RESUMO
BACKGROUND: Smoking poses a serious risk of early preventable death and disease especially for women living with socio-economic disadvantage (SED). A smoking cessation programme, 'We Can Quit', was developed in Ireland tailored to SED women. This includes group-based support delivered by trained lay local community facilitators (CFs) and free nicotine replacement therapy (NRT). The intervention was pilot tested in a cluster randomised controlled trial, 'We Can Quit 2'. This paper reports on the WCQ2 process evaluation which assessed feasibility and acceptability of the programme and trial processes. METHODS: Embedded qualitative design using the UK Medical Research Council's process evaluation framework. Semi-structured interviews with trial participants (N = 21) and CFs (N = 8). Thematic analysis was utilised. RESULTS: Peer-modelling, a non-judgemental environment, CFs facilitation of group support were viewed as acceptable programme related factors. Some participants expressed concerns about NRT side effects. Provision of free NRT was welcomed and accepted by participants, although structural barriers made access challenging. Pharmacists took on a role that became larger than originally envisaged - and the majority provided additional support to women in their quit attempts between group meetings which augmented and supplemented the intervention sessions provided by the CFs. Participants reported good acceptance of repeated measures for data collection, but mixed acceptability of provision of saliva samples. Low literacy affected the feasibility of some women to fully engage with programme and trial-related materials. This was despite efforts made by intervention developers and the trial team to make materials (e.g., participant intervention booklet; consent forms and participant information leaflets) accessible while also meeting requirements under 2018 European General Data Protection Regulation legislation. Hypothetical scenarios of direct (e.g., researcher present during programme delivery) and indirect (e.g., audio recordings of programme sessions) observational fidelity assessments for a future definitive trial (DT) were acceptable. CONCLUSIONS: Intervention and trial-related processes were generally feasible and acceptable to participants and CFs. Any future DT will need to take further steps to mitigate structural barriers to accessing free NRT; and the established problem of low literacy and low educational attainment in SED areas, while continuing to comply within the contemporary legislative research environment. TRIAL REGISTRATION: WCQ2 pilot trial ( ISRCTN74721694 ).
Assuntos
Abandono do Hábito de Fumar , Feminino , Humanos , Irlanda , Fumar , Dispositivos para o Abandono do Uso de TabacoRESUMO
BACKGROUND: Urgent suspected cancer referral guidelines recommend that women with gynaecological cancer symptoms should have a pelvic examination (PE) prior to referral. We do not know to what extent GPs comply, their competency at PE, or if PE shortens the diagnostic interval. OBJECTIVES: We conducted a systematic review of the use, quality and effectiveness of PE in primary care for women with suspected gynaecological cancer. METHOD: PRISMA guidelines were followed. Three databases were searched using four terms: PE, primary care, competency and gynaecological cancer. Citation lists of all identified papers were screened independently for eligibility by two reviewers. Data extraction was performed in duplicate and independently. Paper quality was assessed using the relevant Critical Appraisal Skills Programme checklist. Emergent themes and contrasting issues were explored in a narrative ecological synthesis. MAIN FINDINGS: Twenty papers met the inclusion criteria. 52% or less of women with suspicious symptoms had a PE. No papers directly explored GPs' competence at performing PE. Pre-referral PE was associated with reduced diagnostic delay and earlier stage diagnosis. Ecological synthesis demonstrated a complex interplay between patient and practitioner factors and the environment in which examination is performed. Presenting symptoms are commonly misattributed by patients and practitioners resulting in misdiagnosis and lack of PE. CONCLUSION: We do not know if pre-referral PE leads to better outcomes for patients. PE is often not performed for women with gynaecological cancer symptoms, and evidence that it may result in earlier stage of diagnosis is weak. More research is needed.
Assuntos
Diagnóstico Tardio , Neoplasias dos Genitais Femininos/diagnóstico , Exame Ginecológico/normas , Atenção Primária à Saúde , Feminino , Fidelidade a Diretrizes , HumanosRESUMO
BACKGROUND: Omission of pelvic examination (PE) has been associated with diagnostic delay in women diagnosed with gynaecological cancer. However, PEs are often not carried out by GPs. AIM: To determine the perceptions of GPs about the role of PEs, the barriers to and facilitators of PEs, and GPs' experience of PEs in practice. DESIGN AND SETTING: Qualitative semi-structured interview study conducted in one health board in Scotland (mixed urban and rural) with an approximate population of 500 000. METHOD: Interviews were conducted face-to-face or by telephone between March and June 2019. Framework analysis used the COM-B behaviour change model concepts of capability, opportunity, and motivation. RESULTS: Data was compatible with all three domains of the COM-B framework. Capability related to training in and maintenance of skills. These went beyond carrying out the examination to interpreting it reliably. Opportunity related to the clinical environment and the provision of chaperones for intimate examination. Interviewees described a range of motivations towards or against PEs that were unrelated to either capability or opportunity. These all related to providing high-quality care, but this was defined in different ways: 'doing what is best for the individual', 'doctors examine', and 'GPs as pragmatists'. CONCLUSION: GPs' reasons for carrying out, or not carrying out, PEs in women with symptoms potentially indicating cancer are complex. The COM-B framework provides a way of understanding this complexity. Interventions to increase the use of PEs, and critics of its non-use, need to consider these multiple factors.
Assuntos
Clínicos Gerais , Neoplasias , Humanos , Feminino , Exame Ginecológico , Diagnóstico Tardio , Pesquisa Qualitativa , Atitude do Pessoal de Saúde , Atenção Primária à SaúdeRESUMO
Sustainable access to essential medicines in low-income and middle-income countries requires innovative cross-sectoral collaboration throughout the lifecycle of a medicine. Partnerships are essential to address the systemic challenges of global health and health inequity. Pharmaceutical companies, funders, governments, international non-governmental organisations (I-NGOs) and other key stakeholders can leverage, through effective partnership working, their unique expertise to help drive innovation and share learnings and risks. Here, we reflect on one approach taken in the development and supply of chlorhexidine digluconate 7.1% w/w gel (equivalent to 4% w/w chlorhexidine) for neonatal cord care. We describe and analyse the steps taken by GSK to increase access to chlorhexidine gel, including partnering with the I-NGO Save the Children in Western Kenya. Learning points gained along the journey are shared, together with subsequent steps taken to increase access, with the aim of making recommendations that may be applicable to similar enterprises in the future.
Assuntos
Clorexidina , Governo , Recém-Nascido , Criança , Humanos , Saúde Global , QuêniaRESUMO
BACKGROUND: Identifying what prompts or hinders women's help-seeking behaviour is essential to ensure timely diagnosis and management of gynaecological cancers. AIM: To understand the factors that influence the help-âseeking behaviour of women diagnosed with gynaecological cancer. DESIGN AND SETTING: Systematic review and narrative synthesis of studies from high-income settings worldwide. METHOD: Five databases were searched for studies, of any design, that presented factors related to the help-seeking behaviour of women diagnosed with a gynaecological cancer. Data from the articles were extracted and presented using narrative synthesis, which was both inductive and deductive. The COM-B (capability, opportunity, motivation, behaviour) model of behaviour change was used as a framework. RESULTS: In total, 21 studies were included in the review. Inductive synthesis presented three main themes of factors related to the help-seeking behaviour of women diagnosed with gynaecological cancer: patient factors, such as knowledge of symptoms; emotional factors, including previous healthcare experience, embarrassment, and trust; and practical factors, including time and resources. Deductive synthesis demonstrated that capability (namely, symptom knowledge), opportunity (having the required time and overcoming the cultural taboos surrounding gynaecological symptoms), and motivation (believing that seeking help is beneficial) are all required to initiate help-seeking behaviour. CONCLUSION: Although it is a journey of defined steps, the help-âseeking behaviour of women with symptoms diagnosed with gynaecological cancer is influenced by personal and societal factors. Interventions to improve help seeking will need to address the specific identified factors, as well as capability, opportunity, and motivation.
Assuntos
Neoplasias dos Genitais Femininos , Comportamento de Busca de Ajuda , Feminino , Humanos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Neoplasias dos Genitais Femininos/diagnóstico , Neoplasias dos Genitais Femininos/terapia , MotivaçãoRESUMO
BACKGROUND: "We Can Quit2" (WCQ2) was a pilot cluster randomised controlled trial with an embedded process evaluation assessing the feasibility and acceptability of 'We Can Quit' (WCQ, a peer-delivered community-based stop-smoking programme for women in disadvantaged communities. The control group comprised 'enhanced usual care' offered by the Irish Health Service Executive (HSE). The PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) is a tool to assess whether a trial design is more explanatory (working under ideal conditions) or pragmatic (working under 'real-world' conditions). The aim of this paper was to retrospectively evaluate the WCQ2 pilot trial using PRECIS-2 to inform the decision-making process on progression to a future definitive trial (DT). METHODS: The WCQ2 trial protocol and HSE standard stop-smoking service were described across the nine PRECIS-2 domains: eligibility, recruitment, setting, organisation, flexibility-delivery, flexibility-adherence, follow-up and primary outcome. Team members scored the domains as pragmatic or explanatory for each arm in a half-day workshop. RESULTS: Seven team members (practitioners and researchers) assessed the overall trial design as more explanatory than pragmatic. Important differences emerged between the two arms. WCQ targeted adult women from disadvantaged communities whereas HSE run a limited enhanced service for all quitters. Trial recruitment was challenging, intense efforts were needed as the trial proceeded. WCQ was delivered in a non-clinical community setting, HSE services in a clinical setting. WCQ organisation was co-designed with community partners and comprises peer-to-peer group support delivered by trained lay community facilitators, whereas HSE one-to-one support is delivered by Smoking Cessation Officers with a clinical background. Only WCQ allowed flexibility in delivery and adherence. Follow-up was more intensive in WCQ. Greater efforts to improve participant retention will be required in a future DT. CONCLUSIONS: PRECIS-2 allowed the reflection of practitioners and researchers on similarities and differences between intervention and control arms. Results will inform the decision on progression to an effectiveness DT, which will require more a pragmatic and less explanatory design. This novel use of PRECIS-2 to retrospectively evaluate a complex community-based pilot trial in advance of a full DT will also support learning for those undertaking hybrid trials of implementation and effectiveness. TRIAL REGISTRATION: This trial is registered with the ISRCTN registry ( No. 74721694 ).
RESUMO
OBJECTIVE: To estimate the treatment effects of SB-742457 and donepezil in Alzheimer disease (AD) in a contemporary clinical trial. METHOD: Randomized, controlled, parallel-group, exploratory study with a 4-week, single-blind, placebo run-in phase and 24-week, double-blind treatment phase. Primary endpoints were Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). RESULTS: One hundred ninety eight subjects with mild-to-moderate probable AD (MMSE scores 12-26) were randomized; 196 were included in the intent-to-treat population (placebo, n = 61; SB-742457 35 mg/day, n = 68; donepezil 10 mg/day, n = 67), and 161 completed. Drug-placebo treatment differences in CIBIC+ score at week 24 were -0.17 (90% confidence interval [CI]: -0.50, 0.16) for SB-742457 and -0.28 (90% CI: -0.61, 0.05) for donepezil. Drug-placebo treatment differences (90% CI) in change from baseline ADAS-Cog score at Week 24 were -0.4 (-2.2, 1.4) for SB-742457 and -1.2 (-3.0, 0.6) for donepezil. All treatments were generally safe and well tolerated. CONCLUSIONS: In this exploratory study, SB-742457 and donepezil were associated with improvements in global function. Treatment effect on cognition for both SB-742457 and donepezil was smaller than those previously observed in previous clinical studies with donepezil.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Quinolinas/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Sulfonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Cognição/efeitos dos fármacos , Donepezila , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The Department of Health's End of Life Care Strategy provided the opportunity to develop effective care, regardless of the setting. However, providing end of life care is challenging for all healthcare practitioners, with each care setting experiencing unique challenges. Within one acute NHS trust, the challenges of identifying and diagnosing dying were identified. An electronic resource tool was developed to aid prognostication and provide a single point of reference to assist healthcare practitioners in improving end of life care for patients in an acute hospital setting.
Assuntos
Internet , Assistência Terminal , Projetos Piloto , Qualidade da Assistência à Saúde , Medicina Estatal , Reino UnidoRESUMO
OBJECTIVE: To (1) explore RDNs' descriptions of patient-centered care (PCC), (2) measure Registered Dietitian Nutritionists' (RDNs) preferences for PCC and (3) identify factors that affect RDNs' PCC preferences. METHODS: A survey instrument including two open-ended items exploring RDN descriptions of and experiences with PCC, the Patient-Practitioner Orientation Scale (PPOS), and various factors that could influence PCC (e.g., work intensification, work engagement, and work/demographic characteristics) was expert reviewed, pilot tested, and distributed electronically to 4697 RDNs. A regression analysis was conducted, and two open-ended items were qualitatively analyzed. RESULTS: Three themes emerged when RDNs described PCC (n = 375): dietitian/patient relationship (95.7%), organizational influence (64.4%), and interprofessional teams (26.3%). RDNs (n = 318) scored 4.60/6 on the PPOS. Higher levels of work engagement were predictive of higher PPOS scores, and heavier workloads were predictive of lower PPOS scores (p < 0.05). Primary work position also influenced PPOS scores (p<0.05). CONCLUSION: RDNs have varying personal definitions of and experiences with PCC, however there are common themes. RDNs generally prefer PCC and score moderately high on the PPOS. PRACTICE IMPLICATIONS: To strengthen preferences for PCC, managers should create manageable workloads and prioritize work engagement. Continued emphasis on interprofessional collaboration with and organizational promotion of RDNs could improve PCC.
Assuntos
Dietética , Nutricionistas , Humanos , Assistência Centrada no Paciente , Inquéritos e QuestionáriosRESUMO
A unique experiment in bringing academic and industrial scientists together to tackle endemic infectious diseases has proved a success. The Tres Cantos Open Lab Foundation, guided and advised by independent experts, funds extended stays of academics at the campus of a pharmaceutical company, where they access the firm's resources in partnership with company scientists. Progress in tackling tuberculosis, protozoal infections, and enteric bacterial diseases has sustained the decade-long evolution of the model, whose distinctive features complement other public-private partnerships with similar goals.
Assuntos
Doenças Transmissíveis/tratamento farmacológico , Desenvolvimento de Medicamentos/organização & administração , Indústria Farmacêutica/organização & administração , Doenças Endêmicas , Academias e Institutos/organização & administração , Humanos , Parcerias Público-PrivadasRESUMO
INTRODUCTION: This study investigated the efficacy and tolerability of the highly selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. SUBJECTS AND METHODS: The study was conducted in two parts, each comprising a 4-week baseline period, a 12-week, double-blind, parallel-group treatment period, and a 4-week follow-up period. The study had an adaptive design in that findings of Part 1 of the study were used to inform the conduct of Part 2. Following an interim analysis at the end of Part 1, the trial could be stopped for futility or continued in Part 2 to study the full-dose response or to increase sample size in case initial assumptions had been violated. The primary end-point in both parts of the study was the probability of the occurrence of a migraine headache day during the baseline period and the treatment period. RESULTS: In Part 1, adult male and female patients with migraine received GW274150 60 mg (n = 37), 120 mg (n = 37), or placebo (n = 38) once daily for 12 weeks. In Part 2, female patients with migraine received GW274150 60 mg (n= 160) or placebo (n = 154) once daily for 12 weeks. GW274150 was no more effective than placebo for the primary efficacy end-point or any secondary efficacy end-point in Part 1 or Part 2. GW274150 was generally well tolerated. CONCLUSIONS: GW274150 at doses predicted to inhibit iNOS >80% did not differ from placebo in the prophylaxis of migraine. The results do not support a role of iNOS inhibition in migraine prevention.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Transtornos de Enxaqueca/prevenção & controle , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Sulfetos/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Although in most low- and middle-income countries (LMICs) men are decision makers and control the household budget, their involvement in maternity care is limited. Reports from high-income countries indicate a beneficial effect of involving men in antenatal and delivery care on birth outcomes. METHODS: We conducted a systematic review to assess whether similar effects are observed in LMICs. We searched MEDLINE, PubMed, CINAHL, Embase, NCBI, PsycInfo and other relevant databases using a comprehensive search strategy to retrieve relevant articles. A total of 17 articles were included. Meta-analysis of extracted data was performed, using the generic inverse variance method where possible. All studies were conducted in South Asia and Africa. RESULTS: We found that involving a male partner in antenatal care was associated with skilled birth attendance utilization (pooled OR 3.19 [95% CI 1.55 to 6.55]), having institutional delivery (OR 2.76 [95% CI 1.70 to 4.50]) and post-partum visit uptake (OR 2.13 [95% CI 1.45 to 3.13]). Mother's knowledge of danger signs and modern contraception utilization were also positively affected. However, it had no significant impact on the number of antenatal visits. CONCLUSIONS: Male involvement in antenatal care had a positive impact on the uptake of maternal health services. Further research needs to investigate whether this translates into improved maternal and newborn health in developing countries.
Assuntos
Países em Desenvolvimento/estatística & dados numéricos , Serviços de Saúde Materna/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Cuidado Pré-Natal/psicologia , Cuidado Pré-Natal/estatística & dados numéricos , Parceiros Sexuais/psicologia , Adulto , África , Ásia , Feminino , Humanos , Masculino , Pobreza/estatística & dados numéricos , GravidezRESUMO
BACKGROUND: Gynaecological cancers are the second most common female cancer type, with survival rates in the UK lower than in many comparable countries. A potentially important factor in the UK's poorer cancer outcomes is diagnostic delay; gynaecological cancers are the cancer type most likely to be affected by less timely diagnosis. AIM: To examine current evidence for factors that contribute to patient and primary care delays in the diagnostic pathway of gynaecological cancer. DESIGN AND SETTING: A systematic review of the available literature. METHOD: PRISMA guidelines were followed. MEDLINE and Embase databases and the Cochrane Library were searched using three terms: primary care; gynaecological cancer; and delay. Citation lists of all identified articles were searched. Two authors independently screened the titles, abstracts, and full texts of publications. Data extraction was performed by one author and quality assured by a second reviewer in a 20% sample of selected articles. Synthesis was narrative. RESULTS: A total of 1253 references was identified, of which 37 met the inclusion criteria. Factors associated with delayed diagnosis were categorised as either patient factors (patient demographics, symptoms or knowledge, and presentation to the GP) or primary care factors (doctor factors: patient demographics, symptoms or knowledge, and referral process); and system factors (such as limited access to investigations). CONCLUSION: Delayed diagnosis in the patient and primary care intervals of the diagnostic journey of gynaecological cancer is complex and multifactorial. This review identifies areas of future research that could lead to interventions to enable prompter diagnosis of gynaecological cancers.
Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Neoplasias dos Genitais Femininos/diagnóstico , Atenção Primária à Saúde , Procedimentos Clínicos , Feminino , HumanosRESUMO
BACKGROUND: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing. OBJECTIVES: To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response. DESIGN: Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness. SETTING: Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients. PATIENTS AND OTHER PARTICIPANTS: We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers. Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks. MAIN OUTCOME MEASURES: Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference. RESULTS: Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. CONCLUSIONS: Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.
Assuntos
Afeto/fisiologia , Encéfalo/fisiologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/tratamento farmacológico , Expressão Facial , Fluoxetina/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Percepção Visual/fisiologia , Afeto/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico/métodos , Transtorno Depressivo/psicologia , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Fluoxetina/farmacologia , Humanos , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiologia , Imageamento por Ressonância Magnética/estatística & dados numéricos , Neocórtex/efeitos dos fármacos , Neocórtex/fisiologia , Estudos Prospectivos , Análise de Regressão , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Resultado do Tratamento , Percepção Visual/efeitos dos fármacosRESUMO
In March 2014, GSK announced a number of new strategic investments in Africa. One of these included investment of up to 25 million Pounds Sterling (£25 million) to create the world's first R&D Open Lab to increase understanding of non-communicable diseases (NCDs) in Africa. The vision is to create a new global R&D effort with GSK working in partnership with major funders, academic centres and governments to share expertise and resources to conduct high-quality research. The Africa NCD Open Lab will see GSK scientists collaborate with scientific research centres across Africa. An independent advisory board of leading scientists and clinicians will provide input to develop the strategy and selection of NCD research projects within a dynamic and networked open-innovation environment. It is hoped that these research projects will inform prevention and treatment strategies in the future and will enable researchers across academia and industry to discover and develop new medicines to address the specific needs of African patients.
Assuntos
Cooperação Internacional , Laboratórios/economia , África , Doença Crônica/terapia , Doenças Transmissíveis/terapia , Comportamento Cooperativo , Humanos , Investimentos em SaúdeRESUMO
To understand and exploit centrally acting drugs requires reliable measures of their time course of action in the human brain. Functional magnetic resonance imaging (fMRI) is able to measure noninvasively, drug-induced changes in task-related brain activity. Here, we have characterized, in a specific region of the brain, the time of onset of action and the half-life of action of a clinically relevant dose of a potent opioid analgesic agent, remifentanil. These times were established from the temporal variation of the amplitude of the blood oxygen level-dependent response in the insular cortex contralateral to a painfully hot thermal stimulus, in volunteers receiving a remifentanil infusion. The insular cortex has repeatedly been reported as activated by noxious thermal stimulation. The times of onset and offset of drug action were each characterized by a half-life for changes in fMRI signal from within the insula. These characteristic times agreed with the observed drug-induced analgesia and previous pharmacokinetic-pharmacodynamic measurements for remifentanil. We have successfully measured, for the first time using fMRI, temporal pharmacological parameters for a CNS-active drug based on its effect on task-related activity in a specific brain region. Comparison of the time course of regional brain activity with pain perception could reveal those regions engaged in drug-induced analgesia.
Assuntos
Analgésicos Opioides/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Piperidinas/farmacologia , Adulto , Intervalos de Confiança , Humanos , Masculino , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Remifentanil , Fatores de TempoRESUMO
The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.
Assuntos
Indanos/administração & dosagem , Receptores Opioides mu/agonistas , Triazóis/administração & dosagem , Adulto , Afeto/efeitos dos fármacos , Cognição/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Feminino , Temperatura Alta , Humanos , Indanos/efeitos adversos , Indanos/farmacocinética , Masculino , Pessoa de Meia-Idade , Limiar da Dor/efeitos dos fármacos , Pressão , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto JovemRESUMO
Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.