RESUMO
BACKGROUND: Pediatric migraine prophylaxis is indicated when headaches are frequent and/or disabling. We aimed to conduct a study to compare the efficacy of cinnarizine and amitriptyline in pediatric migraine prophylaxis. METHODS: In a randomized, double-blind trial, patients aged 4-17 years with migraine who were eligible for prophylaxis enrolled. The primary outcome was a reduction response rate of ≥50% with p < 0.005 with respect to headache characteristics. The secondary outcome was migraine disability assessment. We evaluated patients every four weeks for three months: T1: week 4, T2: week 8 and T3: week 12. The safety profile was also assessed. RESULTS: Thirty patients were randomly assigned to each group. However, 43 patients completed the trial. Headache frequency decreased in amitriptyline group more effectively in T1 (p = 0.004). Amitriptyline was more successful in reducing the headache duration in all three periods (p < 0.005). There was no significant difference in severity improvement and reducing disability score between the two groups (p > 0.005). No serious adverse events were observed. CONCLUSIONS: Both medications are effective in ameliorating migraine headaches and related disabilities. However, amitriptyline appears be a preferable option over cinnarizine, given its faster onset of action, efficacy in reducing headache duration and longer-lasting effects.Trial Registration: The study was registered with the Iranian Registry of Clinical Trials (IRCT) under the code IRCT-20191112045413N1.
Assuntos
Cinarizina , Transtornos de Enxaqueca , Humanos , Criança , Cinarizina/uso terapêutico , Amitriptilina/uso terapêutico , Irã (Geográfico) , Resultado do Tratamento , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Transtornos de Enxaqueca/induzido quimicamente , Cefaleia/tratamento farmacológico , Analgésicos/uso terapêutico , Método Duplo-CegoRESUMO
BACKGROUND: In 2014, infliximab (IFX) was listed on the Australian Pharmaceutical Benefits Scheme for acute severe ulcerative colitis (ASUC) and is now the preferred option for medical salvage, superseding cyclosporin A (CsA). Optimal dosing schedules for IFX remain unknown. AIM: The authors aim to evaluate the effect of changing from predominantly CsA to almost exclusively IFX for the treatment of steroid-refractory ASUC on colectomy rates. METHODS: A retrospective review was performed of patients admitted with ASUC between 2012 and 2020. Patients were categorised into two groups according to year of presentation - either 'historical treatment' cohort (2012-2014), when CsA was primarily used, or 'contemporary treatment' cohort (2014-2020), when IFX was mostly prescribed, in either standard or intensive doses. RESULTS: One hundred thirty-nine patients were included; 37 in the historical treatment cohort and 102 in the contemporary treatment cohort. In the historical treatment cohort, 12 of 37 received salvage therapy and eight (67%) received CsA. In the contemporary treatment cohort, 49 of 102 patients received salvage therapy, 40 (82%) with IFX, of whom 22 (53%) received intensified doses. Colectomy rates were similar at 30 days, 6 months and 12 months between historical and contemporary treatment cohorts (14% vs 12% [P = 0.77], 19% vs 18% [P > 0.99],and 22% vs 18% [P = 0.63], respectively). Difference in 12-month colectomy rates between standard versus intensive IFX did not meet statistical significance (three of 21 [14%] vs nine of 22 [41%]. respectively; P = 0.09). CONCLUSION: There was no difference in 30-day, 6-month or 12-month colectomy rates between the historical treatment and contemporary treatment cohorts. The use of IFX, rather than CsA, even at intensified dosing, does not appear to reduce the colectomy rate observed in our patients.
Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/cirurgia , Austrália , Infliximab/uso terapêutico , Ciclosporina/uso terapêutico , Estudos Retrospectivos , Colectomia , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Headaches are common in children and adolescents. Treatments for debilitating migraine are often not FDA approved or lack evidence of efficacy for children. This narrative review looks at the evidence for acute and preventative pharmacologic and non-pharmacologic treatment of pediatric migraine, as well as reviewing any recent or ongoing clinical trials. RECENT FINDINGS: Studies have been published on pharmacological treatments for headache, as well as non-pharmacological treatments. Recent findings in pediatric migraine using onabotulinumtoxinA, calcitonin gene related peptide antagonists, interventional procedures, and devices are reviewed. Pharmacologic as well as non-pharmacologic approaches for the prevention and treatment of migraine show safety and efficacy data that is promising. These treatments should be incorporated in a multi-modal approach to the management of pediatric migraine. Continued studies, prospective and randomized, are needed to further assess these newer treatments for migraine in the pediatric setting.
Assuntos
Transtornos de Enxaqueca , Adolescente , Humanos , Criança , Estudos Prospectivos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , CefaleiaRESUMO
BACKGROUND AND AIMS: Alcoholic hepatitis is a common condition with high mortality. This study aimed to firstly describe the presentation, treatment, and short- and long-term outcomes of an Australian cohort of patients admitted to hospital with alcoholic hepatitis and secondly to validate existing prognostic models. METHODS: This is a retrospective study of consecutive patients admitted with alcoholic hepatitis to a major academic liver center in Melbourne, Australia, between January 1, 2010, and December 31, 2019. Cases were identified through appropriate International Classification of Diseases version 10 coding as well as review of non-coded patients with compatible biochemistry. Baseline demographic data, alcohol consumption, laboratory values, treatment, and outcomes at 30 days, 90 days, and 12 months post-diagnosis were collected from electronic medical records. Mortality data were extracted from an independent state government death registry. RESULTS: In total, 126 patients (72 males [57%], median age 51 years) were included in the final analysis. Ninety-five (75%) were cirrhotic at diagnosis, 81 (64%) met criteria for severe alcoholic hepatitis, and 41 (33%) had an infection during their index admission. 54% of eligible patients were treated with corticosteroids. 30-day and 12-month mortality rates were 8.7% and 27.1%, respectively, with hepatic encephalopathy (hazard ratio 5.45) and neutrophil-to-lymphocyte ratio (hazard ratio 1.09) independent markers for 12-month mortality on Cox regression analysis. Glasgow alcoholic hepatitis score outperformed other major prognostic models for short-term mortality. CONCLUSIONS: The 12-month mortality rate of 27% following alcoholic hepatitis is lower than previously reported studies, with hepatic encephalopathy and neutrophil-to-lymphocyte ratio predictive of long-term outcome.
Assuntos
Encefalopatia Hepática , Hepatite Alcoólica , Austrália/epidemiologia , Feminino , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate. AIMS: To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success. METHODS: Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as 'successes' if remaining on reduced anti-TNF or 'failures' if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12 months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly. RESULTS: Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12 months post-de-escalation. Median time to failure was 6 months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6 months (3.1 vs. 4.6, p = 0.95) and 12 months (3.2 vs. 4.5, p = 0.58) post-de-escalation. CONCLUSION: Nearly two-thirds of patients remained on reduced anti-TNF dosing 12 months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.
Assuntos
Adalimumab , Colite Ulcerativa , Doença de Crohn , Monitoramento de Medicamentos , Infliximab , Adalimumab/administração & dosagem , Adalimumab/imunologia , Adulto , Biomarcadores/análise , Proteína C-Reativa/análise , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Relação Dose-Resposta Imunológica , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Redução da Medicação/métodos , Redução da Medicação/estatística & dados numéricos , Duração da Terapia , Feminino , Humanos , Infliximab/administração & dosagem , Infliximab/imunologia , Masculino , Recidiva , Indução de Remissão/métodos , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/imunologiaRESUMO
The thiazide-sensitive sodium-chloride-cotransporter (NCC) in the kidney distal convoluted tubule (DCT) plays an essential role in sodium and potassium homeostasis. Here, we demonstrate that NCC activity is increased by the ß2-adrenoceptor agonist salbutamol, a drug prevalently used to treat asthma. Relative to ß1-adrenergic receptors, the ß2-adrenergic receptors were greatly enriched in mouse DCT cells. In mice, administration of salbutamol increased NCC phosphorylation (indicating increased activity) within 30 minutes but also caused hypokalemia, which also increases NCC phosphorylation. In ex vivo kidney slices and isolated tubules, salbutamol increased NCC phosphorylation in the pharmacologically relevant range of 0.01-10 µM, an effect observed after 15 minutes and maintained at 60 minutes. Inhibition of the inwardly rectifying potassium channel (Kir) 4.1 or the downstream with-no-lysine kinases (WNKs) and STE20/SPS1-related proline alanine-rich kinase (SPAK) pathway greatly attenuated, but did not prevent, salbutamol-induced NCC phosphorylation. Salbutamol increased cAMP in tubules, kidney slices and mpkDCT cells (model of DCT). Phosphoproteomics indicated that protein phosphatase 1 (PP1) was a key upstream regulator of salbutamol effects. A role for PP1 and the PP1 inhibitor 1 (I1) was confirmed in tubules using inhibitors of PP1 or kidney slices from I1 knockout mice. On normal and high salt diets, salbutamol infusion increased systolic blood pressure, but this increase was normalized by thiazide suggesting a role for NCC. Thus, ß2-adrenergic receptor signaling modulates NCC activity via I1/PP1 and WNK-dependent pathways, and chronic salbutamol administration may be a risk factor for hypertension.
Assuntos
Albuterol , Simportadores de Cloreto de Sódio , Agonistas Adrenérgicos/metabolismo , Albuterol/metabolismo , Albuterol/farmacologia , Animais , Pressão Sanguínea , Túbulos Renais Distais/metabolismo , Camundongos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Simportadores de Cloreto de Sódio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismoRESUMO
PURPOSE OF REVIEW: Headache disorders in children and adolescents are common. Among the different headache disorders, migraine and tension headache are highly prevalent and often debilitating. Pharmacological treatments for pediatric patients are often not approved or effective. Practice guidelines for prevention of pediatric headache and migraine are now incorporating information and recommendations regarding non-pharmacologic therapeutic options. Understanding the mechanism of action, safety, and efficacy of the non-pharmacologic as well as mindful-based therapeutic alternatives currently available for the management and treatment of headache and migraine may allow additional treatment alternatives for children with these conditions. RECENT FINDINGS: Studies have been published looking at non-pharmacologic treatments, and mindful-based approaches, namely relaxation, mindfulness meditation, yoga, and hypnosis as options for the treatment of headache and migraine, although there are few that examine these in children and adolescents. Several recent studies that have relevance to the care of children with headache and migraine are reviewed. Non-pharmacologic and mindful-based approaches for the prevention and treatment of headache and migraine in children show safety and efficacy data that is promising. Consider incorporating these multi-modal approaches into the therapeutic management strategies for the child or adolescent with headache and migraine. Additional prospective studies and/or randomized-controlled trials are necessary to further assess the efficacy and cost-effectiveness of these methods.
Assuntos
Transtornos de Enxaqueca , Atenção Plena , Cefaleia do Tipo Tensional , Adolescente , Criança , Cefaleia/terapia , Humanos , Transtornos de Enxaqueca/terapia , Estudos ProspectivosRESUMO
INTRODUCTION: Bloating is a common yet poorly managed complaint among healthy people, with a complex etiology that impacts health and general well-being. The study intended to evaluate the efficacy and safety of supplementation with a probiotic, Bacillus subtilis MB40 (MB40), on bloating, abdominal discomfort, and gas in healthy participants. METHODS: In this multi-center, double-blind, placebo-controlled, parallel trial, 100 participants were randomized to receive either MB40 at 5 × 109 colony forming units (CFU; n = 50) or a placebo (n = 50) once daily for 4-weeks. Participants completed 3 questionnaires daily: a modified Abdominal Discomfort, Gas, and Bloating (mADGB) questionnaire, a modified Gastrointestinal Symptoms Rating Scale (mGSRS), and a Bowel Habits Diary (BHD). Participants' responses to each question were combined into weekly averages. RESULTS: At the end of 4-weeks, there were no significant differences in average weekly change in daily bloating intensity, number of days with and duration of bloating, abdominal discomfort and gas between MB40 and placebo groups. However, the male sub-group on MB40 achieved clinical thresholds with a greater decrease over placebo in the intensity of (1.38) and number of days with (1.32) bloating, the number of days (1.06) and duration (86-minutes) of gas, the number of days with abdominal discomfort (1.32) and diarrhea symptom score (1.02). Role limitation (physical; P = .026), vitality (P = .034) and social functioning (P = .037) were significantly improved from baseline to week 4 in the MB40 group. At 2-weeks, physical functioning (P = .017) significantly improved in the MB40 group versus placebo. CONCLUSIONS: Although MB40 supplementation did not significantly improve bloating across all populations, the male sub-group demonstrated clinically significant reductions in bloating intensity, number of days with abdominal discomfort, gas, bloating, and duration of gas, compared to placebo. Additionally, the male sub-group receiving MB40 had a 10% improvement in general health score. MB40 supplementation at a dose of 5 × 109 CFU daily for 4-weeks was also safe and well-tolerated as all biometric, vital, and hematological measures remained within normal laboratory ranges (Clinical Trials NCT02950012).
Assuntos
Bacillus subtilis , Probióticos , Dor Abdominal/tratamento farmacológico , Método Duplo-Cego , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Histological and epidemiological data suggest that increased signal intensity at the proximal patellar tendon on magnetic resonance imaging is a response to tendon loading. As patellofemoral geometry is a mediator of loading, we examined the association between patellofemoral geometry and the prevalence of increased signal intensity at the patellar tendon in community-based middle-aged adults. METHODS: Two hundred-one adults aged 25-60 years in a study of obesity and musculoskeletal health had the patellar tendon assessed from magnetic resonance imaging. Increased signal intensity at the proximal patellar tendon was defined as hyper-intense regions of characteristic pattern, size and distribution on both T1- and T2-weighted sequences. Indices of patellofemoral geometry, including Insall-Salvati ratio, patellofemoral congruence angle, sulcus angle, and lateral condyle-patella angle, were measured from magnetic resonance imaging using validated methods. Binary logistic regression was used to examine the association between patellofemoral geometrical indices and the prevalence of increased signal intensity at the patellar tendon. RESULTS: The prevalence of increased signal intensity at the patellar tendon was 37.3%. A greater Insall-Salvati ratio (odds ratio 0.80, 95% confidence interval 0.66-0.97 per 0.1 change in the ratio, p = 0.02), indicative of a higher-riding patella, and a larger patellofemoral congruence angle (odds ratio 0.91, 95% confidence interval 0.85-0.98 per 5 degree change in the angle, p = 0.01), indicating a more laterally placed patella, were associated with reduced odds of increased signal intensity at the patellar tendon. Sulcus angle and lateral condyle-patella angle were not significantly associated with the odds of increased signal intensity at the patellar tendon. CONCLUSIONS: In community-based asymptomatic middle-aged adults, increased signal intensity at the patellar tendon was common and associated with Insall-Salvati ratio and patellofemoral congruence angle, suggesting a biomechanical mechanism. Such work is likely to inform tissue engineering and cell regeneration approaches to improving outcomes in those with tendon pathology.
Assuntos
Ligamento Patelar , Articulação Patelofemoral , Estudos Transversais , Imageamento por Ressonância Magnética , Patela , Ligamento Patelar/diagnóstico por imagem , Articulação Patelofemoral/diagnóstico por imagemRESUMO
OBJECTIVE:: To question the status of the randomised controlled trial (RCT) in the hierarchy of evidence. CONCLUSIONS:: The RCT provides important and clinically relevant information, particularly in psychopharmacology. However, and as with other methodologies, RCTs too are flawed and automatic abdication to their conclusions, especially in complex social interventions, is unwise. A clinical example with conflicting and polarising views, each with their evidence base, is described alongside a suggested clinical strategy for resolving differences of opinion.
Assuntos
Transtornos Mentais/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Humanos , Metanálise como AssuntoRESUMO
Cardiovascular disease is the world's leading cause of morbidity and mortality, with high blood pressure (BP) contributing to increased severity and number of adverse outcomes. Plasma membrane calcium ATPase 4 (PMCA4) has been previously shown to modulate systemic BP. However, published data are conflicting, with both overexpression and inhibition of PMCA4 in vivo shown to increase arterial contractility. Hence, our objective was to determine the role of PMCA4 in the regulation of BP and to further understand how PMCA4 functionally regulates BP using a novel specific inhibitor to PMCA4, aurintricarboxylic acid (ATA). Our approach assessed conscious BP and contractility of resistance arteries from PMCA4 global knockout (PMCA4KO) mice compared to wild-type animals. Global ablation of PMCA4 had no significant effect on BP, arterial structure or isolated arterial contractility. ATA treatment significantly reduced BP and arterial contractility in wild-type mice but had no significant effect in PMCA4KO mice. The effect of ATAin vivo and ex vivo was abolished by the neuronal nitric oxide synthase (nNOS) inhibitor Vinyl-l-NIO. Thus, this highlights differences in the effects of PMCA4 ablation and acute inhibition on the vasculature. Importantly, for doses here used, we show the vascular effects of ATA to be specific for PMCA4 and that ATA may be a further experimental tool for elucidating the role of PMCA4.
Assuntos
Pressão Sanguínea , Artérias Mesentéricas/fisiopatologia , Óxido Nítrico Sintase Tipo I/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/antagonistas & inibidores , Animais , Ácido Aurintricarboxílico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Estado de Consciência , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Camundongos Knockout , Modelos Biológicos , Peptídeos/farmacologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismoRESUMO
PURPOSE OF REVIEW: Episodic migraine is very common in children and adolescents, seen by primary care and specialists. In kids, this can greatly affect quality of life, including significant disability, specifically in terms of missed school and other activities. The goal of this paper is to give an overview of the most up-to-date thoughts on episodic migraine in the pediatric population. RECENT FINDINGS: Current options for both abortive and preventative treatments in kids, as well as specific non-pharmacological and lifestyle management recommendations for children, will be reviewed, as well as options for status migrainosus in the pediatric patient. Migraine pathophysiology is similar in adults and children with episodic migraine, but the approach to the management needs to be modified and adjusted in kids. Recognizing the impact on quality of life especially with regard to school and knowing appropriate treatment options can improve treatment and decrease the disability from this disorder.
Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/terapia , Adolescente , Adulto , Criança , Humanos , Estilo de Vida , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
AIMS: Ischaemic cardiovascular disease is a major cause of morbidity and mortality worldwide. Despite promising results from pre-clinical animal models, VEGF-based strategies for therapeutic angiogenesis have yet to achieve successful reperfusion of ischaemic tissues in patients. Failure to restore efficient VEGF activity in the ischaemic organ remains a major problem in current pro-angiogenic therapeutic approaches. Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway. PMCA4 activity is inhibited by the small molecule aurintricarboxylic acid (ATA). We hypothesize that inhibition of PMCA4 with ATA might enhance VEGF-induced angiogenesis. METHODS AND RESULTS: We show that inhibition of PMCA4 with ATA in endothelial cells triggers a marked increase in VEGF-activated calcineurin/NFAT signalling that translates into a strong increase in endothelial cell motility and blood vessel formation. ATA enhances VEGF-induced calcineurin signalling by disrupting the interaction between PMCA4 and calcineurin at the endothelial-cell membrane. ATA concentrations at the nanomolar range, that efficiently inhibit PMCA4, had no deleterious effect on endothelial-cell viability or zebrafish embryonic development. However, high ATA concentrations at the micromolar level impaired endothelial cell viability and tubular morphogenesis, and were associated with toxicity in zebrafish embryos. In mice undergoing experimentally-induced hindlimb ischaemia, ATA treatment significantly increased the reperfusion of post-ischaemic limbs. CONCLUSIONS: Our study provides evidence for the therapeutic potential of targeting PMCA4 to improve VEGF-based pro-angiogenic interventions. This goal will require the development of refined, highly selective versions of ATA, or the identification of novel PMCA4 inhibitors.
Assuntos
ATPases Transportadoras de Cálcio/metabolismo , Membrana Celular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Ácido Aurintricarboxílico/farmacologia , ATPases Transportadoras de Cálcio/genética , Membrana Celular/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Camundongos , Camundongos Knockout , Neovascularização Fisiológica/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Children and adolescents can experience significant disability from frequent migraine. A number of tools have been developed to help quantify the impact of migraine in this population. Many preventative medications used in adults are routinely used to prevent migraines in children, although there has been less rigorous study. This article reviews the indications and evidence for the use of migraine preventatives, such as antidepressants, antihypertensives, anticonvulsants, antihistamines, and botulinum toxin, in this population.
Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/prevenção & controle , Profilaxia Pré-Exposição/métodos , Adolescente , Anticonvulsivantes/administração & dosagem , Antidepressivos/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Criança , Antagonistas dos Receptores Histamínicos/administração & dosagem , Humanos , PediatriaRESUMO
Excessive salt intake raises blood pressure, but the implications of this observation for human health have remained contentious. It has also been recognized for many years that potassium intake may mitigate the effects of salt intake on blood pressure and possibly on outcomes such as stroke. Recent large randomized intervention trials have provided strong support for the benefits of replacing salt (NaCl) with salt substitute (75% NaCl, 25% KCl) on hard outcomes, including stroke. During the same period of time, major advances have been made in understanding how the body senses and tastes salt, and how these sensations drive intake. Additionally, new insights into the complex interactions between systems that control sodium and potassium excretion by the kidneys, and the brain have highlighted the existence of a potassium switch in the kidney distal nephron. This switch seems to contribute importantly to the blood pressure-lowering effects of potassium intake. In recognition of these evolving data, the United States Food and Drug Administration is moving to permit potassium-containing salt substitutes in food manufacturing. Given that previous attempts to reduce salt consumption have not been successful, this new approach has a chance of improving health and ending the 'Salt Wars'.
Assuntos
Hipertensão , Sódio na Dieta , Acidente Vascular Cerebral , Humanos , Sódio na Dieta/farmacologia , Cloreto de Sódio na Dieta/efeitos adversos , Hipertensão/etiologia , Hipertensão/prevenção & controle , Cloreto de Sódio , Pressão Sanguínea/fisiologia , Potássio , Potássio na Dieta/farmacologiaRESUMO
BACKGROUND: Potassium (K+)-deficient diets, typical of modern processed foods, increase blood pressure (BP) and NaCl sensitivity. A K+-dependent signaling pathway in the kidney distal convoluted tubule, coined the K+ switch, that couples extracellular K+ sensing to activation of the thiazide-sensitive NaCl cotransporter (NCC) and NaCl retention has been implicated, but causality has not been established. METHODS: To test the hypothesis that small, physiological changes in plasma K+ (PK+) are translated to BP through the switch pathway, a genetic approach was used to activate the downstream switch kinase, SPAK (SPS1-related proline/alanine-rich kinase), within the distal convoluted tubule. The CA-SPAK (constitutively active SPS1-related proline/alanine-rich kinase mice) were compared with control mice over a 4-day PK+ titration (3.8-5.1 mmol) induced by changes in dietary K+. Arterial BP was monitored using radiotelemetry, and renal function measurements, NCC abundance, phosphorylation, and activity were made. RESULTS: As PK+ decreased in control mice, BP progressively increased and became sensitive to dietary NaCl and hydrochlorothiazide, coincident with increased NCC phosphorylation and urinary sodium retention. By contrast, BP in CA-SPAK mice was elevated, resistant to the PK+ titration, and sensitive to hydrochlorothiazide and salt at all PK+ levels, concomitant with sustained and elevated urinary sodium retention and NCC phosphorylation and activity. Thus, genetically locking the switch on drives NaCl sensitivity and prevents the response of BP to potassium. CONCLUSIONS: Low K+, common in modern ultraprocessed diets, presses the K+-switch pathway to turn on NCC activity, increasing sodium retention, BP, and salt sensitivity.
Assuntos
Potássio , Proteínas Serina-Treonina Quinases , Animais , Camundongos , Potássio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Potássio na Dieta/metabolismo , Pressão Sanguínea/fisiologia , Cloreto de Sódio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Transdução de Sinais , Fosforilação , Túbulos Renais Distais/metabolismo , Hidroclorotiazida , Sódio/metabolismo , Alanina/metabolismo , Prolina/metabolismoRESUMO
INTRODUCTION: A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring. METHODS AND ANALYSIS: The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants. ETHICS AND DISSEMINATION: Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment. TRIAL REGISTRATION NUMBER: ACTRN12622001458729.
Assuntos
Fármacos Gastrointestinais , Doenças Inflamatórias Intestinais , Infliximab , Humanos , Infliximab/administração & dosagem , Infliximab/uso terapêutico , Infliximab/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Estudos Prospectivos , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/uso terapêutico , Injeções Subcutâneas , Administração Intravenosa , Estudos Multicêntricos como Assunto , Adulto , Austrália , Monitoramento de Medicamentos/métodos , Feminino , MasculinoRESUMO
Concomitant immunomodulation is utilised in combination with anti-TNF therapy for IBD primarily to increase drug levels and prevent anti-drug antibody formation. Whilst thiopurines have traditionally been the immunomodulator of choice in IBD populations, there are concerns regarding the long-term safety of the prolonged use of these agents: particularly an association with lymphoproliferative disorders. Given this, we have explored the existing literature on the use of low-dose oral methotrexate as an alternative immunomodulator for this indication. Although there is a lack of data directly comparing the efficacies of methotrexate and thiopurines as concomitant immunomodulators, the available literature supports the use of methotrexate in improving the pharmacokinetics of anti-TNF agents. Furthermore, low-dose oral methotrexate regimens appear to have comparable efficacies to higher-dose parenteral administration and are better tolerated. We suggest that clinicians should consider the use of low-dose oral methotrexate as an alternative to thiopurines when the primary purpose of concomitant immunomodulation is to improve anti-TNF pharmacokinetics.