Pharmacokinetics and dosing of vancomycin in patients undergoing sustained low efficiency daily diafiltration (SLEDD-f): A prospective study.

BACKGROUND/PURPOSE: The pharmacokinetics of vancomycin in patients who undergo sustained low efficiency daily diafiltration (SLEDD-f) is not clear. This study aimed to determine the appropriate vancomycin dosage regimen for patients receiving SLEDD-f. METHODS: This prospectively observational study enrolled critically ill patients older than 18 years old that used SLEDD-f as renal replacement therapy and received vancomycin treatment. An 8-h SLEDD-f was performed with FX-60 (high-flux helixone membrane, 1.4 m2). Serial blood samples were collected before, during, and after SLEDD-f to analyse vancomycin serum concentrations. Effluent fluid samples (a mixture of dialysate and ultrafiltrate) were also collected to determine the amount of vancomycin removal. RESULTS: Seventeen patients were enrolled, and 10 completed the study. The amount of vancomycin removal was 447.4 ± 88.8 mg (about 78.4 ± 18.4% of the dose administered before SLEDD-f). The vancomycin concentration was reduced by 57.5 ± 14.9% during SLEDD-f, and this reduction was followed by a rebound with duration of one to three hours. The elimination half-life of vancomycin decreased from 64.1 ± 35.7 h before SLEDD-f to 7.0 ± 3.0 h during SLEDD-f. CONCLUSION: Significant amount of vancomycin removed during SLEDD-f. Despite the existence of post-dialysis rebound, a sufficient supplemental dose is necessary to maintain therapeutic range.

Factors driving the use of warfarin and non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

BACKGROUND/PURPOSE: In the past, warfarin was the drug of choice for stroke prevention in patients with atrial fibrillation (AF). Recently, non-vitamin K antagonist oral anticoagulants (NOACs) have been approved as an alternative to warfarin in nonvalvular AF. However, there is a limited amount of real-world data on how NOACs are currently being used in Taiwan. This study was conducted to investigate the factors driving the initiation of anticoagulants and the selection of different anticoagulants in patients with AF. METHODS: We used National Taiwan University Hospital's electronic database to identify all nonvalvular AF patients from January 1, 2007 to December 31, 2013. Multivariate logistic regression models were used to examine the factors driving the initiation of anticoagulants and the selection of different anticoagulants. RESULTS: Among AF patients, 66.4% of anticoagulants users used NOACs instead of warfarin after the era of NOACs. Patients with female sex, hypertension, ischemic heart disease, cancer, hepatic disease, renal disease, bleeding history, and aspirin use were less likely to be anticoagulant users but are more likely to be anticoagulant users with a history of stroke (odds ratio = 2.64; 95% confidence interval, 2.02-3.45). Older age, ischemic heart disease, and aspirin use were the factors associated with NOACs usage, whereas hepatic disease showed the opposite results (odds ratio = 0.09; 95% confidence interval, 0.02-0.42). CONCLUSION: Stroke history was associated with anticoagulant use, whereas comorbidities associated with increased risk of bleeding showed the opposite result. Patients with hepatic disease were less likely to use NOACs.

The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations.

BACKGROUND: Carbapenem antibiotics (CBPMs) may significantly reduce the serum concentration of valproic acid (VPA), but the extent of this effect among various CBPMs is unknown. This study compared the extent and onset of the interactions among ertapenem, imipenem/cilastatin, and meropenem. METHODS: A 5-year retrospective study was performed. Hospitalized patients over 18 years old who received VPA and a CBPM concurrently were enrolled via the pharmacy computer system. Patients who lacked VPA serum concentration measurements before or during CBPMs' use, had concurrent medication(s) that might interfere with VPA metabolism, or had a history of liver cirrhosis were excluded. Total VPA serum concentrations before and during CBPMs' use and after its discontinuation were recorded, and differences among various CBPMs were analyzed. RESULTS: Fifty-two patients were included in this analysis. Irrespective of the route of administration, VPA serum concentrations were subtherapeutic in 90% of the subjects during CBPMs' use. There was a significant decrease (P < 0.001) in VPA serum concentrations during the use of CBPMs: 72% ± 17%, 42% ± 22%, and 67% ± 19% in the ertapenem (N = 9), imipenem/cilastatin (N = 17), and meropenem (N = 26) groups, respectively. The effect of ertapenem and meropenem on VPA was significantly more expressed than that of imipenem/cilastatin (P < 0.005). The onset of this drug interaction occurred within 24 hours of CBPMs' administration, and VPA serum concentrations returned to 90% of baseline within 7 days of CBPMs' discontinuation along with a 20% increase in VPA dose. Increasing VPA dose during the use of ertapenem or meropenem did not result in elevating VPA serum concentrations to therapeutic levels during the combined therapy period. CONCLUSIONS: CBPMs reduced VPA serum concentration within 24 hours of administration by approximately 60%. Ertapenem and meropenem had a greater effect on VPA serum concentration than imipenem/cilastatin. Because of the dramatic reduction of VPA serum concentration during CBPMs' use, concomitant use of VPA and CBPMs should be avoided.

Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: A retrospective analysis.

BACKGROUND/PURPOSE: Ifosfamide, a widely used chemotherapeutic agent, has been frequently associated with encephalopathy. A larger-scale study was conducted to identify risk factors of ifosfamide-related encephalopathy, including hepatic function. METHODS: Adult patients who had completed at least one cycle of ifosfamide between January 2008 and December 2010 were included. Those with renal failure or liver failure were excluded. Data were collected through chart review. Patients with encephalopathy and patients without encephalopathy were compared on age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), baseline serum creatinine (SCr) level, albumin level, white blood cell count, liver function, brain metastasis, and dosage of ifosfamide. Chi-square test or Fisher's exact test, Student t test, and univariate and multivariate logistic regressions were used for analysis. RESULTS: This study enrolled 337 patients. Thirty-eight patients (11%) had ifosfamide-related encephalopathy. They had poorer ECOG PS; higher SCr level, white blood cell count, and aspartate aminotransferase level; and lower serum albumin level compared with patients without encephalopathy. Ifosfamide dosage, brain metastasis, and age were not significant risk factors. Multivariate analysis indicated that only ECOG PS, SCr level, and albumin level contributed significantly to the risk. CONCLUSION: To date, this is the largest-scale study to have analyzed the risk factors of ifosfamide-related encephalopathy. This study confirms that an ECOG PS of 2-4 and increased SCr level are significant risk factors of ifosfamide-related encephalopathy, whereas increased albumin level decreases the risk, consistent with previous reports. Higher aspartate aminotransferase levels have no significant impact. In contrast to previous studies, ifosfamide dosage and brain metastasis are not significant contributing factors.

Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics (PK) of vancomycin in neonates; but data on adults is limited. METHODS: This is a prospective, matched cohort, single center, pharmacokinetic study. For each adult patient who received vancomycin therapy in the ECMO group (with either centrifugal pump or roller pump), a control patient was matched by age (≥ 60 years or < 60 years), gender, and creatinine clearance (CLCr) in intensive care units. After vancomycin was administered for at least four doses, serial blood samples were drawn at 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 11 hours, 23 hours, 35 hours, and 47 hours post vancomycin infusion according to the dosing intervals. The serum concentration-time profile was fitted to a noncompartment model and a nonlinear mixed effect model to determine the PK parameters. RESULTS: Twenty-two critically ill adults without renal replacement therapy were enrolled. There were no significant differences between the ECMO group and the matched group in demographics, renal function, and PK parameters. However, vancomycin clearance in the roller pump group was significantly lower than that in the matched control (0.83 ± 0.43 mL/min/kg vs. 0.97 ± 0.43 mL/min/kg, p = 0.002). CONCLUSION: Vancomycin clearance in patients receiving ECMO with a roller pump was significantly lower than that in the matched cohort. Vancomycin PK parameters in patients on ECMO with a centrifugal pump were comparable to those in the matched control group.

Nephrotoxic Polypharmacy and Risk of Contrast Medium-Induced Nephropathy in Hospitalized Patients Undergoing Contrast-Enhanced CT.

OBJECTIVE: For unknown reasons, there is discordance among previous reports with regard to the association of contrast medium (CM) with nephropathy and the incidence of nephropathy after contrast-enhanced CT. This study aimed to determine the frequency of and possible factors related to CM-induced nephropathy in hospitalized patients, with an emphasis on detailing coprescriptions with nephrotoxic potential. MATERIALS AND METHODS: Of 1378 inpatients who underwent CT, 208 (15.1%) met the inclusion criteria: receipt of IV iodinated CM and baseline serum creatinine level obtained within 45 days before and within 2 weeks after CT. Patient demographics, clinical characteristics, comorbidity, nephrotoxic comedications (nine classes of drugs), and type of CM administered were retrospectively reviewed. Relationships between CM-induced nephropathy (serum creatinine level increase ≥ 25% or ≥ 0.5 mg/dL after CT) and risk factors were assessed by stepwise multivariate logistic regression. RESULTS: The cohort of 208 subjects had a high number of comorbidities (mean [± SD], 5.8 ± 3.5 diagnoses) and a high rate of receiving nephrotoxic comedications (45.2%). CM-induced nephropathy was detected in 27 (13.0%) patients. Concurrent use of four nephrotoxic agents (odds ratio [OR], 26.250; 95% CI, 3.673-233.993) was the most influential factor associated with CM-induced nephropathy; other predictors included preexisting renal disease (OR, 8.218; 95% CI, 1.622-42.357), baseline serum creatinine level less than 0.7 or greater than or equal to 1.3 mg/dL (OR, 3.463; 95% CI, 1.341-9.025), and hemoglobin level less than 9.3 g/dL (OR, 3.141; 95% CI, 1.087-8.946). CONCLUSION: Among the known risk factors, such as preexisting renal disease, high serum creatinine level, and low hemoglobin level, a statistically significant association was identified between CM-induced nephropathy and concurrent receipt of four nephrotoxic medications. Relevant preventive measures are warranted for individuals at risk, especially hospitalized patients receiving multiple nephrotoxic medications who require contrast-enhanced CT.

Medication knowledge to be improved in participants in community universities in Taiwan: Outcome of a nationwide community university program.

BACKGROUND/PURPOSE: To assess knowledge improvement by the participants in a pharmacist-facilitated national community education program over a 4-month semester and to identify the educational needs of adults related to medications. METHODS: This was a single-group, pre- and post-program comparative study. From February 2005 to February 2006, 1983 community residents participating in the education program implemented at 57 community universities nationwide were included. A questionnaire consisting of 50 true/false questions was administered before and after the program to assess the participants' medication knowledge. Paired t test was used to analyze the pre- and post-program differences and generalized linear mixed models were applied to examine the demographic variables that might influence the background knowledge and outcome after adjusting for school effects. RESULTS: A total of 848 participants (42.8%) completed the pre-to-post questionnaire. Baseline medication knowledge was positively correlated with participants' education level and negatively correlated with age. Significant improvement (11.3%, p < 0.001) in medication knowledge was evident at the end of the program. The age and education level were significant determinants in the improvement of the pre-to-post program test score. The specific areas that required improvement most in the knowledge of the participants were: instructions on refill prescriptions, proper storage of medication, the health insurance system, drug use in special populations, and over-the-counter drugs. CONCLUSION: This national program improved participants' medication knowledge over a 4-month period. Patient counseling focusing more on the knowledge deficiency identified in this study during patient care is recommended.

De novo cancer avoidance after renal transplantation: A case-control study on low-dose sirolimus combined with a calcineurin inhibitor.

BACKGROUND/PURPOSE: Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low-dose SRL combined with a CNI could still prevent cancer in renal transplant recipients. METHODS: A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271). RESULTS: The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 ± 37.5 months and 81.7 ± 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation. CONCLUSION: De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients.

Formulation and stability of an extemporaneous 0.02% chlorhexidine digluconate ophthalmic solution.

BACKGROUND/PURPOSE: Acanthamoeba keratitis is difficult to treat because Acanthamoeba cysts are resistant to the majority of antimicrobial agents. Despite the efficacy of 0.02% chlorhexidine in treating Acanthamoeba keratitis, a lack of data in the literature regarding the formulation's stability limits its clinical use. The objective of this study was to develop an optimal extemporaneous 0.02% chlorhexidine digluconate ophthalmic formulation for patients in need. METHODS: With available active pharmaceutical ingredients, 0.02% chlorhexidine digluconate sample solutions were prepared by diluting with BSS Plus Solution or acetate buffer. Influences of the buffer, type of container, and temperature under daily-open condition were assessed based on the changes of pH values and chlorhexidine concentrations of the test samples weekly. To determine the beyond-use date, the optimal samples were stored at 2-8°C or room temperature, and analyzed at time 0 and at Week 1, Week 2, Week 3, Week 4, Week 5, Week 8, Week 12, and Week 24. RESULTS: Despite chlorhexidine exhibiting better stability in acetate buffer than in BSS solution, its shelf-life was < 14 days when stored in a light-resistant low-density polyethylene container. The acetate-buffered 0.02% chlorhexidine digluconate solution stored in light-resistant high-density polyethylene eyedroppers did not exhibit significant changes in pH or strength at any time interval. CONCLUSION: The acetate-buffered 0.02% chlorhexidine digluconate ophthalmic solution stored in light-resistant high-density polyethylene eyedroppers demonstrated excellent stability at 2-25°C for 6 months after being sealed and for 1 month after opening. This finding will enable us to prepare 0.02% chlorhexidine digluconate ophthalmic solutions based on a doctor's prescription.

Intracellular delivery of recombinant arginine deiminase (rADI) by heparin-binding hemagglutinin adhesion peptide restores sensitivity in rADI-resistant cancer cells.

Recombinant arginine deiminase (rADI) has been used in clinical trials for arginine-auxotrophic cancers. However, the emergence of rADI resistance, due to the overexpression of argininosuccinate synthetase (AS), has introduced an obstacle in its clinical application. Here, we have proposed a strategy for the intracellular delivery of rADI, which depletes both extracellular and intracellular arginine, to restore the sensitivity of rADI-resistant cancer cells. In this study, the C terminus of heparin-binding hemagglutinin adhesion protein from Mycobacterium tuberculosis (HBHAc), which contains 23 amino acids, was used to deliver rADI into rADI-resistant human breast adenocarcinoma cells (MCF-7). Chemical conjugates (l- and d-HBHAc-SPDP-rADI) and a recombinant fusion protein (rHBHAc-ADI) were produced. l- and d-HBHAc-SPDP-rADI showed a significantly higher cellular uptake of rADI by MCF-7 cells compared to that of rADI alone. Cell viability was significantly decreased in a dose-dependent manner in response to l- and d-HBHAc-SPDP-rADI treatments. In addition, the ratio of intracellular concentration of citrulline to arginine in cells treated with l- and d-HBHAc-SPDP-rADI was significantly increased by 1.4- and 1.7-fold, respectively, compared with that obtained in cells treated with rADI alone (p < 0.001). Similar results were obtained with the recombinant fusion protein rHBHAc-ADI. Our study demonstrates that the increased cellular uptake of rADI by HBHAc modification can restore the sensitivity of rADI treatment in MCF-7 cells. rHBHAc-ADI may represent a novel class of antitumor enzyme with an intracellular mechanism that is independent of AS expression.

Statins and the risk of liver injury: a population-based case-control study.

OBJECTIVE: This case-control study investigated the association between statin use and liver injury using Taiwan's National Health Insurance Research Database. METHODS: Our study subjects included 4165 cases (patients who had been admitted with a primary diagnosis of liver injury between 2002 and 2009) and 16 660 age-matched, sex-matched and index date-matched controls. Multivariable conditional regression models were used to estimate the association between statin use and liver injury. RESULTS: Users of statins were not associated with risk of liver injury (adjusted odds ratio [aOR] 1.04; 95% confidence interval [0.90-1.19]) when compared with nonusers. Nevertheless, a higher dose of statin (≥1 defined daily dose; aOR 1.55 [1.14-2.11]) and use of rosuvastatin before event of liver injury (aOR 1.38 [1.03-1.85]) were significantly associated with liver injury. CONCLUSIONS: This population-based study extends previous evidence by exploring the potential association between statins use and risk of liver injury. Overall, we found that statin was not associated with risk of liver injury. Nevertheless, special concern should be paid to those who used statin ≥1 defined daily dose and rosuvastatin.

Assessment of an automatic robotic arm for dispensing of chemotherapy in a 2500-bed medical center.

BACKGROUND/PURPOSE: Automation has long been awaited in parenteral drug dispensing. Pharmacists can benefit much in theory from a good automated device to handle the hazardous drugs used in chemotherapy. This paper describes the performance of the first chemotherapy-dispensing robot in the oncology pharmacy of a 2500-bed medical center. The objective of this paper is two-fold: (1) to assess the robot's performance in terms of its success rate and to summarize the causes of failure, and (2) to find out if the robot can decrease the full-time equivalents (FTEs) of the oncology pharmacy. METHODS: We used the computer-generated log from the first week of May 2010 to that of July 2010, supplemented with the pharmacists' notes on the causes of failure, to determine the success rate and to analyze the incidences of failure. We also assessed the FTEs before and after implementing the robot. RESULTS: Data showed that the success rate rose slowly from 76.8% to 95.3% over the 2-month recording period. The major mechanical problems encountered were air, clamping, and waste bin problems. Manual errors, such as loading wrong drugs or syringes, also caused failures. In terms of manpower saving, CytoCare failed to decrease the number of FTE pharmacists/technicians in our oncology pharmacy practice. CONCLUSION: We conclude that even though CytoCare could ease the risk of chemotherapy exposure and increase the precision of dosing, it was not able to improve the FTE pharmacists/technicians in our hospital.

Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Conflicting results have been reported regarding the increased risk of adverse outcomes in the concomitant use of clopidogrel and proton pump inhibitors (PPIs) compared with the use of clopidogrel alone. WHAT THIS STUDY ADDS: Our study indicated no statistically significant increase in the risk of rehospitalization for acute coronary syndrome due to concurrent use of clopidogrel and PPIs in an Asian population with higher prevalence of CYP2C19 intermediate and poor metabolizers. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for acute coronary syndrome. AIMS Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel. METHODS: We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event. RESULTS: The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971-1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066-1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk. CONCLUSIONS: Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.

Does Chinese herb nephropathy account for the high incidence of end-stage renal disease in Taiwan?

BACKGROUND: The incidence of end-stage renal disease (ESRD) in Taiwan ranks highest in the world, but the incidence of Chinese herb nephropathy (CHN) is unknown in this country where Chinese herb use is common. METHODS: The etiologies of incident ESRD cases from 2000 to 2004 in a single tertiary referral medical center in Taiwan were independently reviewed by two nephrologists through medical records and telephone interview. Patients with obvious causes of ESRD were not diagnosed with CHN, in spite of Chinese herb use. Three categories of CHN (A, B and C) were defined according to the stringency of evidence. RESULTS: Obvious causes of ESRD were identified in 1,359 out of 1,696 newly diagnosed ESRD patients. Among the remainders, 263 had histories of Chinese herb use; 164 patients (mean age 52.7 ± 13.2 years, female 71.6%) had CHN (category A: 51, category B: 38 and category C: 75). Among the three categories, there was no difference in age, gender, body mass index (BMI) or elapsed time from Chinese herb use to the detection of renal failure. In comparison with non-CHN patients (n = 99), more CHN patients were female, had lower BMI, lower blood pressure, shorter duration of Chinese herb use, less severe proteinuria, smaller kidney size, lower levels of hemoglobin and higher serum chloride levels (all p values <0.01). CONCLUSION: Based on highly stringent diagnostic criteria, nearly 10% of incident ESRD cases were due to CHN. CHN represents a significant cause of ESRD in Taiwan.

RNA interference of argininosuccinate synthetase restores sensitivity to recombinant arginine deiminase (rADI) in resistant cancer cells.

BACKGROUND: Sensitivity of cancer cells to recombinant arginine deiminase (rADI) depends on expression of argininosuccinate synthetase (AS), a rate-limiting enzyme in synthesis of arginine from citrulline. To understand the efficiency of RNA interfering of AS in sensitizing the resistant cancer cells to rADI, the down regulation of AS transiently and permanently were performed in vitro, respectively. METHODS: We studied the use of down-regulation of this enzyme by RNA interference in three human cancer cell lines (A375, HeLa, and MCF-7) as a way to restore sensitivity to rADI in resistant cells. The expression of AS at levels of mRNA and protein was determined to understand the effect of RNA interference. Cell viability, cell cycle, and possible mechanism of the restore sensitivity of AS RNA interference in rADI treated cancer cells were evaluated. RESULTS: AS DNA was present in all cancer cell lines studied, however, the expression of this enzyme at the mRNA and protein level was different. In two rADI-resistant cell lines, one with endogenous AS expression (MCF-7 cells) and one with induced AS expression (HeLa cells), AS small interference RNA (siRNA) inhibited 37-46% of the expression of AS in MCF-7 cells. ASsiRNA did not affect cell viability in MCF-7 which may be due to the certain amount of residual AS protein. In contrast, ASsiRNA down-regulated almost all AS expression in HeLa cells and caused cell death after rADI treatment. Permanently down-regulated AS expression by short hairpin RNA (shRNA) made MCF-7 cells become sensitive to rADI via the inhibition of 4E-BP1-regulated mTOR signaling pathway. CONCLUSIONS: Our results demonstrate that rADI-resistance can be altered via AS RNA interference. Although transient enzyme down-regulation (siRNA) did not affect cell viability in MCF-7 cells, permanent down-regulation (shRNA) overcame the problem of rADI-resistance due to the more efficiency in AS silencing.

Effects of a pharmacist-managed anticoagulation outpatient clinic in Taiwan: evaluation of patient knowledge, satisfaction, and clinical outcomes.

Objective: The study aimed to evaluate the improvement of patient knowledge of warfarin use, satisfaction with pharmacists, and the quality of international normalized ratio (INR) control after the implementation of an anticoagulant clinic (ACC) service.Methods: This was a prospective single-group pre- and post-comparison study. Patients who were at least 20 years of age and participated in a pharmacist-managed ACC service were enrolled from February 2012 to September 2015. Each participant completed a self-administered questionnaire before and after the ACC service to evaluate changes in warfarin knowledge. Another questionnaire was distributed after the ACC to evaluate participants' satisfaction with the pharmacist service in the ACC. The INR levels before and after the ACC intervention were obtained to calculate the proportion of time spent in the therapeutic INR range (time in therapeutic range, TTR). Paired t-tests were used to compare changes in participants' knowledge related to warfarin use. Multiple linear regressions were performed to explore the predictors associated with the participants' knowledge scores and TTR after the ACC intervention.Results: One hundred and forty-eight participants were enrolled in this study. A significant improvement (31.5%,p<0.001) in the knowledge of warfarin use was observed at the end of the ACC intervention. The interaction between warfarin and food was the most confusing factor for participants in warfarin use. More than 95% of the participants perceived a positive value of the pharmacist-managed ACC service. However, the consultation fee was the least satisfactory of the ACC service. The average TTR increased from 51.0±34.3% to 78.6±24.5% (p<0.001) after the ACC service was implemented. Participants' education levels and baseline knowledge scores were significant determinants associated with the knowledge improvement in the appropriate warfarin use (p<0.001).Conclusions: A pharmacist-managed ACC improved patient knowledge of warfarin use and INR control, and led to high satisfaction with the pharmacist service in the ACC in Taiwan. Pharmacists should focus on patients with lower education levels to facilitate their understanding of the appropriate warfarin use for better health outcomes.

Pharmacokinetics and safety of multiple intravenous doses of daptomycin in a Taiwanese adult population.

BACKGROUND: The pharmacokinetics (PK) and safety of daptomycin have not yet been studied in an adult Taiwanese population. METHODS: A total of 13 healthy adult Taiwanese subjects (7 males and 6 females) were enrolled to receive a 5-day course of multiple intravenous daptomycin infusions at a dose of 4 mg/kg every 24 h. Both single-dose and steady-state serum PK were assessed. RESULTS: PK evaluation showed no relevant accumulation of daptomycin based on the steady-state PK, which could be predicted from the single-dose PK. No gender effect on daptomycin, for either single- or multiple-dose PK, was observed. About 60% of the infused daptomycin was eliminated by the renal system in an unchanged form. Protein binding of daptomycin was about 93.92%. The PK parameters in healthy Taiwanese subjects were similar to those reported in healthy Caucasian subjects. No serious adverse events (AE) or deaths occurred during the study. The most frequently reported AE was leukopenia (3/19, 15.8%), followed by amblyopia (2/19, 10.5%). These AEs were considered to be mild-to-moderate in severity and resolved spontaneously. CONCLUSION: This study demonstrated similarities between Taiwanese and Caucasian healthy subjects in the PK profiles of daptomycin, and thus the dosage regimen used in Caucasian subjects could be applied to Taiwanese.

Decreased acute rejection and improved renal allograft survival using sirolimus and low-dose calcineurin inhibitors without induction therapy.

BACKGROUND: Chronic nephrotoxicity of calcineurin inhibitors (CNIs) causes irreversible renal dysfunction and shortens renal transplant survival. We conducted a retrospective cohort study to test a hypothesis that de novo CNI minimization combined with sirolimus (SRL) improves graft survival in renal transplant patients without antibody induction therapy. METHODS: Between october 2000 and august 2007, we performed 100 cases of renal transplantation with de novo CNI (either cyclosporine or tacrolimus) minimization combined with sirolimus (SRL group). The initial target trough levels were 100-200 ng/ml for cyclosporine (CSA) and 4-8 ng/mL for tacrolimus (TAC). SRL was given at a loading dose of 6 mg plus 2 mg/day for maintenance. The results for the SRL group were compared to those of 104 transplant recipients given standard CNI- (CsA- or TaC-) based immunosuppressive regimens including mycophenolate mofetil (MMF group) during the same period. RESULTS: The 1-year rejection-free survival (94.8%) and 5-year graft survival (87.7%) rates of the SRL group were significantly better than those of the MMF group (85.5% and 75.2%, respectively). On univariate analyses, 6-month estimated glomerular filtration rate (eGFR), acute rejection and SRL therapy had a significant impact on graft survival, and SRL therapy and tacrolimus therapy had a significant impact on rejection-free survival. Multivariate analyses identified 6-month eGFR as the only prognostic factor for graft survival. Acute rejection and SRL therapy were significant for post-transplant renal function. CONCLUSIONS: De novo CNI minimization combined with SRL could decrease acute rejection and improve renal function and graft survival after renal transplantation without the use of antibody induction therapy.

Recombinant arginine deiminase reduces inducible nitric oxide synthase iNOS-mediated neurotoxicity in a coculture of neurons and microglia.

Modulation of nitric oxide (NO) production is considered a promising approach to therapy of diseases involving excessive inducible nitric oxide synthase (iNOS) expression, such as certain neuronal diseases. Recombinant arginine deiminase (rADI, EC3.5.3.6) catalyzes the conversion of L-arginine (L-arg), the sole substrate of NOS for NO production, to L-citrulline (L-cit) and ammonia. To understand the effect of the depletion of L-arg by rADI on NO concentration and neuroprotection, a direct coculture of neuron SHSY5Y cells and microglia BV2 cells treated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was used as a model of iNOS induction. The results showed that rADI preserved cell viability (4-fold higher compared with the cells treated with LPS/IFN-gamma only) by the MTT assay, corresponding with the results of neuronal viability by neuron-specific immunostaining assay. NO production (mean +/- SD) decreased from 67.0 +/- 1.3 to 19.5 +/- 5.5 microM after a 2-day treatment of rADI by the Griess assay; meanwhile, induction of iNOS protein expression by rADI was observed. In addition, rADI substantially preserved the neuronal function of dopamine uptake in the coculture. The replenishment of L-arg in the coculture eliminated the neuroprotective and NO-suppressive effects of rADI in the coculture, indicating that L-arg played a crucial role in the effects of rADI. These results highlight the important role of L-arg in the neuron-microglia coculture in excessive induction of iNOS. Regulation of L-arg by ADI demonstrated that rADI has a potentially therapeutic role in iNOS-related neuronal diseases.