Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

BACKGROUND: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. METHODS: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. RESULTS: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181-300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3-7.44), 2.61 (95% CI, 1.39-4.91), and 2.38 (95% CI, 1.04-5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62-351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35-14.77) and 6.99 (95% CI, 3.22-15.18). The ß value of EB was 2.07 (95% CI, 1.48-2.76), which was classified as a wear-out failure type. CONCLUSIONS: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection.

INTRODUCTION: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. METHODS: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. RESULTS: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4-1.8) µg·h/mL vs. 21.5 (IQR, 17.7-32.3) µg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9-10.9) µg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3-9.3) µg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. CONCLUSIONS: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

Multivalent cation and polycation polymer preparations influence pharmacokinetics of dolutegravir via chelation-type drug interactions.

Dolutegravir (DTG) is an integrase inhibitor, whose gastrointestinal absorption is impaired by the formation of chelates with multivalent metal cation preparations. However, little is known regarding the interactions of DTG with preparations containing other multivalent metal cations or with polycation polymer preparations. This study examined how the pharmacokinetics of DTG are affected by co-administration with Al(OH)3, LaCO3, and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH)3 (150 or 300 mg/kg), LaCO3 (50 or 75 mg/kg), Bxl (250 or 500 mg/kg), or Svl (300 or 600 mg/kg). Serum concentrations of DTG were then measured over the next 24 h. Compared to the administration of DTG alone, its co-administration with Al(OH)3, LaCO3, Bxl, and Svl led to reduced serum concentration of DTG, and consequently, a significantly reduced area under the curve. These comparisons also revealed a considerable reduction in the maximum concentration, suggesting that the interactions of these agents with DTG in the intestinal tract inhibit absorption of DTG. The above results demonstrate that Al(OH)3, LaCO3, Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG.

Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation.

OBJECTIVES: Raltegravir (RAL) that can form chelates with multivalent metal cations shows lateral interactions with multivalent metal cation and polycationic polymer. We investigated the interactions of RAL with multivalent metal cation preparations, Al(OH)3 and LaCO3 , and polycationic polymer preparations, bixalomer (Bxl) and sevelamer (Svl). METHODS: Immediately before the oral administration of 40 mg/kg RAL, the rats were administered orally with the vehicle, Al(OH)3 , LaCO3 , Bxl, or Svl, and the time course of RAL serum concentration was followed. The in vitro binding affinity of RAL with multivalent metal cation and polycationic polymer was also evaluated using isothermal titration calorimetry (ITC). RESULTS: When Al(OH)3 , LaCO3 , Bxl, or Svl was concomitantly administered with RAL, the maximum concentration and area under the curve were significantly lower than those when RAL was administered alone. ITC showed the interaction of RAL with Al(OH)3 as an enthalpy-driven reaction and its interactions with LaCO3 and Bxl as entropy-enthalpy mixed reactions. CONCLUSIONS: The interaction of RAL with Al(OH)3 , LaCO3, Bxl, or Svl can inhibit RAL absorption into the gastrointestinal tract, and thus, the multivalent metal cation and polycationic polymer are the modifying factors that can affect RAL pharmacokinetics.

Evaluation of the Expression Time of Ganciclovir-Induced Adverse Events Using JADER and FAERS.

Investigation of the occurrence time of adverse drug reactions helps to prevent the development and aggravation of adverse reactions, but the expression time of ganciclovir-induced adverse events has not been elucidated. In this study, using databases of spontaneous adverse event reports, the Japanese Adverse Drug Event Report database (JADER) and the U.S. Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), the incidence of adverse reactions due to ganciclovir and their expression time were analyzed. As a result of calculation of the reporting odds ratio (ROR) and 95% confidence interval for individual main adverse reactions of ganciclovir (cytopenia, leukopenia, thrombocytopenia, liver damage, and acute renal failure), a signal was detected for all adverse reactions in both databases, except for liver damage in JADER. Furthermore, the Weibull distribution was performed for the analysis of onset time of each ganciclovir-induced adverse event. The results of Weibull parameter α and ß values of each adverse event in both JADER and FAERS suggested that most adverse events occurred within 30 d and classified into the early failure type, except that thrombocytopenia and acute renal failure in JADER classified into the random failure type. Based on these findings, it concluded that the paying attention to signs of each ganciclovir-induced adverse event is required from the early phase after ganciclovir administration. However, in FAERS, development after a long-term course also accounted for 11%, suggesting that long-term periodic monitoring of adverse reactions would be also required.

Age-Associated Theophylline Metabolic Activity Corresponds to the Ratio of 1,3-Dimethyluric Acid to Theophylline in Mice.

Age is known as one of influencing factor for theophylline (TP)-metabolizing capacity. In a previous our study, the ratio of TP and its major metabolite 1,3-dimethyluric acid (DMU) in serum (DMU/TP) is a useful index to estimate TP-metabolizing capacity, and this value markedly increased by influencing factor, such as the history of smoking. However, it is unknown whether DMU/TP values in serum reflect age-associated changes of TP-metabolizing capacity. In this study, the effect of age on the DMU/TP values in serum were investigated using mice of different age due to the limited blood sampling in human. The concentrations of TP and its metabolites in mouse serum were simultaneously measured using HPLC. As observed in human serum, serum TP concentrations were closely correlated with DMU concentration in mice, which indicates that the DMU/TP ratio is a good indicator of TP metabolic ability in mice. When TP was administered subcutaneously in 2-28-week-old mice, age-associated changes in the DMU/TP ratio in mice were observed. In conclusion, age-associated changes in TP-metabolizing capacity can be estimated by the DMU/TP ratio in serum.

Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

OBJECTIVES: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. METHODS: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. KEY FINDINGS: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC0-∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. CONCLUSIONS: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.

Dosing optimization of meropenem based on a pharmacokinetic analysis in patients receiving hemodiafiltration and an in vitro model.

The purpose of this study was to estimate the in vivo pharmacokinetics of meropenem during intermittent-infusion hemodiafiltration (I-HDF) and clarify its optimal dosage and dosing interval in patients receiving I-HDF. The clearance of meropenem by online hemodiafiltration (OL-HDF) and I-HDF was predicted using an in vitro system and assessed to establish whether the results obtained are applicable to clinical cases. In the in vivo study, the mean volume of distribution (Vd), non-I-HDF clearance (CLnon-I-HDF), and I-HDF clearance (CLI-HDF) were 15.80 ± 3.59 l, 1.05 ± 0.27 l/h, and 5.78 ± 1.03 l/h. Dosing regimens of 0.25 g once daily for a MIC of 8 µg/ml and of 0.5 g once daily for a MIC of 16 µg/ml achieved 40% T > MIC. In the in vitro and in vivo studies, observed CLHDF was similar to predictive CLHDF (= Cf/Cp × (QD + QSUB)). In conclusion, adjustments to the dose and interval of meropenem were developed based on the presumed susceptibility of pathogens to meropenem in patients receiving I-HDF. We suggest 0.5 g once daily as an appropriate regimen for empirical treatment.

Development of HPLC with fluorescent detection using NBD-F for the quantification of colistin sulfate in rat plasma and its pharmacokinetic applications.

Colistin sulfate, composed of a mixture of colistin A sulfate (CLA) and colistin B sulfate (CLB), is available for treating life-threatening infections caused by multidrug-resistant Gram-negative bacteria. In this study, the CLA and CLB were quantified separately. Colistin sulfate was extracted from rat plasma with a solid-phase extraction C18 cartridge and reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and the fluorescent derivatives were subjected to reversed-phase high-performance liquid chromatography analysis and used to investigate the pharmacokinetics of CLA and CLB in rat plasma. The recovery rates of CLA and CLB were 41.2 ± 4.4 and 45.5 ± 3.1%, respectively. The recovery rate calculated from the total area of CLA and CLB was 43.9 ± 3.6%. When 2 mm NBD-F and 10 mm boric acid buffer (pH 9.5) were added to colistin sulfate, the highest recovery rate was obtained. The best heating time was 5 min at 60°C. The lower limits of quantification for CLA, CLB and the total area of CLA and CLB were 0.05, 0.05 and 0.1 µg/mL; the coefficients of variations were 13.5, 14.5 and 14.1%, respectively. This method was found to have acceptable linearity, precision and accuracy, and has been successfully applied to a pharmacokinetic study in rat plasma.

[Development of a New Scholastic Program for Medication Counseling Practice in Preclinical Training, Constructed for Junior Students by Senior Students Based on Their Experiences of On-site Practice].

Long-term practical on-site training, based on the Model Core Curriculum for Pharmaceutical Education, is a core program of the 6-year course of pharmaceutical education, introduced in Japan in 2010. In particular, medication counseling in practical training in 5th-year provides valuable opportunities for communication with real patients rather than simulated patients (SPs). However, it can also cause anxiety in 4th-year students before practical training. To address such concerns, upperclassmen (5th- and 6th-year students), who have already completed practical training, constructed and conducted a new educational program for medication counseling practice in preclinical training based on their experiences. They also developed case scenarios and played the role of patients themselves to create more realistic clinical settings. Advice from professional SPs was also provided. The 5-step program is composed of 1st counseling, 1st small group discussion (SGD) for improving counseling, 2nd revised counseling based on the 1st SGD, 2nd SGD, and development of a counseling plan and presentation. Educational effects of the program were evaluated by questionnaire survey after preclinical training in 4th-year students and after their practical training in 5th-year students. This new program, the Advanced Medication Counseling Practice, was found to be useful to reduce anxiety about communication with patients among 4th-year students (about 90%). Even after their practical training in 5th-year, they still appreciated usefulness of this program (about 80%). This program is still valued 4 years after its development. We developed the Advanced Medication Counseling Practice in preclinical training for junior students by senior students.

Factorial Analysis of Hepatitis B Virus Reactivation-Induced Hepatitis B Using JADER.

Hepatitis B caused by chemotherapy- and immunosuppression-associated hepatitis B virus reactivation is likely to become fulminant, and a high mortality rate has been reported. In this study, using the Japanese adverse drug event report database (JADER), factorial analysis of patients who developed hepatitis B as an adverse event was performed. The number of reported cases of hepatitis B during the survey period was 781 and 185 of them (24%) died. Rituximab and prednisolone were administered to many cases (233, 216 cases, respectively), and the reporting odds ratios were high (65.35, 13.40, respectively), suggesting their strong association with the development of hepatitis B. Regarding the onset time, rituximab-induced hepatitis B developed within one year after administration in 83%, being a high frequency. Prednisolone-induced hepatitis B developed even after one year in 36%. Since prednisolone is used to treat rheumatoid arthritis at a dose ≤10 mg/d, the patients were divided based on the prednisolone dose into the groups treated at >10 and ≤10 mg/d, and the onset time was investigated in each group. The median onset time was 113 and 330 d, respectively, showing a significant difference. On time-to-event analysis using the Weibull distribution, rituximab was classified as the early failure type, and prednisolone and methotrexate for rheumatoid arthritis were classified as the wear out failure type. These findings are important information which may lead to early discovery of and taking actions against hepatitis B being helpful for providing appropriate medical care.

Patients Taking Antihistamines and Their Effects on Driving.

Sleepiness is known as one of the side effects of antihistamines, and impaired performance caused by these drugs has become problematic. Among the 13 second-generation antihistamines causing sleepiness to some extent, the package inserts of 8 drugs prohibit driving, 3 stress driving with care, and 2 give no driving-related warning. It was confirmed that the description did not necessarily reflect the results of the standard deviation of lateral position measurement study, which is considered the most effective study for evaluating the effects of drugs on automobile driving. Do these descriptions reflect actual patients' sleepiness? According to a questionnaire survey involving 2000 individuals taking second-generation antihistamines, 7.3% of respondents answered that they had always become sleepy after taking antihistamines (3.1-12.5% according to the type of antihistamine), 32.8% (27.8-45.8%) had become sleepy sometimes, 9.1% (3.1-15.8%) had previously become sleepy but not anymore, and 40.9% (27.1-49.1%) had never become sleepy. In addition, 10.3% (2.4-21.1%) reported intolerable sleepiness. Patients who had experience of receiving pharmaceutical education from pharmacists numbered 1296 (64.8%), and 80.2% of them had also received driving-related explanations, which included the prohibition of driving (32.8%), stressing the need to drive with care (54.7%), and the prohibition of medication before driving (12.0%). Concerning these explanations, the proportion who paid attention on a daily basis, paid slight attention, and paid no attention was 36.7, 31.2, and 32.1%, respectively. To provide effective and safe pharmacotherapy for the increasing number of patients taking antihistamines, pharmacists should ideally improve pharmaceutical education.

Local Pharmacy Pharmacists' Responses to the Prescription of Drugs That Influence Driving.

In 2013, the Ministry of Health, Labour, and Welfare issued a notification regarding drugs that influence driving. Afterward, a questionnaire survey of these drugs was conducted involving health insurance pharmacies in Tokyo and Shiga Prefectures. As a result, 503 (Tokyo) and 116 (Shiga) pharmacies provided completed questionnaires. The notification was sufficiently and slightly recognized by 20% and 44% of the surveyed pharmacies, respectively, and drugs with a driving-related warning were recognized by 31% of the pharmacies. In addition, 23% of the pharmacies reported that they always asked patients whether they drive. The influence on driving of antianxiety drugs, hypnotics, antiepileptics, and smoking-cessation drugs was always explained to patients by 74%, 72%, 64%, and 40% of the pharmacies, respectively. Concerning responses to the prescription of drugs influencing driving, the proportion of surveyed pharmacies in Tokyo and Shiga Prefectures that directed patients not to drive was 71% and 53%, respectively, and that directed patients to stop driving on developing any symptom was 32% and 49%. Tokyo and Shiga Prefectures showed a significant difference in the reason for not prohibiting driving; the proportion of pharmacies that regarded strict medication adherence as of major importance to treat patients' primary diseases was 22% and 43%, respectively. This difference might have been attributable to a high percentage of patients (80%) driving to pharmacies in Shiga Prefecture. To facilitate the prescription of drugs influencing driving, it is recommended to design drug-specific pharmaceutical education manuals that also give consideration to patients' QOL.

Synthesis of Linezolid Metabolites PNU-142300 and PNU-142586 toward the Exploration of Metabolite-Related Events.

Linezolid (1) is an oxazolidinone antibiotic that is partially metabolized in vivo via ring cleavage of its morpholine moiety to mainly form two metabolites, PNU-142300 (2) and PNU-142586 (3). It is supposed that accumulation of 2 and 3 in patients with renal insufficiency may cause thrombocytopenia, one of the adverse effects of linezolid. However, the poor availability of 2 and 3 has hindered further investigation of the clinical significance of the accumulation of these metabolites. In this paper, we synthesized metabolites 2 and 3 via a common synthetic intermediate, 4; this will encourage further exploration of events related to these metabolites and lead to improved clinical use of linezolid.

Pregabalin prescription for terminally ill cancer patients receiving specialist palliative care in an acute hospital.

BACKGROUND: Pregabalin is recommended as an adjuvant analgesic for neuropathic cancer-related pain, and may be taken at all steps of the World Health Organization analgesic ladder. However, unlike opioids, pregabalin treatments are limited to an oral administration route. If patients have oral feeding difficulties, it is not possible to administer any drug as an adjuvant analgesic for neuropathic cancer-related pain. Therefore, the aim of the present study was to clarify the problems of pain control after pregabalin discontinuation in terminally ill cancer patients. METHODS: Our subjects comprised cancer patients who died during their hospital stay and were referred between April 2013 and October 2015 to the palliative care team of the 899-bed Cancer Hospital at the Nippon Medical School Hospital in Japan. The medical records of each patient were retrospectively reviewed, and patient characteristics were recorded. RESULTS: We obtained data on 183 patients during the study period. Thirty-eight (20.8 %) patients were treated with pregabalin. Thirty-three (86.8 %) out of 38 patients were prescribed pregabalin for neuropathic cancer-related pain. The incidence of bony metastases was significantly higher in patients administered pregabalin than in those not taking the drug (non-pregabalin group 32.4 % vs pregabalin group 57.9 %). Pregabalin was ultimately discontinued in all patients, with the main reason being oral feeding difficulties (81.6 %). After the discontinuation of pregabalin, the amount of opioid drugs administered was increased in 56.5 % of patients with oral feeding difficulties. CONCLUSION: Our results demonstrated that the amount of opioid drugs administered was increased in more than 50 % of patients following the discontinuation of pregabalin, and was repeatedly increased for some patients. A new administration route is required for cancer patients unable to take oral medication. TRIAL REGISTRATION: UMIN000022507. May 28, 2016 retrospectively registered.

Pharmaceutical studies on and clinical application of olanzapine suppositories prepared as a hospital preparation.

BACKGROUND: A new formulation of olanzapine available for terminally ill patients is needed. Rectal administration using suppositories is an alternative for patients for whom administration via the oral route is not feasible. In the present study, we prepared olanzapine suppositories, and confirmed using pharmaceutical tests. Furthermore, we demonstrated the efficacy and safety of olanzapine suppositories in terminally ill patients. METHODS: We prepared olanzapine suppositories using bases consisting of different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test was performed, and the olanzapine suppository with the best dissolution rate was selected. The suppository was assessed using the content uniformity test, content test in suppositories, hardness test, stability test, and clinical efficacy and safety. RESULTS: The dissolution rate at 360 min of olanzapine suppositories with Witepsol H-15 was the best (77.0 ± 3.3 %). The suppositories prepared had a uniform weight (2.47 ± 0.02 g) and content (2.11 ± 0.07 mg). The power required to break suppositories was 7.96 ± 0.55 kgf. When olanzapine suppositories were stored with protection from light, their contents were maintained regardless of whether the temperature was at 4 °C or room temperature. The numbers of patients administered 2.5 mg, 5 mg, and 10 mg of olanzapine suppositories were 4, 19, and 1. The percentages of patients with delirium or nausea and vomiting cured with olanzapine suppositories were 82 and 57 %, respectively. CONCLUSION: We suggest that olanzapine suppositories prepared in the hospital by pharmacists will improve the quality of life of terminally ill patients. TRIAL REGISTRATION: UMIN000022172. May 2, 2016 retrospectively registered.

Pharmacokinetics and brain penetration of carbapenems in mice.

An adverse effect associated with the administration of carbapenems is central nervous system (CNS) toxicity, with higher brain concentrations of carbapenems being linked to an increased risk of seizures. However, the pharmacokinetics and brain penetration of carbapenems have not yet been examined. Thus, the aim of this in vivo investigation was to determine the pharmacokinetics and brain penetration of carbapenems in mice. Blood samples and brain tissue samples were obtained 10, 20, 30, 60, and 120 min after the subcutaneous administration of carbapenems (91 mg/kg). We obtained the following values for the pharmacokinetic parameters of carbapenems in mice: 1.20-1.71 L/h/kg for CLtotal/F, 1.41-2.03 h(-1) for Ke, 0.34-0.51 h for T1/2, 0.66-0.95 L/kg for Vss/F, 0.49-0.73 h for MRT, 83.46-110.58 µg/mL for Cmax, plasma, and 0.28-0.83 µg/g for Cmax, brain tissue. The AUC0-∞ of the carbapenems tested in plasma were in the following order: doripenem > meropenem > biapenem > imipenem, and in brain tissue were: imipenem > doripenem > meropenem > biapenem. The degrees of brain tissue penetration, defined as the AUC0-∞, brain tissue/fAUC0-∞, plasma ratio, were 0.016 for imipenem, 0.004 for meropenem, 0.002 for biapenem, and 0.008 for doripenem. The results of the present study demonstrated that, of the carbapenems examined, imipenem penetrated brain tissue to the greatest extent.

[Basic Studies on the Stability of Flavored Oral Solutions of Rebamipide].

Stomatitis frequently occurs during chemotherapy and radiotherapy for cancer. Because of its pharmacological properties including anti-inflammatory activity and stimulatory effects on endogenous prostaglandin synthesis, rebamipide has been suggested as a potentially effective treatment against stomatitis. In the present study we tested the stability of oral rebamipide solutions prepared in our hospital pharmacy using sodium alginate as a thickener to increase retention of this agent in the oral cavity, and the addition of different flavoring mixtures intended for use in enteral diets to reduce the bitterness of rebamipide and sodium alginate. Samples of oral rebamipide solution prepared with 13 kinds of flavoring and sodium alginate were evaluated in terms of their appearance, redispersibility, pH, viscosity, and rebamipide content immediately after preparation and 1, 3, 7, and 10 days after storage at room temperature under ambient light or in a cool, dark place. After 10 days of storage, favorable stability was observed in four sample solutions supplemented with green apple, pineapple, yogurt, and tomato flavoring mixtures intended for use in Elental(®) diets. These oral solutions may have potential clinical application.

Anti-inflammatory effects of linezolid on carrageenan-induced paw edema in rats.

The immunomodulatory activity of linezolid has recently been reported using in vitro experimental models. However, the anti-inflammatory activity of linezolid has not yet been demonstrated using in vivo experimental models. Therefore, the aim of the present study was to demonstrate the anti-inflammatory activity of linezolid and other anti-MRSA agents using the carrageenan-induced rat paw edema model. The pretreatment with 50 mg/kg linezolid significantly suppressed edema rates, compared with control (5% glucose), with edema rates at 0.5 and 3 h after the administration of carrageenan being 17.3 ± 3.5 and 30.8 ± 3.0%, respectively. On the other hand, edema rates were not suppressed by the pretreatments with 50 mg/kg vancomycin, teicoplanin, arbekacin, and daptomycin. Furthermore, we demonstrated that linezolid exhibited anti-inflammatory activity in a concentration-dependent manner. These effects were observed at linezolid concentrations that are achievable in human serum with conventional dosing. In conclusion, the results of the present study suggest that the anti-inflammatory activities of linezolid, in addition to its antimicrobial effects, have a protective effect against destructive inflammatory responses in areas of inflammation.