A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

Pharmacotherapy for post-traumatic stress disorder: a comprehensive review.

Significant advances have been made in the past 5 years in defining efficacious treatments for post-traumatic stress disorder (PTSD). Currently, sertraline is the first and only FDA-approved medication for this complex and often chronic illness. Other serotonergic antidepressants, such as paroxetine, fluoxetine and nefazodone, have well-controlled or replicated open-label evidence of efficacy. Anticonvulsants are also being studied as potential alternatives to treatment. Finally, atypical antipsychotic medications have shown promise in open-label trials. Clearly, more controlled studies are needed. This is especially true in males and in combat trauma-induced PTSD, where the effects of pharmacotherapy are less robust than in females or civilian trauma-induced PTSD. Also, there are virtually no data on pharmacotherapy for acute stress reaction or for PTSD in children. Future directions for research may focus on combination treatment in the more treatment-resistant patient populations.

Motor neuron-specific overexpression of the presynaptic choline transporter: impact on motor endurance and evoked muscle activity.

The presynaptic, hemicholinium-3 sensitive, high-affinity choline transporter (CHT) supplies choline for acetylcholine (ACh) synthesis. In mice, a homozygous deletion of CHT (CHT-/-) leads to premature cessation of spontaneous or evoked neuromuscular signaling and is associated with perinatal cyanosis and lethality within 1 h. Heterozygous (CHT+/-) mice exhibit diminished brain ACh levels and demonstrate an inability to sustain vigorous motor activity. We sought to explore the contribution of CHT gene dosage to motor function in greater detail using transgenic mice where CHT is expressed under control of the motor neuron promoter Hb9 (Hb9:CHT). On a CHT-/- background, the Hb9:CHT transgene conferred mice with the ability to move and breath for a postnatal period of ∼24 h, thus increasing survival. Conversely, Hb9:CHT expression on a wild-type background (CHT+/+;Hb9:CHT) leads to an increased capacity for treadmill running compared to wild-type littermates. Analysis of the stimulated compound muscle action potential (CMAP) in these animals under basal conditions established that CHT+/+;Hb9:CHT mice display an unexpected, bidirectional change, producing either elevated or reduced CMAP amplitude, relative to CHT+/+ animals. To examine whether these two groups arise from underlying changes in synaptic properties, we used high-frequency stimulation of motor axons to assess CMAP recovery kinetics. Although CHT+/+; Hb9:CHT mice in the two groups display an equivalent, time-dependent reduction in CMAP amplitude, animals with a higher basal CMAP amplitude demonstrate a significantly enhanced rate of recovery. To explain our findings, we propose a model whereby CHT support for neuromuscular signaling involves contributions to ACh synthesis as well as cholinergic synaptic vesicle availability.

Characterization of obstacle negotiation behaviors in the cockroach, Blaberus discoidalis.

Within natural environments, animals must be able to respond to a wide range of obstacles in their path. Such responses require sensory information to facilitate appropriate and effective motor behaviors. The objective of this study was to characterize sensors involved in the complex control of obstacle negotiation behaviors in the cockroach Blaberus discoidalis. Previous studies suggest that antennae are involved in obstacle detection and negotiation behaviors. During climbing attempts, cockroaches swing their front leg that then either successfully reaches the top of the block or misses. The success of these climbing attempts was dependent on their distance from the obstacle. Cockroaches with shortened antennae were closer to the obstacle prior to climbing than controls, suggesting that distance was related to antennal length. Removing the antennal flagellum resulted in delays in obstacle detection and changes in climbing strategy from targeted limb movements to less directed attempts. A more complex scenario - a shelf that the cockroach could either climb over or tunnel under - allowed us to further examine the role of sensory involvement in path selection. Ultimately, antennae contacting the top of the shelf led to climbing whereas contact on the underside led to tunneling However, in the light, cockroaches were biased toward tunnelling; a bias which was absent in the dark. Selective covering of visual structures suggested that this context was determined by the ocelli.

Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression.

Unipolar major depressive disorder (MDD) is a prevalent, disabling condition with multiple genetic and environmental factors impacting disease risk. The diagnosis of MDD relies on a cumulative measure derived from multiple trait dimensions and alone is limited in elucidating MDD genetic determinants. We and others have proposed that MDD may be better dissected using paradigms that assess how specific genes associate with component features of MDD. This within-disease design requires both a well-phenotyped cohort and a robust statistical approach that retains power with multiple tests of genetic association. In the present study, common polymorphic variants of genes related to central monoaminergic and cholinergic pathways that previous studies align with functional change in vitro or depression associations in vivo were genotyped in 110 individuals with unipolar MDD. Subphenotypic characteristics were examined using responses to individual items assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM IV), the 17-item Hamilton Rating Scale for Depression (HAM-D) and the NEO Five Factor Inventory. Multivariate Permutation Testing (MPT) was used to infer genotype-phenotype relationships underlying dimensional findings within clinical categories. MPT analyses show significant associations of the norepinephrine transporter (NET, SLC6A2) -182 T/C (rs2242446) with recurrent depression [odds ratio, OR = 4.15 (1.91-9.02)], NET -3081 A/T (rs28386840) with increase in appetite [OR = 3.58 (1.53-8.39)] and the presynaptic choline transporter (CHT, SLC5A7) Ile89Val (rs1013940) with HAM-D-17 total score {i.e. overall depression severity [OR = 2.74 (1.05-7.18)]}. These relationships illustrate an approach to the elucidation of gene influences on trait components of MDD and with replication, may help identify MDD subpopulations that can benefit from more targeted pharmacotherapy.

The stability of lisinopril as an extemporaneous syrup.

The stability of lisinopril as an extemporaneous syrup compounded from powder was studied. The lisinopril syrup (2mg/mL) was prepared by incorporating lisinopril powder dissolved in water into simple syrup. Samples of the syrup were stored in amber-colored plastic bottles at 5 and 23 deg C. At various times during the 30-day study period, the concentration of lisinopril waas determined by a stability-indicating high performance liquid chromatography assay procedure. Samples were also visually inspeceted for color and clarity. Over the 30-day study period, the percentage of the initial concentration remained between 97.46% and 100.54% for the 23 deg C samples and 98.15% and 100.74% for the 5 deg C samples.

Failure of tolterodine to treat clozapine-induced nocturnal enuresis.

OBJECTIVE: To report the use and subsequent failure of the bladder-selective agent tolterodine, to treat clozapine-induced nocturnal enuresis in an adolescent patient with psychotic illness. CASE SUMMARY: A 16-year-old Hispanic girl was admitted to the state psychiatric hospital with a diagnosis of bipolar disorder with psychotic features. Clozapine therapy was initiated, and after three months of treatment the patient began experiencing episodes of nocturnal enuresis. The bladder-selective agent tolterodine was tried and subsequently failed to resolve the enuresis episodes. Desmopressin was initiated, which resulted in amelioration of symptoms. DISCUSSION: This is the first published report of using tolterodine to treat clozapine-induced nocturnal enuresis. Several methods to decrease clozapine-induced urinary incontinence have been used and typically include the addition of agents with high anticholinergic properties. Tolterodine is a bladder-selective anticholinergic agent indicated for the treatment of urinary urge incontinence and may be employed as a treatment for antipsychotic-induced incontinence. CONCLUSIONS: Nocturnal enuresis is an adverse effect that infrequently occurs with use of clozapine therapy. Although tolterodine was ineffective in our patient to treat clozapine-induced nocturnal enuresis, further trials are required to appropriately evaluate the effectiveness of tolterodine to treat this adverse drug reaction.

Stability of Lisinopril Syrup (2 mg/mL) Extemporaneously Compounded from Tablets.

The stability of lisinopril syrup (2 mg/mL) extemporaneously compounded from tablets was investigated. Zestril tablets (Lot CSC201, Zeneca Pharmaceuticals, Wilmington, Del) were crushed, dissolved in water, filtered, and diluted with syrup NF to a final nominal concentration of 2 mg/mL. The solution was then equally divided among amber-colored prescription bottles and was stored at 5 deg C and 23 deg C. During the 30-day study period, samples were extracted by means of a water:methanol mix, and the concentration of lisinopril was determined by a stability-indicating high-performance liquid chromatography assay procedure. Stability was also determined by pH measurements annd visual inspection for color or clarity change. Over the 30-day study period, the percentage of the inital lisinopril concentration remained between 99.42% +/- 0.19% and 95.68% +/- 1.5% for the 5 deg C samples and 98.83% +/- 0.46% and 96.48% +/- 0.62% for the 23 deg C samples.

Y-site stability of fosphenytoin and sodium phenobarbital.

Fosphenytoin and sodium phenobarbital in 0.9% sodium chloride injection were analyzed in a simulated Y-site admixture. Each drug was analyzed for stability by high-pressure liquid chromatography (HPLC) from three simulated Y-site samples over an eight-hour period. The HPLC assay results indicate that both fosphenytoin and sodium phenobarbital are stable together at a Y site over an eight-hour period. In addition, there was no change in sample clarity or pH over the same period. The results indicate that, when medically necessary, fosphenytoin and sodium phenobarbital in 0.9% sodium chloride injection can be administered via the same intravenous line.

Fosphenytoin y-site stability studies with Lorazepam and midazolam hydrochloride.

The treatment of status epilepticus may require in certain situations the concurrent administration of lorazepam or midazolam with fosphenytoin. Simulated Y-site fosphenytoin/lorazepam and fosphenytoin/midazolam hydrochloride admixtures, respectively, in 0.9% sodium chloride injection were analyzed using a stability-indicating high-performance liquid chromatography (HPLC) method. Each drug was analyzed for stability by HPLC from three simulated Y-site samples over an eight-hour period. The HPLC assay results indicate that both fosphenytoin and lorazepam are stable together at a Y site over an eight-hour period. In addition, there was neither a change in sample clarity nor a change in pH over the same period. The results indicate that, when medically necessary, fosphenytoin and lorazepam in 0.9% sodium chloride injection can be administered via the same intravenous (IV) line. Midazolam free base was precipitated upon admixture of midazolam hydrochloride and fosphenytoin solutions. Therefore, midazolam hydrochloride and fosphenytoin should not be given via the same IV line.

Stability of Dobutamine Hydrochloride 4mg/mL in 5% Dextrose Injection at 5 and 23 deg C.

The stability of dobutamine hydrochloride 4 mg/mL in 5% dextrose injection has been studied using a stability-indicating, high-performance liquid chromatography assay method. The admixture injections were stable for 30 days at 5 and 23 deg C. Concentrations ranged between 98.5% and 102.6% for the room-temperature samples, and 99.6% and 101.8% for the refrigerated samples, of the initial mean concentrations. The standard curves demonstrated linearity (r2>.999). Variations within and between days were less than 3%. None of the samples appeared to form a visible precipitate or changed in color or clarity and the pH of the samples remained between 3.5 and 3.7.