James L. Perhach

Magnetic resonance imaging and neuropsychological results from a trial of memantine in Alzheimer's disease.

This study was designed to assess changes in brain volume and cognitive abilities in memantine‐treated patients with Alzheimers disease (AD) by using an exploratory, single‐arm, delayed‐start design.

The Pharmacokinetics of Taurolidine Metabolites in Healthy Volunteers

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel‐group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. tmax generally occurred at the end of infusion for taurinamide, whereas that of taurultam was reached before completion of infusion. The taurolidine metabolite taurultam demonstrated a shorter half‐life and lower systemic exposure than taurinamide. Shortening of infusion duration increased the Cmax and AUC of taurultam. Changes in infusion rate did not substantially change the pharmacokinetic parameters of taurinamide.

Safety and efficacy of memantine in children with autism: Randomized, placebo-controlled study and open-label extension

Abstract Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. Methods: A total of 121 children 6–12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Acamprosate: safety and tolerability in the treatment of alcohol dependence.

Acamprosate, in conjunction with psychosocial treatment, has demonstrated efficacy in maintaining abstinence in alcohol-dependent patients in multiple clinical trials. Data from 13 short-term (≤26 weeks) and long-term (≥48 weeks) clinical trials were analyzed to assess the safety and tolerability of acamprosate: 4234 patients were randomized to placebo (N = 1962), acamprosate 1332 mg/d (N = 440), 1998 mg/d (N = 1749), or 3000 mg/d (N = 83). Overall incidence of treatment-emergent adverse events (AEs) was 61% for acamprosate and 56% for placebo (P < 0.01). The majority of AEs in all groups were reported as transient and considered “mild” or “moderate” in severity, and discontinuation rates due to AEs were comparable. Most common AEs were diarrhea (16% acamprosate versus 10% placebo, P < 0.01) and flatulence (3% acamprosate versus 2% placebo, P < 0.01). Patients taking concomitant medications commonly used to treat alcohol dependence reported comparable AEs between placebo- and acamprosate-treated groups.Acamprosate was shown to be safe in patients with hepatic impairment. A dose reduction is recommended in patients with renal impairment. No clinically meaningful between-group differences were reported for clinical chemistry tests or vital sign parameters. This ad hoc analysis demonstrates that acamprosate can be used safely in alcohol-dependent patients, including those taking concomitant medications, or having renal or hepatic impairment.

Memantine and Functional Communication in Alzheimer's Disease: Results of a 12-Week, International, Randomized Clinical Trial

Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimers disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10-19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement on the FLCI (placebo: -0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: -5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers.

Effects of memantine on functional communication in patients with moderate AD: Results of a 12-week placebo-controlled trial

Background: EHT 0202 is a GABAA receptor modulator and a PDE4 inhibitor developed for the treatment of Alzheimer’s disease (AD). EHT 0202 is novel because it stimulates a-secretases, increasing the production of procognitive and neurotrophic sAPPa fragment of APP. Preclinical studies have shown that EHT 0202 1 ) protects cortical neurons against Ab42 and associated stresses and neuroprotection is associated with sAPPa induction, 2 ) demonstrates procognitive properties in various preclinical models: age-related memory impairment and scopolamine-induced amnesia and 3 ) chronic oral administrations of EHT 0202 reduce Ab42 levels in brain and CSF in rat and guinea pigs. These data suggest that EHT 0202 is able to reduce Ab burden by redirecting APP processing towards the a-secretase pathway and have favorable effects on neuron viability and cognition. Methods: Phase I studies demonstrated good tolerability of EHT 0202 in healthy young volunteers. No sedative effects or emesis were observed clinically and no alteration of attention and cognition on test battery were detected. Further, repeated doses in aged volunteers (60-75 years old) indicated that overall tolerability of EHT 0202 was good after a 10-day repeated administration up to 160 mg BID. Based on phase I results, a phase 2, parallel group, placebo-controlled, study of EHT 0202 (40 and 80 mg bid) was initiated. This randomized, doubleblind, multicentre study was designed to explore the clinical safety/tolerability and exploratory efficacy of EHT 0202 as adjunctive therapy to acetylcholinesterase inhibitor in ambulatory patients suffering from mild to moderate AD. Results: 135 patients are randomized to receive either 40 or 80 mg EHT 0202 bid or placebo bid. Patients are being followed over a 3-month period to determine the safety of EHT 0202 as well as its efficacy as measured by cognitive measures (ADAS-Cog, NTB, MMSE), global patient’s assessment (CDR-SB, CGI-C), behavior (NPI), activities of daily living (ADCS-ADL) and caregiver’s burden (Zarit’s scale). In addition, EHT 0202’s efficiency will be monitored using ExonHit’s recently developed companion diagnostic that allows quantitation of sAPPa in blood and patients’ transcriptomic profile will be determined using ExonHit’s SpliceArray platform. Conclusions: Trial status and information concerning EHT 0202 development program will be presented.

A long-term, open-label extension study evaluating the safety of extended-release memantine (28 mg) in patients with moderate to severe Alzheimer's disease

clusion of APOE e4 presence/absence as a covariate drastically reduces the strength of association for these SNPs indicating that these associations may be due to LDwith the APOE e4 allele. 36 SNPs showed a p-value lower than 10-5 when only 26 were expected by chance. Conclusions: These results provide further evidence that genetic variation in the APOE region is strongly associated with CSF Aß42 levels. More small p-values than would be expected by chance were detected. This could indicate that true positive results have not reached genome-wide significance levels due to lack of statistical power and that a larger sample is required. Finally, our findings will be strengthened by the analysis of imputed data from the 1,000 genomes project. These imputed genotypes will be available in March 2011 and will be analyzed before ICAD 2011 and included in our presentation.

Memantine and prevention of worsening across multiple domains: Post hoc analysis of a randomized, placebo-controlled trial in patients with moderate Alzheimer's disease

Background: Preclinical research as well as preliminary human studies suggest that blocking of 5 hydroxytrypamine [5 HT6] receptors has an effect on cognitive function by stimulating the release of the two neurotransmitters acetylcholine and glutamate. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized, in part, by a number of deficits in the the function of these neurotransmitters. To date, direct modification of these systems alone leads to only small improvements in the symptoms associated with the disease. Efforts are now underway to evaluate 5 HT6 antagonism as a mechanism for modulating multiple neurotransmitter systems in order to mediate events associated with synpatic plasticity and impact cognition. Methods: Ascending single oral doses of SAM-760 will be administered to healthy young adult and elderly subjects in a placebo controlled, inpatient, 8-12 sequential dose group fashion with 8 subjects per group (6 receiving SAM-760 and 2 receiving matching placebo). Additional cohorts will include a food effect (high fat meal) and drug-drug interaction (ketoconazole, N 1⁄4 12-16) evaluation. Full safety evaluations will be administered at baseline (pretreatment), ongoing during the treatment period and posttreatment to assure appropriate study entry, continuous safety monitoring and final follow up (for any continuing events). Results: Safety and tolerability will be evaluated and presented from adverse events, summaries of physical examinations, supine and orthostatic vital sign measurements, cardiac rhythm monitoring, 12-lead digital ECGs, neurological evaluations, clinical laboratory test results. Preliminary SAM-760 and metabolite (in a limited cohort) pharmacokinetics will also be presented. Conclusions: An initial phase 1 study was designed to assess the safety, tolerability, preliminary pharmacokinetic and CNS effects of SAM-760, a 5 HT6 receptor antagonist, as a potential symptomatic treatment for reducing the cognitive deficits in patients with mild to moderate AD. A drug of similar mechanism of action to that of SAM 760 (i.e., SAM531) is currently in phase 2 development and shows potential as such a treatment: the current compound has been proposed as a promising backup for the this lead compound.