d-Amphetamine Transdermal System in Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Secondary Endpoint Results and Post Hoc Effect Size Analyses from a Pivotal Trial.

Objectives: Amphetamines are a preferred treatment for attention-deficit/hyperactivity disorder (ADHD), with the dextroamphetamine transdermal system (d-ATS) providing an alternative to oral formulations. A pivotal trial of d-ATS in children and adolescents with ADHD met primary and key secondary endpoints. This analysis reports additional endpoints and safety findings from the pivotal trial and evaluates effect size and number needed to treat (NNT) for d-ATS. Methods: In this study, a 5-week, open-label dose-optimization period (DOP) preceded a 2-week, randomized, crossover double-blind treatment period (DBP). Eligible patients received d-ATS 5 mg during the DOP, with weekly evaluations for increase to 10, 15, and 20 mg (equivalent to labeled doses of 4.5, 9, 13.5, and 18 mg/9 hours, respectively) until reaching and maintaining the optimal dose, which was utilized for the DBP. Secondary endpoints included assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores. NNT was calculated for ADHD-RS-IV and CGI-Improvement (CGI-I). Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety. Results: In total, 110 patients entered the DOP, with 106 patients randomized (DBP). During the DBP, the least-squares mean (95% confidence interval) difference for d-ATS versus placebo in ADHD-RS-IV total score was -13.1 (-16.2 to -10.0; p < 0.001), with effect size of 1.1 and NNT of 3 for ADHD-RS-IV remission, ≥30% improvement, and ≥50% improvement. Significant differences between placebo and d-ATS were also observed for CPRS-R:S and CGI-I scales (p < 0.001), with NNT of 2 for CGI-I response. Most TEAEs were mild or moderate, with three leading to study discontinuation in the DOP and none in the DBP. No patients discontinued due to dermal reactions. Conclusions: d-ATS was effective in treating ADHD in children and adolescents, meeting all secondary endpoints, with a large effect size and NNT of 2-3 to achieve a clinically meaningful response. d-ATS was safe and well tolerated, with minimal dermal reactions. Clinical Trial Registration: NCT01711021.

Efficacy and Safety of Dextroamphetamine Transdermal System for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results from a Pivotal Phase 2 Study.

Objectives: To assess efficacy and safety of the new Dextroamphetamine Transdermal System (d-ATS) to treat children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: In this phase 2, randomized, placebo-controlled study, 4 d-ATS patches of differing doses (5, 10, 15, and 20 mg) were evaluated. Patients began a 5-week, open-label, stepwise dose-optimization period in which they received a 5-mg d-ATS patch (applied to hip) for 9 hours. During weekly visits, patients were evaluated for possible adjustments to the next dose level based on efficacy and safety. Once at the optimal dose, that dose was maintained during a 2-week, crossover double-blind treatment period. Primary endpoint was to assess efficacy of d-ATS versus placebo as measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) total score; key secondary endpoints included assessing onset and duration of efficacy by SKAMP total score, and additional secondary endpoints included Permanent Product Measure of Performance (PERMP) scores. Safety was assessed throughout. Results: d-ATS treatment resulted in significant improvements versus placebo in ADHD symptoms as measured by SKAMP total score, with overall least-squares mean difference (95% confidence interval) versus placebo of -5.87 (6.76, -4.97; p < 0.001) over the 12-hour assessment period. Onset of efficacy was observed at 2 hours postdose (p < 0.001), and duration of effect continued through 12 hours (patch removed at 9 hours), with significant differences between d-ATS and placebo at all time points from 2 hours onward (all p ≤ 0.003). Significant improvements versus placebo in PERMP-A and PERMP-C scores were also observed from 2 to 12 hours postdose with d-ATS treatment. d-ATS was safe and well-tolerated, with a systemic safety profile similar to that observed with oral amphetamines. Conclusions: This study demonstrates that d-ATS is an effective and well-tolerated treatment for children and adolescents with ADHD. These data indicate that d-ATS can deliver sustained levels of efficacy along with the advantages of transdermal drug delivery, making it a beneficial new treatment option. Clinical Trial Registration no.: NCT01711021.

Pharmacokinetic Profile of the Asenapine Transdermal System (HP-3070).

PURPOSE/BACKGROUND: The asenapine transdermal system (HP-3070) is the first antipsychotic patch approved in the United States for treatment of adults with schizophrenia. METHODS/PROCEDURES: Three phase 1, open-label, randomized studies characterized the pharmacokinetic (PK) profile of HP-3070 by assessing its relative bioavailability compared with sublingual asenapine, its single-/multiple-dose PK and dose proportionality, and the effects of application site, ethnicity, and external heat on bioavailability. Two studies were conducted in healthy subjects, and 1 was conducted in adults with schizophrenia. FINDINGS/RESULTS: During single HP-3070 administration, asenapine concentrations increased gradually over approximately 12 hours and remained steady until the patch was removed 24 hours after application. Asenapine area under the curve values at HP-3070 3.8 and 7.6 mg/24 hours doses were similar to those for sublingual asenapine 5 and 10 mg twice-daily doses, respectively, whereas peak exposure (maximum observed plasma concentration) was significantly lower. During daily application of HP-3070, steady-state PK was reached within approximately 72 hours after initiating daily dosing and was characterized by peak-to-trough asenapine plasma concentration ratio of approximately 1.5. HP-3070 PK was dose proportional in the dose range studied, not affected by administration site, and similar across the studied ethnic groups. Application of external heat increased the rate of asenapine absorption (time to reach maximum observed plasma concentration) but did not significantly affect peak and total exposure. IMPLICATIONS/CONCLUSIONS: HP-3070 exhibited a dose-dependent PK profile unaffected by site of administration or ethnicity. HP-3070 showed a predictable absorption profile with limited variability, with an area under the curve similar to that of sublingual asenapine. Based on these PK metrics, HP-3070 steadily delivers asenapine with lower peaks and troughs than sublingual administration of asenapine.

Gradiometer Using Separated Diamond Quantum Magnetometers.

The negatively charged nitrogen-vacancy (NV) center in diamonds is known as the spin defect and using its electron spin, magnetometry can be realized even at room temperature with extremely high sensitivity as well as a high dynamic range. However, a magnetically shielded enclosure is usually required to sense weak magnetic fields because environmental magnetic field noises can disturb high sensitivity measurements. Here, we fabricated a gradiometer with variable sensor length that works at room temperature using a pair of diamond samples containing negatively charged NV centers. Each diamond is attached to an optical fiber to enable free sensor placement. Without any magnetically shielding, our gradiometer realizes a magnetic noise spectrum comparable to that of a three-layer magnetically shielded enclosure, reducing the noises at the low-frequency range below 1 Hz as well as at the frequency of 50 Hz (power line frequency) and its harmonics. These results indicate the potential of highly sensitive magnetic sensing by the gradiometer using the NV center for applications in noisy environments such as outdoor and in vehicles.

Specific interactions between tau protein and curcumin derivatives: Molecular docking and ab initio molecular orbital simulations.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world, and there is currently no potent medicine for the treatment of ADs. Curcumin, a primary chemical contained in the ancient Indian herb known as turmeric, has been extensively studied and shown to be effective in inhibiting the aggregations of amyloid-ß and tau proteins, both of which are observed in the brains of AD patients. In the present study, we focused on the tau protein and investigated its specific interactions with curcumin derivatives, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations. Based on the results, we attempted to propose novel potent inhibitors against the tau protein aggregation. Our molecular simulations provide useful information for developing novel medicines for the treatment of ADs.

Anthocyanin regulatory and structural genes associated with violet flower color of Matthiola incana.

MAIN CONCLUSION: MiMYB1 and MibHLH2 play key roles in anthocyanin biosynthesis in Matthiola incana flowers. We established a transient expression system using Turnip mosaic virus vector in M. incana. Garden stock (Matthiola incana (L.) R. Br.) is a popular flowering plant observed from winter to spring in Japan. Here we observed that anthocyanin accumulation in 'Vintage Lavender' increased with flower development, whereas flavonol accumulation remained constant throughout flower development. We obtained five transcription factor genes, MiMYB1, MibHLH1, MibHLH2, MiWDR1, and MiWDR2, from M. incana floral cDNA contigs. Yeast two-hybrid analyses revealed that MiMYB1 interacted with MibHLH1, MibHLH2, and MiWDR1, but MiWDR2 did not interact with any transcription factor. Expression levels of MiMYB1 and MibHLH2 increased in petals during floral bud development. Their expression profiles correlated well with the temporal profiles of MiF3'H, MiDFR, MiANS, and Mi3GT transcripts and anthocyanin accumulation profile. On the other hand, MibHLH1 was expressed weakly in all organs of 'Vintage Lavender'. However, high expression levels of MibHLH1 were detected in petals of other cultivars with higher levels of anthocyanin accumulation than 'Vintage Lavender'. MiWDR1 and MiWDR2 maintained constant expression levels in petals during flower development and vegetative organs. Transient MiMYB1 expression in 1-month-old M. incana seedlings using a Turnip mosaic virus vector activated transcription of the endogenous anthocyanin biosynthetic genes MiF3'H, MiDFR, and MiANS and induced ectopic anthocyanin accumulation in leaves. Therefore, MiMYB1 possibly interacts with MibHLH2 and MiWDR1, and this trimeric protein complex activates the transcription of anthocyanin biosynthetic genes in M. incana flowers. Moreover, MibHLH1 acts as an enhancer of anthocyanin biosynthesis with the MiMYB1-MibHLH2-MiWDR1 complex. This study revealed the molecular mechanism involved in the regulation of anthocyanin accumulation levels in M. incana flowers.

The Influence of Differences in Solvents and Concentration on the Efficacy of Propofol at Induction of Anesthesia.

Background. Propofol is a popular intravenous anesthetic and varieties of formulations were produced from different laboratories. The present study compared efficacy of propofol of different laboratories and different concentrations (1 and 2%) during induction of anesthesia. Methods. Seventy-five scheduled surgical patients were randomly allocated into three groups. The patients of group D1 received AstraZeneca Diprivan 1% (Osaka, Japan) at a rate of 40 mg kg(-1) h(-1). Group M1 was given 1% Maruishi (Maruishi Pharmaceutical, Osaka, Japan) and group M2 was given 2% formulation at the same rate of propofol. Achieving hypnosis was defined as failure to open their eyes in response to a verbal command and the venous blood sample was withdrawn. Results. The hypnotic doses of M2 were significantly larger (D1: 91.4 ± 30.9, M1: 90.7 ± 26.7, and M2: 118.4 ± 40.2 mg, resp. (mean ± SD). p < 0.005). Age and gender were selected as statistically significant covariates using general linear model-ANOVA. The blood concentration showed no significant difference among the groups (3.73 ± 2.34, 4.10 ± 3.04, and 4.70 ± 2.12 µg mL(-1), resp.). Conclusion. The required dose of propofol was different among the formulations; however, the serum concentration showed no significant difference. This trial is registered with UMIN Clinical Trial Registry: UMIN000019925.

Radial artery cannulation decreases the distal arterial blood flow measured by power Doppler ultrasound.

Radial arterial cannulation is a popular technique for continuous hemodynamic monitoring in an area of anesthesia and intensive care. Although the risk for invasive monitoring is considerable, there is scarce information about the change in blood flow of cannulated vessel after the catheterization. In the current investigation, we evaluated the change in the cannulated arterial blood flow. Six volunteers (study 1) and eight post-surgical patients (study 2) were enrolled into the studies. In the study 1, the both side of diameter of radial artery (RA), ulnar artery (UA) and dorsal branch of radial artery (DBRA) of participants were measured using power Doppler ultrasound (PDU) with or without proximal oppression. In the study 2, the diameter of RA, UA and DBRA of the both intact and cannulated side were compared. Study 1: The diameter of RA was 3.4 (0.52) [mean (SD)] mm and the proximal oppression significantly decreased the diameter to 1.8 (0.59) mm. The diameter of DBRA measured by PDU also decreased 2.0 (0.60)-1.3 (0.59) mm. Study 2: There was no difference between the diameters of right and left RA, however, the UA was larger [3.4 (0.60) vs. 2.8 (0.83) mm] and the DBRA was narrower [1.4 (0.43) vs. 2.0 (0.47) mm] in the cannulated side. The diameters of DBRA were different between the intact and cannulated side in the patients. Although there is no information of relationships between cause of severe complication and decreased flow, significant reduction of blood flow should be concerned.

Continuous administration of landiolol reduced QT dispersion in postoperative patients.

STUDY OBJECTIVE: To determine the changes in QT dispersion (QTD) in the standard electrocardiogram (ECG) of postoperative patients and the effect of landiolol on QTD. DESIGN: Randomized, prospective, double-blinded study. PATIENTS: 40 postsurgical patients. INVENTIONS: Patients were allocated to three groups: Control group patients (Group C) were administered saline and patients in the landiolol groups (Group L2 and Group L5) were infused landiolol 2 µg/kg/min and 5 µg/kg/min, respectively. All infusions were started at midnight and discontinued at 6 o'clock in the morning. MEASUREMENTS: Heart rate (HR), systolic (SBP) and diastolic (DBP) invasive blood pressure, and ECG were recorded at 0 (immediately before infusion), at 3 o'clock, and 6 o'clock (immediately before termination). The ECG wave was recorded electronically and QTD was analyzed using PC software. Heart rate, blood pressure, QT interval, and QTD were compared as changes from baseline values. MAIN RESULTS: In Groups L2 and L5, HR was significantly decreased, approximately 10 bpm. Both SBP and DBP showed a decreasing trend at 3 o'clock. Absolute QT interval was prolonged in all groups; however, the decrease in QTD occurred in Group L5. CONCLUSIONS: Continuous administration of landiolol prevents the increase in QTD found on the morning in postoperative patients. Landiolol demonstrated a possible antiarrhythmic effect by improving the imbalance of repolarization.

Electrosprayed molybdenum trioxide aqueous solution and its application in organic photovoltaic cells.

A molybdenum trioxide thin film with smooth surface and uniform thickness was successfully achieved by an electrospray deposition method using an aqueous solution with a drastically low concentration of 0.05 wt%. Previous papers demonstrated that an additive solvent technique is useful for depositing the thin film by the electrospray deposition, and the high vapor pressure and a low surface tension of an additive solvent were found to be important factors. As a result, the smooth molybdenum trioxide thin film was obtained when the acetonitrile was used as the additive solvent. Furthermore, the vapor pressure of acetone is much higher than that of aqueous solution, and this indicates that the acetone is easily evaporated after spraying from the glass capillary. By optimizing a concentration of acetone in the molybdenum aqueous solution, a minimum root mean square roughness of the MoO3 thin film became 3.7 nm. In addition, an organic photovoltaic cell was also demonstrated using the molybdenum trioxide as a hole transport layer. Highest photoconversion efficiency was 1.72%, a value comparable to that using conventional thermal evaporation process even though the aqueous solution was used for the solution process. The photovonversion efficiency was not an optimized value, and the higher value can be achieved by optimizing the coating condition of the active layer.

Dexmedetomidine-induced atrioventricular block followed by cardiac arrest during atrial pacing: a case report and review of the literature.

Sinus bradycardia is a well-known consequence of stimulation of presynaptic α2 adrenergic receptors due the adminstration of dexmedetomidine. One of the most serious adverse effects of dexmedetomidine is cardiac arrest. Some cases demonstrating such an arrest due to the indiscriminate use of this drug were recently reported. We continuously administered dexmedetomidine to a 56-year-old male patient at a rate of 0.3 µg/kg/h (lower than the recommended dose) without initial dosing for sedation in an intensive care unit. The patient had undergone open cardiac surgery and atrial pacing was maintained at a fixed rate, 90/min. The PQ interval in electrocardiography gradually prolonged during the infusion; finally, complete atrioventricular block and subsequent cardiac arrest occurred. Immediate cardiopulmonary resuscitation was carried out, including re-intubation, and recovery of spontaneous circulation was attained 15 min after the event. The patient was discharged from hospital on the 25th postoperative day without any neurological complications.

[Successful extubation in a patient with alacepril-induced tongue angioedema].

We describe a case of marked swelling of the tongue in a patient after a long prone position neurosurgery, who was treated for hypertension with alacepril. The tongue was not congestive and history of taking an angiotensin-converting enzyme inhibitor suggested an alacepril-induced angioedema. The day after surgery, the patient's tongue was still swollen; however, fibrescopic observation of the larynx and pharynx through the nasal cavity revealed that the edema was limited to anterior tongue, and the oral cavity and oropharynx were not involved. Although, tongue angioedema was observed, we introduced a 3-mm tube exchanger to the patient's trachea and removed the endotracheal tube. The ventilation and oxygenation were maintained, and 30 min later, the exchanger was detached. On the second postoperative day, the angioedema disappeared completely and the patient was transferred to a ward without any complication.

Nafamostat prevents hypothermia and improves survival time after administration of lipopolysaccharide in a mouse surgical model.

Lipopolysaccharide (LPS) is an endotoxin known to induce disseminated intravascular coagulation and multiple organ failure followed by septic shock in animals. Nafamostat is a synthetic protease inhibitor with anticoagulant effects. This study investigated the effect of systemic administration of nafamostat on thermogenic homeostasis and survival time in a mouse surgical model. Male C57Bl/6 mice were anesthetized with sevoflurane and implanted with intraabdominal telemetry transmitters. Following the surgery, three groups of animals were administered Escherichia coli LPS (0127: B8) subcutaneously at doses of 0.3, 1.0, or 3.0 mg kg(-1), and one group received saline without LPS. Three other groups received 3 mg.kg(-1) LPS with 1, 3, or 10 mg kg(-1) of nafamostat. In another group 10 mg kg(-1)1 of nafamostat only was administered. The times to the onset of hypothermia (body temperature < 30 degrees C) and death were determined. L LPS significantly shortened the duration of both normothermia and survival, and nafamostat prolonged the normothermic periods that were reduced b 3 mg.kg(-1) LPS. Survival time was significantly correlated with the duration of normothermia (n = 48; r (2) = 0.779; P < 0.000001). The results demonstrated the effect of systemic administration of nafamostat against LPS-induced hypothermia. Nafamostat prevented hypothermia, and the consequent normal thermoregulation may have prolonged the survival period.

[Multiple difficulties for central venous access required the distal femoral vein catheterization: a case report].

The low femoral approach for catheterization of the central venous line is a difficult procedure because the surface landmark technique is not helpful. We report a case of patient who required the distal femoral cannulation. Re-catheter cannulation was planned for the patient after the major cardiovascular surgery. The right internal jugular vein showed the venous thrombus attributed to the previous catheter placement for the operation. The left internal, jugular vein had anatomical anomaly at the level of cricoid cartilage and the last approach for cannulation was not feasible. The right subclavian and right femoral regions were scarred with the surgical procedure. Finally, we performed the distal femoral cannulation using real time ultrasound guidance. When multiple difficulties for venous access are present, ultrasound-guided low approach of femoral vein might be one of the solutions.

[Serotonin syndrome caused by an overdose of dextromethorphan, Medicon].

We report the first case of serotonin syndrome caused by overdose of dextromethorphan in Japan. A 34-year-old woman with schizophrenia received a dextromethorphan (Medicon) for a catarrhal symptom from two individual departments of the university hospital by chance. The daily amount of dextromethorphan was up to 180 mg for several days in addition to other regular antipsychotic drugs including risperidone, amitriptyline and levomepromazine. Finally, she was found in deep comatose state (GCS coma scale: E1V1M1) and the trachea was intubated in the emergency room. After admission to intensive care unit, the consciousness gradually improved; however, she was confused and agitated. The situation was normalized within next 24 hours and she was weaned from the mechanical ventilation next day. Serotonin syndrome demonstrates various signs and might be overlooked in an emergency room. Dextromethorphan is considered as a safe antitussive drug; however, the unexpected interaction should be suspected during chronic medical treatment.

[Apnea and severe respiratory depression induced by dexmedetomidine after general anesthesia in intensive care unit].

Dexmedetomidine (DEX) is widely used in intensive care unit for perioperative sedation. The one advantage of DEX administration for sedation is the lack of significant respiratory depression. However, DEX shows significant interaction with anesthetics and narcotics, and we present a case in which post-anesthetic administration of DEX induced apnea and severe respiratory depression after extubation. A 74-year-old, 38.3 kg, 148 cm woman was scheduled to undergo implantation of internal cardiac defibrillator. General anesthesia was maintained by sevoflurane, remifentanil and intermittent administration of fentanyl. After the surgery, she was transferred to intensive care unit with intubation, and DEX administration was commenced. After 3.5 hr from the end of anesthesia, the patient's trachea was extubated under continuous infusion of DEX (0.26 microg x kg(-1) x hr(-1)). Ninety min later, she showed apnea and severe respiratory depression. The interaction of DEX and residual narcotics might have induced life-threatening respiratory complication.

Determination of subcellular concentrations of soluble carbohydrates in rose petals during opening by nonaqueous fractionation method combined with infiltration-centrifugation method.

Petal growth associated with flower opening depends on cell expansion. To understand the role of soluble carbohydrates in petal cell expansion during flower opening, changes in soluble carbohydrate concentrations in vacuole, cytoplasm and apoplast of petal cells during flower opening in rose (Rosa hybrida L.) were investigated. We determined the subcellular distribution of soluble carbohydrates by combining nonaqueous fractionation method and infiltration-centrifugation method. During petal growth, fructose and glucose rapidly accumulated in the vacuole, reaching a maximum when petals almost reflected. Transmission electron microscopy showed that the volume of vacuole and air space drastically increased with petal growth. Carbohydrate concentration was calculated for each compartment of the petal cells and in petals that almost reflected, glucose and fructose concentrations increased to higher than 100 mM in the vacuole. Osmotic pressure increased in apoplast and symplast during flower opening, and this increase was mainly attributed to increases in fructose and glucose concentrations. No large difference in osmotic pressure due to soluble carbohydrates was observed between the apoplast and symplast before flower opening, but total osmotic pressure was much higher in the symplast than in the apoplast, a difference that was partially attributed to inorganic ions. An increase in osmotic pressure due to the continued accumulation of glucose and fructose in the symplast may facilitate water influx into cells, contributing to cell expansion associated with flower opening under conditions where osmotic pressure is higher in the symplast than in the apoplast.