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PURPOSE: It has been proposed that biological/chemical substances in the intestine might play a role in the occurrence and deterioration of perianal fistulas. Elimination of such unidentified factors from the lower gastrointestinal tract might offer a new strategy for the management of anal fistulas. The aim of this study was to evaluate the clinical effects on non-Crohn's disease perianal fistula healing, and the safety and tolerability of a new medical device that applies high-purity, high-activity granular activated carbon locally into the rectum twice daily of patients with perianal fistulas without any concomitant medication. METHODS: An open, single-arm, prospective study with active treatment for 8 weeks and an optional follow-up until week 24 ( ClinicalTrial.gov identifier NCT01462747) among patients with chronic, uncomplicated perianal fistulas scheduled for surgery was conducted. RESULTS: Of 28 patients included, 10 patients (35.7%) showed complete fistula healing (closed, no discharge on palpation) after 8 weeks; seven of these patients, corresponding to 25% of the enrolled patients, remained in remission for up to 31 weeks. At week 8, there was a statistically significant reduction in the discharge visual analog scale (p = 0.04), a significant improvement in the patient-perceived quality of life for the category of embarrassment (p = 0.002), and a trend toward improvement in the other assessment categories. CONCLUSIONS: The treatment was well tolerated, and patient acceptance was high. The results support the efficacy and safety of locally administered activated carbon for the treatment of patients with chronic uncomplicated perianal fistulas not receiving any other medication for fistula problems.
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Carbón Orgánico/administración & dosificación , Carbón Orgánico/uso terapéutico , Equipos y Suministros/efectos adversos , Fístula Rectal/tratamiento farmacológico , Recto/efectos de los fármacos , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The aim of this study was to examine the relationship between measures of disease severity and costs from a societal perspective in patients with plaque psoriasis. Dermatologists in Sweden recruited 443 consecutive patients who had had no biological treatment during the past 12 months. Following a Psoriasis Area and Severity Index (PASI) assessment, subjects completed self-assessments on health status/quality of life and a healthcare resource utilization/work status questionnaire. The costs of healthcare resources and sick-leave due to plaque psoriasis were estimated and related to the subject's health status. A patient's Dermatology Life Quality Index (DLQI) and being on systemic therapy, or having diagnosis of psoriatic arthritis, appeared to be more strongly associated with direct and indirect costs than did their PASI. The cost of biological therapy should be considered from the perspective of the already high costs of patients with high DLQI undergoing traditional systemic treatment.
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Artritis Psoriásica/diagnóstico , Artritis Psoriásica/economía , Costos de la Atención en Salud , Recursos en Salud/economía , Calidad de Vida , Encuestas y Cuestionarios , Absentismo , Adulto , Anciano , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/psicología , Costo de Enfermedad , Análisis Costo-Beneficio , Costos de los Medicamentos , Femenino , Recursos en Salud/estadística & datos numéricos , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Ausencia por Enfermedad/economía , Suecia , Resultado del TratamientoRESUMEN
Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of over 400 billion EUR annually. Recent advances in diagnostics and approval for new pharmaceutical treatments for Alzheimer's disease (AD), the most common etiology of dementia, heralds the beginning of precision medicine in this field. However, their implementation will challenge an already over-burdened healthcare systems. There is a need for innovative digital solutions that can drive the related clinical pathways and optimize and personalize care delivery. Public-private partnerships are ideal vehicles to tackle these challenges. Here we describe the Innovative Health Initiative (IHI) public-private partnership project PROMINENT that has been initiated by connecting leading dementia researchers, medical professionals, dementia patients and their care partners with the latest innovative health technologies using a precision medicine based digital platform. The project builds upon the knowledge and already implemented digital tools from several collaborative initiatives that address new models for early detection, diagnosis, and monitoring of AD and other neurodegenerative disorders. The project aims to provide support to improvement efforts to each aspect of the care pathway including diagnosis, prognosis, treatment, and data collection for real world evidence and cost effectiveness studies. Ultimately the PROMINENT project is expected to lead to cost-effective care and improved health outcomes.
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OBJECTIVE: To characterize the impact of etanercept (ETN) in AS on cost, work productivity and quality of life (QoL). METHODS: A Phase 4, open-label, multi-centre (UK, Scandinavia) extension study in AS. Eligible subjects (n = 84) were treated for 36-52 weeks with ETN 50 mg s.c. once weekly. Analysis included direct costs (transformed out-patient and in-patient care elements), indirect costs (sick leave and lost working days), efficacy and QoL. RESULTS: Annualized direct and indirect costs decreased (55.5%, P ≤ 0.008) during ETN treatment, as did out-patient and in-patient episodes (physiotherapist/physician visits, P = 0.012). Work productivity and QoL increased. CONCLUSION: ETN therapy significantly reduces direct and indirect health-care costs and increases work ability and QoL in AS. Trial Registration. EUDRACT, https://eudract.ema.europa.eu/, 2006-001061-42.
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Antirreumáticos/administración & dosificación , Costos de la Atención en Salud , Inmunoglobulina G/administración & dosificación , Calidad de Vida , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Espondilitis Anquilosante/tratamiento farmacológico , Adulto , Anciano , Antirreumáticos/efectos adversos , Antirreumáticos/economía , Eficiencia , Empleo , Etanercept , Femenino , Humanos , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/economía , Masculino , Persona de Mediana Edad , Ausencia por Enfermedad/estadística & datos numéricos , Espondilitis Anquilosante/economía , Resultado del Tratamiento , Adulto JovenRESUMEN
Aims: To evaluate the cost-effectiveness of adding prolonged-release (PR)-fampridine to best supportive care (BSC) versus BSC alone for the improvement of walking ability in patients with MS.Methods: A cost-utility analysis based on a Markov model was developed to model responders and timed 25-foot walk (T25FW) scores, accumulated costs, and quality-adjusted life-years (QALY) in adults with MS and Expanded Disability Status Scale (EDSS) scores between 4 and 7. The analysis was conducted from a Swedish societal perspective.Results: In the base-case analysis, PR-fampridine plus BSC led to a higher QALY gain than BSC alone. The largest direct cost was professional care provision followed by hospital inpatient stays while the indirect cost was the loss of earnings due to days off work. The incremental cost-effectiveness ratio (ICER) for PR-fampridine plus BSC compared with BSC alone was 57,109 Swedish Kronor (kr)/QALY (5,607/QALY [1 kr = 0.0981762 on 8 April 2021] and $6,675/QALY [1 kr = $0.116890 on 8 April 2021]). All sensitivity analyses performed resulted in ICERs below 500,000 kr (49,088 and $58,445).Limitations: Resource use data were not specific to the Swedish market.Conclusions: PR-fampridine represents a cost-effective treatment for MS-related walking impairment in Sweden, due to improvements in patients' quality of life and reduced healthcare resource utilization.
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Esclerosis Múltiple , Caminata , Adulto , Análisis Costo-Beneficio , Humanos , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , SueciaRESUMEN
PURPOSE: Ileal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated. PATIENTS AND METHODS: In this phase 2, open-label, multicenter study, children received 10â200 µg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored. RESULTS: Twenty patients were enrolled (8 females; 1â17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n = 13; 3 re-entries), Alagille syndrome (n = 6), biliary atresia (n = 3), and other intrahepatic cholestasis causes (n = 2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26â564) and were reduced in the majority (-123.1 µmol/L; range, -394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 µg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0-10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0-10). Reduced pruritus correlated significantly with reduced serum bile acids (P ≤ 0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient. CONCLUSIONS: Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.
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Benzodiazepinas/uso terapéutico , Butiratos/uso terapéutico , Colestasis Intrahepática , Colestasis , Benzodiazepinas/efectos adversos , Ácidos y Sales Biliares , Butiratos/efectos adversos , Niño , Colestasis/complicaciones , Colestasis/tratamiento farmacológico , Colestasis Intrahepática/complicaciones , Colestasis Intrahepática/tratamiento farmacológico , Femenino , Humanos , Prurito/tratamiento farmacológico , Prurito/etiologíaRESUMEN
BACKGROUND: Spinal muscular atrophy is a rare neuromuscular disorder with a spectrum of severity related to age at onset and the number of SMN2 gene copies. Infantile-onset (≤ 6 months of age) is the most severe spinal muscular atrophy and is the leading monogenetic cause of infant mortality; patients with later-onset (> 6 months of age) spinal muscular atrophy can survive into adulthood. Nusinersen is a new treatment for spinal muscular atrophy. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of nusinersen for the treatment of patients with infantile-onset spinal muscular atrophy and later-onset spinal muscular atrophy in Sweden. METHODS: One Markov cohort health-state transition model was developed for each population. The infantile-onset and later-onset models were based on the efficacy results from the ENDEAR phase III trial and the CHERISH phase III trial, respectively. The cost effectiveness of nusinersen in both models was compared with standard of care in Sweden. RESULTS: For a time horizon of 40 years in the infantile-onset model and 80 years in the later-onset model, treatment with nusinersen resulted in 3.86 and 9.54 patient incremental quality-adjusted life-years and 0.02 and 2.39 caregiver incremental quality-adjusted life-years and an incremental cost of 21.9 and 38.0 million SEK (Swedish krona), respectively. These results translated into incremental cost-effectiveness ratios (including caregiver quality-adjusted life-years) of 5.64 million SEK (551,300) and 3.19 million SEK (311,800) per quality-adjusted life-year gained in the infantile-onset model and later-onset model, respectively. CONCLUSIONS: Treatment with nusinersen resulted in overall survival and quality-adjusted life-year benefits but with incremental costs above 21 million SEK (2 million) [mainly associated with maintenance treatment with nusinersen over a patient's lifespan]. Nusinersen was not cost effective when using a willingness-to-pay threshold of 2 million SEK (195,600), which has been considered in a recent discussion by the Dental and Pharmaceutical Benefits Agency as a reasonable threshold for rare disease. Nonetheless, nusinersen gained reimbursement in Sweden in 2017 for paediatric patients (below 18 years old) with spinal muscular atrophy type I-IIIa.
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Análisis Costo-Beneficio , Oligonucleótidos/uso terapéutico , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Preescolar , Femenino , Costos de la Atención en Salud , Humanos , Lactante , Masculino , Cadenas de Markov , Oligonucleótidos/efectos adversos , Oligonucleótidos/economía , Años de Vida Ajustados por Calidad de Vida , Atrofias Musculares Espinales de la Infancia/mortalidadRESUMEN
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. Physical exercise can result in transient elevations of liver function tests. There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. WHAT THIS STUDY ADDS: Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. Liver function tests are significantly increased for at least 7 days after weightlifting. It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. AIM: To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. METHODS: Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (gamma GT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10-12 days postexercise. RESULTS: Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, gamma GT and ALP remained within the normal range. CONCLUSION: The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.
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Pruebas Enzimáticas Clínicas/tendencias , Hígado/metabolismo , Hígado/patología , Músculo Esquelético/metabolismo , Levantamiento de Peso/fisiología , Adolescente , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Ejercicio Físico/fisiología , Humanos , Pruebas de Función Hepática/tendencias , Masculino , Persona de Mediana Edad , Factores de Tiempo , gamma-Glutamiltransferasa/sangreRESUMEN
OBJECTIVE: Constant exposure of pancreatic islets to high levels of glucose or free fatty acids can lead to irreversible beta-cell dysfunction, a process referred to as glucotoxicity or lipotoxicity, respectively. In this context a role for nitric oxide generated by pancreatic islet has been suggested. The present investigation examined whether the route of glucose administration, i.e., given orally (OG) or infused intravenously (IVG), could have any effect on the expression and activity of inducible nitric oxide synthase (iNOS) in pancreatic islets. METHODS: Rats were infused with glucose (50%) or Intralipid intravenously for 24 h or given glucose orally. A freely fed control group (FF) was also included. At 24 h rats were killed and blood samples were drawn for analysis of plasma insulin, glucagon, and glucose. Pancreatic islets were harvested from each animal and investigated for the occurrence of iNOS by the use of confocal microscopy, western blot, and high-performance liquid chromatographic analysis. The effect of intravenously infused glucose was then compared with the effect of an intravenous infusion of Intralipid (IL). RESULTS: Plasma insulin levels were markedly decreased after 24 h of infusion of glucose (IVG group) or Intralipid (IL group) compared with the FF or OG group. Plasma glucagon and glucose levels were markedly increased in the IVG group, whereas both parameters were decreased in the IL group. No significant differences in plasma insulin, glucagon, or glucose were found between the OG and FF groups. Immunocytochemical (confocal microscopy), western blot, and biochemical (high-performance liquid chromatographic) analyses showed that a sustained increase in plasma level of glucose or free fatty acids by an intravenous infusion of either nutrient for 24 h resulted in a marked expression and activity of iNOS in pancreatic islets. No sign of iNOS expression could, however, be detected in the islets of FF control or OG rats. CONCLUSION: The data suggest that impaired beta-cell function found after 24 h of an intravenous infusion of glucose or Intralipid might be mediated, at least in part, by the induction of iNOS in pancreatic islets. This may subsequently result in an exclusive production of nitric oxide, which is deleterious for beta-cells.
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Glucemia/análisis , Emulsiones Grasas Intravenosas/farmacología , Glucagón/sangre , Glucosa/farmacología , Islotes Pancreáticos/enzimología , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Administración Oral , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Inmunohistoquímica , Infusiones Intravenosas , Insulina/sangre , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Anal fistula is an abnormal tract with an external and internal opening that cause leakage, discomfort, and occasionally pain. Surgery is standard treatment, but recurrence and anal incontinence is common. The objective of the study was to analyze resource use, costs and sick leave for newly diagnosed patients with anal fistula in Sweden. METHODS: The study was based on register data from linkages between Swedish population-based registers including patients treated for anal fistula in Västra Götaland County, Sweden. Health care resource use, costs and sick leave were estimated. RESULTS: The sample included 362 patients of which 27% had no surgery, 37% had one surgery and 36% had multiple surgeries. Patients with multiple surgeries underwent over four surgeries on average. Approximately 67% of the contacts occurred during the first year after diagnosis. Estimated mean sick leave was 10.4 full-time equivalent days per patient. Total discounted costs were 5,561 per patient where approximately 80% were direct costs. DISCUSSION: To our knowledge this is the first study of resource use, costs and sick leave related to anal fistulas. The study indicates that anal fistula is a condition that is costly for society and that the burden of anal fistula in terms of health care resources and sick leave is especially high for patients experiencing multiple surgeries. CONCLUSION: Anal fistula is a condition that is costly for society and there is an unmet need for the group of patients with multiple surgeries to find appropriate treatment interventions.
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Costos de la Atención en Salud/estadística & datos numéricos , Fístula Rectal/economía , Fístula Rectal/terapia , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Ausencia por Enfermedad , Suecia/epidemiologíaRESUMEN
In view of our previous data, showing that ghrelin and nitric oxide (NO) display apparently parallel effects on insulin secretion (inhibitory) and glucagon secretion (stimulatory), we have now investigated the effect of ghrelin on islet hormone secretion in relation to its effect on NO synthase (NOS) isoenzymes in isolated rat pancreatic islets. Dose-response studies revealed that ghrelin at concentrations of 0.01-1 micromol l-1 inhibited insulin secretion stimulated by 8.3 mmol l-1 glucose, while ghrelin at concentrations lower than the physiological range (0.01 pmol l-1 to 1 nmol l-1) were without effect. In contrast, glucagon secretion was stimulated by 1.0 nmol l-1 to 1 micromol l-1 ghrelin. These effects of ghrelin on insulin and glucagon secretion were accompanied by increased NO production through activation of neuronal constitutive NOS (ncNOS). Ghrelin had no appreciable effect on the activity of inducible NOS (iNOS) in the islets. Addition of an NO scavenger (cPTIO) or the NOS inhibitor L-NAME to the incubation medium prevented the effects of ghrelin on hormone secretion from isolated islets. The present results confirm our previous data showing that ghrelin inhibits insulin and stimulates glucagon secretion from pancreatic islets of the mouse and we now show similar effects in rat islets. The effects of ghrelin were accompanied by an increased rate of NO production. Conceivably, ncNOS activation partly accounts for to the inhibitory effect of ghrelin on insulin secretion and the stimulatory effect of ghrelin on glucagon secretion.
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Islotes Pancreáticos/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico Sintasa/metabolismo , Hormonas Peptídicas/farmacología , Animales , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Femenino , Ghrelina , Glucagón/metabolismo , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/enzimología , Islotes Pancreáticos/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Ghrelin derives from endocrine cells (A-like cells) in the stomach (mainly the oxyntic mucosa). Its concentration in the circulation increases during fasting and decreases upon re-feeding. This has fostered the notion that the absence of food in the upper gastrointestinal (GI) tract stimulates the secretion of ghrelin. The purpose of the present study was to determine the concentration of ghrelin in serum and oxyntic mucosa after replacing food with intravenous (iv) infusion of nutrients for 8 days using the technique known as total parenteral nutrition (TPN) MATERIALS AND METHODS: Male Sprague-Dawley rats (200-250 g) were given nutrients (lipids, glucose, amino acids, minerals and vitamins) by iv infusion for 8 days during which time they were deprived of food and water; another group was deprived of food for 24-48 h (fasted controls), while fed controls had free access to food and water. Serum ghrelin, gastrin and pancreastatin concentrations were measured together with the ghrelin content of the oxyntic mucosa. Plasma insulin and glucose as well as serum lipid concentrations were also determined. RESULTS: Fasted rats had higher serum ghrelin than TPN rats and fed controls. The oxyntic mucosal ghrelin concentration (and content) was lower in TPN rats than in fasted rats or fed controls. The serum gastrin and pancreastatin concentrations were lower in TPN rats and fasted rats than in fed controls. The plasma insulin concentration was 87 pmol/l+/-8 (SEM) in TPN rats compared to 101+/-16 pmol/l in fed controls; it was 26+/-14 pmol/l in fasted rats. The basal plasma glucose level was 11+/-0.6 mmol/l in TPN rats and 12+/-0.8 mmol/l in fed controls; it was 7+/-0.3 mmol/l in fasted rats. In TPN rats, the serum concentrations of free fatty acids, triglycerides and cholesterol were increased by 100%, 50% and 25%, respectively, compared to fed controls. Fasted rats had higher circulating concentrations of free fatty acids (20%) and lower concentrations of triglycerides (-40%) than fed controls; fasted rats did not differ from fed controls with respect to serum cholesterol. CONCLUSION: The circulating ghrelin concentration is high in situations of nutritional deficiency (starvation) and low in situations of nutritional plenty (free access to food or TPN). The actual presence or absence of food in the GI tract seems irrelevant. Circulating insulin and glucose concentrations did not differ much between TPN rats and fed controls; serum lipids, however, were elevated in the TPN rats. We suggest that elevated blood lipid levels contribute to the suppression of circulating ghrelin in rats subjected to TPN for 8 days.
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Privación de Alimentos , Nutrición Parenteral Total , Hormonas Peptídicas/sangre , Animales , Glucemia/metabolismo , Cromogranina A , Dieta , Ayuno , Mucosa Gástrica/anatomía & histología , Mucosa Gástrica/metabolismo , Gastrinas/sangre , Ghrelina , Insulina/sangre , Lípidos/sangre , Masculino , Tamaño de los Órganos , Hormonas Pancreáticas/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
The role of PACAP27, PACAP38 and VIP in the regulation of insulin release from pancreatic islets isolated from rats previously subjected to total parenteral nutrition (TPN) for 10 days was studied. Glucose-stimulated insulin secretion from islets of TPN rats was attenuated in parallel with cyclic AMP production. Immunocytochemistry showed an increased number of VIP-immunoreactive nerve fibers in the pancreatic islets of TPN rats. PACAP27, PACAP38 and VIP dose dependently and to the same magnitude potentiated insulin secretion from the islets of freely fed controls in the presence of a substimulatory glucose concentration (8.3 mmol/l). The secretory response of islets from TPN-treated rats to these neuropeptides was, however, markedly exaggerated compared to the controls. The insulin response of islets from TPN-treated rats to PACAP27 and PACAP38 was much greater than to VIP. With respect to insulin secretion, TPN treatment shifted the PACAP27 and PACAP38 dose-response curve to the left by two orders of magnitude. In the presence of 8.3 mmol/l glucose, cAMP accumulation was slightly higher in islets from TPN rats and the PACAP27, PACAP38 and VIP-stimulated increase in the cAMP production was markedly greater compared to the controls. Additional complementary in vivo experiments showed that PACAP27 normalized the defective glucose-stimulated insulin secretory response of TPN-treated rats. The data suggest that the defective nutrient-stimulated insulin secretion seen after long-term TPN treatment could be normalized by agents stimulating cAMP production possibly through cAMP/PK A-pathway.
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Insulina/metabolismo , Neuropéptidos/fisiología , Animales , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Glucosa/metabolismo , Inmunohistoquímica , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Masculino , Neuronas/metabolismo , Neuropéptidos/metabolismo , Nutrición Parenteral , Péptidos/química , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.
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Aberraciones Cromosómicas , Neoplasias del Colon/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Predisposición Genética a la Enfermedad/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras , Neoplasias del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Análisis Mutacional de ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Femenino , Citometría de Flujo , Heterogeneidad Genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Repeticiones de Microsatélite , Homólogo 1 de la Proteína MutL , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares , Ploidias , Células Tumorales CultivadasRESUMEN
The major aim of this study was to investigate the CYP3A4 metabolism and polarized transport of ropivacaine and its metabolite 2',6'-pipecoloxylidide (PPX) in tissue specimens from the human small and large intestine. Ropivacaine has been shown to be effective in the treatment of ulcerative colitis in human colon. This study was conducted using a modified Ussing-chamber technique with specimens from jejunum, ileum and colon collected from 11 patients. The local kinetics of ropivacaine and PPX were assessed from their concentration-time profiles in mucosal and serosal compartments. The permeability (P(app)) in the absorptive direction for both ropivacaine and PPX increased regionally in the order jejunum < ileum < colon. Ropivacaine was not found to be subjected to any carrier-mediated intestinal efflux. However, the CYP3A4 metabolite left the human enterocyte in a polarized manner and both the extent of CYP3A4 metabolism of ropivacaine and the extrusion of its metabolite to the mucosal chamber were more efficient in jejunum than in ileum. P-glycoprotein was probably not involved in the metabolite extrusion. No other metabolite than PPX was found. This in-vitro study with human intestinal tissues provides new mechanistic insights into regional transport and metabolism of drugs.
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Amidas/farmacocinética , Anestésicos Locales/farmacocinética , Bupivacaína/análogos & derivados , Bupivacaína/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Mucosa Intestinal/metabolismo , Amidas/metabolismo , Anestésicos Locales/metabolismo , Transporte Biológico Activo , Bupivacaína/metabolismo , Colon/metabolismo , Citocromo P-450 CYP3A , Femenino , Humanos , Íleon/metabolismo , Técnicas In Vitro , Absorción Intestinal , Yeyuno/metabolismo , Masculino , Permeabilidad , RopivacaínaRESUMEN
OBJECTIVES: Celecoxib for the treatment of pain resulting from osteoarthritis (OA) was reviewed by the Tandvårds- och läkemedelsförmånsverket-Dental and Pharmaceutical Benefits Board (TLV) in Sweden in late 2010. This study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus a PPI in a Swedish setting. METHODS: The National Institute for Health and Care Excellence (NICE) in the UK developed a health economic model as part of their 2008 assessment of treatments for OA. In this analysis, the model was reconstructed and adapted to a Swedish perspective. Drug costs were updated using the TLV database. Adverse event costs were calculated using the regional price list of Southern Sweden and the standard treatment guidelines from the county council of Stockholm. Costs for treating cardiovascular (CV) events were taken from the Swedish DRG codes and the literature. RESULTS: Over a patient's lifetime treatment with celecoxib plus a PPI was associated with a quality-adjusted life year (QALY) gain of 0.006 per patient when compared to diclofenac plus a PPI. There was an increase in discounted costs of 529 kr per patient, which resulted in an incremental cost-effectiveness ratio (ICER) of 82,313 kr ($12,141). Sensitivity analysis showed that treatment was more cost effective in patients with an increased risk of bleeding or gastrointestinal (GI) complications. CONCLUSIONS: The results suggest that celecoxib plus a PPI is a cost effective treatment for OA when compared to diclofenac plus a PPI. Treatment is shown to be more cost effective in Sweden for patients with a high risk of bleeding or GI complications. It was in this population that the TLV gave a positive recommendation. There are known limitations on efficacy in the original NICE model.
Asunto(s)
Diclofenaco/economía , Diclofenaco/uso terapéutico , Osteoartritis/tratamiento farmacológico , Pirazoles/economía , Pirazoles/uso terapéutico , Sulfonamidas/economía , Sulfonamidas/uso terapéutico , Antiinflamatorios no Esteroideos/economía , Antiinflamatorios no Esteroideos/uso terapéutico , Celecoxib , Análisis Costo-Beneficio , Inhibidores de la Ciclooxigenasa 2/economía , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Diclofenaco/administración & dosificación , Diclofenaco/efectos adversos , Quimioterapia Combinada , Humanos , Cadenas de Markov , Modelos Económicos , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/economía , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Años de Vida Ajustados por Calidad de Vida , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , SueciaRESUMEN
BACKGROUND: In late 2007, some Swedish County Councils started 7-valent pneumococcal conjugate vaccine (PCV7) implementation for children, and PCV7 was included in the national immunization program in 2009. By 2010, both PCV10 and PCV13 were licensed, and the selection of vaccine was subject to County Councils tenders. This study investigated the impact of the order of PCV introduction into vaccination programs on the incidence of all-cause pneumonia hospitalizations in children <2 years-old. METHODS: Using population-based data from the publicly available National Inpatient Registry, the incidence of inpatient pneumonia (ICD-10 J12-J18) hospitalizations by County Councils among children <2 years old was identified between 1998 and 2012. Incidence rate ratios (IRR; 95% CI) were calculated during the nationwide implementation of PCV7 and then between County Councils, as based on the higher-valent vaccine chosen for a program. RESULTS: There was a lower risk of all-cause pneumonia hospitalization among <2 year-old children following the introduction of PCV7, as compared to the pre-PCV7 period (0.77; 0.63-0.93). A decreased risk of all-cause pneumonia was also observed in the County Councils that followed the order PCV7 then PCV13 (0.82; 0.66-1.01), while no trend was observed in County Councils with a program in the order PCV7 then PCV10 (1.03; 0.82-1.30). When comparing the higher-valent vaccines, there was a 21% (0.79; 0.66-0.96) lower risk for childhood pneumonia hospitalization in County Councils finally using PCV13 as compared to the experience in County Councils that ultimately adopted PCV10. CONCLUSIONS: Among children <2 years-old, all-cause pneumonia hospitalizations were significantly reduced by 23% one to two years after introduction of PCV7 vaccination in Sweden. In those County Councils that next introduced PCV13, a further decline in all-cause pneumonia hospitalization was observed, in contrast to those County Councils that followed with PCV10; this 21% lower risk for childhood pneumonia hospitalization was statistically significant.
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Vacuna Neumocócica Conjugada Heptavalente/uso terapéutico , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/uso terapéutico , Neumonía/epidemiología , Neumonía/prevención & control , Hospitalización/estadística & datos numéricos , Humanos , Programas de Inmunización , Incidencia , Lactante , Suecia/epidemiologíaRESUMEN
BACKGROUND: The introduction of a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) had profound public health effects across the globe. PCV7 vaccination in a national immunization program is generally considered cost-effective and potentially cost-saving. Two new PCVs have been launched, a 10-valent pneumococcal conjugate vaccine (PCV10) and a 13-valent pneumococcal conjugate vaccine (PCV13). OBJECTIVE: This article examines the public health and economic effects of pediatric national immunization programs of PCV10 and PCV13 in Denmark and Sweden. METHODS: A previously published decision-analytic model was used to estimate the impact of PCV10 and PCV13 on reducing cases of invasive pneumococcal disease (IPD), pneumonia (PNE), and acute otitis media (AOM) by using country-specific incidence, serotype coverage, disease sequelae, mortality, vaccine effectiveness, indirect effects, costs, and utilities. Direct effects for PCV13- and PCV10-covered serotypes were assumed similar to PCV7. PCV13 was assumed to confer an indirect effect, similar to PCV7, whereas PCV10 was not. Assumptions were tested in sensitivity analyses. RESULTS: PCV13 is expected to save 280.7 million DKK (Danish kroner) in Denmark and 288.2 million SEK (Swedish kronor) in Sweden in direct costs compared with a vaccination program with PCV10. In both Denmark and Sweden, the results of this study indicate that, compared with PCV10, PCV13 will have a greater impact on disease in life-years gained (LYG), quality-adjusted life-years (QALYs) gained, IPD cases avoided, PNE cases avoided, AOM cases avoided, and in deaths avoided. For Denmark PCV13, it was estimated to result in 10,051 LYG; 9063 QALYs gained; 237 additional IPD cases avoided; 12,094 additional PNE cases avoided; 958 additional cases of AOM avoided; and 882 additional deaths avoided. For Sweden PCV13, it was estimated to result in 4245 LYG; 3953 QALYs gained; 379 additional IPD cases avoided; 8210 additional PNE cases avoided; 1459 additional cases of AOM avoided; and 378 additional deaths avoided. In all sensitivity analyses, PCV13 was less costly and more effective compared with PCV10. CONCLUSIONS: In this analysis, a national immunization program with PCV13 was found to be good value for money and estimated to prevent additional cases of disease among children and nonvaccinated individuals and save additional costs due to treatment of pneumococcal disease, when compared with PCV10 in Denmark and Sweden.
Asunto(s)
Programas de Inmunización/economía , Otitis Media/prevención & control , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/administración & dosificación , Vacunas Neumococicas/economía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Dinamarca , Vacuna Neumocócica Conjugada Heptavalente , Humanos , Incidencia , Esperanza de Vida , Persona de Mediana Edad , Modelos Econométricos , Otitis Media/economía , Otitis Media/epidemiología , Infecciones Neumocócicas/economía , Infecciones Neumocócicas/epidemiología , Neumonía Neumocócica/economía , Neumonía Neumocócica/epidemiología , Neumonía Neumocócica/prevención & control , Prevalencia , Años de Vida Ajustados por Calidad de Vida , Suecia , Vacunas Conjugadas , Adulto JovenRESUMEN
OBJECTIVE: To estimate the cost-effectiveness, from a Swedish societal perspective, of intermittent use of etanercept (Enbrel) with interruptions of use after 24 weeks compared to continuous use of adalimumab (Humira) as well as non-systemic standard of care in patients with moderate to severe psoriasis. METHODS: A Markov decision-tree model was constructed from clinical trials results. Patients starting etanercept, adalimumab, or non-systemic therapy moved through the model's 10-years horizon. Model input parameters included clinical response rates. Outcome measures included direct and indirect costs and quality-adjusted life-years (QALYs). RESULTS: The incremental total (direct and indirect) costs per QALY were 1,559,939 kr (