(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.

Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.

A nurse-led, unit-based program to reduce restraint use in acute care.

Although the effectiveness of restraints is not proven, the dangers of restraints are clear. Many advocate for the reduction of restraint use in tertiary care settings. The Joint Commission on the Accreditation of Healthcare Organizations is setting the standard by insisting that hospital administrations create a culture that emphasizes restraint reduction. Despite the importance of this task, very little is available in the literature to direct or guide this effort. The purpose of this article is to describe a unit-based Restraint Reduction Program that was successful on a neurology/neurosurgery unit.

AR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats.

Nicotinic acetylcholine systems have been found to be important for learning and memory function. The prototypic nicotinic agonist nicotine has been shown in a variety of studies to improve aspects of cognitive function. The specific involvement of nicotinic receptor subtypes is now being investigated. The involvement of alpha7 nicotinic receptors was assessed in this project using a novel alpha7 nicotinic agonist, AR-R 17779. Repeated doses (subcutaneous injection 20 min before testing) of the racemic mixture AR-R 13489 and its active isomer AR-R 17779 were assessed in adult female Sprague-Dawley rats using the eight-arm radial maze. AR-R 13489 (2 mg/kg) caused a significant improvement of long-term win-shift acquisition after 3 weeks of training (n = 10 per group). The same dose of AR-R 17779 also caused a significant improvement in repeated acquisition within each daily session in the radial-arm maze. In another study, the active isomer AR-R 17779 significantly improved radial-arm maze working memory function in rats with lesions to the septohippocampal projection. Fimbria-fornix lesions significantly impaired working memory performance and AR-R 17779 significantly reversed that impairment. These studies showed that alpha7 nicotinic agonist treatment improved learning in two radial-arm maze tasks and reversed working memory impairment caused by fimbria-fornix sections, providing evidence for alpha7 involvement in learning and memory, and the potential therapeutic use of AR-R 17779.

An early loss in membrane protein kinase C activity precedes the excitatory amino acid-induced death of primary cortical neurons.

Several lines of evidence indicate that a rapid loss of protein kinase C (PKC) activity may be important in the delayed death of neurons following cerebral ischemia. However, in primary neuronal cultures, cytotoxic levels of glutamate have been reported not to cause a loss in PKC as measured by immunoblot and conventional activity methods. This apparent contradiction has not been adequately addressed. In this study, the effects of cytotoxic levels of glutamate, NMDA, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on membrane PKC activity was determined in cortical neurons using an assay that measures only PKC that is active in isolated membranes, which can be used to differentiate active enzyme from that associated with membranes in an inactive state. A 15-min exposure of day 14-18 cortical neurons to 100 microM glutamate, AMPA, or NMDA caused a rapid and persistent loss in membrane PKC activity, which by 4 h fell to 30-50% of that in control cultures. However, the amount of enzyme present in these membranes remained unchanged during this period despite the loss in enzyme activity. The inactivation of PKC activity was confirmed by the fact that phosphorylation of the MARCKS protein, a PKC-selective substrate, was reduced in intact neurons following transient glutamate treatment. By contrast, activation of metabotropic glutamate receptors by trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid was not neurotoxic and induced a robust and prolonged activation of PKC activity in neurons. PKC inactivation by NMDA and AMPA was dependent on extracellular Ca2+, but less so on Na+, although cell death induced by these agents was dependent on both ions. The loss of PKC activity was likely effected by Ca2+ entry through specific routes because the bulk increase in intracellular free [Ca2+] effected by the Ca2+ ionophore ionomycin did not cause the inactivation of PKC. The results indicate that the pattern of PKC activity in neurons killed by glutamate, NMDA, and AMPA in vitro is consistent with that observed in neurons injured by cerebral Ischemia in vivo.

N-methyl-D-aspartate- or glutamate-mediated toxicity in cultured rat cortical neurons is antagonized by FPL 15896AR.

The neuroprotective action of (S)-alpha-phenyl-2-pyridineethanamine dihydrochloride (FPL 15896AR), a novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in primary rat cortical neuronal cultures. Exposure of cortical cultures to NMDA (50 microM) or glutamate (50 microM) for 15 min resulted in the death of 85-95% of the neurons during the next 24 h. This neurotoxicity was completely eliminated by adding FPL 15896AR (50 microM) to the cultures during the time of NMDA or glutamate exposure. Neuroprotective concentrations of FPL 15896AR also inhibited other acute effects of NMDA. FPL 15896AR (50 microM) prevented the loss of membrane-associated protein kinase C activity that developed by 4 h after transient exposure to 50 microM NMDA or 50 microM glutamate. FPL 15896AR also reduced by approximately 35% the magnitude of NMDA-triggered increases in intracellular free Ca2+ concentration in the cortical cultures. These data indicate that NMDA-mediated toxicity in cultured cortical neurons can be blocked by the NMDA antagonist FPL 15896AR.

In vitro muscarinic activity of spiromuscarones and related analogs.

The cholinergic hypothesis of Alzheimer's disease suggests that cholinergic agonists may have therapeutic potential for treating the attendant memory deficits of the disease. As part of a program aimed at preparing metabolically stable, nonquaternary analogs of muscarone, 1-oxa-2,8-dimethyl-8-azaspiro[4.5]decan-3-one, 2a, and related analogs have been synthesized and their in vitro muscarinic activity evaluated. The synthetic strategy in the formation of the 1-spiro[4.5]decan-3-one ring system of 2a involved cyclization of the diol 4 in the presence of Nafion-Hg. The spiromuscarone 2a was found to displace [3H]Oxo-M binding with a Ki value of 7 nM. Affinities of the oxime and hydrazone analogs of 2a were lower than 2a. The compounds in these series were partial muscarinic agonists as demonstrated by stimulation of phosphatidyl inositol hydrolysis assay, with 2a showing the highest intrinsic intrinsic activity (60% as compared with carbachol). The results from this study indicate that an exo double bond at the C-3 position is essential for the receptor binding.

Recommendations for clinicians based on parents' experiences.

Three mothers of children with severe communication disabilities describe their experiences with speech-language pathologists and the intervention process. The parents were asked open-ended and descriptive questions. Their responses provide valuable insights and direction for professionals interested in working more closely with families of children with disabilities. The mothers describe their role as primary case managers for their children's treatment programs. They identify the type of speech-language pathologist they prefer to work with their child and the professional guidance they find most helpful. Several recommendations for communication disorders professionals evolved from the discussion.

FPL 14294: a novel CCK-8 agonist with potent intranasal anorectic activity in the rat.

Cholecystokinin octapeptide (CCK-8) induces satiety in many species including man. However, its therapeutic utility is restricted due to its short biological half-life and poor bioavailability. FPL 14294 [4-(sulfoxy)-phenylacetyl(MePhe6)CCK-6] is a CCK analog with enhanced metabolic stability that was comparable to CCK-8 in potency to contract isolated gallbladder and in affinity at the CCK-A and CCK-B receptor. However, FPL 14294 was more than 200 times more potent than CCK-8 in inhibiting 3-h feeding in 21-h fasted rats. FPL 14294 also possessed intranasal anorectic activity at 5 micrograms/kg, while CCK-8 was inactive at doses up to 500 micrograms/kg. Anorectic activity was inhibited by pretreatment with a CCK-A antagonist (MK-329) but not by a CCK-B antagonist (L365,260). The anorectic effects of CCK-8 and FPL 14294 were the result of a direct effect on feeding and not caused indirectly by effects on water intake. These results indicate that FPL 14294 is a potent, intranasally active, anorectic agent whose enhanced in vivo potency over that of CCK-8 may reflect differences in stability, bioavailability, or receptor kinetics.

A proactive model for treating communication disorders in children and adolescents with traumatic brain injury.

This proactive approach to assessment and intervention focuses both on looking ahead to determine problems the student with TBI is likely to encounter as a result of cognitive-communicative impairments, and on developing solutions to those problems. Intervention places the family and other important people in the student's life at the center of the treatment process. Family members, teachers, peers, and coworkers can be incorporated into the intervention program. Strategies and techniques can be implemented within the home, school, community, and work setting. To do so, professionals must be committed to working closely with others to develop collaborative relationships.

Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat.

Studies conducted by Fisons Pharmaceuticals and the Antiepileptic Drug Development Program (ADD Program) of the Epilepsy Branch (NINDS, NIH) revealed that 'remacemide' (FPL 12924, formerly PR 934-423) was effective orally in the prevention of maximal electroshock seizures (MES) in rats. In this context (-)stereoisomer (FPL 14145) was of equal potency to the racemate (remacemide), while the (+)stereoisomer (FPL 14144) was 54% less potent. With respect to neurotoxicity, remacemide and its enantiomers possessed more favorable therapeutic indices than phenobarbital and valproate and less favorable indices than phenytoin and carbamazepine. The duration of protection of rats in the MES test at the ED50 or 3 x ED50 of remacemide and the (+)isomer was better or on par with the best reference compounds, phenytoin and phenobarbital. After subchronic administration of either the ED50 or the ED97 of remacemide, no tolerance developed in the hexobarbital sleep test, however, the activities of 3 hepatic microsomal enzymes were elevated. In naive rats high doses of remacemide or its (-)isomer and low doses of phenobarbital caused an increase in spontaneous motor activity. Alternatively, motor activity was depressed subsequent to high doses of phenobarbital and phenytoin. Remacemide was inactive against pentylenetetrazol and 'kindling' seizures. It was without effect in 5 electrophysiological tests (evoked responses, recurrent inhibition, long-term potentiation, penicillin-induced discharge rate and veratridine-induced depolarization) employing the in vitro hippocampal slice technique. Moreover, remacemide failed to demonstrate potent binding in vitro to neuronal L-glutamate, gamma-amino-butyrate A, adenosine A1, benzodiazepine, N-methyl-D-aspartate (strychnine-insensitive glycine and ion channel subsites) or muscarinic receptors. In conclusion, remacemide specifically prevents seizures elicited by MES, an action predicting utility in patients with generalized tonic/clonic convulsions.

Flavodilol: a new antihypertensive agent that preferentially depletes peripheral biogenic amines.

Flavodilol, ((+/-)-7-[2-hydroxy-3-(propylamine)-propoxy]flavone maleate), a new orally effective antihypertensive agent, extensively depleted catecholamines and serotonin in heart tissue of normotensive and spontaneously hypertensive rats (SHR). Dose-response studies demonstrated that greater than or equal to 75% depletion of cardiac norepinephrine (NE) was accompanied by marked blood pressure decline in SHR. In contrast, whole brain biogenic amine levels were decreased only by 15-20% after acute or chronic treatment with antihypertensive doses (35-75 mg/kg). Adrenal epinephrine (EPI) stores were unaffected by acute treatment, although chronic treatment for 18 days with an antihypertensive dose of 75 mg/kg flavodilol decreased EPI by 70%. Acute treatment also decreased serotonin content of spleen by 70-80%. In dogs, a cumulative oral dose of 40 mg/kg decreased catecholamines by greater than or equal to 50% in aorta and heart muscle. Although hypothalamic catecholamine stores appeared to be more susceptible to depletion by flavodilol than catecholamines in other brain regions, these changes did not appear functionally related to blood pressure decreases since analogs of flavodilol without antihypertensive properties produced equivalent or greater depletion of hypothalamic catecholamine stores. In vitro flavodilol promoted spontaneous and potassium-evoked release of dopamine from isolated striatal nerve endings (0.3 microM) and blocked uptake of NE by hypothalamus and hippocampal nerve endings (1 microM), suggesting that biogenic amine depletion in vivo may be caused by an interference with storage and release mechanisms. Despite structural features reminiscent of beta-adrenergic antagonists, flavodilol had low affinity for beta-receptors. Neither was there any inhibition of tyrosine hydroxylase. These findings suggest that the antihypertensive activity of flavodilol results, at least in part, from depletion of sympathetic stores of NE in heart and vascular tissues that moderate adrenergic transmission, thereby decreasing heart rate (HR) and prevailing vascular tone.

Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties.

(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.

Correlation of activity of chlorpromazine and respective hydroxy, dimethoxy and sulphoxide analogues on dopamine, muscarinic, histamine and calmodulin sites of action.

1. Chlorpromazine (CPZ) is a unique molecule which has many potential sites of action, as well as a propensity to be transformed into a host of metabolites possessing varying degrees of pharmacological and/or toxic reactions. This investigation examined the rank order of potency of CPZ and eight metabolic derivatives with respect to displacement of 3H-spiperone at central dopamine-2 (DA-2) receptors, 3H-pirenzepine at central muscarinic-1 (M-1) receptors, and inhibition of calmodulin-induced activation of cyclic AMP-dependent phosphodiesterase. 2. The most potent CPZ analogues to displace labelled spiperone from DA-2 receptors in rat striatum were: 3-hydroxy-CPZ, CPZ, 3,7-dihydroxy-CPZ, and 7-hydroxy-CPZ. Intermediate potency was observed with 8-hydroxy-CPZ, 3,7,8-trihydroxy-CPZ, and 7,8-dihydroxy-CPZ. Chlorpromazine sulphoxide and 7,8-dimethoxy-CPZ displayed the least activity at DA-2 receptors. 3. Displacement of labelled pirenzepine from M-1 receptors in rat frontal cortex occurred to the greatest extent with CPZ which was one to two orders of magnitude more potent than noted for 3-hydroxy-CPZ greater than 7-hydroxy-CPZ greater than CPZ-sulphoxide greater than 8-hydroxy-CPZ greater than 7,8-dimethoxy-CPZ. The least potent agents were 3,7-and 7,8-dihydroxy-CPZs and 3,7,8-trihydroxy-CPZ. 4. A partially purified calmodulin-sensitive preparation of cyclic AMP-dependent phosphodiesterase from guinea pig heart was most sensitive to inhibition by 7,8-dihydroxy-CPZ, 7,8-dimethoxy-CPZ, 3-hydroxy-CPZ, 7-hydroxy-CPZ, 8-hydroxy-CPZ and CPZ. Least inhibition occurred with 3,7-dihydroxy-CPZ, 3,7,8-trihydroxy-CPZ and CPZ-sulphoxide. 5. The DA-2 receptors were more sensitive to the active CPZ analogues than were the M-1 receptors while calmodulin-activated phosphodiesterase was the least sensitive preparation. 6. Comparisons of data were made with existing information from other laboratories and in general CPZ, 7-hydroxy-CPZ and 3-hydroxy-CPZ were the most potent compounds across different test conditions.

Flavones. 1. Synthesis and antihypertensive activity of (3-phenylflavonoxy)propanolamines without beta-adrenoceptor antagonism.

The synthesis of a series of (3-phenylflavonoxy)propanolamines is described. These compounds were evaluated for potential antihypertensive activity in spontaneously hypertensive rats, as well as for in vivo and in vitro evidence of beta-adrenoceptor antagonism. Some of the compounds of this series exhibited effective antihypertensive properties but did not antagonize beta-adrenergic receptors. These active compounds represent a unique series of effective antihypertensive agents that, despite possessing structural characteristics typical of beta-blockers, does not have beta-adrenergic receptor blocking activity.

Correlation between anorectic potency and affinity for hypothalamic (+)-amphetamine binding sites of phenylethylamines.

The potencies of a number of phenylethylamines and related compounds to inhibit food intake were compared with their relative affinities for hypothalamic (+)-amphetamine binding sites in vitro. There was a positive correlation (r = 0.78, P less than 0.001, n = 19) between potencies of these compounds to inhibit food intake and their potencies to inhibit [3H](+)-amphetamine binding. Individual enantiomers of amphetamine, ephedrine, norephedrine, pseudoephedrine and norpseudoephedrine all inhibited food intake with a two- to five-fold greater potency than that of their respective optical isomers. However, they did not exhibit a comparable stereospecificity to inhibit [3H](+)-amphetamine binding. Further, several compounds including imipramine and propranolol, without known anorectic properties were among the most potent agents to inhibit [3H](+)-amphetamine binding. Thus, although a positive correlation exists between relative binding affinity and potencies to inhibit food intake, the functional interrelationship is uncertain.

Comparison of the Token Test of Language Development and the Wechsler Intelligence Scale for Children--Revised.

Correlations were calculated between the Token Test of Language Development (Token) and scores of the Wechsler Intelligence Scale for Children--Revised (WISC-R) based on responses from 38 Caucasian children (23 boys and 15 girls) of a semi-rural Northeastern Ohio school district. The relatively low Pearson correlations (.25 to .47) between the standard scores in the Token test and WISC-R IQs are discussed in relation to ability and achievement.

The use of hepatitis B marker prevalences in regional blood center employees as a guide to vaccination policy.

Hepatitis B vaccination has been recommended for health care personnel having frequent contact with blood. Serologic markers of hepatitis B infection were studied in employees of this regional blood center to determine the prevalence of infection in our population.

beta-Adrenergic receptor activation increases acetylcholine receptor number in cultured skeletal muscle myotubes.

Treatment of embryonic chick muscle myotubes with the beta-adrenergic agonist isoproterenol increased the number of surface membrane nicotinic cholinergic receptors. Receptor degradation was unaffected by isoproterenol, suggesting that receptor synthesis was increased. The effect of isoproterenol appears to be mediated by the beta-adrenergic receptor adenylate cyclase system for the following reasons: (a) The response to isoproterenol was dose-dependent and stereospecific. (b) The response to catecholamines followed the order isoproterenol greater than epinephrine greater than norepinephrine. (c) Alprenolol, a beta-adrenergic antagonist, but not phentolamine, an alpha-antagonist, abolished the effect. (d) The maximal effects of isoproterenol and cholera toxin, an activator of adenylate cyclase, were not additive. These results suggest that under certain physiological states catecholamines may play an important role in the regulation of cholinergic receptors.