharing of results and subsequent drafting and distribution of the training manual.Statistical analysis focused on possible differences between the frequencies of the aforementioned switches. Differences were analysed comparing the values recorded in the first quarter with those of the third quarter trough a χ² test. Statistical significance was set at p<0.05. RESULTS: The pharmacist's work showed a statistically significant increase in the conversion from IV to oral antibiotic therapy (χ² (1.496)=9112 ; p=0.0025; df=1). It was also detected a 5% improvement in appropriate dosing, 34% reduction in drug stocks, 4% increase in allergy reports and 275% increase in the number of adverse drug reactions reported. CONCLUSIONS: In this study, the interventions of the antibiotic stewardship pharmacist led to an improvement in quality of care, resource efficiency and healthcare professional awareness.

The European COVID-19 drugs calculation tool: an aid for the estimation of the drugs needed during the SARS-CoV 2 pandemic.

OBJECTIVE: To create an informatics supportive tool, which can assist healthcare professionals in estimating potential requirements for essential drug supplies to respond to the current SARS-CoV-2 pandemic based on epidemiological forecasting. METHODS: The tool was based on a Susceptible-Infected-Removed (SIR) epidemiological model in which the population is divided into three compartments and transmission parameters are specified to define the rate at which people move between stages. Appropriate data entry was guaranteed by the creation of structured guided paths. The drugs needed for the forecasted patients were estimated according to a list of critical care drugs compiled by consulting previous published scientific works, national and international guidelines. For each drug, an estimation was made of the percentage average ICU uptake for each therapeutic group and active principle. RESULTS: The tool consists of a Microsoft Excel template that is based on the initial epidemiological situation, the non-pharmaceutical interventions applied, the risk of hospitalisation based on the population age distribution, and the hospital beds available. The tool provides a forecast of which patients with COVID-19 will need to be treated in a hospital setting. The number of patients is used to estimate the drugs needed based on the average daily dose and the treatment length of each drug. The possibility of editing the type of distribution (exponential or linear) of the number of patients at the beginning of the analysis, the percentage adherence with non-pharmaceutical interventions and their delayed effect, and all the key epidemiological parameters make the estimation tailorable to different clinical contexts and needs. CONCLUSIONS: This model might be an effective supporting tool that could be easily implemented within the workflow of health professionals. All the information reported in this paper could be useful in developing new strategies to tackle the COVID-19 pandemic.

[A prospective observational study on daily intake of drugs, supplements and herbal products and detection of adverse drug reactions in elderly patients.] / Studio osservazionale prospettico relativo all'assunzione giornaliera di farmaci, integratori e prodotti erboristici nei pazienti anziani e rilevazione delle reazioni avverse ai farmaci.

Polytherapy is a common condition in the elderly patient and represents a risk factor for the onset of adverse drug reactions (ADRs). The objectives of this prospective study were the verification of the compliance with implicit criteria (Lipton, MAI and POM) to geriatric prescriptions, the identification of ADRs and the estimatation of the intake of drugs, over-the-counter (OTC) drugs, supplements and herbal products through the administration of a questionnaire. A total of 400 elderly patients (average age 73 years) were analyzed between September 2018 and September 2019. 79.5% of them were in polytherapy (≥4 drugs). The most frequently prescribed drugs were antihypertensives (75%). The use of OTC drugs was reported for 12% patients; the use of supplements for 25% of patients and the use of herbal products only for 2% patients. The prescriptions analysed resulted in compliance with the implicit criteria in terms of dosage, therapeutic indications and the presence of any drug allergies. ADRs were reported for 10% of patients: those related to nintedanib (53%) and pirfenidone (34%) were the most frequent.

Systematic Review and Meta-analysis of Pirfenidone, Nintedanib, and Pamrevlumab for the Treatment of Idiopathic Pulmonary Fibrosis.

BACKGROUND: The comparative efficacy of pirfenidone, nintedanib, and pamrevlumab in slowing the rate of forced vital capacity (FVC) decline and mortality in patients with idiopathic pulmonary fibrosis (IPF) is unknown. OBJECTIVE: To perform a systematic review and meta-analysis (MA) of these drugs for IPF. METHODS: We searched CENTRAL, PubMed, EMBASE, ClincalTrials.gov, and the World Health Organization's registry databases up to March 2020. Phase II/III randomized controlled trials in adults with IPF were eligible. The random-effect model was implemented calculating the effect size and respective 95% CI as Cohen's d for change from baseline FVC (in percentage predicted and liters) and odds ratio (OR) for 10% reduction in FVC and all-cause mortality (ACM). RESULTS: Six studies were included in the MA. For change from baseline in percentage predicted FVC, the MA indicated that the 3 drugs were more effective than placebo (pirfenidone: d=3.30%, 95% CI=2.15-4.45; nintedanib: d=3.15%, 95% CI=2.35-3.95; pamrevlumab: d=4.30%, 95% CI=0.45-8.15). These results are superimposable to those relating to change from baseline FVC in liters (pirfenidone: d=0.09L, 95% CI=0.04-0.14; nintedanib: d=0.13L, 95% CI=0.10-0.16; pamrevlumab: d=0.20L, 95% CI=0.05-0.35). Each drug had a positive effect on 10% reduction in FVC (pirfenidone: OR=0.57, 95% CI=0.45-0.74; nintedanib: OR=0.66, 95% CI=0.51-0.85; pamrevlumab: OR=0.24, 95% CI=0.08-0.73), but only pirfenidone showed an effect on ACM (OR=0.50; 95% CI=0.31-0.83). CONCLUSION AND RELEVANCE: This MA provided encouraging results on pamrevlumab efficacy in slowing the decline in FVC compared with pirfenidone and nintedanib. Actually, in phase 3, it could become a potential IPF treatment.

Evidence-based application of explicit criteria to assess the appropriateness of geriatric prescriptions at admission and hospital stay.

BACKGROUND: Inappropriate prescribing in the elderly is a critical issue in primary care, causing a higher risk of Adverse Drug Reactions (ADRs) and resulting in major patient safety concerns. At international level, many tools have been developed to identify Potentially Inappropriate Medications (PIMs). OBJECTIVE: The aim of this study was the application of Beers, Screening Tool of Older People's Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) and Improving Prescribing in the Elderly Tool (IPET) criteria as key tool to improve the quality of prescribing. METHODS: A retrospective study was conducted using the aforementioned criteria. Two different cohorts of elderly patients were enrolled between January 2015 and December 2016, 1800 at admission and 1466 at hospital stay. The index of each criterion divided by politherapy were correlated with comorbidities (Pearson correlation). A comparison was made between admission and hospital stay through a Student's t test of the average of the index. RESULTS: The Proton Pump Inhibitors (PPIs) were the most prescribed PIMs according Beers criteria in both patient cohorts (56%). The most detected drug-drug and drug-disease interactions at admission and at hospital stay were 3 or more drugs active on the Central Nervous System (CNS) as they can predispose to fall-risk. The most detected PIMs with STOPP criteria at admission were PPIs administered for more than 8 weeks. Inhaled ß2-agonists or antimuscarinics were the most prescribed Potential Prescription Omissions (PPOs) according to START criteria. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in patients with high blood pressure were the most detected PIMs according to IPET criteria during hospital stay. A significant correlation between the comorbidities and the all index at hospital stay, while at admission there was no significant correlation for Beers and IPET index. CONCLUSION: The prescriptive criteria were a useful tool for assessing the quality of prescriptions in the geriatric population and identifying their critical issues.

Covid-19 and drug therapy, what we learned.

COVID-19, the disease associated in December 2019 with the novel coronavirus SARS-CoV-2, was observed for the first time in China and then spread worldwide becoming pandemic. Currently, there is still no licensed specific antiviral treatment for the human coronavirus disease and a vaccine will not be ready soon. However, based on experience from the use of other antiviral agents to treat similar virusses, some treatment options have been tried with some efficacy. Clinical trials for future therapies are still ongoing. In the meantime, prevention, control, active communication and investment in research are the only ways to overcome this challenge.

[Potentially inappropriate prescriptions in elderly outpatiens. Results of implicit criteria applied by clinical pharmacists.] / Prescrizioni potenzialmente inappropriate in pazienti anziani non ospedalizzati. Risultati dell'applicazione di criteri impliciti da parte di farmacisti clinici.

BACKGROUND: Management of therapy in elderly patients is a critical issue in primary care. The physiopathological status is usually complex, and the prescription of multiple drugs is typically required, with a consequent higher risk of adverse effects. Many tools have been developed to cope with this problem, and identify drugs that are inappropriate in the elderly. The objective of the study was to evaluate the appropriateness of therapies in the elderly according to implicit criteria. METHOD: A prospective study of outpatients aged ≥65 years who visited our outpatient clinic on even calendar dates of the week, from Monday to Friday, from September 1, 2013 to March 31, 2014 was performed. Appropriateness of therapy was evaluated by applying three sets of implicit tools: Lipton Criteria, MAI and POM. A questionnaire was used assess information given to patients by physicians, and adherence to therapy. Information about clinical history and therapy was obtained from electronic medical records. Patient diagnosis and allergies, drugs, dosages, pharmacological indications, and questionnaire results, were entered into a database. The results were expressed in percentage. RESULTS: A total of 265 patients aged ≥65 years were included. Of these, 83% (220/265) had 2 to 6 comorbidities. According to the Lipton, MAI and POM criteria, the prescriptions were appropriate for 97% (1289/1327), 96% (1274/1327), and 94% (1251/1327) respectively. Only 33% (87/265) of the patients reported being thoroughly informed about the prescribed therapy and main side effects, and 67% (178/265) reported full compliance with the dosing schedule. DISCUSSION AND CONCLUSIONS: The overall assessment of the elderly patient, with particular reference to comorbidity, is essential in choosing the best tailored-therapy. For this reason, the support of tools that can make safer therapeutic choices is important. The implicit indicators used allow for a reduction of number of the medications, and inappropriate prescriptions, avoiding drugs with greater potential for interactions, and promoting adherence by patients.

Potentially inappropriate drug prescribing in elderly hospitalized patients: an analysis and comparison of explicit criteria.

BACKGROUND: The management of therapy in elderly is a critical aspect of primary care. The physio-pathological complexity of the elderly involves the prescription of multiple drugs, exposing them to a higher risk of adverse reactions. OBJECTIVE: Aim of this study was to assess the medication use and (potential) inappropriate medications and prescribing omissions in the elderly before and during hospitalization, according to the main tools in literature described, and their relation to the number of comorbidities. SETTING: The study was carried out by the Clinical Pharmacists at ISMETT, an Italian Research Institute. METHODS: The prescriptions of elderly, admitted in ISMETT between January and December 2012, were analyzed. The information about clinical profile of elderly and prescriptions was obtained from the electronic medical records. 2012 Beers criteria, Screening Tool of Older Person's Prescriptions/Screening Tool to Alert doctors to Right Treatment criteria, and Improving Prescribing in the Elderly criteria were used to evaluate the appropriateness of prescriptions. The correlation between the number of comorbidities and the different tools was analyzed with the Spearman correlation coefficient. The frequency analysis was done with the Pearson Chi square test. MAIN OUTCOME MEASURE: Percentage of potentially inappropriate medications and prescribing omissions before/during hospitalization in elderly. RESULTS: 1027 elderly were admitted between January and December 2012. At admission and during hospitalization, according to Beers criteria 24 and 49 % of elderly had at least one potentially inappropriate medication, respectively; according to the Screening Tool of Older Person's Prescriptions criteria 21 and 27 %, respectively; according to the Improving Prescribing in the Elderly criteria 28 and 25 %, respectively; and then, according to Screening Tool to Alert doctors to Right Treatment criteria 28 and 33 % had at least one potentially prescribing omission, respectively. A significant correlation between comorbidities number and potentially inappropriate medications was found. CONCLUSION: The number of potentially inappropriate medications globally increased during hospitalization. Statistical analysis showed that the comorbidity affects the level of inappropriate prescriptions. Specific tools can guide clinicians toward a more rational use of medicines and minimize probable complications related to multi-treatments.

[The clinical pharmacist interventions to improve the immunosuppressive therapy management in a pediatric population: education, adherence, pharmacovigilance]. / Interventi del farmacista clinico per il miglioramento della gestione della terapia immunosoppressiva in una popolazione pediatrica: formazione, aderenza, farmacovigilanza.

AIM: To value and improve the adherence to the immunosuppressive therapy in a pediatric population and the pharmacovigilance activity. MATERIALS AND METHODS: From January 2013 to October 2014, the pharmacist has developed an education program for 147 pediatric patients in the management of their home therapy. The methods used to evaluate the adherence were three: the measuring of trough blood concentration of immunosuppressive drugs, a questionnaire and the prescription refill rate. Our secondary goal was to create a family collaboration sensitizing patients and their parents to inform the physician or the pharmacist of any adverse drug reactions. RESULTS: During the education phase, the pharmacist answered patient/family's questions about therapy doubts and curiosities. In the trough blood level monitoring of immunosuppressive drugs, 9% of the patients had an average hematic concentration of immunosuppressive drug out of the expected range. Questionnaires showed that: 12.2% of the patients missed a dose of immunosuppressant drug in the previous month, 2% 2 doses and 1.3% 3 doses. 8.8% of the patients diverged once for about 2 hours the scheduled time in the previous month and 3.4% 2-3 times. 21% of the children/parents said they did not know the correct way of drugs intake in relation to meals. After the training, 45 children/parents followed pharmacist tips more. According the analysis of the prescription refill rate, 10.8% of the patients were late in withdrawing their medications. Through the combination of the three methods, 17.7% of the patients were non-adherent. We identified and reported 15 suspected ADR, of which 4 were serious. CONCLUSION: Children adherence is widely determined by the ability and role of their parents to manage home therapy. On the contrary, teenagers often want to manage their home therapy by themselves. Pharmacist has to talk to the patient to evaluate adherence obstacles and collaborate with the patient in order to overcome them. Parents can have an active role in reporting ADRs to the pharmacist.

Rash and multiorgan dysfunction following lamotrigine: could genetic be involved?

CASE (DESCRIPTION): We report the case of a 38-year-old woman treated with lamotrigine who experienced multi-organ dysfunction. The patient received the drug at the dose of 100 mg per day. One week later, the treatment was suspended because of an extensive body rash. Twenty-four hours later, the patient appeared drowsy and stuporous and was hospitalized. On the fifth day, the patient was admitted with a clinical picture of acute multi-organ failure in our Institute, where, she, despite the support of vital functions with vasoactive drugs, continuous hemofiltration and ventilation with oxygen, died. Serum lamotrigine concentration was measured 110 h after its last dose and the drug resulted to be still present at 1 mg/L. The patient was homozygous for the UGT1A4-70C and UGT2B7-161C alleles and heterozygous for the UGT2B7-372A>G polymorphism. Regarding ABCB1 the patient showed the 3435CC, 2677GT and 1236CT genotypes. CONCLUSION: Our results may suggest a role of the UGT2B7-372A>G polymorphism in this reaction.

Evaluation of treatment of invasive fungal infections.

OBJECTIVE: To identify the risk factors associated with invasive fungal infections (IFI) in immunocompromised patients (IP), and monitor antifungal therapy appropriateness and costs. MATERIALS AND METHODS: The 1-year observational retrospective study was performed on 101 IP, who received antifungal intravenous therapy with fluconazole (F), liposomal amphotericin-B (A), caspofungin (C), itraconazole (I) for ≥4 days. Patient therapy was divided into three groups: Prophylactic, empirical, and target. Immunosuppressive therapy (IT), total parenteral nutrition (TPN), dialysis, central line, steroid therapy, stent use, neutropenia, and mechanical ventilation were evaluated. Variables were therapy duration, defined daily dose (DDD) consumption, DDD average cost. RESULTS: Main risk factors were central line (65.3%), TPN (56.4%), dialysis (46.5%), IT (42.6%), mechanical ventilation (32.7%), neutropenia (24.8%), steroid therapy (23.8%), and stent use (14.9%). Average duration of prophylaxis was 7 days; F (61%), A (26%), and C (13%) were used. Average duration of empirical therapy was 8 days; F (52.9%), A (26.5%), C (8.8%), I (2.9%), and in association A + C, A + F, C + F (8.9%) were used. Average duration of target therapy was 9 days; F (40.4%), A (23.1%), C (15.4%), I (7.7%), and in association A + C, A + F, C + F (13.4%) were used. DDD consumption and DDD average-cost were: C 50 mg vial: 273 DDD, €381.1; C 70 mg vial: 33.6 DDD, €389.6; F 200 mg vial: 768 DDD, €11.8; F 100 mg vial: 89 DDD, €10.6; I 250 mg vials: 62.5 DDD, €68.8; and A 50 mg vial: 2200 DDD, €93.4; respectively. CONCLUSIONS: Data showed an appropriate use of antifungals. Best alternative therapy (cheaper antifungal drug) was prescribed for most patients. The high cost of A and C was justified by IFI resolution.

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients.

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.

Unusual high dose of tacrolimus in liver transplant patient, a case report.

CASE: We describe the case of a liver transplant patient who had great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. The patient was homozygous for the CYP3A5*3 allele. However, the respective donor carried the wild-type CYP3A5*1/*1 genotype. Regarding ABCB1 SNPs at exon 21 and 26, the patient showed the 2677GT and 3435CC genotypes. For the corresponding donor we observed the 2677GG and 3435CC wild-type genotypes. One, two and three weeks after transplantation the patient received daily 0.219, 0.287 and 0.273 mg/kg of tacrolimus, respectively. However, the corresponding tacrolimus trough blood levels were of 4.6, 5.6 and 6.1 ng/mL. The tacrolimus target level of 10.4 ng/mL was finally reached after 1 month of therapy. During the entire period of observation the kidney showed no sign of damage. No other signs of toxicity were reported except for the occurrence of an isolated systolic hypertension. CONCLUSIONS: CYP3A5 genotyping may represent a useful tool to better evaluate the appropriate initial dose of tacrolimus for patients carrying a liver with the CYP3A5*1/*1 genotype.

Incidence of potential drug interactions in a transplant centre setting and relevance of electronic alerts for clinical practice support.

BACKGROUND: Adverse drug events may occur as a result of drug-drug interactions (DDIs). Information technology (IT) systems can be an important decision-making tool for healthcare workers to identify DDIs. OBJECTIVE: The aim of the study is to analyse drug prescriptions in our main hospital units, in order to measure the incidence and severity of potential DDIs. The utility of clinical decision-support systems (CDSSs) and computerised physician order entry (CPOE) in term of alerts adherence was also assessed. DDIs were assessed using a Micromedex® healthcare series database. METHODS: The system, adopted by the hospital, generates alerts for prescriptions with negative interactions and thanks to an 'acknowledgement function' it is possible to verify physician adherence to alerts. This function, although used previously, became mandatory from September 2010. Physician adherence to alerts and mean monthly incidence of potential DDIs in analysed units, before and after the mandatory 'acknowledgement function', were calculated. RESULTS: The intensive care unit (ICU) registered the greatest incidence of potential DDIs (49.0%), followed by the abdominal surgery unit and dialysis (43.4 and 42.0%, respectively). The cardiothoracic surgery unit (41.6%), step-down unit (38.3%) and post-anaesthesia care unit (30.0%) were comparable. The operating theatre and endoscopy registered the fewest potential DDIs (28.2 and 22.7%, respectively). Adherence to alerts after the 'acknowledgement function' increased by 25.0% in the ICU, 54.0% in the cardiothoracic surgery unit, 52.5% in the abdominal surgery unit, 58.0% in the stepdown unit, 67.0% in dialysis, 51.0% in endoscopy and 48.0% in the post-anaesthesia care unit. In the operating theatre, adherence to alerts decreased from 34.0 to 30.0%. The incidence of potential DDIs after mandatory use of the 'acknowledgement function' decreased slightly in endoscopy (-2.9%), the abdominal surgery unit (-2.7%), dialysis (-1.9%) and the step-down unit (-1.4%). CONCLUSIONS: Improving DDI alerts will improved patient safety by more appropriately alerting clinicians.

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients.

Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.