(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

Effects of subchronic phencyclidine on behaviour of female rats on the elevated plus maze and open field.

Female hooded-Lister rats received either subchronic phencyclidine (PCP) (2 mg/kg, n = 20) or vehicle (1 ml/kg, n = 20) intraperitoneally twice daily for 7 days, followed by a 7-day washout period. Rats were challenged with acute PCP or vehicle and tested for locomotor activity to ensure hyperactivity was observed in the subchronic PCP-treated rats. Rats were then tested on the elevated plus maze and in an open field for 10 min. Subchronic PCP did not significantly affect behaviour on the elevated plus maze or in the open field. In conclusion, subchronic PCP does not induce anxiety-like behaviour.

How to obtain excellent response rates when surveying physicians.

This paper outlines ways to maximize response rates to surveys by summarizing the most relevant literature to date and demonstrating how these techniques have resulted in consistently high rates of return in family practice research. We describe the methodology used in recent surveys of physicians conducted by the Centre for Studies in Family Medicine through its Thames Valley Family Practice Research Unit, located in London, Ontario, Canada and funded by the Ontario Ministry of Health and Long-Term Care. The identification and implementation of these techniques to maximize response rates is critical, as primary health care researchers often rely on information gathered through questionnaires to study physicians' practice profiles, experiences and attitudes. Four separate and distinct mailed surveys of physicians using a modified Dillman approach were conducted from 2001 to 2004. The sampling strategies, topics, types of questions and response formats of these surveys varied. The first survey did not use any incentives or recorded delivery/registered mail and received a response rate of 48%. In sharp contrast, the other three surveys obtained responses rates of 76%, 74%, 74%, respectively, achieved through the use of gift certificates and recorded delivery/registered mail. Sending a survey by recorded delivery/registered mail tends to result in the survey package being given priority in the physicians' incoming mail at the practice. Gift certificates partially compensate physicians for time spent completing the survey and recognition of the time required is appreciated. The response rates achieved provide strong evidence to support the use of monetary incentives and recorded delivery/registered mail (along with the Dillman approach) in survey research. It is anticipated that this evidence will be used by other researchers to justify requests for funding to cover the costs associated with incentives and recorded delivery/registered mail. We recommend the use of these strategies to maximize response rates and improve the quality of this type of primary health care research.

Acyclovir topical therapy of cutaneous herpes simplex virus infection in guinea pigs.

The chemotherapeutic efficacy of acyclovir was evaluated by observing the potential of topical acyclovir to reduce the severity of herpes viral lesions and to control the multiplication of this virus in the experimentally induced primary cutaneous infection of guinea pigs. Topical acyclovir showed a substantially high therapeutic efficacy when treatment was initiated after the development of clinically overt skin lesions. The therapeutic response was dose dependent and clearly evident even when the treatment was initiated on day 2 after inoculation. Our results indicate that topical acyclovir treatment improved the cutaneous herpes simplex virus type 1 (HSV-1) infectious process by inhibiting multiplication of HSV-1 in the skin of guinea pigs.

Topical therapeutic efficacy of 9-(2-hydroxyethoxymethyl)guanine and 5-iodo-5'-amino-2',5'-dideoxyuridine on oral infection with herpes simplex virus in mice.

The therapeutic efficacy of two new antiviral agents, 5-iodo-5'-amino-2', 5'-dideoxyuridine (AIdUrd) and 9-(2-hydroxyethoxymethyl)guanine (ACV), in the model of mouse lip inoculated with herpes simplex virus type 2 is reported. The effects on development of clinical lesions, viral replication in the inoculated lips, and establishment of latent viral infection in the trigeminal ganglia were observed. The earlier the treatment with AIdUrd and ACV was initiated after inoculation, the better was the chemotherapeutic effect. AIdUrd and ACV treatment, when initiated 48 and 72 hr after inoculation, respectively, showed no chemotherapeutic efficacy. Establishment of viral latent infection in sensory ganglia was significantly prevented only when ACV treatment was initiated very early (1 or 3 hr) after inoculation. The results indicate that both drugs have significant antiviral activity, in part dependent on the time of initiation of therapy, and that ACV is superior to AIdUrd as a topical agent for therapy of herpes simplex virus type 2 infections.

Acylovir in oral and ganglionic herpes simplex virus infections.

The local and trigeminal ganglionic therapeutic efficacy of two topical and systemic antiviral drugs was studied in mouse lips inoculated with herpes simplex virus type 1 after thermal injury. Application of topical 3% acylovir (acycloguanosine) ointment three times daily for four days completely blocked the replication of virus in the lips, and the healing process was greatly accelerated compared with that in placebo-treated infected controls. However, neither the healing process nor the viral replication was influenced by similar therapy with 3% vidarabine ointment. When given systemically for four days, starting one day after inoculation, acyclovir (40-60 mg/kg per day) and vidarabine (50 mg/kg per day) significantly reduced the clinical manifestations on the lips and viral titers of cultures obtained from the lips. Establishment of viral latency in the trigeminal ganglion was significnatly inhibited by systemic acyclovir (60 mg/kg per day), whereas systemic vidarabine (50 mg/kg per day) was ineffective. These data suggest that acyclovir may be one of the most promising antiviral agents for the management of oral herpes viral infections and trigeminal ganglionic latency of virus as demonstrated in the mouse model.

Therapy of experimental herpes simplex encephalitis with aciclovir in mice.

This report is concerned with the capacities of aciclovir to protect mice challenged intracerebrally with multiple lethal doses of type 1 herpes simplex virus and to control multiplication of this virus in the brain. With treatment initiated 12 h after inoculation and continued for 4 consecutive days, aciclovir administered subcutaneously in daily doses ranging from 40 to 100 mg/kg led to 21-day survival rates of from 33 to 73% and reduced virus titers by 1 to (1/2) x 4 logs on postchallenge day 8. The therapeutic accomplishments of the 100-mg/kg doses of aciclovir were comparable to those of 1,000-mg/kg doses of vidarabine (9-beta-d-arabinofuranosyladenine); however, as measured by impact on body weight, aciclovir was better tolerated than vidarabine at these similarly effective doses.