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ASP8302 is an orally administered positive allosteric modulator of the muscarinic M3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development.
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Backgrounds: Remote cardiac rehabilitation has proven useful in patients with cardiovascular disease; however, the methodology had not been fully validated. This study aimed to investigate the efficacy and safety of remote cardiac rehabilitation (RCR) with real-time monitoring and an ergometer using a bidirectional communication tool during the recovery phase of cardiovascular diseases. Methods: This multicenter, nonrandomized, interventional study was conducted at 29 institutions across Japan and enrolled patients with cardiovascular diseases who met indications for cardiac rehabilitation (CR) after receiving in-hospital treatment. The RCR group exercised at home using an ergometer and was monitored in real-time using interactive video and monitoring tools for 2-3 months. Educational instructions were provided concurrently through e-learning approaches. The safety of the RCR protocol and the improvement in peak oxygen consumption (VO2) were compared with those of the historical control group that participated in center-based CR. Results: Fifty-three patients from the RCR group were compared with 103 historical controls having similar background characteristics. No patients in RCR experienced significant cardiovascular complications while engaging in exercise sessions. After 2-3 months of RCR, the peak VO2 improved significantly, and the increases in the RCR group did not exhibit any significant differences compared to those in the historical controls. During follow-up, the proportion of patients whose exercise capacity increased by 10% or more was also evaluated; this finding did not indicate a statistically significant distinction between the groups. Conclusions: RCR during the recovery phase of cardiovascular diseases proved equally efficient and safe as center-based CR.
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Background/Objectives: Chronic kidney disease (CKD) and anemia are independent prognostic factors for heart failure. In recent years, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have become available for the treatment of renal anemia. This prospective randomized controlled study aimed to investigate the effects of switching from a continuous erythropoietin receptor activator (CERA) to one of four HIF-PH inhibitors in patients with chronic heart failure and renal anemia. Methods: Forty patients were randomized by the envelop method to receive treatment with roxadustat, daprodustat, vadadustat, or molidustat. The primary endpoint was the change in the hemoglobin (Hb) level. Secondary endpoints included changes in erythropoietin, changes in free T3, free T4, and thyroid-stimulating hormone (TSH), adverse effects, and drug dose increases and decreases. This study was preregistered in the University Hospital Medical Information Network Clinical Trials Registry (study ID: UMIN000041651). Results: We found no statistically significant difference between Hb levels with HIF-PH inhibitors and CERA, but at month 6, the Hb level was significantly higher with roxadustat than with vadadustat and daprodustat. Erythropoietin decreased significantly after switching to HIF-PH inhibitors. HIF-PH inhibitors had various significant effects on free T3, free T4, and TSH. No adverse events occurred. The doses of some drugs had to be increased or decreased. Conclusions: In patients with heart failure and renal anemia receiving CERA, Hb, NT-ProBNP, and renal function were similar after switching from CERA to HIF-PH inhibitors. The individual HIF-PH inhibitors appear to have different effects on anemia and thyroid function. However, because this was a single-center study with a limited sample size, the efficacy and potential limitations of HIF-PH inhibitors need to be further clarified.
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PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. CLINICALTRIALS: gov.
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Esclerose Lateral Amiotrófica , Fármacos Neuroprotetores , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Edaravone/farmacocinética , Glucuronídeos/uso terapêutico , Fármacos Neuroprotetores/farmacocinética , Sulfatos/uso terapêuticoRESUMO
Pharmacological studies have demonstrated antibody production and infection prevention with an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19). This clinical trial aimed to investigate the safety and immunogenicity of high doses of AG0302-COVID19 when injected intramuscularly and intradermally. Healthy adults were randomly divided into three intramuscular vaccination groups (2 mg, three times at 2-week intervals; 4 mg, twice at 4-week intervals; and 8 mg, twice at 4-week intervals) and two intradermal groups (1 mg, three times at 2-week intervals or twice at 4-week intervals). After a one-year follow-up, no serious adverse events were related to AG0302-COVID-19. At Week 52, the changes in the geometric mean titer (GMT) ratios of the anti-S antibodies were 2.5, 2.4, and 3.2 in the 2, 4, and 8 mg intramuscular groups, respectively, and 3.2 and 5.1 in the three times and twice injected intradermal groups, respectively. The number of INF-γ-producing cells responsive to S protein increased after the first dose and was sustained for several months. AG0302-COVID-19 showed an acceptable safety profile, but the induction of a humoral immune response was insufficient to justify progressing to a Phase 3 program.
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We investigated humoral immune responses in 222 unvaccinated Japanese people after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2021. Anti-spike-protein IgG antibody levels and neutralizing antibody titers were measured in serum samples obtained within 20-180 days after diagnosis. The geometric mean of antibody titers was 1555 ELU/mL (95% confidence interval (CI) = 1257-1923), and the neutralizing activity (50% inhibitory dilution) was 253 (95% CI = 204-313). The antibody titer and neutralizing activity both increased with increasing disease severity, and both values were approximately fourfold higher for hospitalized patients than for non-hospitalized patients. However, these differences were smaller in older patients. The humoral immune response, which increased with increasing disease severity, gradually decreased over time after SARS-CoV-2 infection. Most patients with mild or moderate symptoms sustained neutralizing activity for up to 180 days after the infection; the decay of the neutralizing activity in the asymptomatic patients was rather faster than in the other groups. Around 11.7% (26/222) of patients had very low neutralizing activity, and half of these were aged in their 20s. Our study's results show the importance of measuring the neutralizing activity to confirm the immune status and to estimate the timing of vaccines.
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COVID-19 , Imunidade Humoral , Idoso , Humanos , COVID-19/imunologia , População do Leste Asiático , Gravidade do Paciente , Japão , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
BACKGROUND: Oral beta-blockers are effective for heart failure and hypertension. Here, we conducted a prospective study to investigate the efficacy of the beta-blocker bisoprolol in patients switching from the oral tablet to the transdermal patch. METHODS: We studied 50 outpatients receiving oral bisoprolol for chronic heart failure and hypertension. After patients switched treatments, we measured heart rate (HR) over 24 h by Holter echocardiography as the primary endpoint. Secondary endpoints were (1) HR at 00:00, 06:00, 12:00, and 18:00, (2) the total number of premature atrial contractions (PACs) over 24 h and the incidence rate per time segment, and the total number of premature ventricular contractions (PVCs) over 24 h and the incidence rate per time segment, (3) blood pressure, (4) atrial natriuretic peptide and B-type natriuretic peptide, and (5) echocardiography. RESULTS: Minimum, maximum, mean, and total HR over 24 h was not significantly different between the two groups. Mean and maximum HR at 06:00, total PACs, total PVCs, and PVCs at 00:00 to 05:59 and 06:00 to 11:59 were significantly lower in the patch group. CONCLUSION: Compared with oral bisoprolol, the bisoprolol transdermal patch lowers HR at 06:00 and inhibits the onset of PVCs during sleep and in the morning.
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Erythropoiesis-stimulating agents improve the NYHA functional class and decrease the hospital readmission rates for heart failure; however, little is known about the influence of continuous erythropoietin receptor activator (CERA) on the heart. Therefore, a prospective study was conducted to investigate the effects of CERA on cardiac and renal function and oxidative stress in chronic heart failure with renal anemia. Sixty patients with chronic heart failure and renal anemia were enrolled and received CERA for 12 months. The primary endpoints were hemoglobin (Hb) and hematocrit, and the secondary endpoints were: (1) atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP); (2) NYHA class; (3) echocardiography; (4) blood urea nitrogen, creatinine, cystatin C, and urinary albumin; (5) high-sensitivity C-reactive protein; (6) oxidized low-density lipoprotein (Ox-LDL); and (7) renin, angiotensin-II, and aldosterone. There was a significant difference in the Hb levels measured before and after CERA administration. The BNP, ANP, NYHA, left ventricular mass index, renal function, and Ox-LDL decreased significantly after CERA administration. This study shows that CERA improves anemia and reduces renal impairment, as well as cardiac and oxidative stress. The result of this study is useful for a study in which switching from CERA to a new renal anemia drug, hypoxia-inducible factor prolyl-hydroxylase inhibitor, is investigated.
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Imeglimin is a diabetic drug excreted mainly in the urine; therefore, the impact of renal impairment on its pharmacokinetics (PK) is of interest. We assessed the PK and safety of imeglimin in Japanese patients with impaired renal function. This was an uncontrolled, open-label, single-dose, phase 1 study. Participants were classified into 4 groups by their estimated glomerular filtration rate (mL/min/1.73 m2 ) as follows: ≥90, normal renal function; and 60 to <90, mild; 30 to <60, moderate; and 15 to <30, severe renal impairment. All participants received imeglimin 1000 mg except those with severe renal impairment, who received imeglimin 500 mg. PK parameters were estimated using noncompartmental analysis, and those after multiple administrations were projected using a noncompartmental superposition method. In total, 24 Japanese participants (6 in each group) were enrolled and completed the study. The mean plasma imeglimin concentration reached the maximum at 2-4 hours after administration and then rapidly decreased. The geometric mean maximum observed plasma concentration and area under the plasma concentration-time curve values were higher in the impaired renal function groups versus normal renal function group. Most imeglimin was excreted in urine by 24 hours after administration. Renal clearance decreased with decreasing renal function. Projected maximum observed plasma concentration and area under the plasma concentration-time curve over the dosing interval after multiple dosing were greater in the renal impairment groups versus normal renal function group. No adverse events were observed. Considering increased plasma exposure along with decreased renal clearance, dose adjustment is required in patients with moderate and severe renal impairment with estimated glomerular filtration rate of 15 to <45 mL/min/1.73 m2 .
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População do Leste Asiático , Insuficiência Renal , Humanos , Área Sob a Curva , Rim/fisiologiaRESUMO
The COVID-19 pandemic caused by SARS-CoV-2 remains a serious health concern worldwide due to outbreaks of SARS-CoV-2 variants that can escape vaccine-acquired immunity and infect and transmit more efficiently. Therefore, an appropriate testing method for COVID-19 is essential for effective infection control and the prevention of local outbreaks. Compared to reverse-transcription polymerase chain reaction (RT-PCR) tests, antigen tests are used for simple point-of-care testing, enabling the identification of viral infections. In this study, we tested the clinical usefulness of the FUJIFILM COVID-19 Ag test, an antigen test based on silver amplification and immunochromatographic technology. The FUJIFILM COVID-19 Ag test was shown to detect a lower viral concentration as compared to other conventional kits without significant performance loss in detecting prevalent SARS-CoV-2 variants. We tested nasopharyngeal and nasal swabs from a single patient during two different epidemic periods dominated by various SARS-CoV-2 variants. We observed that the sensitivity of the FUJIFILM COVID-19 Ag test was 95.7% and 85.7% in nasopharyngeal and nasal swabs, respectively. These results suggest that the FUJIFILM COVID-19 Ag test is highly sensitive and applicable when RT-PCR testing is unavailable. Furthermore, these results indicate that high-frequency testing using nasal swab specimens may be a valuable screening strategy.
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Background: The current status of cardiac rehabilitation (CR) after cardiac surgery and the introduction of early CR (E-CR) in Japan are not fully understood. In this study, the current status of E-CR and its efficacy were investigated by the Academic Committee of the Japanese Association of Cardiac Rehabilitation. MethodsâandâResults: We examined the rate of introduction of E-CR and its effects among 220,122 patients who underwent major cardiac and thoracic vascular surgery, as registered in the Diagnosis Procedure Combination (DPC) classification system, between April 2012 and March 2018. In this study, E-CR was defined as CR starting within 1 day after surgery. Patients with and without E-CR were propensity score matched and analyzed for clinical outcomes. Of all patients participating in CR after surgery, E-CR was initiated in 52.1%, 56.9%, 47.4%, and 54.1% of patients undergoing coronary artery bypass grafting, valve surgery, aortic surgery, and other cardiovascular surgery, respectively. After propensity score matching, outcomes for E-CR were significantly superior to non-E-CR in terms of in-hospital deaths, Barthel Index score at discharge, length of hospital stay, and hospitalization costs. Conclusions: E-CR after cardiac surgery was effective in terms of prognosis, hospital stay, and medical costs. This study is the first report using big data in Japan. The results indicate that further introduction of E-CR needs to be recommended in the future.
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Background: We present results of a 24-week comparative study of the effects of the sodium−glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. Methods: We conducted a post hoc analysis of the CANDLE trial. This subanalysis evaluated NT-proBNP, BMI, and other laboratory parameters, according to the subgroups stratified by BMI ≥ 25 kg/m2 vs. BMI < 25 kg/m2. Results: A group ratio of proportional changes in the geometric means of NT-proBNP was 0.99 (p = 0.940) for the subgroup with BMI ≥ 25 kg/m2 and 0.85 (p = 0.075) for the subgroup with BMI < 25 kg/m2, respectively. When baseline BMI was modeled as a continuous variable, results for patients with BMI < 30 kg/m2 showed a slightly smaller increase in NT-proBNP in the canagliflozin group vs. the glimepiride group (p = 0.295); that difference was not seen among patients with BMI ≥30 kg/m2 (p = 0.948). Irrespective of obesity, the canagliflozin group was associated with significant reduction in BMI compared to the glimepiride group. Conclusion: There was no significant difference in the effects of canagliflozin, relative to glimepiride, on NT-proBNP concentrations irrespective of baseline obesity. UMIN clinical trial registration number: UMIN000017669.
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Adjuvanted vaccines are administered through intramuscular injection. To perform appropriate injection using an appropriate needle in different age groups or different daily living activities, we investigated the depth from the skin surface to muscle fascia and bone in the deltoid muscle area in 156 elderly aged ≥ 50 years by ultrasonic echography. Subjects consisted of 50 healthy elderly aged 50−64 years, 50 subjects aged 65−74 years, and 56 subjects aged ≥ 75 years (20 outpatients, 18 who needed nursing care, and 18 bedridden in a nursing home). The mean depth ± 1.0 SD from the skin surface to muscle fascia was 7.52 ± 2.13 mm for subjects aged ≥ 75 years, being shorter than 9.16 ± 3.02 mm in those aged 50−64years (p < 0.01). The depth from the skin surface to bone was 22.54 ± 3.85 mm for subjects aged ≥ 75 years and 25.41 ± 4.24 mm for those aged 65−74 years, significantly shorter than those aged 50−64 years (p < 0.01), depending on the reduced muscle volume. The subcutaneous volume length was greater in females (8.29 ± 2.63 mm) than in males (5.62 ± 2.80 mm) aged 50−64 years (p < 0.01). A similar result was obtained in those aged 65−74 years, but there was no difference in the muscle volume length. Our study found that a five-eighths of an inch (16 mm) needle was an appropriate length for average-sized elderly aged ≥ 50 years, but it should be longer for those with large body sizes.
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Trazpiroben (TAK-906) is a peripherally selective dopamine D2 /D3 receptor antagonist being developed to treat chronic gastroparesis. This phase I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, parallel-group study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy Japanese men. Findings were compared with those from a prior US trial in healthy individuals. Overall, 24 participants were enrolled into 3 cohorts (each n = 8). Per cohort, 6 participants received trazpiroben (cohort 1, 50 mg; 2, 100 mg; 3, 10 mg) once on day 1 and twice daily on days 3 through 7, and two received placebo. Trazpiroben was well tolerated, with no clinically meaningful adverse events observed. Following single- and multiple-dose administration, trazpiroben was rapidly absorbed and eliminated (mean elimination half-life, 1.89-6.45 hours; median time to maximum serum concentration [steady state], 1.00-1.25 hours). Serum prolactin increased with trazpiroben treatment (mean maximum serum concentration 93.32 ng/mL [10 mg] vs. 10.83 ng/mL [placebo]), illustrating receptor target engagement. Results reflected those from healthy US participants, indicating a lack of differences between these ethnic populations in trazpiroben disposition and safety profile. Trazpiroben may represent a promising therapy for chronic gastroparesis across different populations, with further evaluation ongoing in a phase IIb study (NCT03544229).
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Gastroparesia , Método Duplo-Cego , Gastroparesia/tratamento farmacológico , Voluntários Saudáveis , Humanos , Japão , MasculinoRESUMO
OBJECTIVE: Perampanel is an approved anti-seizure drug. A new formulation of perampanel fine granules (FG; 1% perampanel) has been developed for patients who are unable to take tablets. Bioequivalence between the 4-mg FG and tablet perampanel formulations, as well as their safety and tolerability, were assessed. MATERIALS AND METHODS: In this phase I, single-center, open-label, 2-period, 2-sequence, crossover, bioequivalence study (NCT03399734), healthy Japanese subjects were randomized to receive single doses of the 4-mg FG perampanel and 4-mg perampanel tablet (separated by a ≥ 6-week washout period). Plasma samples for perampanel concentration analysis were collected pre-dose and at intervals up to 168 hours post-dose. The maximum observed concentration (Cmax) and area under the concentration-time curve from time zero to 168 hours (AUC(0-168h)) were used to assess the bioequivalence of the two formulations. RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio of test/reference for Cmax and AUC(0-168h) were within the bioequivalence criteria of 80 - 125% (Cmax 90% CI 90.8%, 110%; AUC(0-168h) 90% CI 98.2%, 112%; N = 21). 10/24 (41.7%) subjects with FG experienced ≥ 1 treatment-emergent adverse event (TEAE). The events were mild in severity and resolved within 4 hours of onset. There were no deaths, severe TEAEs, serious AEs, or TEAEs leading to study-drug withdrawal. CONCLUSION: Bioequivalence of 4-mg FG and 4-mg tablet of perampanel was demonstrated. Both perampanel formulations were generally safe and well tolerated. These data suggest that perampanel FG may be a suitable alternative formulation for patients with epilepsy who have difficulties taking perampanel tablets.
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Piridonas/farmacologia , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Humanos , Japão , Masculino , Nitrilas , Comprimidos , Equivalência TerapêuticaRESUMO
BACKGROUND: The TROFEO trial demonstrated that febuxostat causes greater and more rapid reduction of serum uric acid (s-UA) than topiroxostat. We compared these drugs in patients with chronic kidney disease (CKD) by sub-analysis of the TROFEO trial. METHODS: This sub-analysis targeted patients with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2. The primary endpoint was the s-UA level. Secondary endpoints included creatinine, eGFR, urinary albumin, cystatin-C, oxidized low-density lipoprotein (Ox-LDL), eicosapentaenoic acid/arachidonic acid ratio, lipid biomarkers, high-sensitivity C-reactive protein, and B-type natriuretic peptide (BNP). RESULTS: There was no significant difference of s-UA between the two groups either before or after treatment. However, s-UA did not exceed 6.0 mg/dL in febuxostat group during the study period, but it exceeded this level in seven patients from topiroxostat group, with the number being significantly higher in topiroxostat group. Serum creatinine (s-Cr) and eGFR were significantly better after 6 months of febuxostat treatment compared with topiroxostat Cystatin-C was significantly lower after 6 months of febuxostat treatment compared with topiroxostat. The Ox-LDL was significantly lower after 3 and 6 months of febuxostat treatment compared with topiroxostat. CONCLUSION: Febuxostat had stronger renoprotective and antioxidant effects than topiroxostat in patients with hyperuricemia and CKD.
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Antioxidantes/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Nitrilas/uso terapêutico , Piridinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Ácido Úrico/sangue , Idoso , Antioxidantes/efeitos adversos , Biomarcadores/sangue , Estudos Cross-Over , Regulação para Baixo , Inibidores Enzimáticos/efeitos adversos , Febuxostat/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/sangue , Hiperuricemia/complicações , Hiperuricemia/diagnóstico , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Piridinas/efeitos adversos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Xantina Oxidase/antagonistas & inibidoresRESUMO
BACKGROUND AND OBJECTIVE: This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose. METHODS: This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting. Blood samples were collected prior to administration and up to 72 h post-dose for pharmacokinetic assessment. Safety was assessed up to 7 days post-dose. RESULTS: Peficitinib plasma concentration-time profiles were similar between those with normal and impaired renal function. In subjects with impaired renal function, area under the plasma concentration-time curve and maximum concentration were 0.8- to 1.1-fold those in subjects with no impairment. Two subjects (one in the normal group and one in the mildly impaired group) each experienced a treatment-emergent adverse event (TEAE). There were no serious TEAEs, deaths or TEAEs leading to treatment withdrawal. CONCLUSIONS: Peficitinib exposure and TEAEs were similar in subjects with and without renal impairment after a single oral 150 mg dose. Based on these findings, it is not expected that peficitinib dose adjustment will be required in clinical practice, according to the degree of renal impairment. CLINICALTRIALS. GOV IDENTIFIER: NCT02603497.
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Adamantano/análogos & derivados , Inibidores de Janus Quinases/farmacocinética , Niacinamida/análogos & derivados , Insuficiência Renal/metabolismo , Adamantano/efeitos adversos , Adamantano/farmacocinética , Administração Oral , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Reports that sodium glucose cotransporter 2 inhibitors decrease cardiovascular death and events in patients with diabetes have attracted attention in the cardiology field. We conducted a study of canagliflozin in patients with chronic heart failure and type II diabetes. METHODS: Thirty-five Japanese patients with chronic heart failure and type II diabetes were treated with canagliflozin for 12 months. The primary endpoints were the changes of subcutaneous, visceral, and total fat areas at 12 months determined by computed tomography. Secondary endpoints included markers of glycemic control, renal function, and oxidative stress, as well as lipid parameters, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), flow-mediated dilation (FMD), and echocardiographic left ventricular function. RESULTS: All fat areas (subcutaneous, visceral, and total) showed a significant decrease at 12 months. ANP and BNP also decreased significantly, along with improvement of renal function, oxidized LDL, and E/e', FMD increased significantly after canagliflozin treatment. CONCLUSION: Canagliflozin demonstrated cardiac and renal protective effects as well as improving oxidative stress, diastolic function, and endothelial function. This drug was effective in patients who had heart failure with preserved ejection fraction and could become first-line therapy for such patients with diabetes. Trial registration UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000021239.
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Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adiposidade/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Fator Natriurético Atrial/sangue , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Canagliflozina/efeitos adversos , Doença Crônica , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Coração/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Japão , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Numerous studies have demonstrated a reduction in cardiovascular events when the low-density lipoprotein cholesterol (LDL) level is decreased by statin therapy. However, despite good control of LDL, cardiovascular events may increase if the triglyceride (TG) level is high. We conducted a long-term comparison of treatment of hypertriglyceridemia with ethyl icosapentate (EPA) vs. omega-3-acid ethyl (EPA+docosahexaenoic acid [DHA]).MethodsâandâResults:Cardiac surgery patients with hypertriglyceridemia were randomized to an EPA group (1.8 g t.i.d.) or an EPA+DHA group (2 g s.i.d.) and observed for 3 years. The primary endpoints were the serum TG level and its percent change. Secondary endpoints included lipid markers, fatty acid parameters, serum creatinine, cystatin-C, oxidized LDL, high-sensitivity C-reactive protein, and MACCE. An interview to assess study drug adherence was conducted 6 months after completing the study. TG levels were significantly lower in the EPA+DHA group than in the EPA group. Levels of remnant-like particles-cholesterol, oxidized LDL, and cystatin-C were also significantly lower in the EPA+DHA group than in the EPA group. Compliance with treatment was significantly worse in the EPA group. CONCLUSIONS: Better results were obtained in the EPA+DHA group, but more patients showed poor compliance with treatment in the EPA group, making detailed comparison of the 2 groups difficult. Even so, TG were reduced while EPA and DHA levels were increased in the EPA+DHA group, together with a reduction in oxidative stress and remnant-like particles-cholesterol. Decreased compliance with medication in the EPA group significantly affected the results of this study, clearly indicating the importance of good compliance.
Assuntos
Doenças Cardiovasculares , Ácido Eicosapentaenoico/análogos & derivados , Hipertrigliceridemia , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/terapia , Procedimentos Cirúrgicos Cardiovasculares , LDL-Colesterol/sangue , Cistatina C/sangue , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/terapia , Lipoproteínas LDL/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Objective: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet has demonstrated effective treatment of HDM-induced allergic asthma in patients 18 years or older in European trials. This study investigated its safety and immunology profile in Japanese adult patients with mild-to-moderate HDM-induced allergic asthma. Methods: In this randomized, double-blind, placebo-controlled study, 48 Japanese patients were randomly assigned to a daily treatment of SQ HDM SLIT-tablet or placebo (3:1) for 14 d with or without an up-dosing regimen. Active groups comprised 5000, 10,000 or 20,000 Japanese Allergy Unit (JAU) for 14 d, and the up-dosing group comprised 5,000 JAU in day 1-3, 10,000 JAU in day 4-7 and 20,000 JAU in day 8-14. Results: No marked differences were observed in the incidence rate of adverse events (AEs) and their severity among active groups. The five most common investigational medicinal product (IMP)-related AEs were local events at the application site observed within 30 min after the intake of the SQ HDM SLIT-tablet. Although most events recovered within 1 h, mouth edema indicated a different profile of duration with more than 25% of the events lasting for more than 1 h. Conclusions: The SQ HDM SLIT-tablet of up to 20,000 JAU was well tolerated, and safety profile was acceptable for Japanese subjects with HDM-induced allergic asthma.