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1.
2.
BMC Endocr Disord ; 20(1): 10, 2020 Jan 20.
Article in English | MEDLINE | ID: mdl-31959176

ABSTRACT

BACKGROUND: Medically-tailored meal programs that provide home-delivered medically-appropriate food are an emerging intervention when type 2 diabetes co-occurs with food insecurity (limited or uncertain access to nutritious food owing to cost). We sought to understand the experiences of medically-tailored meal program participants. METHODS: We conducted semi-structured interviews with participants in a randomized trial of medically-tailored meals (NCT02426138) until reaching content saturation. Participants were adults (age > 20 years) with type 2 diabetes in eastern Massachusetts, and the interviews were conducted from April to July 2017. Interviews were transcribed verbatim and coded by two independent reviewers. We determined emergent themes using content analysis. RESULTS: Twenty individuals were interviewed. Their mean age was 58 (SD: 13) years, 60.0% were women, 20.0% were non-Hispanic black, and 15.0% were Hispanic. Key themes were 1) satisfaction and experience with medically-tailored meals 2) food preferences and cultural appropriateness, 3) diabetes management and awareness, and 4) suggestions for improvement and co-interventions. Within these themes, participants were generally satisfied with medically-tailored meals and emphasized the importance of receiving culturally appropriate food. Participants reported several positive effects of medically-tailored meals, including improved quality of life and ability to manage diabetes, and stress reduction. Participants suggested combining medically-tailored meals with diabetes self-management education or lifestyle interventions. CONCLUSIONS: Individuals with diabetes and food insecurity expressed satisfaction with the medically-tailored meal program, and reported that participation reduced stress and the burden of diabetes management. Suggestions to help ensure the success of medically-tailored meal programs included a strong emphasis on culturally acceptability and accommodating taste preferences for provided foods, and combining medically-tailored meals with diabetes education or lifestyle intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT02426138.


Subject(s)
Diabetes Mellitus, Type 2/diet therapy , Diabetes Mellitus, Type 2/epidemiology , Diet, Diabetic/methods , Dietary Services/methods , Food Supply/methods , Meals/psychology , Quality of Life , Cross-Over Studies , Female , Follow-Up Studies , Health Behavior , Humans , Life Style , Male , Massachusetts/epidemiology , Middle Aged , Outcome Assessment, Health Care , Prognosis , Qualitative Research , Surveys and Questionnaires
3.
J Gen Intern Med ; 34(3): 396-404, 2019 03.
Article in English | MEDLINE | ID: mdl-30421335

ABSTRACT

BACKGROUND: Food insecurity, defined as inconsistent food access owing to cost, leads to poor health. OBJECTIVE: To test whether a medically tailored meal delivery program improved dietary quality in individuals with type 2 diabetes and food insecurity. DESIGN: Randomized cross-over clinical trial. PARTICIPANTS: Forty-four adults with diabetes, hemoglobin A1c > 8.0%, and food insecurity (defined as at least one positive item on the two-item "Hunger Vital Sign"). INTERVENTION: In the Community Servings: Food as Medicine for Diabetes cross-over clinical trial (NCT02426138), conducted from June 2015 to July 2017, we randomly assigned the order of "on-meals" (home delivery of 10 meals/week for 12 weeks delivered by Community Servings, a non-profit organization) and "off-meals" (12 weeks usual care and a Choose MyPlate healthy eating brochure) periods. MAIN MEASURES: The primary outcome was Healthy Eating Index 2010 score (HEI), assessed by three 24-h food recalls in both periods. Higher HEI score (range 0-100; clinically significant difference 5) represents better dietary quality. Secondary outcomes included food insecurity and self-reported hypoglycemia. KEY RESULTS: Mean "on-meal" HEI score was 71.3 (SD 7.5) while mean "off-meal" HEI score was 39.9 (SD 7.8) (difference 31.4 points, p < 0.0001). Participants experienced improvements in almost all sub-categories of HEI score, with increased consumption of vegetables, fruits, and whole grains and decreased solid fats, alcohol, and added sugar consumption. Participants also reported lower food insecurity (42% "on-meal" vs. 62% "off-meal," p = 0.047), less hypoglycemia (47% "on-meal" vs. 64% "off-meal," p = 0.03), and fewer days where mental health interfered with quality of life (5.65 vs. 9.59 days out of 30, p = 0.03). CONCLUSIONS: For food-insecure individuals with diabetes, medically tailored meals improved dietary quality and food insecurity and reduced hypoglycemia. Longer-term studies should evaluate effects on diabetes control (e.g., hemoglobin A1c) and patient-reported outcomes (e.g., well-being).


Subject(s)
Diabetes Mellitus, Type 2/diet therapy , Diabetes Mellitus, Type 2/epidemiology , Diet, Healthy/methods , Dietary Services/methods , Food Supply/methods , Aged , Cross-Over Studies , Diabetes Mellitus, Type 2/diagnosis , Female , Follow-Up Studies , Humans , Male , Middle Aged
4.
Contemp Clin Trials ; 124: 107039, 2023 01.
Article in English | MEDLINE | ID: mdl-36470556

ABSTRACT

BACKGROUND: Food insecurity is associated with worse glycemic management for individuals with type 2 diabetes mellitus (T2DM), but whether medically tailored meals (MTM), a food insecurity intervention, can improve glycemic management is unclear. OBJECTIVE: To describe the protocol for a trial assessing whether an MTM plus lifestyle intervention improves hemoglobin A1c (HbA1c) and participant-reported outcomes, relative to a food subsidy (money that can be spent on foods participants choose), for adults with both T2DM and food insecurity. METHODS: The Food as Medicine for Diabetes (FAME-D) randomized clinical trial (goal n = 200) is a pragmatic trial with an active comparator. Participants, who will have T2DM and report food insecurity, will be randomly assigned to a 6-month MTM plus telephone-delivered lifestyle change intervention, or a 6-month food subsidy ($40/month). The primary outcome is HbA1c at 6 months. Secondary outcomes include HbA1c at 12 months to assess whether the intervention effect (if any) is sustained, along with weight, food insecurity, diabetes distress, and health-related quality of life. Qualitative analyses of semi-structured interviews will help understand why, how, and under what circumstances the intervention achieved its observed results. CONCLUSION: Results from FAME-D will help inform clinical management of food insecurity when it co-occurs with T2DM. Further, results may be useful as healthcare payors are considering coverage for MTM interventions. CLINICALTRIALS: gov: NCT04828785.


Subject(s)
Diabetes Mellitus, Type 2 , Adult , Humans , Diabetes Mellitus, Type 2/therapy , Food Insecurity , Glycated Hemoglobin , Meals , Quality of Life , Randomized Controlled Trials as Topic , Pragmatic Clinical Trials as Topic
5.
JAMA Intern Med ; 179(6): 786-793, 2019 06 01.
Article in English | MEDLINE | ID: mdl-31009050

ABSTRACT

Importance: Whether interventions to improve food access can reduce health care use is unknown. Objective: To determine whether participation in a medically tailored meal intervention is associated with fewer subsequent hospitalizations. Design, Setting, and Participants: A retrospective cohort study was conducted using near/far matching instrumental variable analysis. Data from the 2011-2015 Massachusetts All-Payer Claims database and Community Servings, a not-for-profit organization delivering medically tailored meals (MTMs), were linked. The study was conducted from December 15, 2016, to January 16, 2019. Recipients of MTMs who had at least 360 days of preintervention claims data were matched to nonrecipients on the basis of demographic, clinical, and neighborhood characteristics. Interventions: Weekly delivery of 10 ready-to-consume meals tailored to the specific medical needs of the individual under the supervision of a registered dietitian nutritionist. Main Outcomes and Measures: Inpatient admissions were the primary outcome. Secondary outcomes were admission to a skilled nursing facility and health care costs (from medical and pharmaceutical claims). Results: There were 807 eligible MTM recipients. After matching, there were 499 MTM recipients, matched to 521 nonrecipients for a total of 1020 study participants (mean [SD] age, 52.7 [14.5] years; 568 [55.7%] female). Prior to matching and compared with nonrecipients in the same area, health care use, health care cost, and comorbidity were all significantly higher in recipients. For example, preintervention mean (SD) inpatient admissions were 1.6 (6.5) in MTM recipients vs 0.2 (0.8) in nonrecipients (P < .001), and mean health care costs were $80 617 ($312 337) vs $16 138 ($68 738) (P < .001). Recipients compared with nonrecipients were also significantly more likely to have HIV (21.9% vs 0.7%, P < .001), cancer (37.9% vs 11.3%, P < .001), and diabetes (33.7% vs 7.0%, P < .001). In instrumental variable analyses, MTM receipt was associated with significantly fewer inpatient admissions (incidence rate ratio [IRR], 0.51; 95% CI, 0.22-0.80; risk difference, -519; 95% CI, -360 to -678 per 1000 person-years). Similarly, MTM receipt was associated with fewer skilled nursing facility admissions (IRR, 0.28; 95% CI, 0.01-0.60; risk difference, -913; 95% CI, -689 to -1457 per 1000 person-years). The models estimated that, had everyone in the matched cohort received treatment owing to the instrument (and including the cost of program participation), mean monthly costs would have been $3838 vs $4591 if no one had received treatment owing to the instrument (difference, -$753; 95% CI, -$1225 to -$280). Conclusions and Relevance: Participation in a medically tailored meals program appears to be associated with fewer hospital and skilled nursing admissions and less overall medical spending.


Subject(s)
Diet, Healthy/economics , Food Assistance/economics , Food Supply/economics , Health Care Costs/statistics & numerical data , Hospitalization/economics , Adult , Case-Control Studies , Cohort Studies , Female , Humans , Male , Massachusetts , Middle Aged , Nutritive Value , Outcome Assessment, Health Care , Retrospective Studies
6.
Neuropsychopharmacology ; 33(3): 574-87, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17460614

ABSTRACT

The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/therapeutic use , Anxiety Disorders/drug therapy , Depressive Disorder/drug therapy , Tetrahydronaphthalenes/therapeutic use , Adrenergic beta-Agonists/administration & dosage , Aggression/drug effects , Animals , Anti-Anxiety Agents/pharmacology , Antidepressive Agents, Second-Generation/pharmacology , Antidepressive Agents, Tricyclic/pharmacology , Anxiety Disorders/psychology , Behavior, Animal/drug effects , Cognition/drug effects , Depressive Disorder/psychology , Diazepam/pharmacology , Ethanol/pharmacology , Exploratory Behavior/drug effects , Fluoxetine/pharmacology , Gerbillinae , Imipramine/pharmacology , Interpersonal Relations , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Adrenergic, beta-3/genetics , Sleep/drug effects , Substance-Related Disorders/psychology , Swimming/psychology , Tetrahydronaphthalenes/administration & dosage
7.
Pharmacol Biochem Behav ; 91(1): 47-58, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18621075

ABSTRACT

On native human, rat and mouse glycine transporter-1(GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM, respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.


Subject(s)
Antipsychotic Agents/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Schizophrenia/drug therapy , Animals , Antidepressive Agents/pharmacology , Discrimination, Psychological/drug effects , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Extracellular Space/drug effects , Extracellular Space/metabolism , Gerbillinae , Glycine/metabolism , Male , Mice , Motor Activity/drug effects , N-Methylaspartate/physiology , Phencyclidine/pharmacology , Recognition, Psychology/drug effects , Reflex, Startle/drug effects , Stereoisomerism , Swimming/psychology
8.
Health Aff (Millwood) ; 37(4): 535-542, 2018 04.
Article in English | MEDLINE | ID: mdl-29608345

ABSTRACT

Delivering food to nutritionally vulnerable patients is important for addressing these patients' social determinants of health. However, it is not known whether food delivery programs can reduce the use of costly health services and decrease medical spending among these patients. We sought to determine whether home delivery of either medically tailored meals or nontailored food reduces the use of selected health care services and medical spending in a sample of adults dually eligible for Medicare and Medicaid. Compared with matched nonparticipants, participants had fewer emergency department visits in both the medically tailored meal program and the nontailored food program. Participants in the medically tailored meal program also had fewer inpatient admissions and lower medical spending. Participation in the nontailored food program was not associated with fewer inpatient admissions but was associated with lower medical spending. These findings suggest the potential for meal delivery programs to reduce the use of costly health care and decrease spending for vulnerable patients.


Subject(s)
Food Services/statistics & numerical data , Medicaid , Medicare , Patient Acceptance of Health Care/statistics & numerical data , Aged , Emergency Service, Hospital/statistics & numerical data , Female , Health Expenditures , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , United States
9.
Neuropsychopharmacology ; 32(1): 17-34, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16936709

ABSTRACT

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.


Subject(s)
Cognition Disorders/drug therapy , Nicotinic Agonists/therapeutic use , Receptors, Nicotinic/physiology , Analysis of Variance , Animals , Animals, Newborn , Behavior, Animal/drug effects , Cognition Disorders/etiology , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Excitatory Amino Acid Antagonists/pharmacology , Exploratory Behavior/drug effects , Female , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Phencyclidine/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/deficiency , Recognition, Psychology/drug effects , Schizophrenia/complications , alpha7 Nicotinic Acetylcholine Receptor
10.
Neuropsychopharmacology ; 30(11): 1963-85, 2005 Nov.
Article in English | MEDLINE | ID: mdl-15956994

ABSTRACT

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.


Subject(s)
Benzamides/pharmacology , Brain Chemistry/drug effects , Enzyme Inhibitors/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Neurons/drug effects , Piperidines/pharmacology , Acetylcholine/metabolism , Action Potentials/drug effects , Amphetamine/pharmacology , Analysis of Variance , Animals , Animals, Newborn , Behavior, Animal/drug effects , Carbon Isotopes/metabolism , Cells, Cultured , Cerebral Cortex/cytology , Circadian Rhythm/drug effects , Dopamine Uptake Inhibitors/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Female , Glycine/metabolism , Hippocampus/cytology , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Male , Mice , Motor Activity/drug effects , Neural Inhibition/drug effects , Neurons/physiology , Patch-Clamp Techniques/methods , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects
12.
Pharmacol Biochem Behav ; 102(2): 203-14, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22542742

ABSTRACT

SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment ß25₋35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.


Subject(s)
Cognition/drug effects , Histamine H3 Antagonists/pharmacology , Animals , Female , Histamine H3 Antagonists/therapeutic use , Maze Learning , Mice , Rats , Rats, Sprague-Dawley , Rats, Wistar , Schizophrenia/drug therapy
13.
J Pharmacol Exp Ther ; 302(2): 731-41, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12130738

ABSTRACT

SL65.0155 [5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride] is a novel benzodioxanoxadiazolone compound with high affinity for human 5-hydroxytryptamine (5-HT)(4) receptors (K(i) of 0.6 nM) and good selectivity (greater than 100-fold for all other receptors tested). In cells expressing the 5-HT(4(b)) and 5-HT(4(e)) splice variants, SL65.0155 acted as a partial agonist, stimulating cAMP production with a maximal effect of 40 to 50% of serotonin. However, in the rat esophagus preparation, SL65.0155 acted as a 5-HT(4) antagonist with a pK(b) of 8.81. In addition, SL65.0155 potently improved performance in several tests of learning and memory. In the object recognition task, it improved retention at 24 h when administered i.p. or p.o. (0.001-0.1 mg/kg). This effect was antagonized by the 5-HT(4) antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT(4) agonism. SL65.0155 also reversed the cognitive deficits of aged rats in the linear maze task and the scopolamine-induced deficit of mice in the water maze task. Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT(4) receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia.


Subject(s)
Cognition/physiology , Cyclic AMP/metabolism , Dioxanes/pharmacology , Maze Learning/physiology , Oxadiazoles/pharmacology , Receptors, Serotonin/physiology , Serotonin Receptor Agonists/pharmacology , Alternative Splicing , Animals , Blood Pressure/drug effects , CHO Cells , COS Cells , Chlorocebus aethiops , Cognition/drug effects , Cricetinae , Esophagus/drug effects , Esophagus/physiology , Gastrointestinal Motility/drug effects , Guinea Pigs , Heart Rate/drug effects , Ileum/drug effects , Ileum/physiology , Maze Learning/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Radioligand Assay , Rats , Receptors, Serotonin/drug effects , Receptors, Serotonin/genetics , Receptors, Serotonin, 5-HT4 , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Transfection
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