Olanzapine in the treatment of anxiety symptoms due to Alzheimer's disease: a post hoc analysis.

BACKGROUND: Alzheimer's disease (AD) is associated with both cognitive and behavioral symptoms. Agitation, hallucinations, delusions, aggression, irritability, and anxiety are observed in up to 90% of patients with dementia. Although new information has emerged in recent years on the treatment of psychosis and agitation in dementia, very little information is available about the treatment of anxiety symptoms in this population. OBJECTIVES: To assess the efficacy and tolerability of olanzapine in the treatment of significant anxiety symptoms in patients with AD. METHODS: A post hoc analysis of a previously published study was performed. Those post hoc analysis evaluated the response to treatment with olanzapine of a subgroup of AD patients presenting with significant symptoms of anxiety. Patients were considered to have significant symptoms of anxiety if their baseline in the Nursing home version of the Neuropsychiatric Instrument NPI/NH anxiety scores were > or = 2. The analysis included 120 patients. RESULTS: Patients receiving olanzapine 5 mg/d were statistically significantly improved on the NPI/NH Anxiety item compared to those receiving placebo (olanzapine, 5 mg/d: -3.72; placebo: -1.67; p = 0.034). In the group of patients with clinically significant anxiety, somnolence was the only treatment-emergent event that was statistically different in any olanzapine treatment group compared with placebo (olanzapine 5 mg/d: 9 patients [25%], p = 0.034; 10 mg/d: 7 [23%], p = 0.054; 15 mg/d: 7 [26%], p = 0.050; placebo: 1 [3.7%]). When controlling for treatment-emergent somnolence, the improvement in anxiety in the olanzapine 5 mg/d group remained statistically significant (p = 0.049). CONCLUSIONS: These findings suggest that olanzapine could be a safe and effective treatment for anxiety in Alzheimer's disease.

Biphasic urethral sphincter responses to acetic acid infusion into the lower urinary tract in anesthetized cats.

PURPOSE: Varying the concentration of infused acetic acid produced bladder irritation and dose dependent increases in external urethral sphincter electromyography activity in cats. We further characterized acetic acid induced external urethral sphincter electromyography activity in intact and acute spinal cord injured animals. MATERIALS AND METHODS: Bladder cystometrography and external urethral sphincter electromyography were continuously recorded in chloralose anesthetized cats. Dilute 0.05% to 0.8% acetic acid was infused into the lower urinary tract through the bladder dome. Intravesical or intraurethral infusion was performed separately in bladder neck ligated preparations. In some animals the spinal cord was transected at L1 to L2 2 to 8 hours before the study. RESULTS: Acetic acid infusion into the lower urinary tract elicited dose dependent increases in tonic external urethral sphincter activity. However, a prolonged infusion of 0.7% to 0.8% acetic acid usually inhibited external urethral sphincter activity. The excitatory external urethral sphincter response was elicited by intraurethral but not by intravesical infusion. This response remained in acute spinal cord injured animals. The inhibition of tonic external urethral sphincter activity during 0.7% to 0.8% acetic acid infusion was observed when there was extreme bladder irritation characterized by continual contractions. Induced tonic external urethral sphincter activity was attenuated by intrathecal administration of prazosin or scopolamine and abolished by hexamethonium. CONCLUSIONS: Acetic acid infusion into the lower urinary tract elicits biphasic external urethral sphincter responses. The early excitatory response is a spinal urethrourethral reflex and the late inhibitory phase results from negative vesicourethral feedback control. Spinal muscarinic cholinergic and alpha-adrenergic receptors are involved in acetic acid induced excitatory external urethral sphincter responses.

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

Lamotrigine protects hippocampal CA1 neurons from ischemic damage after cardiac arrest.

BACKGROUND AND PURPOSE: Lamotrigine (LTG) is an anticonvulsant drug whose mechanism of action may involve the inhibition of glutamate release by blocking voltage-dependent sodium channels. Glutamate neurotoxicity may contribute to cerebral ischemic damage after recovery from cardiac arrest. Thus, LTG may prevent the brain damage associated with global cerebral ischemia by reducing the release of glutamate from presynaptic vesicles during the ischemic insult or the early recovery period. METHODS: LTG was studied in cardiac arrest-induced global cerebral ischemia with reperfusion in rats. In the first set of experiments, LTG (100 mg/kg, p.o.) was administered before induction of ischemia; and in the second experiment, LTG (10 mg/kg, i.v.) was given 15 minutes after ischemia and a second dose (10 mg/kg,i.v.) was given 5 hours later. RESULTS: In both experiments LTG reduced the damage to the hippocampal CA1 cell population by greater than 50%. Neuroprotection was not associated with changes in brain temperature or plasma glucose concentration. Plasma concentrations of LTG ranged between 8 and 13 micrograms/mL. Patients taking LTG as a monotherapy for epilepsy typically have plasma levels of LTG in the 10 to 15 micrograms/mL range. CONCLUSIONS: These data suggest that LTG may be effective in preventing brain damage after recovery from cardiac arrest. Patients on LTG monotherapy for epilepsy have plasma concentrations very similar to those found to be neuroprotective in this study. Although difficult to extrapolate, our data suggest that LTG at neuroprotective doses may be well tolerated by humans.

1192U90 in animal tests that predict antipsychotic efficacy, anxiolysis, and extrapyramidal side effects.

1192U90 was developed on the assumption that antagonism of 5-HT2 receptors efficacy yields more potently than D2 receptors against positive and negative symptoms of schizophrenia with minimal liability for extrapyramidal side effects (EPSs), and that 5-HT1A agonism further reduces EPSs and provides anxiolytic and antidepressant activity. 1192U90 was submitted to four tests that predict antipsychotic efficacy (antagonism of apomorphine-induced climbing in mouse, antagonism of apomorphine-induced circling in rats with unilateral 6-OHDA lesions, antagonism of amphetamine-induced hyperlocomotion in rat, and inhibition of conditioned avoidance in rat), two tests of 5-HT2 function (antagonism of 5-MeODMT-induced head twitches in mouse and antagonism of 5-HTP-induced wet dog shakes in rat), and three tests that predict EPS liability (antagonism of apomorphine-induced stereotypy in mouse and rat and induction of catalepsy in mouse). ED50s (mg/kg PO) were as follows: climbing 10.1, circling 7.9, hyperlocomotion 6.6, and avoidance 5.7; head twitches 5 and wet dog shakes 4.6; stereotypy in mouse 91.1, stereotypy in rat 133.4, and catalepsy 192.4. The ratio of ED50 for stereotypy antagonism to ED50 for climbing antagonism was 9 (compared to 4, 3, and 4 for clozapine, risperidone, and haloperidol). The ratio of ED50 for catalepsy induction to ED50 for climbing antagonism was 19 (compared to 7, 2, and 17 for clozapine, risperidone, and haloperidol). 1192U90 was also submitted to three tests that predict anxiolysis: It produced only a small increase in punished lever pressing for food in rat (Geller-Seifter conflict test), which is specific for rapid-onset efficacy, but produced large increases in punished key pecking for food in pigeon and cork gnawing in rat, which identify the delayed onset 5-HT1A agonists such as buspirone. The results suggest that 1192U90 would be effective for positive and negative symptoms of schizophrenia, with minimal liability for EPSs, and may also have anxiolytic properties.