Molecular targets of cannabidiol in neurological disorders

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular phar- macology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeu- tics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent with modulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.

Children’s physic: medical perceptions and treatment of sick children in early modern England, c. 1580-1720

Historians of medicine, childhood, and paediatrics, have often assumed that early modern doctors neither treated children, nor adapted their medicines to suit the peculiar temperaments of the young. Through an examination of medical textbooks and doctors’ casebooks, this article refutes these assumptions. It argues that medical authors and practising doctors regularly treated children, and were careful to tailor their remedies to complement the distinctive constitutions of children. Thus, this article proposes that a concept of ‘children’s physic’ existed in early modern England: this term refers to the notion that children were physiologically distinct, requiring special medical care. Children’s physic was rooted in the ancient traditions of Hippocratic and Galenic medicine: it was the child’s humoral makeup that underpinned all medical ideas about children’s bodies, minds, diseases, and treatments. Children abounded in the humour blood, which made them humid and weak, and in need of medicines of a particularly gentle nature.

Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation.

Why cancer patients choose in-patient complementary therapy in palliative care: a qualitative study at Arokhayasala Hospice in Thailand

Cancer patients often choose complementary and alternative medicine (CAM) in palliative care, often in addition to conventional treatment and without medical advice or approval. Herbal medicines (HM) are the most commonly used type of CAM, but rarely available on an in-patient basis for palliative care. The motivations which lead very ill patients to travel far to receive such therapies are not clear. A qualitative study was therefore carried out to investigate influences on choosing to attend a CAM herbal hospice, to identify cancer patients’ main concerns about end-of-life care. Semi-structured interviews with 32 patients were conducted and analysed using thematic analysis. Patients were recruited from Arokhayasala, a Buddhist cancer hospice in Thailand which provides CAM, in the form of HM, a restricted diet, Thai yoga, deep-breathing exercises, meditation, chanting, Dhamma, laughter and music therapy, free-of-charge. The main factors influencing decision-making were a positive attitude towards HMs and previous use of them, dissatisfaction with conventional treatment, the home environment and their relationships with hospital doctors. Patients’ own perceptions and experiences were more important in making the decision to use CAM, and especially HM, in palliative cancer care than referral by healthcare professionals or scientific evidence of efficacy. Patients were prepared to travel far and live away from home to receive such care, especially as it was cost-free. In view of patients’ previously stated satisfaction with the regime at the Arokhayasala, these findings may be relevant to the provision of in-patient cancer palliative care to other patients.

Biodiversity and green open space

Biodiversity has been defined as the totality of genes, species, and ecosystems that inhabit the earth with the field contributing to many aspects of our lives and livelihoods by providing us with food, drink, medicines and shelter, as well as contributing to improving our surrounding environment. Benefits include providing life services through improved horticultural production, improving the business and service of horticulture as well as our environment, as well as improving our health and wellbeing, and our social and cultural relationships. Threats to biodiversity can include fragmentation, degradation and deforestation of habitat, introduction of invasive and exotic species, climate change and extreme weather events, over-exploitation of our natural resources, hybridisation, genetic pollution/erosion and food security issues and human overpopulation. This chapter examines a series of examples that provide the dual aims of biodiversity conservation and horticultural production and service; namely organic horticultural cropping, turf management, and nature-based tourism, and ways of valuing biological biodiversity such as the payment of environmental services and bio-prospecting. Horticulture plays a major role in the preserving of biodiversity.

The Sick Child in Early Modern England, 1580-1720

The Sick Child in Early Modern England is a powerful exploration of the treatment, perception, and experience of illness in childhood, from the late sixteenth to the early eighteenth centuries. At this time, the sickness or death of a child was a common occurrence - over a quarter of young people died before the age of fifteen - and yet this subject has received little scholarly attention. Hannah Newton takes three perspectives: first, she investigates medical understandings and treatments of children. She argues that a concept of 'children's physic' existed amongst doctors and laypeople: the young were thought to be physiologically distinct, and in need of special medicines. Secondly, she examines the family's' experience, demonstrating that parents devoted considerable time and effort to the care of their sick offspring, and experienced feelings of devastating grief upon their illnesses and deaths. Thirdly, she takes the strikingly original viewpoint of sick children themselves, offering rare and intimate insights into the emotional, spiritual, physical, and social dimensions of sickness, pain, and death. Newton asserts that children's experiences were characterised by profound ambivalence: whilst young patients were often tormented by feelings of guilt, fears of hell, and physical pain, sickness could also be emotionally and spiritually uplifting, and invited much attention and love from parents. Drawing on a wide array of printed and archival sources, The Sick Child is of vital interest to scholars working in the interconnected fields of the history of medicine, childhood, parenthood, bodies, emotion, pain, death, religion, and gender.

Resource-dependent livelihoods and the natural resource base

The natural resource base, terrestrial and marine, provides rural households in lower-income countries with income, food, shelter, and medicines, which are variously gathered and hunted in common lands and waters. These resources may be actively managed, whether by the government or local community; or may be de facto open access, with little effort by governments to prevent what may be de jure illegal extraction. This paper provides an appraisal of the literature that encompasses the direct value of wild resources to rural households; the extent to which these resources mitigate poverty and inequality; and the importance of the institutional context. The literature is increasingly addressing competing demands on the resource base both to support nearby livelihoods, and to enhance ecosystem services such as biodiversity; and how initiatives such as community-based payments for ecosystem services are changing how people interact with the resource base.

Oral colonization by Candida species in AIDS pediatric patients

The aim of this study was to assess the prevalence of factors associated with oral colonization by Candida spp. in pediatric patients with AIDS. The sample comprised of 117 children. Clinical status, medicines in use, and laboratory findings were obtained from hospital records; sociodemographic data were given by relatives. A dental examination assessed the prevalence of dental caries. The prevalence of oral colonization by Candida was 62%. Only seven children presented clinical manifestation of oral candidosis despite their high viral load index and low-for-age CD4 count. Candida colonization was directly associated with frequent use of antibiotics (prevalence ratio [PR] = 1.44), sulfa drugs (PR = 1.23), alteration in the oral mucosa (PR = 1.55), and untreated dental caries (PR = 1.93). It was inversely associated with the use of antiretroviral therapies (PR = 0.65). Candida albicans was the most frequently detected species (80%); phenotypic tests did not detect C. dubliniensis strains. This study observed a low prevalence of Candida-related oral lesions in these patients, which is compatible with the hypothesis that antiretroviral medicines may have contributed to reducing oral manifestations from Candida infection. The high prevalence of Candida colonization in HIV+/AIDS children with untreated dental caries reinforces the importance of oral health care in interdisciplinary health units that assist these patients.

Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family.

Äldre och psykofarmaka : Några sjuksköterskors uppfattning

Nearly nine percent of the population in Sweden are 75 years or older. Still they consume more than a quarter of all medicines. This increased use, is specially noticeable in nursing home residents, where the elderly is using a average of 8-10 preparations per day. According to the National Board of Health and Welfare in Sweden, the number of drugs and specially psychotropic drugs, has proved to be a risk factor for drug-related problems among the elderly, such as drug interaction and side effects. Routines for regular and systematic follow-up of drug prescription and utilisation reviews were not extensively implemented. According to the National Board of Health and Welfare its important to start the work to reduce psychotropic drugs among the elderly in nursing homes. Aim: This studie examine nurses apprehension about psychotopic drugs among the elderly in nursing homes. Method: An questionnarie based survey whit 10 closed questions. The questionary was answered of 46 nurses who works in nursing homes. Result: A majority of the nurses, tought the elderly in nursing homes were using to musch psychotropic drugs. The nurses tought that psychotropic drugs often prescribes as a matter of routin, particullary hypnotics and sedeativs. Those drugs was not effectiv in long terms according to the nurses. They also tought that alternative mehtods should be considered before describing pscyhotropic drugs. The nurses tought as a occupational group, that they had a responsibility to follow up and evaluate the elderlys medication whit psychotropic drugs.

Egenvård vid hjärtsvikt- en enkätstudie om vilka egenvårds åtgärder personer med hjärtsvikt säger sig använda i det dagliga livet

Heart failure is an illness that requires life-long treatment and often affects everyday aspects of a person’s life. Self-care is a significant part of the treatment. Good self-care resources make it possible for people with heart failure to make the lifestyle changes they often need to maintain or improve their level of health. Self-care means having knowledge of and being able to recognize the symptoms and signs of deterioration that can occur with heart failure, so that the person can take appropriate measures – and it also means knowing when it is time to seek professional help. The significance of self-care for heart failure has increased and will increase even more in the future, when monitoring one’s condition will be left more and more to the people themselves and those who take care of them. The object of the study was to learn what self-care measures people with heart failure say they apply in everyday life. The quantitative method of a questionnaire study (The European Heart Failure Self-Care Behaviour Scale) was used. Of the 94 people registered at a heart failure unit who were asked to complete the questionnaire, 58 of them consented. The results showed that more than 95% of the people with heart failure applied the recommended self-care measure of taking the medicines prescribed by their doctor. Many also applied the self-care measures of taking a rest during the day (83%) and taking it easy when they felt out of breath (78%). On the other hand, the self-care measures of daily weight control were applied only by 41%, daily exercise by only 48% and salt and fluid restrictions by only 59%. The self-care measures of contacting a doctor/nurse when noticing problems or symptoms of deterioration were applied by only 36% of those who felt out of breath and by only 43% of those who felt increased fatigue. The conclusion is that there is a need to improve the knowledge about and confidence in self-care treatment for people with heart failure. One way of achieving this is to show that people with heart failure check for symptoms and apply measures in their homes as part of the treatment and that this leads to an increased quality of life.

Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania : an open label prospective study

Background: Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home. Methods: An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961. Results: A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p <= 0.046). Conclusions: Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.

Regionalização da assistência farmacêutica no estado de Goiás : dilemas, incertezas e desafios

O estado de Goiás deu início ao seu processo de regionalização das ações de saúde, seguindo as diretrizes do SUS e as normas preconizadas pela NOAS 2001. O Plano Diretor Regionalização (PDR) está pactuado desde 2002, entretanto ainda não se encontra em pleno funcionamento. As ações de assistência farmacêutica (AF) ainda não foram regionalizadas. Com a intenção que identificar quais ações deveriam ser regionalizadas, as maiores dificuldades para a regionalização desse setor e a necessidade de se regionalizar essas ações, questionou-se os servidores da Secretaria de Estado da Saúde SES-GO, do nível central e regional, que trabalham direta ou indiretamente com ações de AF. Utilizando a escala de Likert para medir a intenção (vontade, desejo) das atitudes desses servidores. Demonstrou–se, nesta pesquisa, a predisposição de realizar regionalmente as ações de programação anual, distribuição de medicamentos aos municípios e avaliação das ações básicas dos municípios da sua região, a neutralidade quanto a regionalização das ações de seleção de medicamentos e a dispensação de medicamentos especiais. Apenas com relação à ação de aquisição regionalizada se encontrou uma predisposição desfavorável, ainda que com a predisposição de concordar com a necessidade da regionalização da assistência farmacêutica estadual. As maiores dificuldades são a carência de recursos humanos, agenda política, programação anual e a estrutura física deficitária das administrações regionais de saúde.

O descompasso entre o interno e o externo numa era de interdependência: o caso de acesso a medicamentos para HIV/AIDS no Brasil

Esta pesquisa analisa as relações entre a política doméstica e a política internacional na questão do acesso a medicamentos para o tratamento de HIV/AIDS, focalizando o caso pátrio. Argumenta-se que há um descompasso na estratégia brasileira que, se por um lado, resultou em uma posição de liderança e significativas vitórias no plano externo, por outro lado, não refletiu a mesma preocupação na criação de capacidades internas para a efetiva implementação desses avanços.

A Justiça e a efetividade na saúde pública

Este estudo reflete uma preocupação pessoal com a efetividade da jurisdição na questão do direito fundamental à saúde e os dilemas que se apresentam ao juiz, o- brigado a decidir sobre questões complexas e que transcendem à matéria jurídica. A Constituição Federal de 1988 estabeleceu, no artigo 6o, que a saúde é um direito social a ser disponibilizado pelo Estado. Já o artigo 196 diz que a saúde é direito de todos e dever do Estado, garantindo mediante políticas sociais e econômicas. O acesso às ações e serviços é universal e gratuito, constituindo o SUS em patrimônio social e o único respaldo da maioria da população em caso de doença. A realidade dos serviços oferecidos está distante das formulações constitucionais. Há aspectos, contudo, em que ele funciona e é elogiado, como a política pública de medicamentos para portadores de AIDS. As demandas judiciais são crescentes, em especial em busca de medicamentos, sempre dispendiosos e diferentes dos disponibilizados pelo serviço público. Esta atuação judicial tem se dado de forma pouco racional, não havendo uma fundamentação das decisões, causando fortes impactos nos orçamentos. O Judiciário passa a ser visto como um elemento perturbador, criando pontos de tensão com os gestores públicos. Para contribuir com algum elemento, sem ter a pretensão de esgotar a matéria, a- presento um resumo do percurso histórico-social da matéria na evolução da socie- dade brasileira. A construção das políticas públicas em saúde e seus formuladores. Os princípios em direito sanitário e as políticas em torno dos medicamentos. Reunidos estes elementos, verificam-se as decisões judiciais, procurando identificar os fundamentos e os critérios que orientaram os julgados e as tendências observa- das. Investiga-se sobre a Audiência Pública no 4, percebida como prática inovadora na administração da Justiça, que não se esgota em si, e prossegue gerando repercussões. Constata-se e conclui-se que o direito à saúde se afirma de forma preponderante por políticas públicas e o Poder Judiciário esforça-se por construir uma política institucional para melhor cumprir o seu papel.