Efficacy and Safety of Uninterrupted Periprocedural Edoxaban in Patients Undergoing Catheter Ablation for Atrial Fibrillation　- The Prospective KYU-RABLE Study.

BACKGROUND: The KYU-RABLE study, a prospective, multicenter, single-arm interventional study, evaluated the efficacy and safety of uninterrupted oral edoxaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF).Methods and Results:We enrolled patients with AF from 23 centers in Japan. Edoxaban 60 mg (30 mg in patients indicated for dose adjustment) was administered uninterrupted, once daily in the morning for ≥4 weeks before CA and 4 weeks ±7 days after CA with one dose delayed on the procedural day. The primary endpoint was a composite of thromboembolism and major bleeding during 4 weeks from the procedural day. Among the 513 eligible patients who underwent CA, 63.5% received edoxaban 60 mg/day and 36.1% received 30 mg/day. For the primary endpoint, no thromboembolism and 1 major bleeding event (0.2%, cardiac tamponade) were observed. The plasma edoxaban concentration decreased depending on the time from the last administration to the CA procedure. However, plasma levels of coagulative biomarkers were within appropriate ranges regardless of the interval from the last administration of edoxaban. CONCLUSIONS: The present study provided evidence of the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on procedural day, in patients with AF undergoing CA. Edoxaban was associated with a low risk of periprocedural thromboembolic and bleeding complications.

Sensory evaluation of edoxaban orally disintegrating tablets: an open-label interventional study (secondary publication).

BACKGROUND: This study involved a sensory evaluation of edoxaban orally disintegrating (OD) tablets in patients with nonvalvular atrial fibrillation who had been receiving the existing edoxaban film-coated tablets before the study. METHODS: Edoxaban OD tablets 30 or 60 mg were prescribed for patients who had been receiving the existing 30- or 60-mg edoxaban film-coated tablets before the study. Each dose group was randomized into groups taking the tablets with or without water. After ingestion of the edoxaban OD tablet, each patient was asked to complete a sensory evaluation questionnaire (12 items). RESULTS: In the evaluation of satisfaction with edoxaban OD tablets, 52.8% of the patients perceived "no difference" from the existing edoxaban film-coated tablets and 34.9% indicated that they were more satisfied with the OD tablets, thus demonstrating a relatively high degree of satisfaction. When asked about convenience and reliability in using edoxaban OD tablets, about half of the patients perceived "no difference" from the existing edoxaban film-coated tablets and the remaining half indicated preference for the OD tablets. Responses about taste, flavor, ease of ingestion, and motivation to continue taking edoxaban indicated the overall acceptance of the OD tablets. Recognition of edoxaban OD tablets was rated as "easy" by about half of the patients and "difficult" by the remaining half. Among all patients, 49.5% preferred a change to edoxaban OD tablets. The degree of satisfaction with taste, flavor, and ease of ingestion, as well as overall satisfaction, tended to be greater when the OD tablets were taken with rather than without water, and the percentage of patients who preferred a change was higher in the group taking the OD tablets with water. CONCLUSIONS: This study indicated that the degree of satisfaction with taste, flavor, ease of ingestion, and convenience, as well as overall satisfaction, in addition to motivation to continue drug intake and sense of confidence were greater for OD tablets than for the existing edoxaban film-coated tablets. Edoxaban OD tablet is a promising formulation for inducing greater patient adherence to medication and therefore ensures better treatment response. TRIAL REGISTRATION: UMIN-CTR UMIN000028788, registered 23-Aug-2017.

[Study on the safety and efficacy of sitafloxacin at a dose of 100 mg once a day--results of the use-results survey].

Sitafloxacin (STFX, Gracevit 50 mg, fine granules 10%), an oral quinolone antibacterial agent, was approved additionally for administration at a dose of 100 mg once a day in August 2011. A use-results survey on STFX 100 mg/day was performed from December 2011 to May 2013. In total, 1,186 case cards were collected from 226 medical institutions and 1,089 cases were subjected to a safety evaluation and 1,069 were subjected to an efficacy evaluation. The incidence of adverse drug reactions (ADRs) was 2.11% (23/1,089 cases) and no serious ADRs were observed. The major ADR was diarrhea at 1.10% (12/1,089 cases). Of these 12 cases, 10 cases developed symptoms within 4 days of treatment. All of them, except one case that could not be followed up, either recovered or improved. Nonsteroidal anti-inflammatory drugs of the phenyl acetate and propionate types, which require caution when coadministered with STFX, were used concomitantly by 17.6% (192/1,089 cases) of patients but no central nervous system ADRs were observed. The overall efficacy rate was 96.4% (1,030/1,069 cases) and by types of infections, it was 97.0% (387/399 cases) for respiratory tract infections, 96.7% (353/365 cases) for urinary tract infections, 94.7% (36/38 cases) for gynecological infections, 92.3% (132/143 cases) for otorhinolaryngological infections, 98.4% (122/124 cases) for dental and oral surgical infections. The efficacy rate in every category of site of infection exceeded 90%. The overall eradication rate was 94.4% (185/196 strains) including Gram-positive bacteria at 95.4% (62/65 strains), Gram-negative bacteria at 92.2% (94/102 strains), anaerobes at 100.0% (11/11 strains) and atypical bacteria at 100.0% (18/18 strains). In conclusion, this use-results survey confirmed that STFX 100 mg/day is an effective administration with no serious problems in its safety profile and efficacy rate of over 90% in every category of site of infection.

[In vitro activity of sitafloxacin against clinical isolates in 2012].

In vitro activity of sitafloxacin (STFX) and various oral antimicrobial agents against bacterial isolates recovered from clinical specimens between January and December 2012, at different healthcare facilities in Japan was evaluated. A total of 1,620 isolates including aerobic and anaerobic organisms were available for the susceptibility testing using the microbroth dilution methods recommended by Clinical and Laboratory Standards Institute. The minimum inhibitory concentration of STFX at which 90% of isolates (MIC90) was 0.5 microg/mL for methicillin-susceptible Staphylococcus aureus and was 2 times lower than that of garenoxacin (GRNX), 4 times lower than that of moxifloxacin (MFLX), and 16 times lower than that of levofloxacin (LVFX). STFX inhibited the growth of all the isolates of Streptococcus pneumoniae at 0.06 microg/mL or less. The MIC90 of STFX was 0.03 microg/mL and was 2 times lower than that of GRNX, 4 times lower than that of MFLX, and 32 times lower than that of LVFX. Against Streptococcus pyogenes, the MIC90 of STFX was 0.06 microg/mL and was 2 times lower than that of GRNX, 8 times lower than that of MFLX, and 32 times lower than that of LVFX. The MIC90 of STFX was 2 microg/mL for Enterococcus faecalis, and was 4 times lower than that of GRNX, 8 times lower than that of MFLX, and 32 times lower than that of LVFX. The MIC90 of STFX for Escherichia coli was 2 microg/mL, and the MIC90(s) of other 10 species of Enterobacteriaceae which were the lowest values of the quinolones tested ranged from 0.03 to 1 microg/mL. The MIC90 of STFX for Pseudomonas aeruginosa isolates recovered from urinary infections was 4 microg/mL and was 32 times lower than those of GRNX, MFLX and LVFX. The MIC90 of STFX for P. aeruginosa isolates recovered from respiratory infections was 4 microg/mL and was 8 to 16 times lower than those of GRNX, MFLX, and LVFX. STFX inhibited the growth of all the isolates of Haemophilus influenzae at 0.004 microg/mL or less, and was 4 times lower than that of GRNX, 16 times lower than that of MFLX, and 8 times lower than that of LVFX. The MIC90 of STFX was 0.015 microg/mL for Moraxella catarrhalis, and was equal to that of GRNX, 4 times lower than those of MFLX and LVFX. The MIC90(s) of STFX ranged from 0.03 to 0.25 microg/mL for all the species of anaerobic bacteria and were the lowest values of all the antimicrobial agents tested. In conclusion, the activity of STFX against Gram-positive cocci was comparable or superior to those of GRNX, MFLX and LVFX. STFX showed the most potent activity against Gram-negative bacteria and anaerobic bacteria of all the antimicrobial agents tested in this study.

[Efficacy and safety of sitafloxacin in patients with urinary tract infections].

Sitafloxacin (STFX, Gracevit 50mg, fine granules 10%), a new quinolone antibacterial agent, was approved in January 2008, and the use-results survey was carried out over the 2 years between December 2008 and November 2010. We studied the efficacy and safety of STFX in 1,452 patients with urinary tract infections (cystitis, pyelonephritis, urethritis). The total efficacy rate for urinary tract infections was 91.4% (1,235/1,351 patients). Efficacy rates, classified by the type of infection, were: uncomplicated cystitis 95.9% (466/486 patients), complicated cystitis 87.2% (511/586 patients), uncomplicated pyelonephritis 96.1% (49/51 patients), complicated pyelonephritis 93.5% (145/155 patients), and urethritis 87.7% (64/73 patients). Efficacy rates were 86.0% (49/57 patients) for non-responders to cephems and 77.4% (48/62 patients) for non-responders to quinolones. The eradication rate of indicated strains was 90.5% (545/602 strains). The eradication rates of major causative bacteria were; Escherichia coli 92.7% (294/317 isolates), Enterococcus faecalis 86.0% (43/50 isolates), Pseudomonas aeruginosa 66.7% (16/24 isolates), Klebsiella pneumoniae 95.2% (20/21 isolates), and Chlamydia trachomatis 88.9% (8/9 isolates). The incidence of adverse drug reactions (ADRs) was 2.71% (37/1,365 cases). Major ADRs were diarrhoea (0.88%, 12 cases) and hepatic function disorders (0.51%, 7 cases). A serious ADR (hepatic function abnormality) was observed in 1 case, and the hepatic function in this patient returned to normal after treatment with STFX was discontinued. In conclusion, these results suggest that STFX is a useful antibacterial agent with an efficacy rate of 91.4% against urinary tract infections, with a minimum efficacy rate of 87.2% (against complicated cystitis), and has no serious problems in its safety profile.

[Study on the safety and efficacy of sitafloxacin--results of the use-results survey].

Sitafloxacin (STFX, Gracevit 50 mg, fine granules 10%), a new quinolone antibacterial agent, was approved in January 2008, and the use-results survey was performed for 2 years from December 2008 to November 2010. In total, 3558 case cards were collected from 287 medical institutions and 3331 cases were subjected to a safety evaluation and 3225 were subjected to an efficacy evaluation. Incidence of adverse drug reactions (ADRs) was 4.44% (148/3331 cases). Major ADRs were diarrhea (55 cases) and hepatic function disorders (39 cases), and the incidences were 1.65% and 1.17%, respectively. Serious ADRs were observed in 5 cases (7 episodes); gastrointestinal haemorrhage, hepatic function abnormal, white blood cell count decreased, drug eruption, hypoglycemia, pneumonia, and superinfection in one case each. Efficacy rate was 92.9% (2997/3225 patients) in total with a range of 91.4 to 97.8% by type of infection such as respiratory tract and urinary tract. Eradication rate of indicated strains was 91.5% (808/883 strains) including Gram-positive bacteria at 92.3% (310/336 strains), Gram-negative bacteria at 90.7% (458/505 strains), anaerobes at 100.0% (28/28 strains) and atypical bacteria at 85.7% (12/14 strains). In conclusion, this use-results survey confirmed that STFX is a useful antibacterial agent with no serious problems in its safety profile and efficacy rates of over 90% against all infections.

Bleeding risks associated with anticoagulant therapies after percutaneous coronary intervention in Japanese patients with ischemic heart disease complicated by atrial fibrillation: A comparative study.

BACKGROUND: Current guidelines recommend early termination of triple therapy and the use of direct oral anticoagulants (DOAC) for non-valvular atrial fibrillation (NVAF) patients who undergo percutaneous coronary intervention (PCI), due to safety concerns. However, to date, real-world medication usage and safety outcomes (specifically bleeding) in NVAF patients with stent implantation have not been well assessed. METHODS: This was a retrospective, observational, medical database cohort study in Japanese ischemic heart disease (IHD) patients with NVAF who underwent PCI between 2012 and 2017. The primary outcome was clinically relevant bleeding; secondary outcomes included individual bleeding events. A multivariate analysis was conducted to identify risk factors affecting the occurrence of clinically relevant bleeding events. RESULTS: The analysis population comprised 5695 patients [3530 received DOACs and 2165 received vitamin K antagonists (VKAs)]. The incidence of primary outcome events (clinically relevant bleeding/100 patient-years) was 6.05 in the DOAC group and 8.42 in the VKA group, resulting in a nonsignificant 21% lower risk in the DOAC group. The DOAC group also had a nonsignificant 24%, 24%, and 34% lower risk of bleeding requiring transfusion, intracranial bleeding, and lower gastrointestinal bleeding, respectively, compared with the VKA group. A multivariate analysis of the primary outcome showed a significantly higher risk of bleeding among older patients and those with lower body weight and abnormal renal function. CONCLUSIONS: In this retrospective real-world evaluation of IHD patients with NVAF and PCI, DOAC-treated patients had a lower risk of developing clinically relevant bleeding compared with the VKA group.

[In vitro activity of sitafloxacin against clinical isolates in 2009].

In vitro activity of sitafloxacin (STFX) and various oral antimicrobial agents against bacterial isolates recovered from clinical specimens between January and December 2009, at different healthcare facilities in Japan was evaluated. A total of 1,620 isolates including aerobic and anaerobic organisms was available for the susceptibility testing using the microbroth dilution methods recommended by Clinical Laboratory Standard Institute. The minimum inhibitory concentration of STFX at which 90% of isolates (MIC90) was 0.06 microg/mL for methicillin-susceptible Staphylococcus aureus and was equal to that of garenoxacin (GRNX), 2 times lower than that of moxifloxacin (MFLX), and 8 times lower than that of levofloxacin (LVFX). STFX inhibited the growth of all the isolates of Streptococcus pneumoniae at 0.06 microg/mL or less. The MIC90s of STFX ranged from 0.03 to 0.06 microg/mL and were 1 to 2 times lower than those of GRNX, 2 to 4 times lower than those of MFLX, and 16 to 32 times lower than those of LVFX. Against Streptococcus pyogenes, the MIC90 of STFX was 0.06 microg/mL and was 2 times lower than that of GRNX, 4 times lower than that of MFLX, and 32 times lower than that of LVFX. The MIC90 of STFX was 0.25 microg/mL for Enterococcus faecalis, and was 2 times lower than those of GRNX and MFLX, and 8 times lower than that of LVFX. The MIC90 of STFX for E. coli was 2 microg/mL, and the MIC90s of other 10 species of Enterobacteriaceae which were the lowest values of the quinolones tested ranged from 0.03 to 1 microg/mL. The MIC90 of STFX for Pseudomonas aeruginosa isolates recovered from urinary infections was 8 microg/mL and was 16 times lower than those of GRNX, MFLX and LVFX. The MIC90 of STFX for P aeruginosa isolates recovered from respiratory infections was 2 microg/mL and was 32 times lower than those of GRNX and MFLX, and 16 times lower than that of LVFX. STFX inhibited the growth of all the isolates of Haemophilus influenzae at 0.004 microg/mL or less, and was 2 to 4 times lower than those of GRNX, 8 times lower than those of MFLX, and 4 times lower than those of LVFX. The MIC90 of STFX was 0.008 microg/mL for Moraxella catarrhalis, and was 2 times lower than that of GRNX, 8 times lower than those of MFLX and LVFX. The MIC90s of STFX ranged from 0.015 to 0.12 microg/mL for all the species of anaerobic bacteria and were the lowest values of all the antimicrobial agents tested. In conclusion, the activity of STFX against Gram-positive cocci was comparable or superior to those of GRNX, MFLX and LVFX. STFX showed the most potent activity against Gram-negative bacteria and anaerobic bacteria of all the antimicrobial agents tested in this study.

Registry of antithrombotic therapy in atrial fibrillation patients with bioprosthetic valves: A retrospective observational study.

BACKGROUND: The incidence of cardiovascular diseases, including valvular heart disease and atrial fibrillation (AF), is rising as the elderly population increases. For patients with AF and bioprosthetic valves, current treatment guidelines for antithrombotic therapy vary by country, likely due to a lack of robust study data. METHODS: We conducted a multicenter, retrospective, observational analysis of 214 Japanese AF patients after bioprosthetic valve replacement in real-world clinical practice. The primary efficacy endpoint was the incidence of stroke/systemic embolism, and the primary safety endpoint was major bleeding. RESULTS: The mean observation period was 46.0 months. Warfarin was administered to 176 patients (82.2%), direct oral anticoagulants (DOAC) to 16 patients (7.5%), and antiplatelet drugs to 13 patients (6.1%). The number of patients who were treated with DOAC was increasing in the later period of registration. Stroke/systemic embolism was observed in 14 patients [1.77 patients/100 person-years (PY)]. Major bleeding was observed in 22 patients (2.83/100 PY). CONCLUSIONS: In a current real-world setting in Japan, warfarin was the most commonly used treatment in AF patients with bioprosthetic valves, but there was an increasing trend of DOAC-treated patients. Further investigations are needed to confirm the efficacy and safety of DOAC in patients with bioprosthetic valves.

Recent prescription status of oral analgesics in Japan in real-world clinical settings: retrospective study using a large-scale prescription database.

Background: Information on prescriptions of oral analgesics for the treatment of pain is beneficial. However, there have been few reports on the prescription status of oral analgesics from a nation-wide, large-scale prescription database in Japan. Research design and methods: The authors analyzed the prescription data of 2,042,302 patients prescribed oral analgesics in 2017. The numbers/proportions of patients prescribed oral analgesics, adherence with approved doses, co-prescription patterns, dose changes, drug adherence, and treatment-discontinuation rates were evaluated. Results: Loxoprofen was prescribed to 32.5% of the patients, followed by celecoxib, prescribed to 16.0% of patients. Acetaminophen and pregabalin were prescribed to 10.5% and 9.4% of patients, respectively. Many analgesics were prescribed at lower doses than the approved doses. The most frequently used concomitant medication was pregabalin. For duloxetine and pregabalin, high proportions of patients were prescribed these drugs for > 90 days. Conclusions: Loxoprofen was the most prescribed of the non-steroidal anti-inflammatory drugs in Japan. The information obtained provides an overview of prescribed oral analgesics in Japan and could be useful for potential research into prescribed oral analgesics in the future.

Design and rationale of the STroke secondary prevention with catheter ABLation and EDoxaban clinical trial in patients with non-valvular atrial fibrillation: The STABLED study.

BACKGROUND: Catheter ablation (CA) has been reported to reduce risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) in retrospective studies. However, the risks and benefits of CA have not been well elucidated in patients with NVAF and who have suffered a recent ischemic stroke in prospective randomized trials. Thus, the aim of the STABLED clinical trial is to investigate the efficacy and safety of CA with anticoagulant therapy using edoxaban in patients with NVAF and a history of recent ischemic stroke. METHODS AND DESIGN: The STABLED trial is a multicenter, prospective, randomized, open-label, standard medication-controlled study in Japan. The target patient number is 250, comprising 125 patients receiving standard medication and 125 receiving CA. For patients allocated to the CA group, ablation is to be performed between 1 to 6 months from the onset of index stroke. The observation period will be 3 years from the day of random allocation of the final patient to any of the groups. The primary outcome measure is the composite of recurrence of ischemic stroke, systemic embolism, all-cause death, and hospitalization for heart failure. CONCLUSION: This study will investigate the effectiveness and safety of CA and basic anticoagulation treatment with edoxaban for patients with NVAF who have suffered a recent ischemic stroke. The aim is to determine the best evidence for an optimal treatment strategy for patients with NVAF and recent stroke. TRIAL REGISTRATION: UMIN000031424/NCT03777631.

Memantine in Japanese patients with moderate to severe Alzheimer's disease: meta-analysis of multiple-index responder analyses.

BACKGROUND: Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer's disease (AD). RESEARCH DESIGN AND METHODS: This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013. RESULTS: Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician's Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003). CONCLUSIONS: Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.

Post-marketing surveillance of the safety of levofloxacin in Japan.

BACKGROUND: Central nervous system reactions to new quinolones, such as convulsions due to interaction with nonsteroidal anti-inflammatory drugs (NSAIDS), have attracted increased attention in Japan. METHODS: The safety of levofloxacin (LVX) was investigated in Japan by post-marketing surveillance and reviewing spontaneous reports. RESULTS: Post-marketing surveillance was performed in 16,117 patients between 1994 and 1996. The incidence of adverse reactions was 1.3% (203/16,117), being comparable with that for ofloxacin or that shown by phase II/III studies. Among 4,977 patients receiving concomitant NSAID treatment, the overall incidence of adverse reactions and the incidence of neurological reactions (including convulsions) did not significantly differ from those in patients without anti-inflammatory therapy. Review of the spontaneous reports on convulsions showed that patients with nephropathy, patients over 75 years and patients with a history of convulsive diseases were more likely to develop convulsions during LVX therapy. CONCLUSION: LVX should be used cautiously in patients with the above risk factors.

[Use of the antibacterial agent levofloxacin for acute upper respiratory tract infection accompanied by fever (> or = 38 degrees C)].

The appropriate administration method of levofloxacin in relation to symptoms was investigated by following up 2,353 patients prescribed either levofloxacin (300 mg divided into 3 doses) or 400 mg (divided into 2 doses) for the treatment of acute upper respiratory tract infection accompanied by fever (temperature (> or = 38 degrees C) of suspected bacterial infection. 1) The cure rate based on body temperature as an index was significantly higher in the group administered 400 mg/day compared with the group administered 300 mg/day. No significant difference between the two regimens was observed in patients with a temperature < or = 38.5 degrees C at the start of administration, but patients with a temperature > or = 38.6 degrees C showed a significantly higher cure rate when administered 400 mg/day compared with 300 mg/day. 2) No significant difference between the groups was observed with respect to the improvement of quality of life (QOL), assessed using a VAS. In patients with a temperature > or = 38.6 degrees C, however, significantly higher improvement rates were demonstrated on days 3, 5 and 6 of treatment at 400 mg/day compared with 300 mg/day. 3) The reconsultation rate was significantly lower in the group administered 400 mg/day compared with the group administered 300 mg/day. No significant difference between the groups was observed in patients with a temperature < or = 38.5 degrees C. However, in the patients with a temperature > or = 38.6 degrees C, treatment at 400 mg/day achieved a significantly lower reconsultation rate compared with 300 mg/day. 4) Nonsteroidal anti-inflammatory drugs (NSAIDs) were concomitantly administered to 64.3% of the patients, but no significant difference in the cure rate was observed between patients with or without concomitant use of NSAIDs. 5) Among all of the patients, 12.7% were positive for the influenza virus, and anti-influenza drugs were concomitantly administered to 41.3% of them. However, no significant difference in the cure rate was observed between the group administered levofloxacin alone and the group concomitantly administered anti-influenza drugs. 6) The incidence of adverse drug reactions was 0.84% in the group administered 400 mg/day and 0.50% in the group administered 300 mg/day. No significant difference was observed between these groups and no serious adverse drug reactions occurred. In conclusion, for treating patients with acute upper respiratory tract infection accompanied by fever (> or = 38.6 degrees C) and suspected bacterial infection, levofloxacin dosage of 400 mg/day (divided into 2 doses) was superior to 300 mg/day (divided into 3 doses) in terms of therapeutic effect, QOL, and the reconsultation rate. This was considered to be an administration method worth recommending, including its safety. In patients with a temperature of 38.0 degrees C to 38.5 degrees C, administration of levofloxacin at 300 mg/day was confirmed to demonstrate a sufficient therapeutic effect.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a long-term special survey.

BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. OBJECTIVE: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the ß-adrenergic receptor antagonist (ß-blocker) Artist® tablets 10 mg, 20 mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. RESULTS: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5 mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL).[n = 141; p = 0.310]. In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). CONCLUSIONS: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a drug use survey.

BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14.4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a drug use survey, which we conducted as a post-marketing survey. OBJECTIVE: This prospective post-marketing drug use survey was conducted to assess the safety and efficacy of the ß-adrenergic receptor antagonist (ß-blocker) Artist® Tablets (carvedilol) in patients with hypertension in Japan. PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: This was a prospective survey conducted over 3 years from October 1993 to September 1996. The standard observation period for the patients was defined as 12 weeks of treatment with carvedilol. RESULTS: We collected data on 4961 patients at 561 medical institutions who had not been previously treated with carvedilol; 4574 patients were included in the safety analysis and 4422 in the efficacy analysis. The incidence of adverse drug reactions (the proportion of patients with adverse drug reactions) was 4.31% (197 of 4574 patients), which is less than that shown in the pre-approval clinical trial of carvedilol (6.85% [68 of 993]). The most common adverse drug reactions were bradycardia, dizziness, hypotension, headache, and feeling light-headed. After 12 weeks' treatment with carvedilol, systolic/diastolic blood pressure (SBP/DBP) was reduced from 168.2 ± 18.6/95.7 ± 11.3 mmHg at baseline to 144.3 ± 17.3/83.4 ± 10.8 mmHg. Patients were classified according to which antihypertensive drug they had been using when carvedilol treatment was initiated. Coadministered agents were calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), diuretics, and α-adrenergic receptor antagonists (α-blockers). At 12 weeks, the change in SBP/DBP in the monotherapy group was -22.7/-12.2 mmHg and that of each combination therapy subgroup, CCB, ACEI, diuretic, and ß-blocker, was -26.1/-12.7 mmHg, -25.4/-11.9 mmHg, -26.3/-13.0 mmHg, and -24.4/-11.5 mmHg, respectively. The achievement rates for target BP (<140/90 mmHg) were 29.5% in the monotherapy group, 34.8% in the CCB group, 31.3% in the ACEI group, 31.8% in the diuretic group, and 32.4% in the ß-blocker group. There was no significant difference in the achievement of target BP among the four combination therapy subgroups (p = 0.475). These results indicate that carvedilol exerts reasonable BP reduction regardless of whether it is used as monotherapy or in combination therapy, and that the effect is not influenced by the coadministered drug. Moreover, carvedilol was also effective in reducing BP levels in elderly patients (≥65 years) and in patients with diabetes mellitus or renal diseases. CONCLUSIONS: The results of this study reflect the results of clinical trials up to the time of approval and it was confirmed that carvedilol is a highly useful drug in the treatment of hypertension.

Effect of concomitant treatment with a CYP3A4 inhibitor and a calcium channel blocker.

PURPOSE: Grapefruit juice has been found to interact with calcium channel blockers (CCB). This interaction is due to certain nutrients found in grapefruit juice that block the activity of cytochrome P-450 (CYP) 3A4 in the small intestine and liver. Inhibition of CYP3A4 markedly increases bioavailability and increases the risk of an adverse drug reaction (ADR). Many drugs are known to have CYP3A4-blocking activity. This study was performed to investigate whether the concomitant use of a CYP3A4 inhibitor and a CCB in hypertensive patients results in an elevated incidence of ADRs. METHODS: The study included data on 17,430 patients receiving a CCB. Data were obtained from an anti-hypertensive drug database developed by the RAD-AR Council, Japan. A nested case-control design was employed for this study. Cases are defined as patients experiencing an ADR during the follow-up period of 12 weeks. Four controls per case, matched for CCB use, were selected via incidence density sampling. An estimate of the association between the CYP3A4 inhibitor and the ADR was obtained via multivariate conditional logistic regression. RESULTS: Univariate analysis revealed that the odds ratio for experiencing an ADR for the group treated concomitantly with a CCB and a CYP3A4 inhibitor was 1.35 (95% confidence intervals (95%CI), 1.02-1.78), compared with CCB monotherapy. The odds ratio based on multivariate analysis using the 1:4 matched dataset was 1.53 (95%CI, 0.95-2.47) after adjusting for possible confounding factors. CONCLUSIONS: The concomitant treatment with a CYP3A4 inhibitor and a CCB increases the risk of an ADR by 53%, compared with CCB monotherapy.