MIJ821 (onfasprodil) in healthy volunteers: First-in-human, randomized, placebo-controlled study (single ascending dose and repeated intravenous dose).

This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUCinf values of MIJ821 increased in a dose-proportional manner across the dose range 0.016-0.48 mg/kg and the Cmax values in a slight overproportional manner across the dose range 0.048-0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUCinf was 708 h ng/mL and the geometric mean Cmax was 462 ng/mL. Inspection of 1-h post-dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose-dependent.

Intravenous Dosing as an Alternate Approach to Safely Achieve Supratherapeutic Exposure for Assessments of Cardiac Repolarization: A Randomized Clinical Trial with Mavoglurant (AFQ056).

PURPOSE: The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high Cmax values while controlling tolerability. METHODS: This study was a randomized, placebo- and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). FINDINGS: Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmax values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association between mavoglurant plasma concentrations and ΔΔQTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. IMPLICATIONS: This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.

Voltage gated potassium channel antibodies positive autoimmune encephalopathy in a child: A case report and literature review of an under-recognized condition.

Autoimmune limbic encephalitis (LE) associated with voltage gated potassium channel antibodies (VGKC-Abs) in children is more common than previously thought and is not always paraneoplastic. Non-neoplastic, autoimmune LE associated with VGKC-Abs has been described recently. However, only few case reports in children as the disease is predominantly described in the adult population. It is likely that this type of autoimmune encephalitis is currently under-diagnosed and hence, under-treated, especially in children. We present a 13-year-old previously fit and healthy African girl diagnosed with LE and we reviewed the literature for its current management.

Acute longitudinal myelitis as the first presentation in child with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-system auto-immune disorder that is characterized by widespread immune dysregulation, formation of auto-antibodies, and immune complexes, resulting in inflammation and potential damage to variety of organs. It is complicated by neurological manifestations in 25-95% of the patients. Acute transverse myelitis (ATM) may be a complication in 1-2% of patients with SLE but in some patients it may be the initial manifestation of SLE. This sub-group of patients where ATM is the presenting feature may not fulfil the ACR criteria for the diagnosis of SLE which may delay the diagnosis and may affect the outcome. In those patients where the involvement is more than four segments of the spine are believed to have poor prognosis, but early diagnosis and treatment may alter the course and lead to a better outcome. We describe a young Polish girl where ATM was the initial manifestation of SLE involving almost the whole length of spine but she had a reasonably good outcome following early diagnosis and aggressive treatment.

Mathematical modeling of a carrier-mediated transport process in a liquid membrane.

An analysis of the reaction diffusion in a carrier-mediated transport process through a membrane is presented. A simple approximate analytical expression of concentration profiles is derived in terms of all dimensionless parameters. Furthermore, in this work we employ the homotopy perturbation method to solve the nonlinear reaction-diffusion equations. Moreover, the analytical results have been compared to the numerical simulation using the Matlab program. The simulated results are comparable with the appropriate theories. The results obtained in this work are valid for the entire solution domain.

Life threatening complication of sore throat: Lemierre's syndrome.

The authors report a case of previously healthy toddler who presented with acute sore throat that led to bacteremia, septic shock, disseminated intravascular coagulopathy, encephalopathy and pleural effusion. Magnetic resonance imaging and venogram showed thrombosis of the internal jugular vein. He was successfully treated with antibiotics and low molecular weight heparin. The authors review the literature and explore the presentation, management and the role of anticoagulation in this condition. To the authors' knowledge, this is one of the youngest patient reports with this condition in the literature.

Tuberculous radiculomyelitis presenting as urinary retention in a child with Down's syndrome.

Tuberculous radiculomyelitis (TBRM) is an uncommon complication of TB meningitis. The authors report the case of a 10-year-old Asian girl with trisomy 21, who presented with acute urinary retention and fever. She was initially treated for a urinary tract infection. After an acute neurological deterioration she was found to have evidence of TB meningitis with TBRM. She developed acute hydrocephalus requiring ventriculo-peritoneal shunt. She was treated with quadruple antituberculous therapy and high dose intravenous dexamethasone. She needed tracheostomy with continuous positive airway pressure (CPAP) support. Although she showed gradual neurological improvement in her cognitive functions, she persisted to have quadriparesis with the need for tracheostomy and CPAP support overnight and gastrostomy feeding. Acute urinary retention in children is uncommon, and should serve as a 'red flag' to consideration of further underlying neurological problems. This presentation and subsequent events should serve as a learning point to clinicians.

Development and validation of a HPLC method for quantification of rivastigmine in rat urine and identification of a novel metabolite in urine by LC-MS/MS.

A sensitive, specific and accurate HPLC method for the quantification of rivastigmine (RSM) in rat urine was developed and validated. The method involves the simple liquid-liquid extraction of RSM and pyridostigmine as an internal standard (IS) from rat urine with tertiary methyl butyl ether. The chromatographic separation of RSM and IS was achieved with 20 mm ammonium acetate buffer (pH 6.5) and acetonitrile (65:35, v/v) delivered at flow-rate of 1 mL/min on a Kromasil KR-100. The method was in linear range from 50 to 5000 ng/mL. The validation was done as per FDA guidelines and the results met the acceptance criteria. The method was successfully applied for the quantification of RSM in rat urine. Besides method validation, we have identified two metabolites of RSM in urine. Both the metabolites were characterized by HPLC-PDA and LC-MS/MS and it was found that one metabolite is novel.

Gender differences in the pharmacokinetics of rivastigmine in rats.

The effect of gender on the pharmacokinetics of rivastigmine (CAS 123441-03-2) was studied in male and female Wistar rats following intravenous bolus administration. The area under the plasma concentration-time curve (AUC), apparent volume of distribution (Vd), systemic clearance (CL), and terminal plasma halflife (t1/2) of rivastigmine were compared between male and female rats. Compared to male rats, female rats exhibited higher plasma rivastigmine levels showing significantly (p < 0.05) larger AUC (226.77 vs. 149.68 ng h/ml), Vd (6.70 vs. 4.13 L), t1/2 (0.84 vs. 0.34 h) and a lower CL (5.51 vs. 8.35 L/h). The male rats had a 2.5 fold greater elimination rate constant than female rats (2.02 vs. 0.82 h(-1)). Gender had a significant effect on the pharmacokinetics of rivastigmine. Gender differences were reported due to gonadal hormones, and the observed difference in pharmacokinetics of rivastigmine might be attributed to testosterone in male rats.