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1.
Addict Sci Clin Pract ; 19(1): 49, 2024 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-38872214

RESUMO

BACKGROUND: The 15-method is a targeted screening and treatment approach for alcohol problems in primary care. The 15-method used in primary care has proven as effective as specialized treatment for mild to moderate alcohol dependence in Sweden. A feasibility study of the 15-method in Danish primary care found the method acceptable and feasible. AIMS: To evaluate the effectiveness of the 15-method in a Danish primary care setting in (1) lowering the proportion of patients exceeding the Danish low-risk alcohol consumption limit of ten standard units per week and a maximum of four standard units on a single day for men and women, and (2) increasing the likelihood of alcohol use being addressed during a consultation in general practice. Further, the rate of prescribed pharmacological treatment for alcohol problems (Disulfiram, Naltrexone, Acamprosate, and Nalmefene) will be measured along with the use of the biomarkers Alanine Transaminase and Gamma-Glutamyl Transferase. METHODS: Stepped wedge cluster randomized controlled trial in sixteen general practices in the Region of Southern Denmark. Following a three-month baseline, the practices are randomly assigned to launch dates in one of four clusters. General practitioners and nurses receive three hours of training in the 15-method before launch. Patient questionnaires will collect data on alcohol consumption levels among patients affiliated with the practices. The healthcare professionals will register consultations in which alcohol is addressed in their patient filing system. Pharmacological treatment rates and the use of biomarkers will be collected through Danish national registries. The study follows the Medical Research Council's guidelines for developing and evaluating complex interventions. DISCUSSION: From the patient's perspective, the 15-method may help identify alcohol-related problems at an earlier stage with flexible treatment offers in a familiar setting. For healthcare professionals, it addresses a traditionally challenging topic by equipping them with concrete tools, communication training, and clear treatment directives. From a societal perspective, primary care holds a unique position to identify hazardous and harmful alcohol use across different age groups, with potential public health and economic benefits through early identification and intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT05916027. Retrospectively registered 22 June 2023.


Assuntos
Dissuasores de Álcool , Alcoolismo , Dissulfiram , Naltrexona , Atenção Primária à Saúde , Humanos , Atenção Primária à Saúde/organização & administração , Dinamarca , Naltrexona/uso terapêutico , Naltrexona/análogos & derivados , Alcoolismo/diagnóstico , Alcoolismo/tratamento farmacológico , Alcoolismo/terapia , Masculino , Feminino , Dissuasores de Álcool/uso terapêutico , Dissulfiram/uso terapêutico , Acamprosato/uso terapêutico , Adulto , Taurina/análogos & derivados , Taurina/uso terapêutico , Alanina Transaminase/sangue , gama-Glutamiltransferase/sangue , Pessoa de Meia-Idade , Programas de Rastreamento/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Expert Opin Pharmacother ; 25(7): 791-799, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38814590

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.


Assuntos
Doença de Alzheimer , Pró-Fármacos , Doença de Alzheimer/tratamento farmacológico , Humanos , Pró-Fármacos/farmacocinética , Animais , Peptídeos beta-Amiloides/metabolismo , Ciclopropanos/uso terapêutico , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Ciclopropanos/administração & dosagem , Combinação de Medicamentos , Fragmentos de Peptídeos , Disponibilidade Biológica , Meia-Vida , Valina/análogos & derivados , Valina/farmacocinética , Valina/administração & dosagem , Taurina/análogos & derivados
3.
Nutr Hosp ; 41(3): 702-705, 2024 Jun 27.
Artigo em Espanhol | MEDLINE | ID: mdl-38726617

RESUMO

Introduction: Objectives: the prevention of central line-associated bloodstream infections is a critical aspect of care for patients with intestinal failure who are treated with parenteral nutrition. The use of taurolidine in this context is becoming increasingly popular, however there is a lack of standardization in its pediatric application. The objective of this work is to develop a guide to support its prescription. Methodology: the guide is based on a review of the literature and expert opinions from the Intestinal Failure Group of the SEGHNP. It was developed through a survey distributed to all its members, addressing aspects of usual practice with this lock solution. Results: this manuscript presents general recommendations concerning taurolidine indications, commercial presentations, appropriate forms of administration, use in special situations, adverse reactions, and contraindications in the pediatric population Conclusions: taurolidine is emerging as the primary lock solution used to prevent central line-associated bloodstream infections, proving to be safe and effective. This guide aims to optimize and standardize its use in pediatrics.


Introducción: Objetivo: la prevención de las infecciones asociadas a catéter ocupa un papel fundamental en los cuidados del paciente en situación de fracaso intestinal en tratamiento con nutrición parenteral. El empleo del sellado del catéter con taurolidina con ese fin se ha generalizado sin que exista una estandarización sobre su uso en población pediátrica. El objetivo de este trabajo es elaborar una guía clínica que sirva de apoyo en su utilización. Métodos: la guía se basa en una revisión de la literatura y en la opinión de expertos del Grupo de Trabajo de Fracaso Intestinal de la SEGHNP recogida a través de una encuesta realizada a todos sus integrantes sobre aspectos de la práctica habitual con este sellado. Resultados: este manuscrito expone unas recomendaciones en cuanto a las indicaciones, presentaciones comerciales disponibles, forma adecuada de administración, uso en situaciones especiales, reacciones adversas y contraindicaciones de la taurolidina en población pediátrica. Conclusiones: el sellado con taurolidina para la prevención de la infección asociada a catéter venoso central se ha mostrado como un tratamiento eficaz y seguro. La presente guía pretender optimizar y homogeneizar su uso en pediatría.


Assuntos
Insuficiência Intestinal , Nutrição Parenteral , Taurina , Tiadiazinas , Humanos , Tiadiazinas/uso terapêutico , Tiadiazinas/efeitos adversos , Criança , Taurina/análogos & derivados , Taurina/uso terapêutico , Nutrição Parenteral/normas , Nutrição Parenteral/métodos , Insuficiência Intestinal/terapia , Infecções Relacionadas a Cateter/prevenção & controle , Cateterismo Venoso Central/efeitos adversos , Anti-Infecciosos/uso terapêutico , Lactente , Pré-Escolar
4.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732141

RESUMO

Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAß; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 µM), CU (10 µM), or SP (1 µM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 µM) concentration was efficient in diminishing the iAß, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAß compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAß-induced ChLN damage in FAD.


Assuntos
Doença de Alzheimer , Antracenos , Curcumina , Presenilina-1 , Taurina/análogos & derivados , Curcumina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Antracenos/farmacologia , Animais , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Peptídeos beta-Amiloides/metabolismo , Humanos , Proteínas tau/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos
5.
ACS Appl Bio Mater ; 7(5): 3179-3189, 2024 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-38581305

RESUMO

Ruxolitinib (RXL) is a Janus kinase inhibitor used for treating intermediate- or high-risk myelofibrosis. This study presents an electrode modified with electrochemically polymerized taurine on a carbon paste electrode via cyclic voltammetry (CV). The surface characterization of the poly(taurine)-CP electrode was evaluated by using electrochemical (electrochemical impedance spectroscopy─EIS, CV), morphological (scanning electron microscope─SEM), and spectroscopic (Fourier-transform infrared spectroscopy─FT-IR) techniques. Under optimized conditions, RXL exhibited good linearity within the 0.01-1.0 µM concentration range, with a limit of detection (LOD) of 0.005 µM. The proposed electrochemical sensor demonstrated excellent selectivity, accuracy, precision, and repeatability. Furthermore, it effectively detected RXL in human urine and pharmaceutical samples.


Assuntos
Carbono , Técnicas Eletroquímicas , Eletrodos , Teste de Materiais , Nitrilas , Pirazóis , Pirimidinas , Taurina , Nitrilas/química , Nitrilas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Carbono/química , Humanos , Pirazóis/química , Pirazóis/farmacologia , Taurina/química , Taurina/análogos & derivados , Taurina/farmacologia , Tamanho da Partícula , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/farmacologia , Polimerização , Estrutura Molecular
6.
JPEN J Parenter Enteral Nutr ; 48(4): 486-494, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38605559

RESUMO

BACKGROUND: Children with chronic IF require long-term home parenteral nutrition (HPN), administered through a central venous catheter. Catheter-related bloodstream infection (CRBSI) with Staphylococcus aureus is known to be a serious infection with a high mortality rate and risk of complications. A standardized protocol on the management of S aureus CRBSIs in children receiving HPN is lacking. The aim of this study is to evaluate the effectiveness and safety of the current management in an HPN expertise center in the Netherlands. METHODS: We performed a retrospective descriptive cohort study between 2013 and 2022 on children 0-18 years of age with chronic IF requiring long-term HPN. Our primary outcomes were the incidence of S aureus CRBSI per 1000 catheter days, catheter salvage attempt rate, and successful catheter salvage rate. Our secondary outcomes included complications and mortality. RESULTS: A total of 74 patients (39 male; 53%) were included, covering 327.8 catheter years. Twenty-eight patients (38%) had a total of 52 S aureus CRBSIs, with an incidence rate of 0.4 per 1000 catheter days. The catheter salvage attempt rate was 44% (23/52). The successful catheter salvage rate was 100%. No relapse occurred, and no removal was needed after catheter salvage. All complications that occurred were already present at admission before the decision to remove the catheter or not. No patients died because of an S aureus CRBSI. CONCLUSION: Catheter salvage in S aureus CRBSIs in children receiving HPN can be attempted after careful consideration by a multidisciplinary team in an HPN expertise center.


Assuntos
Infecções Relacionadas a Cateter , Insuficiência Intestinal , Nutrição Parenteral no Domicílio , Infecções Estafilocócicas , Staphylococcus aureus , Taurina/análogos & derivados , Tiadiazinas , Humanos , Nutrição Parenteral no Domicílio/métodos , Nutrição Parenteral no Domicílio/efeitos adversos , Masculino , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/epidemiologia , Estudos Retrospectivos , Feminino , Criança , Pré-Escolar , Lactente , Infecções Estafilocócicas/prevenção & controle , Adolescente , Países Baixos , Insuficiência Intestinal/terapia , Recém-Nascido , Cateteres Venosos Centrais/efeitos adversos , Cateteres Venosos Centrais/microbiologia , Doença Crônica , Incidência , Remoção de Dispositivo , Estudos de Coortes , Cateterismo Venoso Central/efeitos adversos , Cateteres de Demora/efeitos adversos , Cateteres de Demora/microbiologia , Bacteriemia/prevenção & controle , Bacteriemia/epidemiologia , Bacteriemia/etiologia
7.
Protein Sci ; 33(5): e4977, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38591646

RESUMO

Chemical warfare nerve agents and pesticides, known as organophosphorus compounds inactivate cholinesterases (ChEs) by phosphorylating the serine hydroxyl group located at the active site of ChEs. Over the course of time, phosphorylation is followed by loss of an organophosphate-leaving group and the bond with ChEs becomes irreversible, a process known as aging. Differently, structurally related irreversible catalytic poisons bearing sulfur instead of phosphorus convert ChEs in its aged form only by covalently binding to the key catalytic serine. Kinetic and crystallographic studies of the interaction between Torpedo californica acetylcholinesterase (TcAChE) and a small organosulfonate, methanesulfonyl fluoride (MSF), indeed revealed irreversibly methylsulfonylated serine 200, to be isosteric with the bound aged sarin/soman analogues. The potent bulky reversible inhibitor 7-bis-tacrine (BTA) adopts, in the active site of the crystal structure of the MSF-enzyme adduct, a location and an orientation that closely resemble the one being found in the crystal structure of the BTA-enzyme complex. Remarkably, the presence of BTA accelerates the rate of methanesulfonylation by a factor of two. This unexpected result can be explained on the basis of two facts: i) the steric hindrance exerted by BTA to MSF in accessing the active site and ii) the acceleration of the MSF-enzyme adduct formation as a consequence of the lowering of the rotational and translational degrees of freedom in the proximity of the catalytic serine. It is well known that pralidoxime (2-Pyridine Aldoxime Methyl chloride, 2-PAM) alone or in the presence of the substrate acetylcholine cannot reactivate the active site serine of the TcAChE-MSF adduct. We show that the simultaneous presence of 2-PAM and the additional neutral oxime, 2-[(hydroxyimino)methyl]-l-methylimidazol (2-HAM), triggers the reactivation process of TcAChE within the hour timescale. Overall, our results pave the way toward the likely use of a cocktail of distinctive oximes as a promising recipe for an effective and fast reactivation of aged cholinesterases.


Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Compostos de Pralidoxima , Sulfonas , Taurina/análogos & derivados , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Oximas/química , Serina
8.
Cochrane Database Syst Rev ; 4: CD015042, 2024 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-38682758

RESUMO

BACKGROUND: Despite the known harms, alcohol consumption is common in pregnancy. Rates vary between countries, and are estimated to be 10% globally, with up to 25% in Europe. OBJECTIVES: To assess the efficacy of psychosocial interventions and medications to reduce or stop alcohol consumption during pregnancy. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register (via CRSLive), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO, from inception to 8 January 2024. We also searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). All searches included non-English language literature. We handsearched references of topic-related systematic reviews and included studies. SELECTION CRITERIA: We included randomised controlled trials that compared medications or psychosocial interventions, or both, to placebo, no intervention, usual care, or other medications or psychosocial interventions used to reduce or stop alcohol use during pregnancy. Our primary outcomes of interest were abstinence from alcohol, reduction in alcohol consumption, retention in treatment, and women with any adverse event. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included eight studies (1369 participants) in which pregnant women received an intervention to stop or reduce alcohol use during pregnancy. In one study, almost half of participants had a current diagnosis of alcohol use disorder (AUD); in another study, 40% of participants had a lifetime diagnosis of AUD. Six studies took place in the USA, one in Spain, and one in the Netherlands. All included studies evaluated the efficacy of psychosocial interventions; we did not find any study that evaluated the efficacy of medications for the treatment of AUD during pregnancy. Psychosocial interventions were mainly brief interventions ranging from a single session of 10 to 60 minutes to five sessions of 10 minutes each. Pregnant women received the psychosocial intervention approximately at the end of the first trimester of pregnancy, and the outcome of alcohol use was reassessed 8 to 24 weeks after the psychosocial intervention. Women in the control group received treatment as usual (TAU) or similar treatments such as comprehensive assessment of alcohol use and advice to stop drinking during pregnancy. Globally, we found that, compared to TAU, psychosocial interventions may increase the rate of continuously abstinent participants (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.14 to 1.57; I2 =0%; 3 studies; 378 women; low certainty evidence). Psychosocial interventions may have little to no effect on the number of drinks per day, but the evidence is very uncertain (mean difference -0.42, 95% CI -1.13 to 0.28; I2 = 86%; 2 studies; 157 women; very low certainty evidence). Psychosocial interventions probably have little to no effect on the number of women who completed treatment (RR 0.98, 95% CI 0.94 to 1.02; I2 = 0%; 7 studies; 1283 women; moderate certainty evidence). None of the included studies assessed adverse events of treatments. We downgraded the certainty of the evidence due to risk of bias and imprecision of the estimates. AUTHORS' CONCLUSIONS: Brief psychosocial interventions may increase the rate of continuous abstinence among pregnant women who report alcohol use during pregnancy. Further studies should be conducted to investigate the efficacy and safety of psychosocial interventions and other treatments (e.g. medications) for women with AUD. These studies should provide detailed information on alcohol use before and during pregnancy using consistent measures such as the number of drinks per drinking day. When heterogeneous populations are recruited, more detailed information on alcohol use during pregnancy should be provided to allow future systematic reviews to be conducted. Other important information that would enhance the usefulness of these studies would be the presence of other comorbid conditions such as anxiety, mood disorders, and the use of other psychoactive substances.


Assuntos
Consumo de Bebidas Alcoólicas , Ensaios Clínicos Controlados Aleatórios como Assunto , Feminino , Humanos , Gravidez , Acamprosato/uso terapêutico , Abstinência de Álcool/psicologia , Dissuasores de Álcool/uso terapêutico , Consumo de Bebidas Alcoólicas/prevenção & controle , Viés , Complicações na Gravidez/prevenção & controle , Complicações na Gravidez/psicologia , Intervenção Psicossocial/métodos , Taurina/uso terapêutico , Taurina/análogos & derivados
10.
Arch Toxicol ; 98(4): 1135-1149, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38446233

RESUMO

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.


Assuntos
Reativadores da Colinesterase , Compostos de Pralidoxima , Taurina/análogos & derivados , Ratos , Humanos , Animais , Reativadores da Colinesterase/farmacologia , Trimedoxima/farmacologia , Butirilcolinesterase , Acetilcolinesterase , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Antídotos/farmacologia , Inibidores da Colinesterase/toxicidade , Fósforo , Oxigênio
11.
BMJ Open ; 14(2): e074393, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316585

RESUMO

OBJECTIVE: To assess the uptake of services provided by community health workers who were trained as community health entrepreneurs (CHEs) for febrile illness and diarrhoea. DESIGN: A cross-sectional survey among households combined with mapping of all providers of basic medicine and primary health services in the study area. PARTICIPANTS: 1265 randomly selected households in 15 rural villages with active CHEs. SETTING: Bunyangabu district, Uganda. OUTCOME MEASURES: We describe the occurrence and care sought for fever and diarrhoea in the last 3 months by age group in the households. Care provider options included: CHE, health centre or clinic (public or private), pharmacy, drug shop and other. Geographic Information Ssystem (GIS)-based geographical measures were used to map all care providers around the active CHEs. RESULTS: Fever and diarrhoea in the last 3 months occurred most frequently in children under 5; 68% and 41.9%, respectively. For those who sought care, CHE services were used for fever among children under 5, children 5-17 and adults over 18 years of age in 34.7%, 29.9% and 25.1%, respectively. For diarrhoea among children under 5, children 5-17 and adults over 18 years of age, CHE services were used in 22.1%, 19.5% and 7.0%, respectively. For those who did not seek care from a CHE (only), drug shops were most frequently used services for both fever and diarrhoea, followed by health centres or private clinics. Many households used a combination of services, which was possible given the high density and diversity of providers found in the study area. CONCLUSIONS: CHEs play a considerable role in providing care in rural areas where they are active. The high density of informal drug shops and private clinics highlights the need for clarity on the de facto roles played by different providers in both the public and private sector to improve primary healthcare.


Assuntos
Assistência Farmacêutica , População Rural , Taurina/análogos & derivados , Criança , Adulto , Humanos , Adolescente , Estudos Transversais , Uganda/epidemiologia , Saúde Pública , Febre/epidemiologia , Febre/terapia , Diarreia/epidemiologia , Diarreia/terapia , Instituições de Assistência Ambulatorial , Serviços de Saúde Comunitária
12.
Zhongguo Zhong Yao Za Zhi ; 49(1): 224-231, 2024 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-38403355

RESUMO

This study aims to reveal the effect of acteoside on gouty arthritis(GA) in rats based on liver metabolomics. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to search for the potential biomarkers and metabolic pathways. SD rats were randomly assigned into blank, model, colchicine(0.3 mg·kg~(-1)), and high-, medium-, low-dose(200, 100, and 50 mg·kg~(-1), respectively) acteoside groups(n=7). The rats were administrated once a day for 7 continuous days. Monosodium urate(MSU) was used to induce GA model in rats during administration. The degree of joint swelling and pathological changes of synovial tissue in rats were observed, and the levels of interleukin(IL)-1ß, IL-18 and tumor necrosis factor(TNF)-α in the synovial tissue of rats were measured. UPLC-Q-TOF-MS was employed to collect rat liver data, and Progenesis QI and EZ info were used for data analysis. Human Metabolomics Database(HMDB) and Kyoto Encyclopedia of Genes and Genomes(KEGG) were employed to predict the potential biomarkers and metabolic pathways. The results showed that acteoside alleviated joint swelling, reduced synovial tissue damage, and lowered the levels of inflammatory cytokines in GA rats. A total of 19 common biomarkers were identified, 17 of which can be regulated by acteoside. Seven metabolic pathways were enriched, such as glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism, among which glycerophospholipid metabolism was strongly disturbed. The metabolomics analysis suggested that acteoside may down-regulate the expression of inflammatory cytokines and alleviate the symptoms of GA rats by regulating glycerophospholipid metabolism, linoleic acid metabolism, and taurine and hypotaurine metabolism. The findings provide a reference for future research and development of acteoside.


Assuntos
Artrite Gotosa , Glucosídeos , Polifenóis , Taurina/análogos & derivados , Humanos , Ratos , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Ácido Linoleico , Ratos Sprague-Dawley , Metabolômica , Fígado/metabolismo , Citocinas , Biomarcadores/metabolismo , Glicerofosfolipídeos , Cromatografia Líquida de Alta Pressão
13.
Pancreas ; 53(4): e301-e309, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38373081

RESUMO

OBJECTIVE: A significant number of patients experience early recurrence after surgical resection for pancreatic ductal adenocarcinoma (PDAC), negating the benefit of surgery. The present study conducted clinicopathologic and metabolomic analyses to explore the factors associated with the early recurrence of PDAC. MATERIALS AND METHODS: Patients who underwent pancreatectomy for PDAC at Kagawa University Hospital between 2011 and 2020 were enrolled. Tissue samples of PDAC and nonneoplastic pancreas were collected and frozen immediately after resection. Charged metabolites were quantified by capillary electrophoresis-mass spectrometry. Patients who relapsed within 1 year were defined as the early recurrence group. RESULTS: Frozen tumor tissue and nonneoplastic pancreas were collected from 79 patients. The clinicopathologic analysis identified 11 predictive factors, including preoperative carbohydrate antigen 19-9 levels. The metabolomic analysis revealed that only hypotaurine was a significant risk factor for early recurrence. A multivariate analysis, including clinical and metabolic factors, showed that carbohydrate antigen 19-9 and hypotaurine were independent risk factors for early recurrence ( P = 0.045 and P = 0.049, respectively). The recurrence-free survival rate 1 year after surgery with both risk factors was only 25%. CONCLUSIONS: Our results suggested that tumor hypotaurine is a potential metabolite associated with early recurrence. Carbohydrate antigen 19-9 and hypotaurine showed a vital utility for predicting early recurrence.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Taurina/análogos & derivados , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Carcinoma Ductal Pancreático/patologia , Pâncreas/patologia , Pancreatectomia/métodos , Carboidratos , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Antígeno CA-19-9
14.
Placenta ; 147: 59-67, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38325050

RESUMO

INTRODUCTION: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, coinciding with reduced hypotaurine levels in fetal plasma. This study aims to elucidate the expression and role of hypotaurine transporters within the placenta. METHODS: We employed quantitative RT-PCR to measure mRNA expression of GAT transporter family members in the placenta during mid-to-late gestation. LC/MS/MS was used to analyze the distribution of hypotaurine in different placental subregions. Immunohistochemistry was utilized to examine the localization of GAT2 in mice. Placental hypotaurine uptake from fetal circulation was studied via umbilical perfusion in rats. RESULTS: Among hypotaurine transporters, GAT2 exhibited increased mRNA and protein expression in murine placenta during mid-to-late gestation. Notably, GAT2/Slc6a13 mRNA and hypotaurine were most concentrated in the labyrinth of murine placenta. In contrast, enzymes responsible for hypotaurine synthesis, such as cysteine dioxygenase, cysteine sulfinic acid decarboxylase, and 2-aminoethanethiol dioxygenase, showed minimal expression in the labyrinth. These findings suggest that GAT2 is a key determinant of hypotaurine levels in the placental labyrinth. Immunohistochemical examination unveiled that GAT2 was predominantly localized on the fetal-facing plasma membrane within syncytiotrophoblasts, which co-localized with ezrin. In rat umbilical perfusion experiments, the GAT2/3 and TauT inhibitor, SNAP-5114, significantly reduced hypotaurine extraction from fetal circulation to the placenta. DISCUSSION: The results suggest that GAT2 plays a pivotal role in the concentrative uptake of hypotaurine from fetal plasma within syncytiotrophoblasts of the placenta.


Assuntos
Placenta , Espectrometria de Massas em Tandem , Taurina/análogos & derivados , Ratos , Camundongos , Gravidez , Feminino , Animais , Placenta/metabolismo , Trofoblastos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Membrana Celular/metabolismo , Taurina/metabolismo , Taurina/farmacologia , Camundongos Knockout , RNA Mensageiro/metabolismo
15.
Sci Total Environ ; 915: 169897, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38184250

RESUMO

pH treatment promotes single-cell lipid accumulation and significantly affects microalgae growth. This study investigates the correlation between lipid content and environmental pH using the model diatom Phaeodactylum tricornutum (P. tricornutum). We compared three distinct pH treatment strategies-continuous, intermittent, and a two-phase culture-in P. tricornutum. Rigorous analysis of chlorophyll content, cell density, and lipid content indicated that ongoing pH treatment at pH 9.5 (CHES) emerged as the most effective approach for lipid accumulation in P. tricornutum. The CHES buffer treatment significantly boosted total lipid yield and led to a reduction in protein content. Carbohydrate content experienced a slight decline under CHES buffer treatment, but changes were observed in the activities of key enzymes. Specifically, [acyl-carrier-protein] S-malonyltransferase (MAT) activity decreased after 3 days in the control treatment, while no significant change was noted under the CHES buffer treatment. In contrast, diacylglycerol O-acyltransferase (DGAT) activity showed upregulation 2 and 3 days post-CHES buffer treatment. Moreover, the study identified differentially expressed genes enriched in Gene Ontology (GO) terms associated with protein biosynthesis, photosynthesis, nucleoside metabolism, and transferase activity. These outcomes underscore the pivotal role of CHES buffer in orchestrating primary metabolism, potentially steering carbon flux towards lipogenesis. As a result, the potential of microalgae as a sustainable source of biofuels contributes significantly to the transition towards a more environmentally friendly energy landscape.


Assuntos
Diatomáceas , Taurina/análogos & derivados , Fotossíntese , Lipídeos , Concentração de Íons de Hidrogênio
16.
Pancreatology ; 24(1): 184-187, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176963

RESUMO

BACKGROUND/OBJECTIVES: The impact of competency-based training programs on pancreatic endoscopic retrograde cholangiopancreatography (ERCP) performance remains unclear. This study aimed to describe the learning curves of pancreatic ERCP and subsequent performance during independent practice. METHODS: This was a multicenter prospective cohort study involving advanced endoscopy trainees (AETs). In the 1st phase, trainees were assessed on every 5th ERCP using the ERCP and EUS Skills Assessment Tool (TEESAT). Cumulative sum (CUSUM) analysis of pancreatic ERCP evaluations was used to establish learning curves. During the 2nd phase (1st year of independent practice), now-graduated participants documented their performance on key ERCP quality indicators. RESULTS: A total of 24 AETs (20 training programs) received sufficient evaluations for CUSUM analysis. Pancreatic ERCP accounted for 14.6 % (196/1339) of all ERCPs evaluated with 45 % of pancreatic ERCPs carrying a Grade 3 level of complexity. A minority of AETs (16.7 %) performed enough pancreatic ERCPs to generate meaningful learning curves with no AETs achieving competence in pancreatic cannulation, sphincterotomy, or stone clearance during Phase 1. In Phase 2, a total of 3620 ERCPs were performed, of which 281 (7.8 %) were pancreatic ERCPs. While the overall pancreatic duct cannulation rate was 92.2 %, the native papilla pancreatic duct cannulation rate was 85.7 %, which was below the recommended 90 % threshold. CONCLUSIONS: Advanced endoscopy training offers a low level of exposure to pancreatic ERCP, which is mirrored in independent practice, highlighting the inadequate training in pancreatic ERCP. Given the complexity of pancreatic ERCP, novel strategies are warranted to improve training in pancreatic ERCP.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Gastroenterologia , Taurina/análogos & derivados , Humanos , Estudos Prospectivos , Gastroenterologia/educação , Cateterismo
17.
Drug Des Devel Ther ; 18: 133-159, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38283137

RESUMO

Purpose: Alzheimer's disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs. Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo. Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs (hAChE: IC50 = 1.57 µM, hBuChE: IC50 = 0.43 µM) and MAOs (hMAO-A: IC50 = 2.30 µM, hMAO-B: IC50 = 4.75 µM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics. Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Taurina/análogos & derivados , Camundongos , Animais , Tacrina/farmacologia , Tacrina/química , Tacrina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Colinesterases/metabolismo , Selegilina/farmacologia , Selegilina/uso terapêutico , Monoaminoxidase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Doenças Neurodegenerativas/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Acetilcolinesterase/metabolismo , Desenho de Fármacos , Relação Estrutura-Atividade , Peptídeos beta-Amiloides
18.
J Hosp Infect ; 143: 76-81, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37972710

RESUMO

BACKGROUND: Taurolidine lock, a technique used to prevent or treat catheter-related bloodstream infection (CRBSI), is effective in adult and paediatric patients but has been described rarely in neonates. The aim of this descriptive retrospective study, was to determine the feasibility and direct outcomes of prophylactic and therapeutic taurolidine locks in term and preterm neonates. METHODS: We implemented the use of therapeutic taurolidine lock in addition to antibiotic treatment with the aim of catheter salvage in critical neonates with difficult vascular access (group 1). In addition, we introduced taurolidine lock as a preventive measure in neonates with a central venous catheter (CVC) at high risk of developing CRBSI (group 2). Every 24 h (in the treatment group) a 2% taurolidine solution was injected and the catheter locked for at least 120 min, until infection clearance (group 1). In the preventive group, the catheter was locked for 30 min every 48 h until CVC removal (group 2). FINDINGS: Thirty-seven neonates who received taurolidine were included in this study. We did not observe any major adverse events. In group 1 (21 cases), clinical symptom disappearance and bacteraemia clearance were achieved without catheter removal in 18 cases (85.7%); in the other three neonates the catheter was removed shortly after the start of the locks as it was possible to replace the CVC. In group 2 (16 neonates), no CRBSI was observed during the duration of the catheter placement. CONCLUSIONS: In this retrospective study, taurolidine was successfully used in neonates both for prevention and treatment of CRBSI, without major undesired effects. A larger cohort and a randomized clinical trial is warranted in order to establish its efficacy and safety in neonates.


Assuntos
Bacteriemia , Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Cateteres Venosos Centrais , Taurina/análogos & derivados , Tiadiazinas , Adulto , Recém-Nascido , Humanos , Criança , Estudos de Viabilidade , Estudos Retrospectivos , Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Relacionadas a Cateter/diagnóstico , Cateteres Venosos Centrais/efeitos adversos , Cateterismo Venoso Central/efeitos adversos , Bacteriemia/tratamento farmacológico , Bacteriemia/prevenção & controle
19.
JPEN J Parenter Enteral Nutr ; 48(2): 165-173, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38062902

RESUMO

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) in patients receiving home parenteral nutrition (HPN) for chronic intestinal failure (CIF) are associated with significant morbidity and financial costs. Taurolidine is associated with a reduction in bloodstream infections, with limited information on the cost-effectiveness as the primary prevention. This study aimed to determine the cost-effectiveness of using taurolidine-citrate for the primary prevention of CRBSIs within a quaternary hospital. METHODS: All patients with CIF receiving HPN were identified between January 2015 and November 2022. Data were retrospectively collected regarding patient demographics, HPN use, CRBSI diagnosis, and use of taurolidine-citrate. The direct costs associated with CRBSI-associated admissions and taurolidine-citrate use were obtained from the coding department using a bottom-up approach. An incremental cost-effective analysis was performed, with a time horizon of 4 years, to compare the costs associated with primary and secondary prevention against the outcome of cost per infection avoided. RESULTS: Forty-four patients received HPN within this period. The CRBSI rates were 3.25 infections per 1000 catheter days before the use of taurolidine-citrate and 0.35 infections per 1000 catheter days after taurolidine-citrate use. The incremental cost-effectiveness ratio indicates primary prevention is the weakly dominant intervention, with the base case value of $27.04 per CRBSI avoided. This held with one-way sensitivity analysis. CONCLUSION: Taurolidine-citrate in the primary prevention of CRBSIs in patients with CIF receiving HPN is associated with reduced hospital costs and infection rates.


Assuntos
Infecções Relacionadas a Cateter , Cateteres Venosos Centrais , Enteropatias , Insuficiência Intestinal , Nutrição Parenteral no Domicílio , Sepse , Taurina/análogos & derivados , Tiadiazinas , Humanos , Ácido Cítrico/uso terapêutico , Análise Custo-Benefício , Estudos Retrospectivos , Citratos/uso terapêutico , Cateteres Venosos Centrais/efeitos adversos , Sepse/etiologia , Enteropatias/complicações , Enteropatias/terapia , Nutrição Parenteral no Domicílio/efeitos adversos , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle
20.
Epidemiol Psychiatr Sci ; 31: e75, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36245402

RESUMO

Mental disorders are one of the largest contributors to the burden of disease globally, this holds also for children and adolescents, especially in low- and middle-income countries. The prevalence and severity of these disorders are influenced by social determinants, including exposure to adversity. When occurring early in life, these latter events are referred to as adverse childhood experiences (ACEs).In this editorial, we provide an overview of the literature on the role of ACEs as social determinants of mental health through the lenses of global mental health. While the relation between ACEs and mental health has been extensively explored, most research was centred in higher income contexts. We argue that findings from the realm of global mental health should be integrated into that of ACEs, e.g. through preventative and responsive psychosocial interventions for children, adolescents and their caregivers. The field of global mental health should also undertake active efforts to better address ACEs in its initiatives, all with the goal of reducing the burden of mental disorders among children and adolescents globally.


Assuntos
Experiências Adversas da Infância , Transtornos Mentais , Adolescente , Criança , Humanos , Renda , Transtornos Mentais/epidemiologia , Saúde Mental , Taurina/análogos & derivados
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