Investigation of a Potential Pharmacokinetic Interaction Between Nebivolol and Fluvoxamine in Healthy Volunteers.

PURPOSE: To investigate whether fluvoxamine coadministration can influence the pharmacokinetic properties of nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) and to assess the consequences of this potential pharmacokinetic interaction upon nebivolol pharmacodynamics. METHODS: This open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1 (Reference), during which each volunteer received a single dose of 5 mg nebivolol and Period 2 (Test), when a combination of 5 mg nebivolol and 100 mg fluvoxamine was given to all subjects, after a 6-days pretreatment regimen with fluvoxamine (50-100 mg/day). Non-compartmental analysis was used to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest after each nebivolol intake, during both study periods. RESULTS: Fluvoxamine pretreatment increased Cmax and AUC0-∞  of nebivolol (Cmax: 1.67 ± 0.690  vs 2.20 ± 0.970  ng/mL; AUC0-∞: 12.1 ± 11.0  vs 19.3 ± 19.5  ng*h/mL ) and of its active metabolite (Cmax: 0.680  ± 0.220  vs 0.960 ± 0.290  ng/mL; AUC0-∞: 17.6 ±20.1  vs 25.5 ± 29.9  ng*h/mL). Apart from Cmax,AUC0-t and AUC0-∞, the other pharmacokinetic parameters (tmax, kel and t½) were not significantly different between study periods. As for the pharmacodynamic analysis, decreases in blood pressure and heart rate after nebivolol administration were similar with and without fluvoxamine concomitant intake. CONCLUSIONS: Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite in healthy volunteers. This did not influence the blood pressure and heart-rate lowering effects of the beta-blocker administered as single-dose. However, more detail studies involving actual patients are required to further investigate the clinical relevance of this drug interaction. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers.

BACKGROUND/AIMS: Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). METHODS: Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. RESULTS: The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. CONCLUSION: FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies.

Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers.

PURPOSE: To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers. METHODS: An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods. RESULTS: Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively. CONCLUSIONS: These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Assessment of a Potential Pharmacokinetic Interaction between Nebivolol and Bupropion in Healthy Volunteers.

BACKGROUND/AIMS: The study aimed at investigating the effects of multiple-dose bupropion (potent inhibitor of CYP2D6) on the pharmacokinetics (PKs) of single-dose nebivolol (CYP2D6 substrate) and to evaluate the clinical relevance of this potential drug interaction. METHODS: This open-label, nonrandomized clinical study had a 2-period design: during period 1 (reference), a single dose of 5 mg nebivolol was administered, while during period 2 (test), 5 mg nebivolol + 300 mg bupropion were ingested concomitantly, after a pretreatment regimen with bupropion (7 days). The PK parameters of nebivolol and its active metabolite were analyzed by noncompartmental modeling, while the pharmacodynamic (PD) parameters (blood pressure and heart rate) were assessed at rest. RESULTS: Bupropion plus nebivolol increased the mean peak plasma concentrations (Cmax) of nebivolol (1.67 ± 0.69 vs. 3.80 ± 1.70 ng/ml) and its active metabolite (0.68 ± 0.22 vs. 1.13 ± 0.38 ng/ml) compared to nebivolol alone. After bupropion pretreatment, the exposure to nebivolol was increased by 7.2-fold for the parent drug and 4-fold for the hydroxylated active metabolite. The difference between the PD parameters measured during the 2 periods was not significant. CONCLUSION: The study concluded that bupropion influenced the PKs of nebivolol in healthy volunteers, but a clinical relevance was not established. However, this latter aspect requires further investigation.

Acceptability of compounded preparations - A Romanian pediatric hospital perspective.

Compounded medicines are widely used, especially for pediatric patients. The aim of this study was to evaluate children's acceptability of compounded preparations and to provide information regarding compounding practices' characteristics in a Romanian hospital setting. An observational, cross-sectional, and retrospective study was conducted in three Clinical Pediatric Departments (Emergency Clinical Hospital for Children, Cluj-Napoca). The study population comprised patients under 18 years old taking at least one compounded medication. Study data was collected mainly through an interviewer-administered questionnaire and medicine acceptability was assessed based on the children's first reaction to the preparations using a 3-point facial hedonic scale. A total of 162 compounded medications were evaluated. A positive/negative reaction was reported for 20.83%/58.33%, 20.63%/49.21%, and 66.67%/7.41% of oral, oromucosal and cutaneous dosage forms. Although patient disapproval was recorded for various reasons, medication administration was successful in over 75% of cases. Factors such as fewer steps required for intake of a dose, capsule dosage form, no additional food/drink immediately after drug intake, medication perceived as "easy/very easy" to swallow, were correlated with a better acceptability of oral preparations. This study highlights the importance of identifying factors that can improve the acceptability of compounded preparations and, subsequently, treatment outcomes in pediatric patients.

Effect of fluvoxamine on the pharmokinetics of zolpidem: a two-treatment period study in healthy volunteers.

1. Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and fluvoxamine in healthy volunteers. 2. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem; and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. 3. Pharmacokinetic parameters of zolpidem given in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. 4. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 56.4 ± 25.6 ng/mL (zolpidem alone) and 67.3 ± 25.8 ng/mL (zolpidem after pretreatment with fluvoxamine). The t(max), times taken to reach C(max), were 0.83 ± 0.44 and 1.26 ± 0.74 h, respectively, and the total areas under the curve (AUC(0-∞)) were 200.9 ± 116.8 and 512.0 ± 354.6 ng h/mL, respectively. The half-life of zolpidem was 2.24 ± 0.81 h when given alone and 4.99 ± 2.92 h after pretreatment with fluvoxamine. 5. Fluvoxamine interacts with zolpidem in healthy volunteers and increases its exposure by approximately 150%. The experimental data showed the pharmacokinetic interaction between zolpidem and fluvoxamine, and suggest that the observed interaction might be clinically significant, but its relevance has to be confirmed.

An Overview of Healthcare Associated Infections and Their Detection Methods Caused by Pathogen Bacteria in Romania and Europe.

Healthcare-associated infections can occur in different care units and can affect both patients and healthcare professionals. Bacteria represent the most common cause of nosocomial infections and, due to the excessive and irrational use of antibiotics, resistant organisms have appeared. The most important healthcare-associated infections are central line-associated bloodstream infections, catheter-associated urinary tract infections, surgical site, soft tissue infections, ventilator-associated pneumonia, hospital acquired pneumonia, and Clostridioides difficile colitis. In Europe, some hospitalized patients develop nosocomial infections that lead to increased costs and prolonged hospitalizations. Healthcare-associated infection prevalence in developed countries is lower than in low-income and middle-income countries such as Romania, an Eastern European country, where several factors contribute to the occurrence of many nosocomial infections, but official data show a low reporting rate. For the rapid identification of bacteria that can cause these infections, fast, sensitive, and specific methods are needed, and they should be cost-effective. Therefore, this review focuses on the current situation regarding healthcare-associated infections in Europe and Romania, with discussions regarding the causes and possible solutions. As a possible weapon in the fight against the healthcare-associated infections, the diagnosis methods and tests used to determine the bacteria involved in healthcare-associated infections are evaluated.

Linezolid Administration to Critically Ill Patients: Intermittent or Continuous Infusion? A Systematic Literature Search and Review.

A judicious antibiotic therapy is one of the challenges in the therapy of critically ill patients with sepsis and septic shock. The pathophysiological changes in these patients significantly alter the antibiotic pharmacokinetics (PK) and pharmacodynamics (PD) with important consequences in reaching the therapeutic targets or the risk of side effects. The use of linezolid, an oxazolidinone antibiotic, in intensive care is such an example. The optimization of its therapeutic effects, administration in intermittent (II) or continuous infusion (CI) is gaining increased interest. In a systematic review of the main databases, we propose a detailed analysis of the main PK/PD determinants, their relationship with the clinical therapeutic response and the occurrence of adverse effects following II or CI of linezolid to different classes of critically ill patients or in Monte Carlo simulations.

Assessing the Efficacy of Anastomosis between Ansa Cervicalis and Facial Nerve for Patients with Concomitant Facial Palsy and Peripheral Neuropathy.

Background: For decades, patients with facial asymmetry have experienced social interaction difficulties, leading them to seek treatment in the hope of restoring facial symmetry and quality of life. Researchers evaluated numerous surgical techniques, but achieving results remains a significant hurdle. Specifically, anastomosis between the ansa cervicalis (AC) and facial nerve (FN) can hinder the patient's physical appearance. Objective: Our study goal was to examine the efficiency of anastomosis between AC and FN for facial motor function recovery even in the presence of peripheral neuropathy. Materials and Methods: Four patients diagnosed with facial palsy grade VI on the House & Brackmann Scale (HB) after vestibular schwannoma (VS) resection (Koos grade IV) via the retrosigmoid approach underwent AC and FN anastomosis. Outcomes were related to tumor grade, previous therapy, and the time between postoperative facial palsy and anastomosis. Images and neurophysiological data were evaluated. Results: After vs. resection, all four patients demonstrated HB grade VI facial palsy for an average of 17 months. During the follow-up program, lasting between 6 and 36 months, two patients were evaluated as having HB grade III facial palsy; the other two patients were diagnosed with grade IV HB facial palsy. None of the patients developed tongue atrophy, speech disorder, or masticatordys function. Conclusions: Anastomosis between the AC and FN is a safe and effective treatment for facial paralysis after cerebellopontine tumor resection. Nerve reanimation may be feasible even for patients with peripheral polyneuropathy. This study also offers a new option for patients with a progression-free status.

Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers.

Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 500 mg ciprofloxacin. Between the two periods, the subjects were treated for 5 days with a single daily dose of 500 mg ciprofloxacin. Plasma concentrations of zolpidem were determined during a 12-hour period following drug administration. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. In the two periods of treatments, the mean peak plasma concentrations (Cmax) were 75.73±28.34 ng/ml (zolpidem alone) and 80.58±22.40 ng/ml (zolpidem after pre-treatment with ciprofloxacin). The tmax, times taken to reach Cmax, were 0.91±0.42 and 1.44±0.61 h, respectively, and the total areas under the curve (AUC0-∞) were 300.2±115.5 and 438.1±142.6 ng h/ml, respectively. The half-life of zolpidem was 2.39±0.53 h when administered alone and 3.34±0.87 h after pre-treatment with ciprofloxacin. These differences were statistically significant for Cmax, tmax, AUC0-∞, half-life and mean residence time. Ciprofloxacin interacts with zolpidem in healthy volunteers, raising its bioavailability by about 46%. This magnitude of effect is likely to be clinically significant.

Pharmacokinetic interaction between fluoxetine and omeprazole in healthy male volunteers: a prospective pilot study.

BACKGROUND: Fluoxetine is an inhibitor of the main metabolizing enzymes (cytochrome P450 [CYP] 2C19 and CYP3A4) of omeprazole and thus might influence that drug's pharmacokinetics. The changes in omeprazole's pharmacokinetics may have clinical significance concerning efficacy and tolerability of the treatment. OBJECTIVE: The aim of this study was to assess the pharmacokinetic interaction of fluoxetine with omeprazole in healthy volunteers. METHODS: The study enrolled healthy adult men and consisted of 2 periods. In the first period, all subjects received a single 40-mg dose of omeprazole. This was followed by an 8-day period during which fluoxetine monotherapy (60 mg/d) was administered as a single oral daily dose. At the end of those 8 days, the subjects were administered a 40-mg dose of omeprazole with a 60-mg dose of fluoxetine. Plasma concentrations of omeprazole were determined at 0.5, 1, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hour(s) after study drug administration. Omeprazole plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of omep-razole were calculated using noncompartmental analysis. Adverse events were assessed throughout the study duration. RESULTS: Eighteen healthy male volunteers (mean [SD] age, 22.11 [2.52] years [range, 18-26 years]; body mass index, 23.34 [2.31] kg/m(2) [range, 19.1-27.1 kg/m(2)]) were enrolled and completed the study. In the 2 periods of treatment, the mean Cmax of omeprazole was 730.8 ng/mL (omeprazole monotherapy) and 1725.5 ng/mL (combination treatment with fluoxetine). The observed AUC0-∞ was 1453.3 and 5072.5 ng/mL/h and AUC0-t was 1465.0 and 5185.3 ng/mL/h, respectively. The Tmax was 1.30 and 1.63 hours and the elimination rate constant was 0.753 and 0.482 hr(-1). The t½ was 0.96 and 1.47 hours, whereas the mean residence time was 2.33 and 3.35 hours, respectively. Statistically significant differences were observed for all parameters between periods 1 and 2 (all, P < 0.001). CONCLUSION: The data found in this prospective pilot study suggest a pharmacokinetic interaction between fluoxetine and omeprazole in these healthy volunteers, but its relevance has to be confirmed.

New insights in the molecular pathways linking obesity, type 2 diabetes and cancer.

Steadily, cancer is becoming the first cause of mortality, with over 9 million deaths estimated in 2018. Increasing evidence supports a direct association between obesity, type 2 diabetes mellitus (T2DM) and cancer, with a higher risk of cancer mortality especially for some of the most common malignancies, such as breast, colon, and rectal cancers. So far, several mechanisms underlying the cancer-diabetes relationship have been investigated revealing dysregulations of the insulin-insulin-like growth factor (IGF) system as the most important paradigm. Other molecular mechanisms that seem to play a role in the association cancer-T2DM consist of alteration of the signaling pathways activated by inflammatory cytokines, adipocytokines or adhesion molecules. The overall aim of this review is to provide an overview of the molecular mechanisms linking obesity, T2DM and cancer, as related to the receptors and signaling pathways involved in these associations.

Prevalence of dyslipidemia and its association with cardiometabolic factors and kidney function in the adult Romanian population: The PREDATORR study.

The aims were to assess the prevalence and characteristics of dyslipidemia phenotypes in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological study with a cross-sectional, cluster random sampling design. Participants were classified into four dyslipidemia phenotypes based on the NCEP ATP III criteria: isolated hypertrigliceridemia, isolated hypoHDL-C, isolated hyperLDL-C and mixed dyslipidemia (≥2 standard lipid abnormalities). Overall, 2656 were included in the analysis by dyslipidemia phenotypes. RESULTS: An estimated 67.1% of Romanian adults have at least one lipid abnormality: 27.5% (95%CI26.0-28.9%) have elevated TG, 29.4% (95%CI27.9-30.8%) have low HDL-C and 47.8% (95%CI46.3-49.2%) have elevated LDL-C (26.2% had LDL-C levels ≥2.58 mmol/l associated with CHD or CHD risk equivalent). Also, 30% Romanian adults have mixed dyslipidemia with 7.6% (95%CI6.1-9.0%) having all three lipid abnormalities. THE AGE: and sex-adjusted prevalence of isolated dyslipidemia phenotypes in Romanian adult population was 23.7% (95%CI22.2-25.1%) for hyperLDL-Cholesterolemia, 9.3% (95%CI7.8-10.7%) for hypoHDL-Cholesterolemia and 4.1% (95%CI2.6-5.5%) for hypertriglyceridemia. Among participants with triglycerides ≥2.25 mmol/l, 15.2% (95%CI13.7-16.6%) of Romanian adults have non-HDL-C levels ≥3.36 mmol/l. CONCLUSIONS: The PREDATORR survey indicated a high prevalence of dyslipidemia phenotypes in the Romanian population aged 20-79 years, providing data on its association with several cardiometabolic risk factors.

Associations of smoking with cardiometabolic profile and renal function in a Romanian population-based sample from the PREDATORR cross-sectional study.

BACKGROUND: The impact of smoking on morbidity is well known, but in Romania, limited data are available regarding the smoking prevalence and relationship with cardiometabolic profile and kidney function. OBJECTIVES: To assess the association of smoking with cardiometabolic traits and kidney function, in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological cross-sectional study. Between 2012 and 2014, participants were randomly selected from the lists of general practitioners and enrolled if they were aged 20 to 79 years, born and living in the past 10 years in Romania. Sociodemographic and lifestyle characteristics were collected through interviewer-administered questionnaires. RESULTS: Overall, 2704 participants were included in the analysis, 18% of them being current smokers and 30.8% former smokers. Current smokers compared to non-smokers had higher total cholesterol (220.6 ± 50.4 versus 213.9 ± 86.8 mg/dl, P = 0.017), LDL-cholesterol (137.8 ± 45.2 versus 130.7 ± 83.7 mg/dl, P = 0.004) and glomerular filtration rate (96.9 ± 16.8 versus 90.7 ± 19.1 ml/min/1.73 m2, P <0.001) in women and higher triglycerides (170.7 ± 129.8 versus 144.3 ± 94.2 mg/dl, P = 0.007), glomerular filtration rate (97.6 ± 17 versus 90.3 ± 18 ml/min/1.73 m2, P < 0.001) and lower HDL-cholesterol (48 ± 15.5 versus 50.4 ± 14.1 mg/dl, P = 0.002) in men. Active smoking was associated with hypercholesterolaemia [OR: 1.40 (95% CI: 1.01-1.96), P = 0.04] and low HDL-cholesterolaemia [OR: 1.39 (95% CI: 1.01-1.91), P = 0.04] and negatively associated with overweight/obesity [OR: 0.67 (95% CI: 0.48-0.94), P = 0.02]. Male former smokers had higher prevalence of abdominal obesity (82.4% versus 76.4%, P = 0.02), hypertriglyceridaemia (43.6% versus 35.6%, P = 0.01), hypertension (64% versus 56.4%, P = 0.01) and ischaemic vascular disease (40.5% versus 30.9%, P = 0.003) than male non-smokers. CONCLUSION: The PREDATORR study showed a high prevalence of smoking in the adult Romanian population providing data on the association of smoking with cardiometabolic traits.

Potentially inappropriate medications in elderly ambulatory and institutionalized patients: an observational study.

BACKGROUND: The elderly are frequently exposed to drug related problems causing hospitalizations and increased costs of care. Information about Romanian prescribing practices among the elderly and potential medication associated- risks is lacking. The objective of this study was to identify and compare the most frequent potentially inappropriate medications (PIM) recommended to ambulatory and institutionalized Romanian elderly, through an observational retrospective design. METHODS: All reimbursed medications prescribed to a sample of ambulatory elderly accessing two community pharmacies and all medications recommended to a group of institutionalized elderly (urban facilities, Romania, same month) were analyzed. The STOPP/START criteria and the PRISCUS list were used for PIM identification and for classification as misprescribed, underprescribed or overprescribed -subtypes. RESULTS: The analysis involved 345 prescriptions recommended to ambulatory elderly and 91 medical files available for the institutionalized patients. The ambulatory elderly had a mean age of 74.8 years old and were daily exposed to a median number of 3 prescribed medications. The institutionalized elderly were older (mean age 80.77) received 8 medications daily and 69 % of them were functionally dependent. Cardiovascular and neuropsychiatric indications were the most frequent: 64.34 % and 18.55 % of the ambulatory prescriptions, 93.40 % and 41.75 % of the institutionalized patients' medical files. 159 PIM were identified on 34.49 % of the ambulatory prescriptions. 82.41 % of the institutionalized patients' medical files contained 140 PIM. The potential underprescribing of cardiovascular therapies was the most frequent PIM category on the ambulatory prescriptions (55.34 % of all PIM), while for the institutionalized patients' medical files, the misprescribed and overprescribed PIM were those predominantly represented (62.14 % and 27.14 % of all PIM). In both subgroups of data, NSAIDs (56.66 % of ambulatory prescriptions and 35.63 % of institutionalized patients' data) and benzodiazepines (26.66 % of ambulatory prescriptions and 24.13 % of institutionalized patient's data) were predominantly misprescribed. Anticholinergics were rarely used (0.62 % of total PIM from ambulatory prescriptions, 2.14 % of total PIM from institutionalized patients' data). CONCLUSIONS: The PIM identified in both elderly groups suggested potential risks for the occurrence of adverse events specific to the elderly population. Larger studies, both observational and interventional, are needed to ensure a safer therapeutic approach.

Evaluation of restricted antibiotic use in a hospital in Romania.

BACKGROUND: Antibiotics are the most frequently used drugs among hospitalised patients. Antimicrobial resistance is a major health issue and therefore antibiotic consumption should be under strict surveillance. OBJECTIVE: To evaluate the use of restricted antibiotics in an academic hospital in Romania. METHODS: Retrospective evaluation of the use of 11 restricted antibiotics issued based on the antibiotics formularies for the year 2012. Therapeutic guidelines and the summary of product characteristics were used for the evaluation. The appropriateness antibiotics use was verified, according to three main criteria: appropriate indication (type of treatment, localization and type of infection), dose and duration of treatment. Descriptive statistics and multiple logistic regression analysis were performed. Results 664 prescribing formularies were analyzed, of these 319 were from the intensive care unit (48.04 %). The most prescribed antibiotics were vancomycin (171, 25.75 %), imipenem (151, 22.74 %) and meropenem (116, 17.47 %). Overall, 285 prescriptions (42.92 %) were considered inappropriate. Vancomycin, meropenem and imipenem were prescribed inappropriate in 49.71, 46.55 and 44.06 % of such cases. Of the total 285 prescriptions deemed as inappropriate, for 49.82 % the dose was incorrect, 20 % were inadequate in terms of treatment duration and 15.44 % were wrongly indicated. Inappropriate use was significantly higher among empirical prescriptions than the documented ones (69.75 vs. 30.25 %, p < 0.001). Multiple stepwise logistic regression identified that the duration of the treatment was significant for inappropriate antibiotic use (p < 0.05). The risk of inappropriate use in the case of empirical prescriptions is higher than for documented prescriptions (OR 5.78, p < 0.001, CI 3.65-9.15). CONCLUSIONS: the results suggest the need to intensify the control of the use of restricted antibiotics. The implementation of drug formularies in hospitals and the involvement of the clinical pharmacist may ensure rational antibiotic therapy.

Phenotypic differences in nebivolol metabolism and bioavailability in healthy volunteers.

INTRODUCTION: Nebivolol, a third-generation ß-blocker, is subject to extensive first-pass metabolism and produces active ß-blocking hydroxylated metabolites, like 4-OH-nebivolol. It is primarily a substrate of CYP2D6, a metabolic pathway that is under polymorphic genetic regulation. The objective of this study was to assess the metabolizer phenotype and to evaluate the interphenotype bioavailability and metabolism of nebivolol. MATERIAL AND METHODS: Forty-three healthy volunteers were included in this open-label, non-randomized clinical trial and each volunteer received a single dose of 5 mg nebivolol. Non-compartmental pharmacokinetic analysis was performed to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The phenotypic distribution was assessed based on the AUC (aria under the curve) metabolic ratio of nebivolol/4-OH-nebivolol and statistical analysis. An interphenotype comparison of nebivolol metabolism and bioavailability was performed based on the pharmacokinetic parameters of nebivolol and its active metabolite. RESULTS: Nebivolol/4-OH-nebivolol AUC metabolic ratios were not characterized by a standard normal distribution. The unique distribution emphasized the existence of two groups and the 43 healthy volunteers were classified as follows: poor metabolizers (PMs)=3, extensive metabolizers (EMs)=40. The phenotype had a marked impact on nebivolol metabolism. The exposure to nebivolol was 15-fold greater for PMs in comparison to EMs. CONCLUSION: 40 EMs and 3 PMs were differentiated by using the pharmacokinetic parameters of nebivolol and its active metabolite. The study highlighted the existence of interphenotype differences regarding nebivolol metabolism and bioavailability.

The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

BACKGROUND AND AIMS: To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. METHODS: 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. RESULTS: Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. CONCLUSIONS: Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

Description of a systematic pharmaceutical care approach intended to increase the appropriateness of medication use by elderly patients.

BACKGROUND & AIMS: The pharmaceutical care practice represents a model of responsible pharmacist involvement in the pharmacotherapy optimization of various population groups, including the elderly, known to be at risk for drug-related problems. Romanian pharmacists could use validated pharmaceutical care experiences to confirm their role as health-care professionals. This descriptive research presents the application in two real and different environments of practice of a structured pharmaceutical care approach conceived as the basis for a medication review activity and aiming at the identification and resolution of the drug related problems in the elderly. PATIENTS AND METHODS: Two patients with similar degree of disease-burden complexity, receiving care in different health-care environments (The Geriatric Ward of the Royal Victoria Hospital from the McGill University Health Centre in Montréal, Québec, Canada, in November 2010, and an urban nursing-home facility in Cluj-Napoca, Romania, in March 2011), were chosen for the analysis. One clinical pharmacist suggested solutions for the management of each of the active drug-related problems identified, using the systematic pharmaceutical care approach and specific published geriatric pharmacotherapy recommendations. The number of the drug-related problems identified and the degree of the care-team acceptance of the pharmacists' solutions were noted for each patient. RESULTS: The pharmacist found 6 active drug-related problems for the hospitalized patient (72 year-old, Chronic Disease Score 9) and 7 potential ones for the nursing-home resident (79 year-old, Chronic Disease Score 8), involving misuse, underuse and overuse of medications. Each patient had 3 geriatric syndromes at baseline. The therapy changes suggested by the pharmacist were implemented for the hospitalized patient, through collaboration with the health-care team. For the nursing home resident, the pharmacist identified the need for additional 6 medications and safety and efficacy arguments to cease 7 initial therapies, simplifying the therapeutic daily schedule (from 24 daily doses to 15). CONCLUSION: The pharmacist's potential contribution to the optimization of the Romanian elderly patients' pharmacotherapy needs further exploration, as potential drug related problems reported as characteristic for this population were easily identified. The presented structured and validated model of pharmaceutical care approach could be used to this end. Its dissemination and use could be encouraged along with the enhancement of pharmacotherapy information and care team collaboration skills.

Pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects.

BACKGROUND: Phenytoin is an inductor of the main metabolizing enzyme of ivabradine and it could influence its pharmacokinetics. Changes in ivabradine pharmacokinetics could have clinical significance regarding the safety of the treatment. OBJECTIVE: The study objective was evaluation of the pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects. METHODS: A single dose of ivabradine 10 mg was administered alone or in combination with phenytoin 150 mg to 18 healthy subjects in a two-treatment study design, separated by 5 days in which the phenytoin alone was administered at a dose of 150 mg twice daily. Plasma concentrations of ivabradine were determined during a 12-hour period following drug administration, using a high-throughput liquid chromatography coupled with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment were calculated using non-compartmental analysis and compared to determine if the differences were statistically significant. RESULTS: In the two treatment periods, the mean ± SD peak plasma concentrations (C(max)) were 18.6 ± 8.0 ng/mL (ivabradine alone) and 6.5 ± 3.1 ng/mL (ivabradine after pre-treatment with phenytoin). The mean ± SD times taken to reach C(max) (t(max)) were 1.2 ± 0.7 h and 0.8 ± 0.6 h, respectively, and the total areas under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were 62.3 ± 18.7 ng · h/mL and 19.2 ± 17.0 ng · h/mL, respectively. Statistically significant differences were observed for the C(max) and AUC(∞) of ivabradine when administered alone or with phenytoin, whereas for t(max) and the half-life the differences were non-significant. CONCLUSION: This study showed that phenytoin has an important effect on the pharmacokinetics of ivabradine in healthy subjects, reducing its bioavailability by approximately 70%.