Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis

Background: Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation. Objective: We investigated the plant cannabinoids Delta-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors. Methods: A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR analysis confirmed presence of CB1 and CB2 receptors. Results: The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either C81 /C82 antagonists. Conclusion: The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis. (c) 2006 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Early identification of stimulant treatment responders, partial responders and non-responders using objective measures in children and adolescents with hyperkinetic disorder

Background: The aim of this study was to evaluate stimulant medication response following a single dose of methylphenidate (MPH) in children and young people with hyperkinetic disorder using infrared motion analysis combined with a continuous performance task (QbTest system) as objective measures. The hypothesis was put forward that a moderate testdose of stimulant medication could determine a robust treatment response, partial response and non-response in relation to activity, attention and impulse control measures. Methods: The study included 44 children and young people between the ages of 7-18 years with a diagnosis of hyperkinetic disorder (F90 & F90.1). A single dose-protocol incorporated the time course effects of both immediate release MPH and extended release MPH (Concerta XL, Equasym XL) to determine comparable peak efficacy periods post intake. Results: A robust treatment response with objective measures reverting to the population mean was found in 37 participants (84%). Three participants (7%) demonstrated a partial response to MPH and four participants (9%) were determined as non-responders due to deteriorating activity measures together with no improvements in attention and impulse control measures. Conclusion: Objective measures provide early into prescribing the opportunity to measure treatment response and monitor adverse reactions to stimulant medication. Most treatment responders demonstrated an effective response to MPH on a moderate testdose facilitating a swift and more optimal titration process.

Non-pain goal pursuit inhibits attentional bias to pain

Although dealing with pain is a vital goal to pursue, most individuals are also engaged in the pursuit of other goals. The aim of the present experiment was to investigate whether attentional bias to pain signals is inhibited when one is pursuing a concurrent salient but nonpain task goal. Attentional bias to pain signals was measured in pain-free volunteers (n=63) using a spatial cueing task with pain cues and neutral cues. The pursuit of a concurrent goal was manipulated by including additional trials in which a digit appeared at the middle of the screen. Half of the participants (goal group) were instructed to name these additional stimuli aloud. In order to increase the affective-motivational value of this non-pain-related goal, monetary reward and punishment were made contingent upon the performance of this task. Participants of the control group did not perform the additional task. As predicted, the results show attentional bias to pain signals in the control group, but not in the goal group. This indicates that attentional bias to signals of impending pain is inhibited when one is engaged in the pursuit of another salient but nonpain goal. The results of this study underscore a motivational view on attention to pain, in which the pursuit of multiple goals, including nonpain goals, is taken into account.

Treatment non-adherence in teenage and young adult patients with cancer

Adhering to treatment can be a significant issue for many patients diagnosed with chronic health conditions and this has been reported to be greater during the adolescent years. However, little is known about treatment adherence in teenage and young adult (TYA) patients with cancer. To increase awareness of the adherence challenges faced by these patients, we have reviewed the published work. The available evidence suggests that a substantial proportion of TYA patients with cancer do have difficulties, with reports that up to 63% of patients do not adhere to their treatment regimens. However, with inconsistent findings across studies, the true extent of non-adherence for these young patients is still unclear. Furthermore, it is apparent that there are many components of the cancer treatment regimen that have yet to be assessed in relation to patient adherence. Factors that have been shown to affect treatment adherence in TYA patients include patient emotional functioning (depression and self-esteem), patient health beliefs (perceived illness severity and vulnerability), and family environment (parental support and parent–child concordance). Strategies that foster greater patient adherence are also identified. These strategies are multifactorial, targeting not only the patient, but the health professional, family, and treatment regimen. This review highlights the lack of interventional studies addressing treatment adherence in TYA patients with cancer, with only one such intervention being identified: a video game intervention focusing on behavioural issues related to cancer treatment and care. Methodological issues in measuring adherence are addressed and suggestions for improving the design of future adherence studies highlighted, of which there is a great need.

Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors

Neuropathic pain is an important clinical problem and it is usually resistant to the current therapy. We have recently characterized a novel analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in an experimental model of neuropathic pain induced in rats by chronic constriction, of sciatic nerve. The effect of the peptide was compared to that induced by the crude venom, which confirmed that crotalphine is responsible for the antinociceptive effect of the crotalid venom on neuropathic pain. For characterization of neuropathic pain, the presence of hyperalgesia, allodynia and spontaneous pain was assessed at different times after nerve constriction. These phenomena were detected 24 h after surgery and persisted at least for 14 days. The pharmacological treatments were performed on day 14 after surgery. Crotalphine (0.2-5 mu g/kg) and the crude venom (400-1600 mu g/kg) administered p.o. inhibited hyperalgesia, allodynia and spontaneous pain induced by nerve constriction. The antinociceptive effect of the peptide and crude venom was long lasting, since it was detected up to 3 days after treatment. Intraplantar injection of naloxone (1 mu g/paw) blocked the antinociceptive effect, indicating the involvement of opioid receptors in this phenomenon. Gabapentin (200 mg/kg, p.o.), and morphine (5 mg/kg, s.c.), used as positive controls, blocked hyperalgesia and partially inhibited allodynia induced by nerve constriction. These data indicate that crotalphine induces a potent and long lasting opioid antinociceptive effect in neuropathic pain that surpasses that observed with standard analgesic drugs. (C) 2008 Elsevier B.V. All rights reserved.

Women's acceptability of misoprostol treatment for incomplete abortion by midwives and physicians : secondary outcome analysis from a randomized controlled equivalence trial at district level in Uganda

OBJECTIVE: This study aimed to assess women´s acceptability of diagnosis and treatment of incomplete abortion with misoprostol by midwives, compared with physicians. METHODS: This was an analysis of secondary outcomes from a multi-centre randomized controlled equivalence trial at district level in Uganda. Women with first trimester incomplete abortion were randomly allocated to clinical assessment and treatment with misoprostol by a physician or a midwife. The randomisation (1:1) was done in blocks of 12 and stratified for health care facility. Acceptability was measured in expectations and satisfaction at a follow up visit 14-28 days following treatment. Analysis of women's overall acceptability was done using a generalized linear mixed-effects model with an equivalence range of -4% to 4%. The study was not masked. The trial is registered at ClinicalTrials.org, NCT 01844024. RESULTS: From April 2013 to June 2014, 1108 women were assessed for eligibility of which 1010 were randomized (506 to midwife and 504 to physician). 953 women were successfully followed up and included in the acceptability analysis. 95% (904) of the participants found the treatment satisfactory and overall acceptability was found to be equivalent between the two study groups. Treatment failure, not feeling calm and safe following treatment, experiencing severe abdominal pain or heavy bleeding following treatment, were significantly associated with non-satisfaction. No serious adverse events were recorded. CONCLUSIONS: Treatment of incomplete abortion with misoprostol by midwives and physician was highly, and equally, acceptable to women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01844024.

Synthesis, Characterization and Pharmacological Evaluation of 1-(2-Chloro-6-Fluorophenyl)-5-Methylindolin-2-One: A New Anti-Inflammatory Compound with Reduced Gastric Ulceration Properties

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Influence of thermal annealing treatment in oxygen atmosphere on grain boundary chemistry and non-ohmic properties of SnO2 center dot MnO polycrystalline semiconductors

The present work studied the influence of thermal treatment in oxygen rich atmosphere on heterogenous junctions in Mn-doped SnO2 polycrystalline system presenting varistor behavior. The samples were prepared by conventional oxide mixture methodology, and were submitted to heat treatment in oxygen rich atmosphere at 900 degrees C for 2h. The samples were characterized by X-ray diffraction, scanning electron microscopy, dc and ac electrical measurements. The results showed that there is an evident relationship between the microstructure heterogeneity and non-ohmic electrical properties. It was found that for this SnO2 center dot MnO-based varistor system the heat treatment in oxygen rich atmosphere does not necessarily increase the varistors properties, which was related to the decrease in the grain boundary resistance. The results are compared with Co-doped SnO2 varistors and ZnO based varistors. (C) 2008 WILEY-VCH Verlay GmbH & Co. KGaA, Weinheim.

Treatment of venous ulcers with fibrin sealant derived from snake venom

Venous ulcers of the lower limbs complicated by infection or chronicity represent a serious public health problem. The elevated number of those afflicted burdens the health services, interferes in quality of life and causes absenteeism. Although there are 2,500 items on the market, ranging from the simplest dressing up to the most complex types of dressing, treatment remains a challenge. Among the substances used, fibrin sealant is the one that promotes diminution of bacterial colonization and of edema, controls hemorrhaging, alters the pain threshold by protecting the nerve endings, hydrates the wound bed and forms granulation tissue that favors healing. Its disadvantages include higher cost and utilization of human fibrinogen that can transmit infectious diseases. The Center for the Study of Venoms and Venomous Animals (CEVAP) at São Paulo State University (UNESP) developed a new sealant made up of fibrinogen extracted from large animals and from an enzyme obtained from snake venom. The present study, developed in the Health Education Clinic (CEPS) of Sacred Heart University (USC) aimed to evaluate the effect of the new sealant on the healing process of venous ulcers in 24 adult patients, seven of whom were male and 17 female. Two study groups were formed as follows: Group 1 (G1) - control group of 11 patients treated with essential fatty acid (EFA) and Unna's boot, and Group 2 (G2) - 13 patients treated with essential fatty acid (EFA), fibrin sealant and Unna's boot. The follow-up lasted eight weeks and the sealant was applied at only the first and fourth weeks. The results showed that Group 2 presented worse lesion conditions as to healing, but, when comparing the two groups, it was noteworthy that the the sealant was effective in healing venous ulcers. There is evidence that the new sealant is recommended for leg ulcers with the following advantages: ease of application, preparation of the wound bed, diminution of pain and a higher number of discharges in the eighth week. More important, other positive characteristics are non-transmission of infectious diseases, absence of adverse reactions, and economic advantage of being produced by Brazilian technology. Finally, it is suggested that the weekly application of sealant, for at least eight weeks, could improve the healing process and consequently life quality.

Short-Term Antiandrogen Flutamide Treatment Causes Structural Alterations in Somatic Cells Associated with Premature Detachment of Spermatids in the Testis of Pubertal and Adult Guinea Pigs

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Pharmacological and toxicological studies of Drimys angustifolia Miers. (Winteraceae)

Drimys angustifolia Miers. (Winteraceae) is a Brazilian medicinal plant used as analgesic, antiulcer and anti-inflammatory without studies to assure its efficacy and safety Leaf and stem bark extracts were evaluated to determine the antiulcer, analgesic, antiinflammatory and antioxidant activities. Preliminary toxic effects and qualitative phytochemical profile were also performed. The antiulcer activity was detected in both extracts. Administration of the leaf extract at 250 mg/kg inhibited total lesion area by 76.50% (p < 0.01 in ethanol/HCl method), while carbenoxolone at 250 mg/kg reduced lesions by 69.48%. Stem bark extract (250 mg/kg) inhibited lesion by 81.42%, while carbenoxolone by 74.10%. Similar effects were observed in the ethanol-induced ulcer method, but no activity was observed in piroxican model. The effects involve nitric oxide in gastric protection, since the L-NAME treatment reversed the protection given by the extracts. Antioxidant effects suggest an involvement against oxidative stress. In the pain (writhing, tail-flick and hot-plate tests) and inflammation (carrageenan-induced paw edema) models, the extracts did not present any effect. The phytochemical studies demonstrated that both extracts contain flavonoids, saponins, glycosilated triterpenoids, fixed acids, cyanogenic glycosides, quinones, tannins, xanthone and steroidal aglycones. Toxicological studies showed that the extracts are safe at the effective antiulcer doses. (c) 2006 Elsevier B.V.. All rights reserved.

Plant derived alkaloid (-)-cassine induces anti-inflammatory and anti-hyperalgesics effects in both acute and chronic inflammatory and neuropathic pain models

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)