Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze

Administration of a non-competitive NMDA antagonist dizocilpine (MK-801) was proposed to be an animal model of psychosis. NMDA-receptor blockade is accompanied by increased locomotion, behavioral deficits, and other changes resembling psychotic symptoms. However, the role of NMDA-receptors in organizing brain representations is not understood yet. We tested the effect of NMDA-receptor blockade by systemic administration of dizocilpine at two different doses (0.1 or 0.2 mg/kg) in a recently designed Active Allothetic Place Avoidance (AAPA), a task which requires rats to separate spatial stimuli from two continuously dissociated subsets. The effect of dizocilpine on learning in the AAPA task was compared with its effect on acquisition of the reference memory version of the Morris Water Maze task. Both doses impaired performance in the Morris Water Maze task, whereas only the higher dose impaired performance in the AAPA task. The Morris Water Maze appears to be more sensitive to dizocilpine-induced behavioral deficit than the AAPA task. These findings support the notion that these two tasks are differentially dependent on the NMDA-receptor function.     

Exercise programs for older men: mode and intensity to induce the highest possible health-related benefits

BACKGROUND: Although health-related benefits of fitness training in older men are well established, it is not clear yet which mode and intensity of a exercise program is most effective. This study addresses whether the combination of endurance (ED) and resistance training in older men have supplementary health-related benefits in addition to profits attained through endurance training alone. Additionally, effects of moderate- and low-intensity resistance training are compared. METHODS: Men, 55-75 years of age, were randomly assigned to a control group (N = 13) or one of three exercise groups (20 weeks, two to three times per week): endurance plus moderate resistance (MR) training (N = 22), endurance plus low resistance (LR) training (N = 22) and endurance training only (N = 22). Cardiovascular (CV) risk factors, muscular fitness and postural control were assessed before and after training. RESULTS: All exercise groups revealed significant (P < 0.05) improvements in resting heart rate, work capacity and recovery, waist girth, insulin response and knee-extensor strength with no differences among groups. Body composition, resting metabolic rate (RMR), VO2peak and postural control did not change in exercise groups. CONCLUSION: In older men, a fitness program consisting of 20 weeks endurance training combined with resistance training is equally effective as endurance training alone. Moderate vs. low resistance training added to endurance training yields similar health-related benefits.     

Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers

Solid dispersions were prepared of itraconazole-Eudragit E100, itraconazole-PVPVA64, and itraconazole-Eudragit E100/PVPVA64 using a corotating twin-screw hot-stage extruder. Modulated temperature differential scanning calorimetry (MTDSC) was used to evaluate the miscibility of the extrudates, and dissolution experiments were performed in simulated gastric fluid without pepsin (SGF(sp)). Itraconazole and Eudragit E100 are miscible up to 13% w/w drug loading. From that concentration on, phase separation is observed. Pharmaceutical performance of this dispersion was satisfactory because 80% of the drug dissolved after 30 min. Extrudates of itraconazole and PVPVA64 were completely miscible but the pharmaceutical performance was low, with 45% of drug dissolved after 3 h. Combination of both polymers in different ratios, with a fixed drug loading of 40% w/w, was evaluated. MTDSC results clearly indicated a two-phase system consisting of itraconazole-Eudragit E100 and itraconazole-PVPVA64 phases. In these extrudates, no free crystalline or glassy clusters of itraconazole were observed; all itraconazole was mixed with one of both polymers. The pharmaceutical performance was tested in SGF(sp) for different polymer ratios, and Eudragit E100/PVPVA64 ratios of 50/50 and 60/40 showed significant increases in dissolution rate and level. Polymer ratios of 70/30 and 80/20, on the other hand, had a release of 85% after 30 min. Precipitation of the drug was never observed. The combination of the two polymers provides a solid dispersion with good dissolution properties and improved physical stability compared with the binary solid dispersions of itraconazole.     

Effects of MDMA (ecstasy), and multiple drugs use on (simulated) driving performance and traffic safety

Rationale The effects of MDMA on driving behaviour are not clear, since the direct effects of MDMA on cognitive performance are reported as not generally negative.Objectives To assess in an advanced driving simulator acute effects on simulated driving behaviour and heart rate of MDMA, and effects of polydrug use.Methods A group of young participants who had indicated that they regularly used MDMA were asked to complete test rides in an advanced driving simulator, shortly after the use of MDMA, just before going to a party. They were tested again after having visited the rave, while they were under the influence of MDMA and a number of different other active drugs. Participants were also tested sober, at a comparable time at night. Separately, a control group of participants was included in the experiment.Results Driving performance in the sense of lateral and longitudinal vehicle control was not greatly affected after MDMA, but deteriorated after multiple drug use. The most striking result was the apparent decreased sense for risk taking, both after MDMA and after multiple drug use. This was clear from gap acceptance data, while the ultimate indicator of unsafe driving, accident involvement or even causation, was increased by 100% and 150%, respectively.Conclusions Driving under the influence of MDMA alone is certainly not safe; however, driving back (home) after a dance party (rave) where MDMA users regularly combine MDMA with a host of other drugs can be described as extremely dangerous.     

Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy

In this work, we investigated the anticancer activity of orally administered recombinant human lactoferrin (rhLF) alone and in combination with chemotherapy in tumor-bearing mice. rhLF inhibited the growth of squamous cell carcinoma (O12) tumors in T cell-immunocompromised nu/nu mice by 80% when administered at 1,000 mg/kg (2.9 g/m2) by oral gavage twice daily for 8 days (p < 0.001). Similar activity was observed in syngeneic, immunocompetent BALB/c mice, where orally administered rhLF (1,000 mg/kg, 2.9 g/m2 once daily) halted the growth of mammary adenocarcinoma TUBO. Oral rhLF (200 mg/kg, 0.57 g/m2) was also used alone and in combination with cis-platinum (5 mg/kg) to treat head-and-neck squamous cell carcinoma in a syngeneic murine model. Monotherapy with oral rhLF or cis-platinum caused 61% or 66% tumor growth inhibition over placebo, respectively. Mice receiving both therapies showed 79% growth inhibition, a statistically significant improvement over each drug alone. We then demonstrated that administration of oral rhLF (300 mg/kg, 0.86 g/m2) to tumor-bearing or naive mice resulted in (i) significantly increased production of IL-18 in the intestinal tract, (ii) systemic NK cell activation and (iii) circulating CD8+ T-cell expansion. These data suggest that oral rhLF is an immunomodulatory agent active against cancer as a single agent and in combination chemotherapy, exerting its systemic effect through stimulation of IL-18 and other cytokines in the gut enterocytes. rhLF has been administered orally to 211 people without a single serious drug-related adverse event. Thus, rhLF shows promise as a safe and well-tolerated novel immunomodulatory anticancer agent.     

Lessons for neuropsychology from functional MRI in patients with epilepsy

This contribution aims to review the major findings of pre- and postsurgical functional magnetic resonance imaging (fMRI) in patients with refractory epilepsy from a neuropsychological perspective. We compared the contribution of fMRI with the intracarotid amytal procedure (IAP) with respect to functional mapping of language and memory in patients with therapy-resistant epilepsy. We conclude that using comprehensive language paradigms, fMRI has been able (1) to provide estimates of the degree of language lateralization including the degree of involvement of the nondominant hemisphere, (2) to provide information on the location of its activated network during expressive and receptive language, and (3) to help delineate eloquent language regions in the vicinity of the surgical target, thus preventing postoperative complications. The contribution of the frequently observed nondominant hemisphere activation to language should be explored and its clinical relevance determined. Evidence from fMRI studies is accumulating that reorganization of cognitive and motor function favors the activation of contralateral homotopic areas, although this process is far from understood. The exact functional contribution of atypical areas of activation should be investigated critically. In the presurgical evaluation process, detailed and reliable localization of language and memory functions of the individual patient is mandatory and should be the ultimate goal in the development of comprehensive clinical fMRI protocols.     

Contact dermatitis to cosmetics, fragrances, and botanicals

Cosmetics, fragrances, and botanicals are important causes of allergic contact dermatitis. Identifying and avoiding the causative allergens can pose a challenge to both the patient and the dermatologist. The site of involvement can give the investigator clues to the cause of the eruption in many cases. Fragrances and preservatives are the two most clinically relevant allergens in cosmetics. Botanicals are being added to cosmetics because of consumer demand and are now being recognized as sources of allergy as well. Patch testing allows for the detection of allergens that are potentially relevant in the genesis of the patient's eczema. Common skin-care product allergens, including fragrances and botanicals as well as those found in sunscreen, nail, and hair-care products, are reviewed. Practical methods of allergen avoidance are also discussed.     

Synthesis and antimycobacterial activity of pyridylmethylsulfanyl and naphthylmethylsulfanyl derivatives of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbothioamide/-2-carbonitrile

A set of four types of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbonitrile/-2-carbothioamide substituted with 1-naphthylmethylsulfanyl or pyridylmethylsulfanyl was prepared to modify the structure of benzylsulfanyl derivatives of the above-mentioned heterocycles. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration (MIC). The MIC values fall into a range of 2 to >1000 micromol/L. Introduction of a pyridyl moiety into the molecule mostly decreased the activity. A naphthyl moiety did not influence the activity in comparison with a phenyl. The most active substances were 4-(3-pyridylmethylsulfanyl)pyridine-2-carbothioamide (7b) (MIC = 2 - >62.5 micromol/L) and 4-(1-naphthylmethylsulfanyl)pyridine-2-carbothioamide (7d) (MIC = 2 - >32 micromol/L).