Anticholinergic and Sedative Drug Burden and Functional Recovery after Cerebrovascular Accident: A Retrospective Descriptive Study.

OBJECTIVES: Medications with anticholinergic or sedative effects induce impaired cognitive and physical performances. The aim of this study was to evaluate the associations of anticholinergic and sedative drug burden with recovery of physical function and activities of daily living in patients admitted to a Japanese rehabilitation hospital after cerebrovascular accidents. METHODS: We retrospectively reviewed the medical records of patients aged 18 years or older who had undergone the inpatient rehabilitation program for cerebrovascular disease in Nerima Ken-ikukai Hospital. Patients who did not complete the rehabilitation program because of acute unexpected changes of physical or psychological condition or the need for surgical procedures were excluded. The primary outcome was recovery of activities of daily living as measured by the motor and cognitive subscores of the Functional Independence Measure. The secondary outcome was recovery of physical function as assessed by the 10-m walk test and the Berg balance scale. Multiple Cox proportional hazard regression analyses were conducted to calculate hazard ratios with 95% confidence intervals for the outcome measures. RESULTS: Of 122 patients included in the study, 81 (66%) were exposed to anticholinergics and sedatives. Patients' age, body mass index, and average daily drug burden during hospitalization were independently associated with achieving the cutoff Functional Independence Measure-motor subscore. Patients' age and average daily drug burden during hospitalization were independently associated with achieving the Berg balance scale cut-off score. CONCLUSIONS: Our study of Japanese patients who were transferred from acute stroke care hospitals to a rehabilitation facility identified the drug burden of anticholinergics and sedatives as an independent factor associated with the time to recovery of activities of daily living and postural balance.

Clinical Predictors of the Hypoglycemic Effect of Sodium-Glucose Co-transporter-2 Inhibitors in Hyperuricemic Patients: A Retrospective Descriptive Observational Study.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors decrease glycated hemoglobin (HbA1c) and prevent the progression of cardiovascular and kidney diseases. Because uric acid and electrolytes are physiologically similar to blood glucose in renal excretion, we assessed predictors for the hypoglycemic effect of SGLT2 inhibitor treatment by focusing on serum uric acid and serum electrolytes. We performed a retrospective descriptive observational study at the Tokyo Women's Medical University, Medical Center East, from June 2015 to July 2018. Patients who received treatment with any type of SGLT2 inhibitor were selected, which included a total of 165 patients. The response to SGLT2 inhibitors defined as changes in HbA1c after SGLT2 inhibitor treatment was the main outcome measure. Multiple linear regression analysis was used to assess predictors for the hypoglycemic effect by SGLT2 inhibitors. Among the 165 patients, SGLT2 inhibitor treatment decreased HbA1c from 8.2 to 7.6% after 12 weeks (p < 0.01). Multiple linear regression analysis revealed that predictors of early response to SGLT2 inhibitors were serum uric acid values (p = 0.014) and baseline HbA1c (p < 0.001). Furthermore, late response to SGLT2 inhibitors was associated with serum uric acid value (p = 0.047) and baseline HbA1c (p < 0.001). Serum uric acid did not vary during SGLT2 inhibitor treatment; specifically, the SGLT2 inhibitors did not reduce serum uric acid levels. There was no correlation between changes in serum uric acid and HbA1c (p = 0.13). Thus, this study showed that serum uric acid value is associated with the control of diabetes mellitus during SGLT2 inhibitor treatment. Further studies are required to validate these results.

[A Retrospective Evaluation of the Impact of Multi-disciplinary Approach for Improving the Quality of Anticoagulation Therapy in Ambulatory Patients with Non-valvular Atrial Fibrillation Receiving Warfarin].

While percent time within therapeutic range (%TTR) of international normalized ratio of prothrombin time (PT-INR) represents the quality of anticoagulation therapy with warfarin, it is often maintained less than 50% in patients with non-valvular atrial fibrillation (NVAF). We aimed to study if implementation of a multi-disciplinary ambulatory anticoagulation service (MAAS) may improve %TTR. Collaborating with cardiologists at Kanto Rosai Hospital, we conducted a MAAS for NVAF patients receiving warfarin from April 2013 to December 2015. Patients who agreed to utilize the service in addition to their appointments with cardiologists visited pharmacists to have counseling about diet, concomitant medications, and lifestyle. According to a protocol, pharmacists made dose adjustment proposals to cardiologists, if necessary. Upon approval by cardiologists, dose modifications were made. We retrospectively reviewed medical records of the patients who participated in the MAAS before and during the service. The study protocol was approved by the institutional review board. We identified 78 eligible patients (44 males and 34 females, aged 51 to 91 years). Their median %TTR increased significantly (p<0.05) from 57% during the pre-MAAS period to 77% during the MAAS period. In addition, the median percent time below therapeutic range (%TBTR) decreased significantly (p<0.05) from 35% during the baseline period to 11% during the MAAS period. The present study indicates that MAAS improves the quality of anticoagulation therapy with warfarin in ambulatory patients with NVAF. Further prospective, randomized studies with a greater number of patients are required to confirm the results of the present study.

Relationship between Recurrent Falls and Medication Use during Acute-Care Hospitalization: A Retrospective Descriptive Study.

Although recurrent falls during hospitalization lead to discharge to nursing homes, their association with medications has not been comprehensively assessed. We aimed to assess risk factors for recurrent falls focusing on medications during hospitalization in an acute-care setting. This retrospective descriptive study was conducted in Tokyo Women's Medical University, Medical Center East. Patients who experienced a fall during hospitalization were included and the incidence of recurrent falls was assessed during hospitalization. Multivariate logistic regression analysis was performed to assess the relationship between recurrent falls and medications and to calculate odds ratio and 95% confidence interval. Sensitivity analysis was performed on data stratified by sex or age. This study included 124 patients with an incidence of 20 (16%) recurrent falls. Multivariate logistic regression analysis revealed that selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants were associated with recurrent falls (odds ratio = 5.98, 95% confidence interval: 1.38-25.9, p = 0.02). Additionally, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants were significant risk factors for recurrent falls in women and those aged > 80 years. Selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants were associated with an increased risk of recurrent falls during hospitalization in an acute-care setting. Clinicians should pay attention to patients receiving selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants, especially women and aged > 80 years old.

Reduced Clearance of Phenobarbital in Advanced Cancer Patients near the End of Life.

BACKGROUND AND OBJECTIVES: Little is known about the pharmacokinetics of phenobarbital in terminally ill cancer patients. We investigated whether phenobarbital clearance alters depending on the length of survival. METHODS: We retrospectively reviewed the clinical, laboratory, and therapeutic drug monitoring (TDM) records of patients who received parenteral or oral phenobarbital for 21 consecutive days or longer between 2000 and 2016. Patients were divided into non-cancer and cancer groups. Cancer patients were further stratified according to the survival interval after TDM: those who survived > 3 months were classified as long-surviving and the remainders short-surviving cancer patients. Phenobarbital clearance (CLPB) was calculated at steady state. Multiple comparisons of median CLPB were conducted among the three groups. RESULTS: Data were collected from 44 non-cancer patients and 34 cancer patients comprising 24 long-surviving and 10 short-surviving cancer patients. Among 10 short-surviving cancer patients, 4 had hepatic metastasis. Median CLPB (range) in short-surviving cancer patients [0.076 (0.057‒0.114) L/kg/day] was significantly (p < 0.05) lower than that in non-cancer patients [0.105 (0.060‒0.226) L/kg/day] and in long-surviving cancer patients [0.100 (0.082‒0.149) L/kg/day]. CONCLUSION: Terminally ill patients with advanced cancer may have reduced CLPB, thereby TDM is recommended for these patients particularly near the end of life.

Impact of relative dose intensity on bone marrow suppression induced by S-1: retrospective observational study.

BACKGROUND: S-1 (a combination of tegafur, gimeracil, and oteracil) is used to treat various cancers. Bone marrow suppression is a dose-limiting toxicity of S-1. The relationship between relative dose intensity (RDI) and bone marrow suppression has not been investigated. Hence, we aimed to elucidate the threshold for RDI to identify bone marrow suppression induced by S-1. METHODS: In this retrospective cohort study, patients who initiated S-1 treatment at Tokyo Women's Medical University, Medical Center East between June 2015 and June 2017 were included. Bone marrow suppression induced by S-1 was assessed using Common Terminology Criteria for Adverse Events version 4.0. The relationships between grade 3 or higher bone marrow suppression induced by S-1 and RDIs (i.e., 70, 75, and 80%) were investigated using the multivariate Cox proportional hazard model. RESULTS: We identified 143 patients in this study. The median RDI was 78.8%. Bone marrow suppression induced by S-1 developed in 19 (13.3%) patients. The multivariate Cox proportional hazard model revealed that grade ≥ 2 lymphocytopenia was associated with bone marrow suppression induced by S-1 regardless of the threshold for RDI. In addition, RDI > 75% [hazard ratio (HR) = 1.71, p < 0.05] and RDI > 80% (HR = 1.65, p < 0.05) were associated with bone marrow suppression induced by S-1. CONCLUSIONS: Reduced dose of S-1 still has the risk of developing bone marrow suppression. Clinicians should assess RDI to identify high risk patients with bone marrow suppression induced by S-1.

NSAIDs may prevent EGFR-TKI-related skin rash in non-small cell lung cancer patients
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OBJECTIVES: Skin rash is a common adverse event induced by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Here, we aimed to predict factors that reduce EGFR-TKI-related skin rash. MATERIALS AND METHODS: We conducted a single-center, retrospective study to predict factors that reduce skin rash in patients undergoing treatment for non-small cell lung cancer (NSCLC) with EGFR-TKIs using Cox proportional hazards model. RESULTS: Cox proportional hazard analysis revealed that coadministration of non-steroidal anti-inflammatory drug (NSAID) had protective effects against rash. Steroid coadministration showed a trend to being effective in reducing rash. CONCLUSION: NSAIDs may be useful in preventing EGFR-TKI-related skin rash.
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[Approach to Practical Training in Basic Clinical Pharmacy for Third-Year Pharmacy Students: Literature Appraisal and Professional Writing].

　Training pharmacy students to become future clinical pharmacists is an important mission in the 6-year school of pharmacy curriculum in Japan. Since 2014, we have conducted an on-campus practical training program to develop basic skills in clinical pharmacy for third-year pharmacy students at Meiji Pharmaceutical University. This training program includes searching for and retrieving drug information; interpretation of laboratory findings, vital signs, and physical examinations; literature appraisal; and professional writing. These training sections are arranged in the above-mentioned order to facilitate effective understanding of each. In the literature appraisal section, each student group is assigned a report on a prospective controlled study of a given drug published in English and reads it critically according to the literature appraisal worksheet. Then the group writes a monograph on the drug described in the report based on the literature and other information. Thereafter, all students are reshuffled into new groups so that students who were assigned different drugs are placed together, in the so-called jigsaw learning method. Students then discuss which two or three drugs in a specific pharmacological class should be adopted in the hospital formulary according to the knowledge gained through this training program series. The themes were novel oral anticoagulants in the 2014 academic year, dipeptidyl peptidase 4 inhibitors in 2015, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in 2016. Although there are some problems that need to be resolved in the future, this approach appears effective in helping students build drug information skills as a basic competence of clinical pharmacists.

Consequences of Different Corticosteroids on Serum Potassium and Prostate-Specific Antigen in Patients Receiving Abiraterone for Castration-Resistant Prostate Cancer: A Retrospective Observational Study.

BACKGROUND: Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co-administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown. METHODS: We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate-specific antigen (PSA) level were retrieved from the electronic medical records. RESULTS: Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment. CONCLUSIONS: Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia.

Safety of human papillomavirus vaccines in healthy young women: a meta-analysis of 24 controlled studies.

BACKGROUND: Human papillomavirus (HPV) vaccines have been shown to be effective for the eradication of HPV and prevention of cervical cancer. However, the number of women who receive HPV vaccinations has decreased over the last several years in Japan, due to concerns about adverse reactions associated with the vaccines. We evaluated the safety of three types of HPV vaccines separately in young women and the difference in the risk of adverse reactions between HPV and other vaccines by conducting a meta-analysis. METHODS: Primary literature was retrieved from MEDLINE, the Cochrane Central Register of Controlled Trials, and Japana Centra Revuo Medicina. Prospective controlled studies with participants consisting exclusively of healthy women who received bivalent, quadrivalent, or 9-valent HPV (2vHPV, 4vHPV or 9vHPV) vaccines were included. Primary safety outcome was the incidence of solicited local and systemic symptoms, and unsolicited symptoms. When two or more studies were found for the same analysis, a meta-analysis was applied. RESULTS: A total of 24 controlled studies from 22 articles were included in our study. Of the 24 studies, 16 were placebo-controlled and eight were active-controlled (different HPV vaccine or hepatitis vaccine). Average ages of the participants ranged from 12 to 37 years. A significantly higher incidence of solicited local symptoms was observed following injection of HPV vaccines (2vHPV and 4vHPV) compared to placebo, but there was no difference between HPV vaccines [risk ratio (RR) for 2vHPV: 1.25, 95% confidence interval (CI): 1.09 to 1.43, RR for 4vHPV: 1.16, 95% CI: 1.11 to 1.20]. The incidence of solicited systemic symptoms was not different between HPV vaccines and placebo (RR: 1.04, 95% CI: 0.99 to 1.09). The incidence of unsolicited symptoms was significantly higher for 2vHPV vaccine compared to placebo (RR: 1.28, 95% CI: 1.01 to 1.63), but was not significantly different between 2vHPV and hepatitis B vaccines. CONCLUSIONS: HPV vaccines had significantly higher risk of any injection site symptom compared to placebo or other vaccines (hepatitis A and B vaccines), and the incidence of solicited local symptoms was no difference between 2vHPV vaccination and 4vHPV vaccination. However, the most adverse reactions were transient.

Induration at Injection or Infusion Site May Reduce Bioavailability of Parenteral Phenobarbital Administration.

BACKGROUND: Phenobarbital is well tolerated and effective for controlling agitation or preventing convulsion at the end of life. No information is available concerning parenteral bioavailability of phenobarbital when induration develops at the injection or infusion site. We investigated whether induration at injection or infusion site is related to phenobarbital bioavailability via parenteral routes of continuous subcutaneous infusion and intermittent subcutaneous or intramuscular injection. METHODS: A retrospective analysis was conducted on the medical data obtained from 18 patients who received chronic subcutaneous or intramuscular injections of phenobarbital for the prevention of convulsions and underwent plasma concentration monitoring of the drug. Patients whose concomitant medications were altered during the observation periods were excluded from the analysis. Comparisons were performed for concentration/dose (C/D) ratios obtained from patients with induration at injection or infusion sites (induration group, n = 6) and those without induration (noninduration group, n = 12). P < 0.05 was considered statistically significant. RESULTS: The induration group showed significantly reduced C/D ratio compared with the noninduration group [median (range): 0.131 (0.114-0.334) versus 0.219 (0.180-0.322) d/L, P < 0.05). Assuming that systemic clearance was constant in our patients, changes in the C/D ratio would have contributed to 40% (median) reduction in bioavailability of the drug from the injection or infusion site. CONCLUSIONS: Our data suggest that absolute bioavailability of phenobarbital may be reduced when induration develops at the injection or infusion site in patients treated parenterally by continuous subcutaneous infusion or intramuscular injection.

Impact of Pharmacists' audit on improving the quality of prescription of dabigatran etexilate methanesulfonate: a retrospective study.

BACKGROUND: Appropriate prescription of dabigatran etexilate methanesulfonate (JAN) is more complicated than assumed, because there are totally 10 items of contraindications and instructions for dosage reduction depending on patients' characteristics. We aimed to study whether the routine audit of first-time prescriptions of dabigatran performed by pharmacists is effective in improving the quality of prescription. METHODS: A retrospective re-audit was performed on all the prescriptions of dabigatran issued at Kitahara International Hospital, Tokyo between March 2011 and February 2014, by evaluating the prescriptions rigorously against the approved prescribing information of the drug. The original routine audit of the prescriptions for inpatients was performed by hospital pharmacists using electronic medical records (EMR), whereas the audit for ambulant patients receiving external prescriptions was performed by community pharmacists using information obtained mainly by questioning patients. The frequencies of inappropriate prescriptions detected by the re-audit in the two groups were compared. RESULTS: Two hundred and twenty-eight patients (131 ambulant patients and 97 inpatients) were prescribed dabigatran for the first time during the study period. All patients met the approved indications. While 33% of the prescriptions for ambulant patients showed at least one violation of the approved usage, only 11% of the prescriptions for inpatients showed violations (p < 0.001). Two ambulant patients with creatinine clearance < 30 mL/min were dispensed dabigatran, whereas no such case was found among inpatients. A significantly greater proportion of ambulant patients aged ≥70 years showed violation of the instruction for dosage reduction compared to inpatients of the same age group (18 and 4%, respectively). CONCLUSION: The present study suggests that pharmacists may achieve better performance in auditing prescriptions of dabigatran when medical records are fully available than when information is available mainly by questioning patients. Further large-scale studies are required to clarify whether the audit of dabigatran prescriptions improves ultimate therapeutic outcomes or complications.

Influence of proton pump inhibitors and histamine H2 receptor antagonists on serum phosphorus level control by calcium carbonate in patients undergoing hemodialysis: a retrospective medical chart review.

BACKGROUND: Hyperphosphatemia is one of the common complications in patients undergoing hemodialysis. Although calcium carbonate (CaC) is often used to control serum inorganic phosphorus level in dialysis patients, co-administration of gastric acid reducers (ARs) may interfere with the phosphate binding effect of CaC. We performed a retrospective medical chart review to study whether ARs attenuate the hypophosphatemic effect of CaC in patients undergoing hemodialysis. METHODS: One hundred and eight chronic hemodialysis patients receiving either CaC alone or CaC concomitant with one of the ARs (proton pump inhibitors and histamine H2-receptor antagonists) were retrieved from the medical charts in Juntendo University Nerima Hospital. The patients were subdivided according to the interval between hemodialysis sessions (interdialysis interval of 48 or 72 h). A multivariate analysis was performed to identify clinical covariates associated with the variability of serum inorganic phosphorus levels. The study protocol was approved by the Institutional Review Board before the study was begun. RESULTS: Among patients on hemodialysis with a 72-h interdialysis interval, the magnitude of increase in serum inorganic phosphorus concentration in patients receiving CaC and AR was significantly greater than in those receiving CaC alone. While a similar trend was observed among patients with a 48-h interdialysis interval, the difference did not reach a significant level. A multivariate regression analysis revealed that concomitant administration of ARs with CaC and a longer interdialysis interval (72 h) were significantly and independently associated with the magnitude of increase in serum phosphorus concentration between dialysis sessions. No significant differences in albumin-corrected serum calcium concentrations and incidence of pathological fractures were observed between patients receiving CaC alone and those receiving CaC with ARs. CONCLUSIONS: Concomitant use of ARs with CaC may attenuate the hypophosphatemic effect of CaC in patients undergoing chronic hemodialysis. When hemodialysis patients require prescription of ARs for the prevention of upper gastrointestinal mucosal diseases (such as peptic ulcer), it may be prudent to choose a phosphate binder other than CaC.

Eculizumab Dosing Intervals Longer than 17 Days May Be Associated with Greater Risk of Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Eculizumab given bi-weekly is widely recommended for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). We undertook a retrospective analysis on the medical records of 763 dosings of 14 PNH patients to investigate whether a threshold would exist in dosing intervals associated with breakthrough hemolysis. We identified 12 events of breakthrough hemolysis in 4 patients. Multivariate logistic regression and receiver operating characteristics (ROC) analysis revealed a significant association between increased risk of breakthrough hemolysis and prolonged dosing intervals of 17 days or more and concomitant inflammation: odds ratios (OR) and 95% confidence intervals (CIs) were 1.6 (1.3-2.0, p<0.01) and 5.5 (1.3-22.8, p=0.02), respectively. ROC analysis showed that the best cut-off dosing interval discriminating breakthrough hemolysis was 16.5 days. We consider that eculizumab dosing intervals longer than 17 days may be associated with an increased risk for developing breakthrough hemolysis in patients with PNH.

Clinical pharmacokinetics of drugs in patients with heart failure: an update (part 2, drugs administered orally).

The purpose of the present review article is to update the information regarding pharmacokinetics of drugs in patients with heart failure that has accumulated since the last review article published in 1988 in Clinical Pharmacokinetics. Since this last review, our understanding of the pathophysiology of heart failure has changed from the cardio-renal model to the neuro-humoral model, and the pharmacologic approach to treatment of heart failure has been shifted from inotropic agents to those acting on the renin-angiotensin-aldosterone system. The pharmacologic agents now used for heart failure include many important classes of drugs, such as ACE inhibitors, angiotensin receptor blockers (antagonists) (ARBs), and mineralocorticoid receptor antagonists. In Part 1 of this review, we summarized the pharmacokinetic properties of relevant drugs administered intravenously. In Part 2, the present article, we describe pharmacokinetics of drugs following oral administration. For this purpose we conducted a systematic search of literature using MEDLINE, EMBASE, and Japan Centra Revuo Medicina (in Japanese). We retrieved a total of 110 relevant publications for 49 drugs and updated the information for ten drugs and provided new information for 31 drugs. We recognized that the pharmacokinetic data were obtained primarily from stable heart failure patients with moderate severity [New York Heart Association (NYHA) class II or III]. In addition, most patients were classified as heart failure with reduced ejection fraction. Furthermore, because most of the studies retrieved had no comparative groups of healthy subjects or patients without heart failure, historical controls from previous studies were used for comparisons. In Part 2, we also discuss the pharmacokinetics of active metabolites as well as parent drugs, because many drugs given by oral administration for the treatment of heart failure are prodrugs (e.g., ACE inhibitors and ARBs). The pharmacokinetic changes of drugs in patients with heart failure are discussed in the light of a physiologically based pharmacokinetic model. In addition, we discuss the effects of intestinal tissue heart failure-associated edema on drug absorption as it relates to the biopharmaceutical classification system, particularly for drugs demonstrating reduced systemic exposure as measured by the area under the plasma concentration-time curve after oral administration (AUCpo) in patients with heart failure as compared with healthy subjects. After review of the available data, it was seen that among patients with asymptomatic or compensated chronic heart failure there seemed to be no or minimal alterations in the maximum concentration (C max) and AUCpo of the included drugs, unless there was concurrent liver and/or renal dysfunction. In contrast, the AUCpo of at least 14 drugs (captopril, cilazaprilat, enalapril/enalaprilat, perindopril, carvedilol, candesartan, pilsicainide, felodipine, furosemide, enoximone, milrinone, flosequinan, molsidomine, and ibopamine) were suspected or documented to increase after oral administration by 50% or more in patients with symptomatic or decompensated heart failure.

Simultaneous determination of N(1)-methylnicotinamide, L-carnitine, and creatinine in human plasma and urine by liquid chromatography with mass spectrometry for assessing the activities of multiple renal cationic transporters.

Organic cation transporters are responsible for the disposition of various endogenous and therapeutic agents in humans; thus, there is a great need for the development of a simple assay for simultaneous assessment of the activities of multiple transporters. Using liquid chromatography-mass spectrometry (LC/MS), we developed an assay that allows for simultaneous quantitation of plasma and urinary levels of N(1)-methylnicotinamide (a substrate of hOCT2/hMATEs), L-carnitine (a substrate of hOCTN2), and creatinine (an indicator of glomerular filtration). Samples were diluted with ultrapure water, deproteinized with trichloroacetic acid, filtered, and then injected on a cation exchange column. The analytes were separated with a gradient LC technique and detected by MS. The total assay time was less than 8 min. The lower detection limits for N(1)-methylnicotinamide, L-carnitine, and creatinine were 2, 10, and 24 ng/mL, respectively. Recovery of the analytes was almost complete. A preliminary clinical study conducted in 25 healthy subjects revealed that the mean±SD for the renal clearance (CLR) of N(1)-methylnicotinamide (272.7±81.0 mL/min) far exceeded the glomerular filtration rate (116.3±19.6 mL/min), indicating the involvement of active tubular secretion, while the mean CLR of clearance of L-carnitine was close to nil (1.5±1.4 mL/min), indicating almost complete tubular reabsorption. The present method is potentially useful for clinical studies on the genetic control of cationic transporter activities and the transporter-mediated drug interactions.

Population pharmacokinetic and pharmacodynamic analyses of teicoplanin in Japanese patients with systemic MRSA infection.

BACKGROUND: Teicoplanin is a glycopeptide antibiotic used for the treatment of MRSA infection. An initial loading dose of 400 mg every 12 hours for three doses is the standard dosing regimen. This study aimed to assess whether this regimen was appropriate based on the pharmacokinetic/pharmacodynamic (PK/PD) analyses in Japanese patients. METHODS: We conducted a population pharmacokinetic (PPK) analysis of teicoplanin by NONMEM using serum drug concentrations obtained from 116 patients with MRSA infection. PD of the drug was analyzed by a model assuming that the variability of therapeutic responses (assessed by body temperature, serum C-reactive protein concentrations, and white blood cell counts) on the 3rd, 7th or 14th day of treatment is associated with the logarithm of serum unbound drug concentration (Cmax,unbound) divided by the MIC against MRSA (log[Cmax,unbound/MIC]). RESULTS: The final PPK model showed that creatinine clearance and serum albumin concentration were significant (p < 0.01) covariates of systemic clearance and peripheral volume of distribution of teicoplanin, respectively. The PD analyses indicated that log[Cmax,unbound/MIC] of 0.30 on Day 3 of teicoplanin therapy was the threshold for achieving successful clinical responses. Integrating the PK and PD data, we consider that the standard loading dose regimen would attain the threshold serum level within the initial 3 days in only less than 50% of the patients. CONCLUSION: We propose that an extended loading regimen (400 mg every 12 hours for the first 5 doses) would be a treatment option to maximize the therapeutic effects of teicoplanin in patients with systemic MRSA infection.

Clinical pharmacokinetics of drugs in patients with heart failure: an update (part 1, drugs administered intravenously).

Heart failure is one of the leading causes of death in developed countries, and its prevalence is expected to increase further in the coming years. While the pharmacokinetic changes observed in patients with heart failure have been reviewed twice in Clinical Pharmacokinetics, approximately a quarter century has passed since the latest article was published in 1988. Since then, many important classes of agents (e.g. ACE inhibitors, angiotensin receptor antagonists and inotropes) have been introduced for the treatment of heart failure. The aim of the present article is to update the information regarding the pharmacokinetics of these drugs. For this purpose we have made a systematic survey of literature using MEDLINE, EMBASE and Japan Centra Revuo Medicina (in Japanese) and found a total of 111 relevant publications for 58 drugs. Heart failure is a pathophysiological state where the damaged heart, from whatever causes, no longer pumps enough blood for the needs of body tissues at rest or during the normal daily activities. The spectrum of heart failure ranges from acute decompensated heart failure (including circulatory shock) to chronic compensated or decompensated heart failure. Because hypoperfusion of organs may influence drug absorption from the gastrointestinal tract, distribution into tissues and elimination either by the liver or kidneys, it is conceivable that the pharmacokinetics of many drugs may be altered in patients with heart failure. The pharmacokinetic changes of drugs in these patients in the light of a physiologically based pharmacokinetic model are discussed, since this model can interpret altered pharmacokinetics in terms of changes in the binding of drugs in plasma and tissue, blood flow to drug-eliminating organs and intrinsic activity of drug elimination. Pharmacokinetic changes of drugs after intravenous administration are described here in Part 1 and those after oral administration will be discussed in Part 2 in a later issue of the Clinical Pharmacokinetics. Reviewing the retrieved data, it was considered that patients with asymptomatic or compensated chronic heart failure seem to have no or minimal alterations in the pharmacokinetics of parenterally administered drugs as long as there was no concurrent liver and/or kidney dysfunction. In contrast, it was found that the systemic clearance of at least six drugs (i.e. milrinone, carperitide, molsidomine, theophylline, ciclosporin and hydralazine) was reduced after intravenous administration by 50 % or more in patients with acute decompensated heart failure or chronic severe heart failure (New York Heart Association class III or IV) as compared with healthy subjects. Because there is a paucity of information regarding the pharmacokinetics of drugs in patients with severe heart failure, close attention should be paid to monitoring the efficacy of these agents and their associated adverse effects.

Clinically significant drug interactions with antacids: an update.

One may consider that drug-drug interactions (DDIs) associated with antacids is an obsolete topic because they are prescribed less frequently by medical professionals due to the advent of drugs that more effectively suppress gastric acidity (i.e. histamine H(2)-receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]). Nevertheless, the use of antacids by ambulant patients may be ever increasing, because they are freely available as over-the-counter (OTC) drugs. Antacids consisting of weak basic substances coupled with polyvalent cations may alter the rate and/or the extent of absorption of concomitantly administered drugs via different mechanisms. Polyvalent cations in antacid formulations may form insoluble chelate complexes with drugs and substantially reduce their bioavailability. Clinical studies demonstrated that two classes of antibacterials (tetracyclines and fluoroquinolones) are susceptible to clinically relevant DDIs with antacids through this mechanism. Countermeasures against this type of DDI include spacing out the dosing interval - taking antacid either 4 hours before or 2 hours after administration of these antibacterials. Bisphosphonates may be susceptible to DDIs with antacids by the same mechanism, as described in the prescription information of most bisphosphonates, but no quantitative data about the DDIs are available. For drugs with solubility critically dependent on pH, neutralization of gastric fluid by antacids may alter the dissolution of these drugs and the rate and/or extent of their absorption. However, the magnitude of DDIs elicited by antacids through this mechanism is less than that produced by H2RAs or PPIs; therefore, the clinical relevance of such DDIs is often obscure. Magnesium ions contained in some antacid formulas may increase gastric emptying, thereby accelerating the rate of absorption of some drugs. However, the clinical relevance of this is unclear in most cases because the difference in plasma drug concentration observed after dosing shortly disappears. Recent reports have indicated that some of the molecular-targeting agents such as the tyrosine kinase inhibitors dasatinib and imatinib, and the thrombopoietin receptor agonist eltrombopag may be susceptible to DDIs with antacids. Finally, the recent trend of developing OTC drugs as combination formulations of an antacid and an H2RA is a concern because these drugs will increase the risk of DDIs by dual mechanisms, i.e. a gastric pH-dependent mechanism by H2RAs and a cation-mediated chelation mechanism by antacids.

Drug-drug interaction profiles of proton pump inhibitors.

Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastric acid-related disorders and the eradication of Helicobacter pylori. In addition, they are routinely prescribed for the prevention of gastrointestinal bleeding in patients receiving a dual antiplatelet therapy consisting of clopidogrel and aspirin (acetylsalicylic acid) after myocardial infarction or percutaneous coronary intervention and stenting. Because PPIs are given to these patients for long periods, there is a concern about the potential for clinically significant drug-drug interactions (DDIs) with concomitantly administered medications. Because PPIs give rise to profound and long-lasting elevation of intragastric pH, it is not surprising that they interfere with the absorption of concurrent medications. Drug solubility may be substantially reduced at neutral pH compared with acidic conditions. In this context, PPIs have been shown to reduce the bioavailability of many clinically relevant drugs (e.g. ketoconazole, atazanavir) by 50% or more compared with the control values. Soon after the introduction of omeprazole (a prototype PPI) into the market, it was reported that omeprazole was associated with 30% and 10% reductions in systemic clearance of diazepam and phenytoin, respectively. In vitro studies demonstrating the inhibitory effects of omeprazole on the metabolism of these drugs with human liver microsomes gave a mechanistic explanation for the DDIs. Numerous subsequent studies have been performed to investigate the DDI potential of PPIs associated with the metabolic inhibition of cytochrome P450 (CYP) enzyme activities; however, most such attempts have failed to find clinically relevant results. Nevertheless, recent large-scale clinical trials have raised concerns about possible DDIs between PPIs and an antiplatelet drug, clopidogrel. It has been suggested that coadministration of PPIs with a dual antiplatelet therapy consisting of clopidogrel and aspirin may attenuate the anti-aggregation effects of those medications and augment the risk of cardiovascular ischaemic events. There is a possibility that PPIs may elicit detrimental effects by inhibiting CYP2C19-dominated metabolism of clopidogrel to its active metabolite. Further studies are urgently required to clarify the mechanism of this DDI and to explore new aspects of the DDI potential of PPIs.