Safety and immunogenicity of an oral, inactivated, whole-cell vaccine for Shigella sonnei: preclinical studies and a Phase I trial.

Orally delivered, inactivated whole-cell vaccines are safe methods of inducing local and systemic immunity. To increase surface proteins associated with adherence and invasion, Shigella sonnei were grown in BHI broth containing deoxycholate. A whole-cell vaccine (SsWC) was then produced by formalin inactivation. In pre-clinical studies, the SsWC vaccine was immunogenic and protected against S. sonnei-induced keratoconjunctivitis in the guinea pig model. In a randomized, double-blind, placebo-controlled, Phase I study, 10 evaluable subjects received either three doses of SsWC on Days 0, 14, and 28 (N = 3); five doses of SsWC on Days 0, 2, 4, 6, and 28 (N = 4); or placebo (N = 3). Each dose contained 2.0 x 10(10) inactivated cells. Serum and fecal antibodies against SsWC, LPS, and IpaC were measured by ELISA. A > or = 4-fold increase in titer was considered significant. Both SsWC dosing regimens were well tolerated. No fever or severe gastrointestinal symptoms were noted by any of the vaccinated subjects. Antibody responses were similar in the two dosing groups. Serum IgG or IgA responses to SsWC were seen in six of seven vaccinees (86%), to LPS in four of seven (57%), and to IpaC in five of seven (61%). Fecal IgA responses to these three antigens developed in five of five, three of five, and three of five subjects, respectively. Among the seven vaccinees, geometric mean rises in serum IgA levels to all three immunogens were significant; IgG increases trended toward significance (paired one-tailed t-test). We conclude that SsWC was immunogenic and protective in animal studies and well tolerated and immunogenic in a Phase I trial.

Sex dimorphisms in the cognitive-enhancing action of the Alzheimer's drug donepezil in aged Rhesus monkeys.

Brain acetylcholinesterase has been targeted for the development of novel treatments for memory deficits associated with Alzheimer's disease (AD) and other neurodegenerative disorders. The long-acting AChE inhibitor donepezil (Aricept) is used to improve memory and other aspects of cognition in AD patients. Because donepezil and other cholinesterase inhibitors are effective in a restricted population of AD patients, this study was to designed to determine whether aged females monkeys receive the same level of benefit to the mnemonic action of donepezil as do males. In this study, six male and six female rhesus monkeys (>20 years) who were proficient in the performance of a delayed matching-to-sample task each received an ascending series of four doses of donepezil (0.01-0.1 mg/kg) over 5 weeks. As a group, male subjects exhibited improvement in task accuracy across the three highest doses, with the maximum effect occurring after the 0.025 mg/kg dose. However, the females exhibited increased task accuracy only after the highest dose. When data were combined for sessions run 10 min after drug administration and for sessions run 24 h later (in the absence of drug), improvements in task accuracy were greater on average for males. Most of this difference was attributed to the fact that task accuracy by females actually declined during sessions run after the two lowest doses of donepezil. When task performance after donepezil was determined as the individualized Best Dose, as a group, males responded maximally to less than half the dose that was maximal for females. These findings support the concept that aged males and females respond differently to this class of agents, perhaps representing fundamental sex-related differences in memory processing, or in the manner that age affects these processes.

Evaluation of two rodent delayed-response memory tasks: a method with retractable levers versus a method with closing doors.

The purpose of this study was to evaluate and compare two similar rodent memory tasks developed in our laboratory that employ stimulus discrimination and delayed response (light and tone stimuli and variable length delays) and to determine their sensitivity to the muscarinic-acetylcholine receptor (mAChR) antagonist, scopolamine hydrobromide (SCOP HBr), and its quaternary (methylbromide) analog (SCOP MBr). Male Wistar rats were trained in either an open chamber that employed retracting levers (RLM) during the delays, or a method that utilized closing doors (CDM) that separated the rats from the levers during delays to reduce positional (nonmnemonic) strategies. When the rats were well trained, dose-effect studies (microg/kg doses, s.c., 30 min before test sessions) of SCOP HBr or MBr were performed. Baseline performance was characterized by delay-dependent decreases in accuracy in both methods except when the tone was the stimulus in the RLM. SCOP HBr impaired performance in both tasks at the higher doses tested, although the effects were more consistent in the CDM task and accuracy associated with each stimulus was affected similarly. Surprisingly, SCOP MBr also impaired performance of each task, especially when the tone was the stimulus, while accuracy associated with the light was not affected in the CDM task. Overall, the results indicated that the CDM was a somewhat more reliable task, appearing to reduce positional strategies with less variability in response to the mAChR antagonists, although some stimulus-modality specific effects were noted. It also appears important to consider the peripheral effects of mAChR antagonists (and potential central effects of quaternary mAChR antagonists) when interpreting results from behavioral studies, especially those involving conditional discrimination and delayed response.

Immediate and delayed implant placement into extraction sockets: a 5-year report.

BACKGROUND: As a complement to the earlier reported 3-year results from a prospective multicenter study of immediate and delayed placement of implants into fresh extraction sockets, the 5-year results are reported. PURPOSE: The purpose of this 5-year report was to evaluate the immediate and long-term success of implants placed into fresh extraction sockets, with respect to implant size and type, bone quality and quantity, implant position, initial socket depth, and reason for tooth extraction. MATERIALS AND METHODS: This paper presents the 5-year results of the original 12 centers that participated with 143 consecutively included patients. A total of 264 implants were placed either immediately after tooth extraction or after a short soft-tissue healing time (3-5 weeks). The patients were divided into five subgroups, depending on the type of insertion method used. RESULTS: The outcome demonstrated that the cumulative implant survival rate after 5 years of loading has not changed and remains 92.4% in the maxilla and 94.7% in the mandible. No difference in failure rates can be seen between the groups when relating the failures to insertion method. CONCLUSION: This prospective study demonstrated that placing Brånemark implants into fresh extraction sites can be successful over a period of 5 years of loading. One of the outcomes of the study shows that there is a clinical correlation between implant failure and periodontitis as a reason for tooth extraction, even if it is difficult to give it a casual association. It can be hypothesized that periodontitis affected tissues might have a negative local influence because of the presence of infrabony defects that could possibly increase the gap between bone and implant or jeopardize achievement of primary stability.

A 3-year prospective multicenter follow-up report on the immediate and delayed-immediate placement of implants.

A total of 264 implants was placed in 143 patients using different immediate or delayed-immediate implant placement techniques in 12 different centers participating in a prospective multicenter study. The reason for tooth extraction was evaluated; bone quality and quantity were classified; socket depths were registered; and data on implant type, size, and position were collected. One hundred thirty-nine suprastructures were placed on 228 implants in 126 patients. A follow-up evaluation was done on 125 patients after 1 year of loading and on 107 patients after 3 years of loading. Clinical parameters (bleeding or not bleeding, pocket depth, and implant mobility) were evaluated after 1 and 3 years, and the marginal bone level after 1 year of loading was measured on radiographs. Clinical comparisons were performed to evaluate implant loss in relation to implant type, size, position, bone quality and quantity, socket depth, reason for tooth extraction, and placement method. In addition, life table analysis was done for cumulative implant survival rates. There was no clinical difference with respect to socket depth or when comparing the different placement methods. A higher failure rate was found for short implants in the posterior region of the maxilla and when periodontitis was cited as a reason for tooth extraction. Mean marginal bone resorption from the time of loading to the 1-year follow-up was 0.8 mm in the maxilla and 0.5 mm in the mandible. Over a period of 3 years, the implant survival rate was 92.4% in the maxilla and 94.7% in the mandible.

Differential improvement in memory-related task performance with nicotine by aged male and female rhesus monkeys.

Central nicotinc acetylcholine receptors have been targeted for the development of novel treatments for memory deficits in Alzheimer's disease (AD) and other neurodegenerative disorders. Nicotine itself has been shown to improve memory-related task performance in aged animals and in AD patients. Administration of nicotinic receptor agonists to laboratory animals, and the effects of cigarette smoking in humans attributed to nicotine, have in many instances been shown to exert sexually dimorphic actions. Low doses (2.5-20 microg/kg, intramuscularly) of nicotine have been shown to improve the performance of an automated delayed matching-to-sample (DMTS) task in aged rhesus monkeys. The purpose of this study was to determine whether aged females receive the same level of benefit to the positive mnemonic action of nicotine as do males. In this study six male (21.7+/-1.2 years) and seven female (22.5+/-0.9 years) rhesus monkeys each received an ascending series of four doses of nicotine over 5 weeks. Most control parameters were similar between the two sexes, although task latencies were longer and more variable in the female subjects. The males maintained a significant improvement in task performance over the entire nicotine dose range. This level of improvement extended to 24 h after nicotine administration. Task accuracy by females appeared to improve only after they received the two higher doses of nicotine, and their responses exhibited considerable variability over the entire dose range. However, in calculating an individualized 'Best Dose', males and females exhibited a similar level of task improvement (15-30% above baseline). Therefore, aged female subjects may require a greater level of individualized treatment and perhaps higher doses of nicotinic agonists to achieve the maximal mnemonic benefit.

Age-related differences in distractibility and response to methylphenidate in monkeys.

Increased susceptibility to distraction is a symptom of normal aging and several clinical syndromes, including Alzheimer's disease and attention deficit disorders. In the present study, aged and young adult macaques were well-trained to perform an automated delayed matching-to-sample (DMTS) task which assesses both attention and short-term memory. On 19% of all trials, a task-relevant distracting stimulus was presented during either the initial 1 or 3 s of delay intervals (early onset) or the final 1 or 3 s of delay intervals (late onset). In aged monkeys, both early and late onset distractors lasting 1 or 3 s impaired delayed recall on trials with the shortest delay intervals, but did not affect accuracy on trials with long delay intervals. In contrast, young adult monkeys were impaired only by the presence of an early onset distractor lasting 3 s. Impairment was selective for only those trials with the shortest delay intervals. Late onset distractors were relatively ineffective in producing distractibility in young adult animals. Methylphenidate (MPH; 0.005-1.0 mg/kg) failed to reduce distractibility in aged monkeys, producing locomotor abnormalities and hypophagia at doses ranging from 0.25 to 1.0 mg/kg. In young adult monkeys, however, distractibility was significantly attenuated by administration of the 0.125 mg/kg dose. Habituation to the distracting stimulus (under saline conditions) was assessed throughout the study and was not evident at any time point of testing. These data indicate that attention and recall after brief delays are impaired following exposure to a task-relevant distracting stimulus in both aged and young adult monkeys, but that aged monkeys are more susceptible to distraction and do not receive significant benefit from MPH administration.

Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys.

Increased distractibility is associated with both Alzheimer's disease and attention deficit disorder. The present study examined the effects of (-)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (i.m.) administration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, i.m.) and ABT-089 (16.4-32.8 nmol/kg, i.m.) prevented distractibility, producing increases of 7.5-25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (-)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.

Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017.

Recent evidence indicates that the 5-HT4 subtype of serotonin receptor may modulate central cholinergic activity in regions of the mammalian CNS important to memory such as the frontal cortex, hippocampus and amygdala. These receptors could represent targets for drugs designed for the symptomatic therapy of Alzheimer's disease (AD) and other disorders of memory. In the present study, the binding activity of RS 17017 (previously described as a selective 5-HT4 agonist) was assessed across a number of neurotransmitter receptors and binding sites, pharmacokinetic data were obtained, and the compound was evaluated in macaques for mnemonic effects via a computer-assisted delayed matching-to-sample task (DMTS). Binding data confirmed the 5-HT4 selectivity of the compound, while pharmacokinetic results revealed low oral bioavailability, but a large volume of distribution of the compound. Significant and reproducible improvements in DMTS accuracy were observed after oral administration of the compound across a dose-effect series in both younger and older monkeys. The results suggest that RS 17017 offers a potential for memory enhancement in disorders involving cognitive decline, and are consistent with a role for central 5-HT4 receptors in memory. Improvements in DMTS performance in aged monkeys may have particular implications for neurodegenerative conditions such as AD, whereas positive results in the younger monkeys indicate that RS 17017 (or similar compounds) may have additional potential in the therapeutics of memory disorders not necessarily associated with advanced age.

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys.

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (-)-nicotine, was tested in a variety of cognitive tests in rats and monkeys. Administered acutely, ABT-089 only marginally improved the spatial discrimination water maze performance of septal-lesioned rats. However, more robust improvement (45% error reduction on the last training day) was observed when ABT-089 was administered continuously via subcutaneous osmotic pumps (minimum effective dose: 1.3 micromol/kg/day). Continuous infusion of (-)-nicotine produced comparable improvement in the spatial discrimination water maze performance of septal-lesioned rats, but a 40-fold higher dose of (-)-nicotine was required (62 micromol/kg/day). Continuous infusion of ABT-089 to aged rats enhanced spatial learning in a standard Morris water maze, as indexed by spatial bias exhibited during a probe trial conducted after 4 days of training, but not when they were subsequently trained in a two-platform spatial discrimination water maze. The compound induced a small impairment in young rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training in the standard water maze revealed no age or drug effects. ABT-089 did not affect performance of either the aged or young rats during inhibitory (passive) avoidance training. Also, continuous infusion of ABT-089 did not affect responses to acoustic startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor activity in either sham-lesioned or septal-lesioned rats. In monkeys, acute administration of ABT-089 modestly improved the delayed matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys. Improved performance in the aged monkeys was restricted to the longest delay intervals and was not accompanied by changes in response latencies.

Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo.

(2.4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human alpha 4 beta 2 nAChR (K1-20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally. GTS-21 stimulated [5H]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 microM (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (< or = 2.5 micromol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine, GTS-21 (-62 micromol/kg.s.e.) also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.).

Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

Nitric oxide synthase inhibition impairs delayed recall in mature monkeys.

The gaseous neuromodulator nitric oxide (NO) is formed in brain regions known to mediate learning and memory processes. In rodent models, pharmacologic inhibition of NO synthesis impairs such processes. In the present study, N omega-nitro-L-arginine methyl ester (L-Name), an inhibitor of the constitutive form of the NO synthetic enzyme, was administered to seven non-aged, mature monkeys (Macaca Fascicularis, Macaca Mulatta, and Macaca Nemestrima) trained to perform a delayed matching-to-sample task (DMTS). L-Name (1.5, 25, and 50 mg/kg) produced marked decrements in task performance, as well as a reduction in the number of trials completed at the highest dose. This impairment of DMTS accuracy by the 50 mg/kg doses of L-Name appears to be associated with an aversive state marked by gastrointestinal disturbance and lethargy. The detrimental effects of the 25 mg/kg dose of L-Name on DMTS accuracy were completely blocked by concurrent administration of a mole-equivalent dose of the NO amino acid precursor L-arginine. As a whole, these data suggest that L-Name impairs processes involved in delayed recall in monkeys and that this impairment is associated with attenuated synthesis of NO. However, at higher doses (> or = 25 mg/kg) this impairment is associated with aversive effects of L-Name, possibly at both central and peripheral sites.

The 5-HT3 receptor antagonist, RS-56812, enhances delayed matching performance in monkeys.

Substantial evidence indicates that serotonin receptors are involved in the regulation of acetylcholine release in CNS regions important to mnemonic processes, and may thus be exploited pharmacologically as targets for memory improvement. In the present study, the (R) and (S) isomers of a potent serotonin (5-HT3) receptor ligand, RS-56812 were evaluated for potential memory effects in five macaques trained to perform a delayed matching-to-sample (DMTS) task. While both isomers enhanced certain aspects of task performance, the (R) isomer produced more systematic improvements. This differential sensitivity to the isomers in regard to DMTS performance appears to parallel the higher 5-HT3 receptor affinity of the R enanantiomer. The results are consistent with a potential therapeutic role for RS-56812 in disorders involving cognitive decline.

Expression of extracellular matrix macromolecules around demineralized freeze-dried bone allografts.

In the present study histochemical techniques were used to identify specific macromolecular components of the extracellular matrix associated with the tissue reaction to demineralized freeze-dried bone allografts (DFDBA) placed under barrier membranes for ridge augmentation. Small biopsies were obtained from tissues underneath the membranes at various times after placement of the DFDBA and processed for routine immunohistochemistry. Sections were stained with antibodies to osteocalcin, collagen type I, collagen type III, decorin, and biglycan. Non-immune serum, irrelevant antibodies, and omission of the primary antibodies served as negative controls. Histologic examination of the biopsies revealed allograft particles surrounded by well-formed fibrous connective tissue with little or no evidence of new bone formation. Vital autogenous bone fragments were present in the peripheral portions of the biopsies and served as positive controls for comparative purposes with the DFDBA particles. Only 7 out of the 20 biopsies studied were found to have any signs of bone formation around the DFDBA particles and in these such bone formation was irregular and inconsistent around the DFDBA particles. Around the periphery of the allograft particles, osteocalcin, collagen type I, collagen type III, decorin, and biglycan all showed relatively strong staining. Osteocalcin staining was also noted within the vital bone matrix but not in the surrounding fibrous connective tissue. Decorin, biglycan, collagen type I, and collagen type III were also found within the vital bone matrix. None of these antibodies stained the DFDBA particles. The unremarkable osteogenic response of the tissues to the DFDBA particles after healing periods of up to 12 months raises questions as to the predictability of these agents in inducing new bone.

Effects of stimulation or blockade of central nicotinic-cholinergic receptors on performance of a novel version of the rat stimulus discrimination task.

This study evaluated the effects of two central nicotinic-cholinergic receptor agonists and an antagonist on performance accuracy of a rat, delayed stimulus discrimination task (DSDT). Rats were trained to discriminate between an auditory and visual stimulus by pressing a right or left lever. To diminish the rat's ability to use mediating spatial strategies to solve the task, computer automated, retractable doors separated the animal from the levers during delay intervals, thus reducing positioning at the lever. After stable baselines were achieved, rats were grouped and administered placebo (saline) and nicotine, lobeline or mecamylamine in a randomized dose series. Each group received two complete series of the selected compound on different occasions. Mecamylamine impaired DSDT accuracy in a dose-dependent manner while optimal doses of nicotine and lobeline significantly improved accuracy. Nicotine differed from lobeline in regard to its interaction with a dose of mecamylamine (1.0 mg/kg) that had not impaired DSDT accuracy. Combined administration of lobeline and mecamylamine was followed by a significantly increased level of DSDT accuracy that was similar to the improvement following administration of lobeline alone. In contrast, combined administration of nicotine and mecamylamine did not result in increased DSDT accuracy. Furthermore, lobeline administration similarly improved accuracy of trials associated with both the light and the tone, while nicotine improved accuracy of trials associated with the light to a much greater degree. These data suggest that the increases in DSDT accuracy associated with lobeline may be expressed through non-nicotinic mechanisms or a nicotinic receptor which is not blocked by mecamylamine.

Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement.

ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular administration of ABT-418 significantly enhanced DMTS performance at low (2-32.4 nmol/kg) doses. In fact, the drug was slightly more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly tested with their individualized "Best Dose", DMTS performance increased on average by 10.1 +/- 3.5 percentage points correct, which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times, i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity.

Velnacrine maleate improves delayed matching performance by aged monkeys.

Velnacrine maleate is a novel, orally active acetylcholinesterase inhibitor of the acridine class with a longer duration of action than physostigmine. Velnacrine has shown efficacy in the treatment of Alzheimer's disease and in improving both normal and experimentally impaired mnemonic function in animals and humans. To characterize this action further, the present study evaluated velnacrine for its ability to ameliorate the decline in short-term memory associated with aging in non-human primates at two time points after velnacrine administration: (1) 30 min and (2) 24 h. Initially, doses of 1, 2, 4, and 6 mg/kg, PO (free base corrected) were administered once to each of six aged (25-40 years), memory-impaired macaques that had been trained to perform a delayed matching-to-sample (DMTS) paradigm. The dose associated with the greatest improvement in session performance was administered three more times to the same individual. Four of the six monkeys showed improved DMTS performance during the repeated best dose phase (phase 2). Almost all of the improvement occurred during long-delay trials. Compared to placebo trials, velnacrine induced a significant improvement of long delay DMTS (58.0-66.7%, 13.4% of the placebo value). Long delay DMTS remained significantly improved during the test session conducted 24 h following velnacrine administration. Pharmacokinetic analysis following administration of 4 or 6 mg/kg velnacrine to three aged monkeys revealed peak plasma concentrations ranging from 27 to 166 ng/ml, 30-60 min after dosing. Six hours after dosing velnacrine plasma levels decreased to 5.1-11.8 ng/ml; and 24 h after dosing velnacrine plasma levels were less than the limit of quantitation (5 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Isoarecolone-induced enhancement of delayed matching to sample performance in monkeys: role of nicotinic receptors.

Nicotine enhances memory performance in young and aged monkeys performing a version of the delayed matching to sample (DMTS) task. However, the beneficial actions of nicotine are often limited by debilitating side effects. Isoarecolone is a piperidine derivative with nicotine-like activity, but having a slightly different profile of behavioral actions in rodents. In young monkeys, isoarecolone produced a dose-dependent enhancement of the DMTS task on the same day of testing, with a trend towards enhanced performance in animals tested 24 h after administration. Isoarecolone was about 1500-fold less potent than nicotine in enhancing DMTS performance. The ability of isoarecolone to enhance DMTS performance was well correlated with its ability to interact with cortical nicotinic receptors in vitro.

Electrical studies as a prognostic factor in the surgical treatment of carpal tunnel syndrome.

We attempted to determine if a prognostic value could be associated with preoperative electrodiagnostic testing in patients with carpal tunnel syndrome. Three groups of patients were included in the study of 151 workers whose symptoms were thought to be causally related to their jobs. A clinical diagnosis was made without electrical testing in 26 of the 151 patients. Normal electrical test values were present in 50 of the 125 patients tested, and abnormal values were noted in 75 patients. Pinch, power, and static grasp function were recorded monthly. Similar recovery patterns after operation were seen between the groups and within each group. Return to work time correlated well with measured functional recovery to preoperative levels, but some workers returned to their jobs before they had regained full function. Electrodiagnostic test results did not provide significant data for prediction of functional recovery or re-employment after carpal tunnel release.