R-Modafinil Attenuates Nicotine-Taking and Nicotine-Seeking Behavior in Alcohol-Preferring Rats

(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long–Evans rats. As Long–Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long–Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine''s effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans.     

Involvement of histamine in naloxone-resistant and naloxone-sensitive models of swim stress-induced antinociception in the mouse

The antinociceptive activity of histamine in male mice has been demonstrated using chemical and thermal noxious stimuli and its involvement in naloxone-sensitive and naloxone-insensitive models of stress-induced antinociception investigated. In the abdominal constriction test, histamine and dimaprit but not histidine, induced antinociception. Compound 48/80 and H1 antagonists (diphenhydramine, mepyramine and promethazine) and large doses of H2 antagonists (cimetidine and zolantidine) produced antinociception in this test. Antinociception induced by histamine was refractory to mepyramine, metiamide and naloxone. Histamine and non-antinociceptive doses of its antagonists had no influence on the naloxone-resistant warm water swim stress-induced antinociception. In the hot-plate test, histamine agonists, except the H3 agonist (R) alpha-methyl histamine (alpha-MeHA), were antinociceptive but all these agents augmented the naloxone-sensitive room temperature swim stress-induced antinociception, after either intraperitoneal or intraventricular injection. The antinociceptive action of dimaprit was not antagonized by zolantidine which, like other histamine antagonists excluding metiamide, also produced antinociception and enhanced room temperature swim stress-induced antinociception. These findings suggest that histamine is involved in pathways mediating antinociception in the mouse and that such pathways are activated in a naloxone-sensitive model of stress-induced antinociception but not in a naloxone-insensitive model.     

Structure-Activity Relationships at the Monoamine Transporters for a Novel Series of Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) Analogues

A series of modafinil (1) analogues was synthesized wherein 1) para-halo-substitutents were added to the aryl rings, 2) the sulfoxide function was removed, and 3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on DAT, SERT and NET binding. In addition, the locomotor-stimulant effects in mice of (±)-modafinil (1), its R- and S-enantiomers and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine.     

Prevalence and correlates of suicidal behaviour among adolescents in southwest Nigeria

BACKGROUND: Despite being recognized by the World Health Organization as a significant social and health concern, information on suicidal behaviours in Nigerian adolescents is unknown. AIMS: To establish the prevalence and associated psychosocial correlates of suicidal ideation and attempts in Nigerian youth. METHODS: Stratified sampling was used to identify youth aged 10-17 years who completed the Nigeria version of the Global School Health Questionnaire (GSHQ) and the Diagnostic Predictive Scale (DPS) for youths (suicidal behaviour questions) in a classroom setting. RESULTS: A total of 1429 youth completed the instruments. Over 20% reported suicidal ideation and approximately 12% reported that they had attempted suicide in the last year. Adolescents living in urban areas, from polygamous or disrupted families, had higher rates of suicidal behaviour. Multiple psychosocial factors such as sexual abuse, physical attack and involvement in physical fights were significant predictors of suicidal behaviour. CONCLUSION: Factors associated with suicidal ideation and behaviours are similar to those found in other studies but the rates of both suicidal ideation and attempts are towards the upper limit of rates for youth. This study suggests that there is an urgent need for Nigerian policymakers and health providers to review and address this issue.     

Evaluation of metal nanoparticles for drug delivery systems

Diminazene aceturate is a trypanocide with unwanted toxicity and limited efficacy.It was reasoned that conjugating diminazene aceturate to functionalized nanoparticle would lower untoward toxicity while improving selectivity and therapeutic efficacy.Silver and gold nanoparticles were evaluated for their capacities to serve as carriers for diminazene aceturate.The silver and gold nanoparticles were synthesized,functionalized and coupled to diminazene aceturate following established protocols.The nanoparticle conjugates were characterized.The free diminazene aceturate and drug conjugated nanoparticles were subsequently evaluated for cytotoxicity in vitro.The characterizations by transmission electron microscopy or UV/Vis spectroscopy revealed that conjugation of diminazene aceturate to silver or gold nanoparticles was successful.Evaluation for cytotoxic actions in vitro demonstrated no significance difference between free diminazene aceturate and the conjugates.Our data suggest that surface modified metal nanoparticles could be optimized for drug delivery systems.     

Extranodal Rosai-Dorfman disease arising in the right atrium: a case report with literature review

Rosai-Dorfman disease is a rare, benign histiocytic proliferative disorder that commonly affects the lymph nodes. Although extranodal involvement has been reported in diverse sites, manifestation in the cardiovascular system is extremely uncommon. Specifically, the involvement of the heart by Rosai-Dorfman disease is an extraordinarily infrequent event. Here, the authors present a case of Rosai-Dorfman disease arising in the right atrium in a symptomatic 61-year-old man who initially presented with pleuritic chest pain and was found to have a large, lobulated, and circumscribed right atrial mass. The lesion exhibited an exuberant histiocytic and chronic fibroinflammatory process with focal emperipolesis within histiocytes. Immunohistochemical studies demonstrated strong S100 positivity in CD68+ CD1a- histiocytes. Although rare, Rosai-Dorfman disease should be considered in the differential diagnosis of a right atrial mass.     

Differential effects of prednisolone and indomethacin on zymosaninduced inflammation in a modified murine tissue-chamber model

A tissue-chamber model of inflammation in mice has been modified and used to investigate the kinetics of zymosan-induced inflammatory mediators such as tumour necrosis factor (TNF), interleukin-1 (IL-1) and prostaglandin E₂ (PGE₂). In addition, the influx of polymorphonuclear leukocytes (PMN) into the chamber fluid and the granuloma surrounding the chamber was measured by myeloperoxidase (MPO) activity using a new microtitre plate assay. TNF and IL-1 reached peak concentrations at 3 and 6 h respectively after zymosan injection. Intermediate high concentrations of IL-1 were observed until the end of the experiment at 72 h, but TNF concentrations decreased from 24 h to biologically insignificant values. In contrast, exudate PGE₂ and MPO activity increased up to 24 h after zymosan injection and remained high until 72 h. At 6h after zymosan challenge, oral pre-treatment with prednisolone (3 to 30mg/kg) dose-dependently reduced TNF, IL-1 and PGE₂ concentrations while indomethacin (0.3 to 3 mg/kg) significantly attenuated PGE₂, slightly enhanced TNF and had no effect on IL-1 concentrations in the exudate. Both drugs had similar potencies against exudate and tissue MPO activities. Prednisolone inhibited IL-1 at 72 h post-zymosan. Indomethacin was more potent than prednisolone against PGE₂ (ID₅₀ of <0.3 versus 0.6mg/kg). The data obtained confirm the usefulness and reliability of this model in evaluating the effects of anti-inflammatory agents on inflammatory mediators induced by zymosan.