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AIMS: To investigate how Chief Medical Officers experience their role in the municipalities´ work with making the public health overview documents, demanded by the Norwegian Public Health Act from 2012. METHODS: A qualitative study with semi-structured focus group interviews with 21 Chief Medical Officers from 20 different municipalities in Norway. The interviews were conducted in 2017. The data were analyzed thematically. RESULTS: The Chief Medical Officers were mainly positive to participating in making public health overview documents. They took on roles as leaders of the work, medical advisors, data collectors towards local GPs and listening post to other sectors. Organizational factors like too small positions and a lack of tradition to involve the CMO in public health work were experienced as barriers to their involvement. The collaboration with the public health coordinators was said to be rewarding, and the intersectoral process involved employees from other sectors in a new way in public health. Although there were some positive experiences, several CMOs considered the use and impact of the public health overview document as limited. CONCLUSION: There was a large variation in the amount and the type of involvement the Chief Medical Officers had in making the public health overview documents in Norwegian municipalities. More research is needed to understand if this has any consequences for the quality of public health work in the municipalities and whether it is a sign of a changing role of the Chief Medical Officers.
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Grupos Focales , Investigación Cualitativa , Noruega , Humanos , Salud Pública , Ciudades , Rol Profesional , Ejecutivos Médicos , Entrevistas como Asunto , Masculino , FemeninoRESUMEN
AIM: The aim was to explore how general practitioners experienced being involved in local public health work and how they worked with prevention and health promotion clinically after the introduction of the Public Health Act in 2012. DESIGN, SETTING AND SUBJECTS: Qualitative study with focus groups interviews with 18 GPs from different municipalities in Norway. RESULTS: The GPs said that they either had not at all or only to a limited extent been involved in local public health work in their municipalities. They reported finding it hard to prioritize individual disease prevention and health promotion in their clinical work. GPs thought of health promotion as something that mainly concerned healthy people at a group level. CONCLUSIONS: Based on the experiences of the GPs in this study, there is a gap between governmental expectations to the role of GPs in public health, and how it works in practice.KEY POINTSWith the Norwegian Public Health Act launched in 2012, GPs were expected to contribute to better population health in their clinical work and as data providers to local public health surveillance.The GPs interviewed in this study said they had not been involved in local public health work, and they found it hard to give disease prevention and health promotion priority in their clinical work.GPs expressed various perceptions of what prevention and health promotion entails.
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Médicos Generales , Humanos , Salud Pública , Actitud del Personal de Salud , Investigación Cualitativa , NoruegaRESUMEN
A cross-industry survey was conducted by EFPIA/IQ DruSafe in 2018 to provide information on photosafety evaluation of pharmaceuticals after implementation of ICH S10. This survey focused on the strategy utilized for photosafety risk assessment, the design of nonclinical (in vitro and in vivo) and clinical evaluations, the use of exposure margins in risk assessment, and regulatory interactions. The survey results indicated that a staged approach for phototoxicity assessment has been widely accepted by regulatory authorities globally. The OECD-based 3T3 NRU Phototoxicity Test is the most frequently used in vitro approach. Modifications to this assay suggested by ICH S10 are commonly applied. For in-vitro-positives, substantial margins from in vitro IC50 values under irradiation to Cmax (clinical) have enabled further development without the need for additional photosafety data. In vivo phototoxicity studies typically involve dosing rodents and exposing skin and eyes to simulated sunlight, and subsequently evaluating at least the skin for erythema and edema. However, no formal guidelines exist and protocols are less standardized across companies. A margin-of-safety approach (based on Cmax at NOAEL) has been successfully applied to support clinical development. Experience with dedicated clinical phototoxicity studies was limited, perhaps due to effective de-risking approaches employed based on ICH S10.
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Dermatitis Fototóxica/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Organización para la Cooperación y el Desarrollo Económico/normas , Preparaciones Farmacéuticas/normas , Luz Solar/efectos adversosRESUMEN
Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.
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Anorexia/inducido químicamente , Antineoplásicos/efectos adversos , Factor 15 de Diferenciación de Crecimiento/fisiología , Neoplasias/terapia , Platino (Metal)/efectos adversos , Vómitos/inducido químicamente , Animales , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Pérdida de PesoRESUMEN
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.
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Isoindoles/farmacología , Lactamas/farmacología , Oxazoles/farmacología , Receptor Muscarínico M1/agonistas , Convulsiones/inducido químicamente , Regulación Alostérica , Anfetamina/farmacología , Animales , Ataxia/inducido químicamente , Diarrea/inducido químicamente , Perros , Donepezilo , Diseño de Fármacos , Femenino , Humanos , Indanos/farmacología , Isoindoles/administración & dosificación , Isoindoles/síntesis química , Isoindoles/toxicidad , Lactamas/administración & dosificación , Lactamas/síntesis química , Lactamas/toxicidad , Masculino , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Oxazoles/administración & dosificación , Oxazoles/síntesis química , Oxazoles/toxicidad , Piperidinas/farmacología , Ratas Wistar , Receptor Muscarínico M1/antagonistas & inhibidores , Escopolamina/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacología , Tiadiazoles/farmacología , Vómitos/inducido químicamenteRESUMEN
Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-ß42 (Aß42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.
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It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
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Descubrimiento de Drogas , Ácidos Picolínicos/farmacología , Receptor Muscarínico M1/agonistas , Tiazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/química , Ratas , Receptor Muscarínico M1/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Phototoxicity is a relatively common phenomenon and is an adverse effect of some systemic drugs. The fundamental initial step of photochemical reactivity is absorption of a photon; however, little guidance has been provided thus far regarding how ultraviolet-visible (UV-vis) light absorption spectra may be used to inform testing strategies for investigational drugs. Here we report the results of an inter-laboratory study comparing the data from harmonized UV-vis light absorption spectra obtained in methanol with data from the in vitro 3T3 Neutral Red Uptake Phototoxicity Test. Six pharmaceutical companies submitted data according to predefined quality criteria for 76 compounds covering a wide range of chemical classes showing a diverse but "positive"-enhanced distribution of photo irritation factors (22%: PIF<2, 12%: PIF 2-5, 66%: PIF>5). For compounds being formally positive (PIF value above 5) the lowest reported molar extinction coefficient (MEC) was 1700 L mol⻹ cm⻹ in methanol. However, the majority of these formally positive compounds showed MEC values being significantly higher (up to almost 40,000 L mol⻹ cm⻹). In conclusion, an MEC value of 1000 L mol⻹ cm⻹ may represent a reasonable and pragmatic threshold warranting further experimental photosafety evaluation.
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Dermatitis Fototóxica/etiología , Drogas en Investigación/toxicidad , Animales , Células 3T3 BALB , Colorantes/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Ratones , Rojo Neutro/metabolismo , Estándares de Referencia , Espectrofotometría Ultravioleta/normas , Luz SolarRESUMEN
CONTEXT: Selective inhibitors of glycine transporter type 1 (GlyT1) increase synaptic glycine concentrations and are being developed to treat cognitive and negative symptoms of schizophrenia. However, increases in systemic glycine levels have been associated with visual disturbances and electroretinogram (ERG) alternations. OBJECTIVE: To determine whether the selective GlyT1 inhibitor PF-03463275 causes changes in ERG responses in albino rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were administered PF-03463275 subcutaneously at 1, 3 and 10 mg/kg 1 h prior to ERG acquisition. Scotopic and photopic luminance responses, photopic adaptometry and flicker responses were measured. Plasma and vitreous samples were obtained at necropsy for determination of PF-03463275 concentrations. RESULTS: A dose-dependent reduction (up to â¼70%) in the amplitude of the scotopic ERG oscillatory potentials (OPs) was observed following PF-03463275 administration. The amplitude of the OPs was also negatively correlated to the concentration of PF-03463275 in the vitreous humor (r = -0.64, p < 0.0001). With the exception of a small increase in scotopic ERG a-wave amplitude and latency no effects were observed on other ERG parameters tested. CONCLUSIONS: We conclude that inhibition of the GlyT1 transporter in the retina causes ERG changes which may underlie recent reports of visual disturbance with GlyT1 inhibitors in clinical trials.
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Compuestos de Azabiciclo/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Imidazoles/farmacología , Retina/efectos de los fármacos , Animales , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/farmacocinética , Electrorretinografía/efectos de los fármacos , Imidazoles/sangre , Imidazoles/farmacocinética , Masculino , Estimulación Luminosa , Ratas Sprague-Dawley , Retina/fisiología , Cuerpo Vítreo/metabolismoRESUMEN
The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.
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Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Indoles/síntesis química , Piperidinas/síntesis química , Piranos/síntesis química , Agonistas del Receptor de Serotonina 5-HT4/síntesis química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/psicología , Animales , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Perros , Agonismo Parcial de Drogas , Células HEK293 , Haplorrinos , Humanos , Técnicas In Vitro , Indoles/farmacocinética , Indoles/farmacología , Células de Riñón Canino Madin Darby , Masculino , Microsomas Hepáticos/metabolismo , Permeabilidad , Piperidinas/farmacocinética , Piperidinas/farmacología , Isoformas de Proteínas/metabolismo , Piranos/farmacocinética , Piranos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/farmacocinética , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Previous work studying vegetarians has often found that they have lower blood pressure (BP). Reasons may include their lower BMI and higher intake levels of fruit and vegetables. Here we seek to extend this evidence in a geographically diverse population containing vegans, lacto-ovo vegetarians and omnivores. DESIGN: Data are analysed from a calibration sub-study of the Adventist Health Study-2 (AHS-2) cohort who attended clinics and provided validated FFQ. Criteria were established for vegan, lacto-ovo vegetarian, partial vegetarian and omnivorous dietary patterns. SETTING: Clinics were conducted at churches across the USA and Canada. Dietary data were gathered by mailed questionnaire. SUBJECTS: Five hundred white subjects representing the AHS-2 cohort. RESULTS: Covariate-adjusted regression analyses demonstrated that the vegan vegetarians had lower systolic and diastolic BP (mmHg) than omnivorous Adventists (ß = -6.8, P < 0.05 and ß = -6.9, P < 0.001). Findings for lacto-ovo vegetarians (ß = -9.1, P < 0.001 and ß = -5.8, P < 0.001) were similar. The vegetarians (mainly the vegans) were also less likely to be using antihypertensive medications. Defining hypertension as systolic BP > 139 mmHg or diastolic BP > 89 mmHg or use of antihypertensive medications, the odds ratio of hypertension compared with omnivores was 0.37 (95 % CI 0.19, 0.74), 0.57 (95 % CI 0.36, 0.92) and 0.92 (95 % CI 0.50, 1.70), respectively, for vegans, lacto-ovo vegetarians and partial vegetarians. Effects were reduced after adjustment for BMI. CONCLUSIONS: We conclude from this relatively large study that vegetarians, especially vegans, with otherwise diverse characteristics but stable diets, do have lower systolic and diastolic BP and less hypertension than omnivores. This is only partly due to their lower body mass.
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Presión Sanguínea/fisiología , Dieta Vegetariana , Dieta/estadística & datos numéricos , Conducta Alimentaria/fisiología , Hipertensión/epidemiología , Población Blanca/estadística & datos numéricos , Adulto , Anciano , Antihipertensivos/uso terapéutico , Índice de Masa Corporal , Canadá/epidemiología , Estudios de Cohortes , Femenino , Frutas , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Carne , Persona de Mediana Edad , Oportunidad Relativa , Estados Unidos/epidemiología , VerdurasRESUMEN
The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.
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Ciclobutanos/síntesis química , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos/síntesis química , Pirrolidinas/síntesis química , Receptores Histamínicos H3/metabolismo , Animales , Proteínas Sanguíneas/metabolismo , Barrera Hematoencefálica/metabolismo , Línea Celular , Ciclobutanos/farmacología , Ciclobutanos/toxicidad , Perros , Conducta de Ingestión de Líquido/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/toxicidad , Humanos , Técnicas In Vitro , Riñón/metabolismo , Lipidosis/inducido químicamente , Lipidosis/metabolismo , Pulmón/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Fosfolípidos/metabolismo , Unión Proteica , Pirrolidinas/farmacología , Pirrolidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Recent developments in health services in the local arena in Norway have challenged the theoretical and applied scientific basis for both public health medicine and management. During the 1990s although public health physicians in Norway increased in number, they worked less with public health, as well as public health management. The effects of these developments on public health management are largely unknown. We studied public health physicians' involvement in management and their self-reported managerial competence. METHODS: Cross-sectional study of physicians working in local public health medicine in all Norwegian municipalities, using a mail-back questionnaire. RESULTS: Public health physicians reduced their administrative tasks and evaluated their own managerial competence rather conservatively and somewhat lower in 1999 than in 1994. Many had supplementary training in management in addition to their medical education and specialty training. CONCLUSIONS: Public health physicians may be fading out of management. To address this there is a need for development of both public health management training programmes and provision of adequate resources for managerial activities.
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Médicos/provisión & distribución , Administración en Salud Pública , Estudios Transversales , Humanos , Noruega , Encuestas y CuestionariosRESUMEN
BACKGROUND: We have studied physicians' experience with and attitudes to interaction between health care levels, and their opinions on how this can be improved. MATERIAL AND METHODS: Three focus groups were established. They consisted of 15 male and 2 female physicians with 3 months to 28 years of experience. Interviews with the participants were transcribed and qualitatively analysed. RESULTS: Physicians had different opinions on which characteristics are important to establish a good professional interaction, and their opinions varied according to which health care level they represent. While GPs emphasised confidence, respect, knowledge of each other and accessibility, that is a relational perspective; the local hospital physicians put more emphasis on capacity, i.e. competence, stability and accessibility. Physicians at the central Hospital emphasized capacity and structure, i.e. their own and collaborators' professional interest, accessibility and formalised structures for interactions. A sense of personal knowledge and verbal and written contact was important, but guidelines and treatment plans were also considered to be important for interaction. There was a strong ownership to the individual patient across all three levels, which was an unexpected finding. CONCLUSIONS: Good interaction seems to be a balance between the relational perspective, with emphasis on dialogue, structural arrangements, accessibility and continuity and professional competence. In addition, there is a need to clarify responsibilities for each patient.
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Actitud del Personal de Salud , Relaciones Interprofesionales , Médicos/psicología , Competencia Clínica , Comunicación , Continuidad de la Atención al Paciente , Medicina Familiar y Comunitaria/organización & administración , Femenino , Grupos Focales , Accesibilidad a los Servicios de Salud , Administración Hospitalaria , Médicos Hospitalarios , Humanos , Entrevistas como Asunto , Masculino , Médicos de Familia/psicología , Médicos Mujeres/psicologíaRESUMEN
AIM: The object was to assess changes in work priorities in local public health medicine in Norway over the period from 1994 to 1999. METHODS: Two cross-sectional studies were undertaken of physicians working in local public health medicine in all Norwegian municipalities, using a postal questionnaire. RESULTS: Half of the physicians working in public health in 1999 were recruited after 1994. Although the number of physicians working in public health increased from 505 in 1994 to 555 in 1999 (10%) an estimation of the total weekly hours worked decreased by 3.7% from 8,715 hours in 1994 to 8,386 hours in 1999. The vast majority of physicians worked in combined posts (87%), and they reduced their engagement in public health by 2.6 hours on average from 1994 to 1999. The reduction depended on remuneration model, speciality in community medicine, and municipality size. CONCLUSIONS: Local public health in Norway was under pressure in the 1990s. For public health physicians, preventive medicine lost out to clinical work. No promising signals of change in the professional or political framework or in incentives for public health work are seen.