Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

Medications for attention-deficit/hyperactivity disorder in Japan: A retrospective cohort study of label compliance.

AIM: To assess label compliance in prescription of medications approved for treatment of attention-deficit/hyperactivity disorder (ADHD) in Japan at the time of this study: methylphenidate (MPH), atomoxetine, and guanfacine. METHODS: Retrospective descriptive study was conducted in prevalent-user cohorts from the Japan Medical Data Center database. Patients who were prescribed a study drug between January 1, 2013 and September 30, 2018 and were in the database for ≥30 days were included. A prescription was considered compliant if all 4 criteria were satisfied: appropriate age, daily dose not exceeding the approved maximum, no contraindicated concurrent medications, and no contraindicated conditions. RESULTS: Among 17 418 patients who were prescribed a study drug during 2013-2018, 73% were male and 53% were children (aged <18 years). Fewer than 2% of prescriptions were for patients outside the approved age, 10%-13% of patients in the atomoxetine and MPH cohorts received ≥1 prescription exceeding maximum approved dose, no patients were co-prescribed a contraindicated medication, and 16%-18% of patients in the MPH cohorts had ≥1 contraindicated condition. During their first 500 days of use, for approximately 73%-86% of patients, all prescriptions were compliant with all label requirements. CONCLUSIONS: Among patients exposed to ADHD medications in Japan during 2013-2018, nearly all prescriptions for these medications were label-compliant for age. For >85% of patients, all prescriptions were label-compliant for dose, and for approximately 80%, all prescriptions were label-compliant for contraindicated conditions. We did not find evidence of widespread abuse or noncompliant use of prescribed ADHD medications.

A randomized, multicenter, crossover psychometric evaluation study of an iPad-administered cognitive test battery in participants with major depressive disorder who responded to treatment with oral antidepressants.

BACKGROUND: Performance validity and test-retest reliability of ReVeRe.D, an iPad-administered cognitive test battery in major depressive disorder (MDD) were analyzed. METHODS: Participants aged 18-59 years had DSM-5 diagnosis of MDD with adequate visual and hearing acuity. All had responded to oral antidepressant treatment for a major depressive episode within the most recent 24-months and were stable with no greater than mild depressive symptoms as evidenced by Montgomery Asberg Depression Rating Scale total score <17. Participants were randomly assigned to 1 of 2 test sequences (AABB or BBAA; A=ReVeRe.D; B=examiner-administered tests) in a crossover design. RESULTS: 244 randomized participants (AABB: n=123; BBAA: n=121) had mean age of 38.3 years; 54.9% had a college, baccalaureate, or higher education. At first administration, Pearson correlation coefficients (PCC) for 6/10 pairs of corresponding ReVeRe.D vs examiner-administered tests exceeded the pre-specified acceptance criterion (PCC=0.53) for the primary analysis; 8 test score pairs had PCC exceeding 0.40. At second administration, PCC for 9/10 test scores pairs exceeded PCC=0.53. Together, the series of PCCs supports the concurrent validity for ReVeRe.D. Test-retest reliability for ReVeRe.D test scores was generally moderate to high. LIMITATIONS: The study included stable participants with MDD who had responded to oral antidepressant treatment, with most in at least partial remission. The sample was limited to English-speaking participants, and skewed towards white, college-educated women. Further studies in acutely ill MDD patients who represent a broader demographic, are warranted. CONCLUSIONS: iPad-administered ReVeRe.D is a valid and reliable computerized test battery for assessment of cognitive performance in MDD.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral ß-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

BACKGROUND: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. AIMS: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. RESULTS: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. CONCLUSIONS: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study.

BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Effect of ketamine pretreatment on cocaine-mediated hepatotoxicity in rats.

Cocaine (COC) produces hepatotoxicity by a mechanism, which remains undefined, but has been linked to its oxidative metabolism. Ketamine (KET) is also a potentially hepatotoxic agent. The abuse of KET with COC is currently popular among young abusers therefore; this study was conducted to investigate the possible potentiation of COC-mediated hepatotoxicity (CMH) by KET. Male Sprague Dawley (SD) rats were administered oral KET hydrochloride for three consecutive days at a dose of 100 mg/kg with and without a single dose of COC (5 mg/kg, i.v.) administered 18 h after the last KET dose. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Liver reduced glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that KET pretreatment potentiated the hepatotoxicity of COC. Serum ALT and AST were significantly elevated with the combined KET and COC treatment versus all other treatments. While COC alone resulted in focal inflammatory cell infiltration, COC administration after KET pretreatment produced sub-massive hepatic necrosis. Hepatic GSH content was significantly reduced in KET-pretreated COC group compared to the other treatment groups, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the KET-pretreated COC group. In addition, norcocaine (NC) was only detected in the plasma of rats received COC after KET pretreatment. In conclusion, this study demonstrates that KET pretreatment potentiates the hepatotoxicity of COC as revealed by an array of biochemical and morphological markers most probably due to increase in COC oxidative metabolism.

Immunomodulation by cocaine and ketamine in postnatal rats.

The abuse of cocaine (COC) in combination with ketamine (KET) among pregnant women was shown to be high. Transplacental exposure is not the only route by which a newborn may be exposed to these agents, but they can also distribute into breast milk. Chronic COC exposure is associated with immunological modulation in human and animal models. The effect of sub-chronic exposure to COC and KET alone and in combination on the developing immune system was assessed in neonatal male Sprague-Dawley (SD) rats. To simulate the route of exposure during lactation, newborn male rats were treated orally with saline, COC alone (20 mg/kg), KET alone (50 mg/kg), or KET (50 mg/kg) followed 15 min later by COC (20 mg/kg) from days 1 to 21 of life. Pups were sacrificed 30 min following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, while spleen/body weight ratio and IgM antibody response to sheep red blood cells (SRBCs) were increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin 10 (IL-10) concentration; however, it did not affect serum interferon gamma (IFN-gamma) concentration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when co-administered with COC, the immunomodulatory effects of COC were prevented. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. Lack of significant change of plasma and tissue concentrations of norcocaine (NC) suggested no role for COC metabolism in COC-induced immunomodulation. However, the results of this study indicate that COC-induced immunomodulatory reactions and their prevention by KET most likely occurred through neuroendocrinal mechanisms.

Reduction of tissue concentration of cocaine in rat by ketamine.

The coabuse of cocaine and ketamine occurs with high frequency. The presence of another active substance with cocaine allows for the potential of various drug-drug interactions to occur. This study investigated the tissue distribution after the administration of cocaine or ketamine alone and their combination in rat. Cocaine (5 mg/kg iv), ketamine (100 mg/kg by gavage), or ketamine followed by cocaine (same doses and routes of administration) was utilized. Tissue contents of cocaine and norcocaine were significantly lowered at 5, 15, and 30 min following ketamine administration versus cocaine alone. However, tissue contents of benzoylecgonine were significantly higher in the combination group compared to cocaine alone. On the other hand, cocaine administration did not affect the tissue disposition of ketamine. The results suggest that ketamine decreased cocaine tissue content, which may affect its pharmacological and toxicological profiles.

The role of ketamine on plasma cocaine pharmacokinetics in rat.

Ketamine has gained attention recently because of re-emergence of its abuse especially in combination with cocaine. When more than one drug is present simultaneously, the potential for drug--drug interaction exists, which can be pharmacokinetic, pharmacodynamic or both in nature. The objective of this study was to investigate the effect of ketamine on plasma cocaine pharmacokinetics to assess the role that the kinetic component may play in the interaction of these agents. Moreover, the effect of repetitive administration of ketamine pretreatment on the pharmacokinetics of cocaine was addressed. Male Sprague-Dawley rats were treated with cocaine alone (5 mg/kg i.v.), ketamine alone (100 mg/kg by gavage), or ketamine followed by cocaine (the same routes and doses). Blood samples were withdrawn at different time points post-injection and analyzed for determination of cocaine, its metabolites (benzoylecgonine and norcocaine) and ketamine. The results demonstrated that ketamine caused a significant decrease in cocaine's area under the curve (AUC) and elimination half-life while its total clearance was increased. The AUC of benzoylecgonine was increased by 1.5-fold after the combination compared with cocaine alone. However, cocaine did not affect ketamine's pharmacokinetic parameters. In the pretreatment study, ketamine was given orally for 3 days, followed 18 h later by a single i.v. of cocaine. Further enhancement of cocaine metabolism occurred with the appearance of norcocaine. This investigation revealed that ketamine enhances cocaine metabolism and may affect its toxicological profile.

Development and validation of a high-performance liquid chromatography method for the determination of cocaine, its metabolites and ketamine.

Cocaine abuse is an extensive problem in the USA. During the past decade, ketamine abuse also has emerged as a public health concern and is now considered a controlled substance. The prevalence of the simultaneous use of cocaine and ketamine has been shown to be high. Previous research indicates that ketamine affects the enzymes that metabolize cocaine. In order to investigate this pharmacokinetic interaction, it was necessary to identify and quantitate each compound. The aim of this study is to develop a method of detecting and resolving cocaine, its metabolites and ketamine. A new precise, accurate and sensitive reversed-phase high-performance liquid chromatography method has been developed and validated. This assay employed a phosphate-buffered aqueous mobile phase (pH 6.9) with an organic component consisting of acetonitrile and methanol and a C-18 column as stationary phase at 225 nm wavelength. Minimum detection limits were 5 ng ml(-1) for cocaine and 10 ng ml(-1) for benzoylecgonine, norcocaine and ketamine. Linearity was demonstrated over a broad range of concentration in plasma, with good sensitivity for ketamine, cocaine and cocaine metabolites.