A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder.

NSI-189 is a novel neurogenic compound independent of monoamine reuptake pathways. This trial evaluated oral NSI-189 as monotherapy in major depressive disorder. To improve signal detection, the sequential-parallel comparison design (SPCD) was chosen. Two hundred and twenty subjects were randomized to NSI-189 40 mg daily, 80 mg daily, or placebo for 12 weeks. The primary outcome measure was the Montogmery Asberg Depression Rating Scale (MADRS). Secondary subject-rated measures included the Symptoms of Depression Questionnaire (SDQ), the Cognitive and Physical Functioning Scale (CPFQ), the patient-rated version of the Quick Inventory of Depressive Symptomatology Scale (QIDS-SR), and subtests from the CogScreen and Cogstate cognitive tests. MADRS score reduction versus placebo did not reach significance for either dose (40 mg pooled mean difference -1.8, p = 0.22, 80 mg pooled mean difference -1.4, p = 0.34, respectively). However, the 40 mg dose showed greater overall reduction in SDQ (pooled mean difference -8.2; Cohen's d for Stages 1 and 2 = -0.11 and -0.64, p = 0.04), and CPFQ scores (pooled mean difference -1.9; Cohen's d for Stages 1 and 2 = -0.28 and -0.47, p = 0.03) versus placebo, as well as QIDS-SR scores in Stage 2 of SPCD (-2.5; Cohen's d Stages 1 and 2 = -0.03 and -0.68, p = 0.04). The 40 mg dose also showed advantages on some objective cognitive measures of the CogScreen (absolute Cohen's d ranged between 0.12 and 1.12 in favor of NSI-189, p values between 0.002 and 0.048 for those with overall significance), but not the Cogstate test. Both doses were well tolerated. These findings replicate those of phase 1b study, and warrant further exploration of the antidepressant and pro-cognitive effects of NSI-189.

Promoting effective teaching and learning in the clinical setting.

This article explores the nature of teaching and learning in the clinical area. Many of the issues that mentors encounter in promoting a good learning environment and undertaking effective teaching are discussed.

Myocardial infarction: Part 2.

Complications can and often do arise following myocardial infarction. Patients can be offered several tests and treatments. Nurses have an important health promotion role at all stages.

Myocardial infarction: Part 1.

Informed nursing care is crucial in effective treatment and rehabilitation of the patient following MI. The National Service Framework for Coronary Heart Disease should be integrated into nursing practice.

Blood and the classification of anaemia.

This article gives a brief overview of the function and composition of blood, focusing on the red blood cell and the development of the various types of anaemia. Good patient care and effective treatment of this complex condition is dependent on informed nursing practice.

The use of intravenous therapy.

Nurses have a professional and legal responsibility to understand the rationale for the use of prescribed fluids. Safe administration requires an understanding of the role of electrolytes and water and of the mechanisms of movement between different body compartments.

Shock.

Shock is a life-threatening condition and to provide the best treatment, nursing care needs to focus on the cause of shock. Different types of shock and their causes are discussed to provide a better understanding of the nursing priorities involved.

The development of diabetic ketoacidosis.

To provide nurses with a greater understanding of the condition, Helen Hand describes the underlying processes responsible for the development of diabetic ketoacidosis and discusses the need for health promotion.

Reduced muscarinic receptor binding in tissues of rats tolerant to the insecticide disulfoton.

Tolerance to the toxic effects of exposure to the organophosphate acetylcholinesterase inhibitor, disulfoton, was induced by giving multiple, sublethal doses of the compound to male rats. Tolerance was judged to have been induced when toxic signs of exposure, including weight loss, were reversed or diminished. Binding of the specific muscarinic radioligand, [3H] quinuclidinyl benzilate ([3H] QNB) to ileal muscle, forebrain, and hindbrain from treated animals was significantly less than the amount bound to tissue from the control animals. Binding of [3H] QNB to heart tissue from tolerant animals was not different from control values. After a typical tolerance-inducing regimen of 7 doses of 2 mg/kg/day disulfoton followed by 4 doses of 3 mg/kg/day, [3H] QNB binding to heart from treated animals was 104% of controls, while binding to ileal muscle, forebrain, and hindbrain was 67, 69, and 77% of control values (p less than .001, .001 and .01), respectively. [3H] QNB binding was not decreased due to competition for binding sites with excess acetylcholine. Neither were decreases due to displacement by disulfoton, as an acute dose of disulfoton (which caused marked inhibition of acetylcholinesterase) did not result in decreased binding. The maximal binding (Bmax) to forebrain of tolerant animals was 56% of control (1.06 vs 1.88 pmol [3H] QNB mg protein-1, p less than 0.01), but no statistically significant change could be seen in equilibrium dissociation constants (Kd, 0.35 vs 0.36 nM). No changes in [3H] QNB binding constants occurred in hearts form tolerant animals. Differences between tolerant and control groups could be seen in [3H] QNB binding to striatum, but no alterations occurred in this brain area in the binding of dopaminergic or gabaergic radiolabels. The data presented in consistent with the hypothesis that cholinergic receptors are involved in organophosphate tolerance.

Tolerance to the carbamate insecticide propoxur.

Male mice were given the carbamate insecticide propoxur (2-isopropoxy phenyl methylcarbamate; Baygon) in the drinking water at weekly increasing concentrations (from 50 to 2000 ppm), for a period of 6 weeks. At the end of the treatment the LD50 for propoxur was significantly higher in the treated animals as compared with controls. Propoxur-treated animals were also resistant to the hypothermic effect of an acute administration of the same compound. Groups of mice were challenged with the cholinergic agonist carbachol at intervals during the drinking water dosing and at its end. No differences in sensitivity to carbachol acute toxicity were found between control and treated animals. Propoxur-tolerant animals were also not resistant to the hypothermic effect of oxotremorine, another cholinergic agonist. [3H]Quinuclidinyl benzilate ([3H]QNB) binding (a measure of muscarinic receptor density and affinity) in forebrain, hindbrain and ileum never differed in control and treated mice. The possibility that repeated administrations of propoxur induced increased metabolic inactivation was tested by measuring hexobarbital sleeping time and carboxylesterase activity in treated and control mice. No changes in tissue carboxylesterase activities occurred but hexobarbital sleeping time was significantly reduced in propoxur treated animals suggesting an induction of hepatic microsomal enzymes. These results suggest that tolerance to propoxur is not mediated by a decrease of cholinergic receptors, as reported for other acetylcholinesterase inhibitors, but possibly by an enhancement of its metabolism.