RESUMO
Disengagement from care among people with HIV (PWH) and hepatitis C (HCV) increases the risks of adverse health outcomes and poses significant barriers to achieving global HIV and HCV elimination goals. In accordance with the Joanna Briggs Institute framework, a scoping review was conducted to synthesize and highlight existing gaps in the literature on (dis)engagement in care among PWH and HCV. We searched for original studies on (dis)engagement in care among PWH and HCV in high-income countries using eight electronic databases from inception to May 2023. Our search yielded 4462 non-duplicated records, which were scoped to 27 studies. Definitions of (dis)engagement in care were diverse, with considerable heterogeneity in how retention was operationalized and temporally measured. Studies identified predictors of (dis)engagement to be related to drug and substance use (n = 5 articles), clinical factors (n = 5), social and welfare (n = 4), and demographic characteristics (n = 2). When engagement in care was treated as an exposure, it was associated with HCV treatment initiation (n = 3), achieving sustained virological response (n = 2), and maintaining HIV viral suppression (n = 1). Interventions to improve care engagement among PWH and HCV were limited to five studies using cash incentives (n = 1) and individual case management (n = 4). (Dis)engagement in care is a dynamic process influenced by shifting priorities that may 'tip the balance' towards or away from regularly interacting with healthcare professionals. However, inconsistent definitions render cross-study comparisons and meta-analyses virtually impossible. Further research needs to establish a standardized definition to identify patients at high risk of disengagement and develop interventions that leverage the nested HIV/HCV care cascades to retain and recover patients lost from care.
RESUMO
Background: Among youth, symptoms of depression, anxiety, and alcohol use are associated with considerable illness and disability. Youth face many personal and health system barriers in accessing mental health care. Mobile applications (apps) offer youth potentially accessible, scalable, and anonymous therapy and other support. Recent systematic reviews on apps to reduce mental health symptoms among youth have reported uncertain effectiveness, but analyses based on the type of app-delivered therapy are limited. Objectives: We conducted this systematic review with youth co-researchers to ensure that this review addressed the questions that were most important to them. The objective of this review is to synthesize the best available evidence on the effectiveness of mobile apps for the reduction of depressive symptoms (depression, generalized anxiety, psychological distress) and alcohol use among youth. Search Methods: We conducted electronic searches of the following bibliographic databases for studies published between January 1, 2008, and July 1, 2022: MEDLINE (via Ovid), Embase (via Ovid), PsycINFO (via Ovid), CINAHL (via EBSCOHost), and CENTRAL (via the Cochrane Library). The search used a combination of indexed terms, free text words, and MeSH headings. We manually screened the references of relevant systematic reviews and included randomized controlled trials (RCTs) for additional eligible studies, and contacted authors for full reports of identified trial registries or protocols. Selection Criteria: We included RCTs conducted among youth aged 15-24 years from any setting. We did not exclude populations on the basis of gender, socioeconomic status, geographic location or other personal characteristics. We included studies which assessed the effectiveness of app-delivered mental health support or therapy interventions that targeted the management of depressive disorders and/or alcohol use disorders. We excluded apps that targeted general wellness, apps which focused on prevention of psychological disorders and apps that targeted bipolar disorder, psychosis, post-traumatic stress disorder, attention-deficit hyperactivity disorder, substance use disorders (aside from alcohol), and sleep disorders. Eligible comparisons included usual care, no intervention, wait-list control, alternative or controlled mobile applications. We included studies which reported outcomes on depressive symptoms, anxiety symptoms, alcohol use and psychological distress over any follow-up period. Data Collection and Analysis: We standardized the PICO definitions (population, intervention, comparison, and outcome) of each included study and grouped studies by the type of therapy or support offered by the app. Whenever app design and clinical homogeneity allowed, we meta-analyzed outcomes using a random-effects model. Outcome data measured using categorical scales were synthesized using odds ratios. Outcome data measured using continuous scales were synthesized as the standardized mean difference. We assessed the methodological quality of each included study using the Cochrane Risk of Bias 2.0 tool and we assessed certainty of the evidence using the GRADE approach. Main Results: From 5280 unique citations, we included 36 RCTs published in 37 reports and conducted in 15 different countries (7984 participants). Among the 36 included trials, we assessed two with an overall low risk of bias, 8 trials with some concern regarding risk of bias, and 26 trials with a high risk of bias. Interventions varied in the type of therapy or supports offered. The most common intervention designs employed mindfulness training, cognitive behavioral therapy (CBT), or a combination of the two (mindfulness + CBT). However, other interventions also included self-monitoring, medication reminders, cognitive bias modification or positive stimulation, dialectical behavioral therapy, gamified health promotion, or social skill building. Mindfulness apps led to short term improvements in depressive symptoms when compared to a withheld control (SMD = -0.36; 95% CI [-0.63, -0.10]; p = 0.007, n = 3 RCTs, GRADE: very low certainty) and when compared to an active control (SMD = -0.27; 95% CI [-0.53, -0.01]; p = 0.04, n = 2 RCTs, GRADE: very low). Apps delivering this type of support also significantly improved symptoms of anxiety when compared to a withheld control (SMD = -0.35; 95% CI [-0.60, -0.09]; p = 0.008, n = 3 RCTs, GRADE: very low) but not when compared to an active control (SMD = -0.24; 95% CI [-0.50, 0.02]; p = 0.07, n = 2 RCTs, GRADE: very low). Mindfulness apps showed improvements in psychological stress that approached statistical significance among participants receiving the mindfulness mobile apps compared to those in the withheld control (SMD = -0.27; 95% CI [-0.56, 0.03]; p = .07, n = 4 RCTs, GRADE: very low). CBT apps also led to short-term improvements in depressive symptoms when compared to a withheld control (SMD = -0.40; 95% CI [-0.80, 0.01]; p = 0.05, n = 2 RCTs, GRADE: very low) and when compared to an active control (SMD = -0.59; 95% CI [-0.98, -0.19]; p = 0.003, n = 2 RCTs, GRADE: very low). CBT-based apps also improved symptoms of anxiety compared to a withheld control (SMD = -0.51; 95% CI [-0.94, -0.09]; p = 0.02, n = 3 RCTs, GRADE: very low) but not when compared to an active control (SMD = -0.26; 95% CI [-1.11, 0.59]; p = 0.55, n = 3 RCTs, GRADE: very low). Apps which combined mindfulness and CBT did not significantly improve symptoms of depression (SMD = -0.20; 95% CI [-0.42, 0.02]; p = 0.07, n = 2 RCTs, GRADE: very low) or anxiety (SMD = -0.21; 95% CI [-0.49, 0.07]; p = 0.14, n = 2 RCTs, GRADE: very low). However, these apps did improve psychological distress (SMD = -0.43; 95% CI [-0.74, -0.12]; p = 0.006, n = 2 RCTs, GRADE: very low). The results of trials on apps to reduce alcohol use were inconsistent. We did not identify any harms associated with the use of apps to manage mental health concerns. All effectiveness results had a very low certainty of evidence rating using the GRADE approach, meaning that apps which deliver therapy or other mental health support may reduce symptoms of depression, anxiety and psychological distress but the evidence is very uncertain. Authors' Conclusions: We reviewed evidence from 36 trials conducted among youth. According to our meta-analyses, the evidence is very uncertain about the effect of apps on depression, anxiety, psychological distress, and alcohol use. Very few effects were interpreted to be of clinical importance. Most of the RCTs were small studies focusing on efficacy for youth at risk for depressive symptoms. Larger trials are needed to evaluate effectiveness and allow for further analysis of subgroup differences. Longer trials are also needed to better estimate the clinical importance of these apps over the long term.
RESUMO
BACKGROUND: Adverse childhood experiences (ACEs), in combination with adverse community environments, can result in traumatic stress reactions, increasing a person's risk for chronic physical and mental health conditions. Family resilience refers to the ability of families to withstand and rebound from adversity; it involves coping with disruptions as well as positive growth in the face of sudden or challenging life events, trauma, or adversities. This study aimed to identify factors contributing to family and community resilience from the perspective of families who self-identified as having a history of adversity and being resilient during the COVID-19 pandemic. METHODS: This study used Photovoice, a visual participatory research method which asks participants to take photographs to illustrate their responses to a research question. Participants consisted of a maximum variation sample of families who demonstrated family level resilience in the context of the pair of ACEs during the COVID-19 pandemic. Family members were asked to collect approximately five images or videos that illustrated the facilitators and barriers to well-being for their family in their community. Semi-structured in-depth interviews were conducted using the SHOWeD framework to allow participants to share and elucidate the meaning of their photos. Using thematic analysis, two researchers then independently completed line-by-line coding of interview transcripts before collaborating to develop consensus regarding key themes and interpretations. RESULTS: Nine families were enrolled in the study. We identified five main themes that enhanced family resilience: (1) social support networks; (2) factors fostering children's development; (3) access and connection to nature; (4) having a space of one's own; and (5) access to social services and community resources. CONCLUSIONS: In the context of additional stresses related to the COVID-19 pandemic, resilient behaviours and strategies for families were identified. The creation or development of networks of intra- and inter-community bonds; the promotion of accessible parenting, housing, and other social services; and the conservation and expansion of natural environments may support resilience and health.
Assuntos
COVID-19 , Resiliência Psicológica , Criança , Humanos , Saúde da Família , Pandemias , Poder Familiar/psicologiaRESUMO
The study aimed to develop a sensitive and high-throughput liquid chromatography coupled with tandem mass spectrometry method to quantify concentrations of tramadol and paracetamol simultaneously in human plasma. Sample preparation involved single-step protein precipitation using methanol and two deuterated internal standards, tramadol D6 and paracetamol D4. Agilent Poroshell 120 EC-C18 (100 × 2.1 mm, 2.1 µm) analytical column was employed to achieve chromatographic separation. Detection was in positive ion multiple reaction monitoring mode. A tailing factor (Tf) of <1.2, separation factor (K prime) of >1.5 from the column dead time and signal-to-noise (S/N) ratio >10, were obtained for analytes and internal standards. The standard curve was linear over the concentration range of 2.5-500.00 ng/mL for tramadol and 0.025-20.00 µg/mL for paracetamol. A small injection volume of 1 µL, low flow rate of 440 µL/min and short analysis time of 3.5 min reduced the solvent consumption, analysis cost and system contamination. The results of method validation parameters fulfilled the acceptance criteria of bioanalytical guidelines. The method was successfully applied to a bioequivalence study of fixed-dose combination products of tramadol and paracetamol in Malaysian healthy subjects.
Assuntos
Tramadol , Humanos , Cromatografia Líquida , Tramadol/química , Espectrometria de Massas em Tandem/métodos , Acetaminofen , Cromatografia Líquida de Alta Pressão/métodos , Equivalência TerapêuticaRESUMO
BACKGROUND: Intrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into transplanted recipients across the placenta may directly influence donor-specific alloresponsiveness, limiting DCC. We hypothesized that dendritic cells (DC) among trafficked MMc influence the development of tolerogenic or immunogenic responses towards donor cells, and investigated if maternal DC-depletion reduced recipient alloresponsiveness and enhanced DCC. METHODS: Using transgenic CD11c.DTR (C57BL/6) female mice enabled transient maternal DC-depletion with a single dose of diphtheria toxin (DT). CD11c.DTR females and BALB/c males were cross-mated, producing hybrid pups. IUT was performed at E14 following maternal DT administration 24 h prior. Bone marrow-derived mononuclear cells were transplanted, obtained from semi-allogenic BALB/c (paternal-derived; pIUT), C57BL/6 (maternal-derived; mIUT), or fully allogenic (aIUT) C3H donor mice. Recipient F1 pups were analyzed for DCC, while maternal and IUT-recipient immune cell profile and reactivity were examined via mixed lymphocyte reactivity functional assays. T- and B-cell receptor repertoire diversity in maternal and recipient cells were examined following donor cell exposure. RESULTS: DCC was highest and MMc was lowest following pIUT. In contrast, aIUT recipients had the lowest DCC and the highest MMc. In groups that were not DC-depleted, maternal cells trafficked post-IUT displayed reduced TCR & BCR clonotype diversity, while clonotype diversity was restored when dams were DC-depleted. Additionally, recipients displayed increased expression of regulatory T-cells and immune-inhibitory proteins, with reduced proinflammatory cytokine and donor-specific antibody production. DC-depletion did not impact initial donor chimerism. Postnatal transplantation without immunosuppression of paternal donor cells did not increase DCC in pIUT recipients; however there were no donor-specific antibody production or immune cell changes. CONCLUSIONS: Though maternal DC depletion did not improve DCC, we show for the first time that MMc influences donor-specific alloresponsiveness, possibly by expanding alloreactive clonotypes, and depleting maternal DC promotes and maintains acquired tolerance to donor cells independent of DCC, presenting a novel approach to enhancing donor cell tolerance following IUT. This may have value when planning repeat HSC transplantations to treat haemoglobinopathies.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Feminino , Masculino , Gravidez , Animais , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Toxina Diftérica , Células Dendríticas , AloenxertosRESUMO
Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation. The objective of the current study was to develop a sensitive, fast and high-throughput HPLC-ESI-MS/MS method to measure etoricoxib levels in human plasma using a one-step methanol protein precipitation technique. A tandem mass spectrometer equipped with an electrospray ionization (ESI) source operated in a positive mode and multiple reaction monitoring (MRM) were used for data collection. The quantitative MRM transition ions were m/z 359.15 > 279.10 and m/z 363.10 > 282.10 for etoricoxib and IS. The linear range was from 10.00 to 4000.39 ng/mL and the validation parameters were within the acceptance limits of the European Medicine Agency (EMA) and Food and Drug Analysis (FDA) guidelines. The present method was sensitive (10.00 ng/mL with S/N > 40), simple, selective (K prime > 2), and fast (short run time of 2 min), with negligible matrix effect and consistent recovery, suitable for high throughput analysis. The method was used to quantitate etoricoxib plasma concentrations in a bioequivalence study of two 120 mg etoricoxib formulations. Incurred sample reanalysis results further supported that the method was robust and reproducible.
Assuntos
Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Etoricoxib , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Equivalência TerapêuticaRESUMO
OBJECTIVE: The study aimed to develop a rapid, simple and sensitive LC/ESI-MS/MS method to measure prazosin concentration in human plasma and apply bedside sampling in bioequivalence study of two prazosin tablets to resolve the adverse effect of orthostatic hypotension. SIGNIFICANCE: The LC/ESI-MS/MS prazosin method was highly sensitive and selective. Bedside sampling reduced the orthostatic hypotension incidence and subject dropout rate. METHODS: After sample preparation, prazosin and terazosin (IS) were detected on mass spectrometer operating in multiple reaction monitoring mode using positive ionization. Mobile phase flow rate was set at 0.40 mL/min with sample run time of 1.75 min. The bioanalytical method was validated as per EMEA and FDA guidelines. Bedside sampling was performed in bioequivalence study for the first 4 h after dosing. The three primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞ and 90% confidence interval were determined. RESULTS: The small injection volume of 1 µL minimized instrumentation contamination and prolonged the analytical column lifespan. Linearity was obtained between 0.5 and 30.0 ng/mL, with coefficient of determination, r2 ≥ 0.99. The mean extraction recovery of prazosin and IS was >92%, with precision value (CV, %) ≤ 10.3%. Only two orthostatic hypotension adverse events were reported. The two prazosin formulations were found to be bioequivalent. CONCLUSION: The LC/ESI-MS/MS method has shown robustness and reliability exemplified by the incurred sample re-analysis result. Bedside sampling should be proposed for bioequivalence or pharmacokinetic studies of drugs demonstrating adverse event of orthostatic hypotension.
Assuntos
Hipotensão Ortostática , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Equivalência Terapêutica , Reprodutibilidade dos Testes , Hipotensão Ortostática/induzido quimicamente , Prazosina/efeitos adversosRESUMO
The European Alliance of Associations for Rheumatology recently defined difficult to treat (D2T) rheumatoid arthritis (RA) and provided points to consider in its management. This review summarises the key concepts of D2T-RA that underpinned this recent guidance. D2T-RA is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. The basis for progressive disease, however, is not limited to clear inflammatory joint pathology, capturing wider contributors to treatment cycling such as comorbidity, obesity and fibromyalgia. This means D2T-RA comprises a heterogeneous population, with a proportion within this exhibiting bona fide treatment-refractory disease. The management points to consider, however, emphasise the importance of checking for the presence of inflammatory pathology before further treatment change. This review suggests additional considerations in the definition of D2T-RA, the potential value in identifying D2T traits and intervening before the development of D2T-RA state and the need for real world evidence of targeted synthetic DMARD in this population to compare to recent trial data. Finally, the review asks whether the presence of D2T-RA implies a failure to treat effectively from the outset, and the need for pharmacological and non-pharmacological management approaches to address the wider D2T-RA population effectively.
Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Reumatologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Produtos Biológicos/uso terapêutico , Comorbidade , HumanosRESUMO
A fast, selective and reproducible LC-MS/MS method with simple sample preparation was developed and validated for a polar compound, allopurinol in human plasma, using acyclovir as internal standard (IS). Chromatographic separation was achieved using Agilent Poroshell 120 EC-C18 (100 × 2.1â mmID, 2.7â µm) analytical column. The mobile phase was comprised of 0.1%v/v formic acid-methanol (95:05; v/v), at a flow rate of 0.45â mL/min. The effect of different protein precipitation agents used in sample preparation such as methanol, acetonitrile, a mixture of acetonitrile-methanol and a mixture of acetonitrile-acetone were evaluated to optimize the extraction efficiency of allopurinol and IS. The use of acetone-acetonitrile (50:50, v/v) as protein precipitating agent shortened the sample preparation time and improved the recovery of allopurinol to above 93%. The IS-normalised matrix factors at two concentration levels were 1.0, with CV of 5.1% and 4.2%. Allopurinol in plasma was stable at benchtop for 24â h, in autosampler tray for 48â h, in instrumentation room for 48â h, in freezer after 7 freeze-thaw cycles and in freezer for 140 days. Allopurinol stock standard solutions were stable for 140 days at room temperature and in the chiller. The short sample run time of the validated bioanalytical method allowed high throughput analysis of plasma samples in pharmacokinetic study of an allopurinol formulation. The robustness and reproducibility of the bioanalytical method was reaffirmed through incurred sample reanalysis (ISR).
Assuntos
Alopurinol , Espectrometria de Massas em Tandem , Acetona , Acetonitrilas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Humanos , Metanol , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND AND OBJECTIVES: To develop a digital communication tool to improve the implementation of up-to-date COVID-19 recommendations. Specifically, to improve patient, caregiver and public understanding of healthcare recommendations on prevention, diagnoses and treatment. METHODS: Multi-stakeholder engagement design. In conjunction with the COVID-19 Recommendations and Gateway to Contextualization RecMap, we co-developed a stakeholder prioritization, drafting and editing process to enhance guideline communication and understanding. RESULTS: This paper presents the multi-stakeholder development process with three distinct plain language recommendation formats: formal recommendation, good practice statement, and additional guidance. Our case study of COVID-19 plain language recommendations PLRs addresses both public health interventions (e.g., vaccination, face masks) and clinical interventions (e.g., home pulse oximetry). CONCLUSION: This paper presents a novel approach to engaging stakeholders in improving the communication and understanding of published guidelines during the COVID-19 pandemic.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Cuidadores , Máscaras , Saúde PúblicaRESUMO
Refugees and asylum seekers often face delayed mental health diagnoses, treatment, and care. COVID-19 has exacerbated these issues. Delays in diagnosis and care can reduce the impact of resettlement services and may lead to poor long-term outcomes. This scoping review aims to characterize studies that report on mental health screening for resettling refugees and asylum seekers pre-departure and post-arrival to a resettlement state. We systematically searched six bibliographic databases for articles published between 1995 and 2020 and conducted a grey literature search. We included publications that evaluated early mental health screening approaches for refugees of all ages. Our search identified 25,862 citations and 70 met the full eligibility criteria. We included 45 publications that described mental health screening programs, 25 screening tool validation studies, and we characterized 85 mental health screening tools. Two grey literature reports described pre-departure mental health screening. Among the included publications, three reported on two programs for women, 11 reported on programs for children and adolescents, and four reported on approaches for survivors of torture. Programs most frequently screened for overall mental health, PTSD, and depression. Important considerations that emerged from the literature include cultural and psychological safety to prevent re-traumatization and digital tools to offer more private and accessible self-assessments.
Assuntos
COVID-19 , Refugiados , Transtornos de Estresse Pós-Traumáticos , Tortura , Adolescente , COVID-19/diagnóstico , COVID-19/epidemiologia , Criança , Feminino , Humanos , Saúde Mental , Refugiados/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Tortura/psicologiaRESUMO
Background: Depressive symptoms and alcohol use in youth doubled in the first year of the COVID-19 pandemic. The COVID-19 pandemic has created sustained disruption in society, schools, and universities, including increasing poverty and discrimination. Public health restrictions have caused isolation and reduced social and emotional support. Together, these factors make depressive symptoms and alcohol use in youth a global public health emergency. Mobile applications (apps) have emerged as potentially scalable intervention to reduce depressive symptoms and alcohol use in youth that could meet increased demands for mental health resources. Mobile apps may potentially reduce psychological distress with accessible technology-based mental health resources. Objectives: This systematic review and meta-analysis aims to assess the effect of mobile apps on depressive symptoms and alcohol use in youth. Search Methods: We will develop a systematic search strategy in collaboration with an experienced librarian. We will search a series of databases (MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL) from January 2008 to July 2021. Selection Criteria: Following the PRISMA reporting guidelines for systematic reviews, two independent reviewers will identify eligible studies: randomized controlled trials on mobile apps for the management of depressive disorders (depression and anxiety) and alcohol use in youth aged 15-24 years of age. Data Collection and Analysis: Eligible studies will be assessed for risk of bias, and outcomes pooled, when appropriate, for meta-analysis. Heterogeneity, if present, will be examined for gender. ethnicity, and socioeconomic status contributions. A narrative synthesis will highlight similarities and differences between the included studies. We will report GRADE summary of finding tables.
RESUMO
Aim: To develop an LC-MS/MS method for simultaneous determination of duloxetine and its metabolite, 4-hydroxy duloxetine glucuronide (4HDG) in human plasma and to investigate the potential back-conversion of 4HDG to duloxetine using stability study. Materials & methods: The LC-MS/MS method was validated according to the EMA and USFDA Bioanalytical Method Validation Guidelines and applied to pilot bioequivalence study. Results & conclusion: The method validation results were within the acceptance limits. The stability study and incurred sample reanalysis results ruled out the occurrence of back-conversion. The study highlighted the conduct of back-conversion test and the advantages of LC-MS/MS method in terms of sensitivity, specificity and low consumption of organic solvents.
Assuntos
Cromatografia Líquida de Alta Pressão , Cloridrato de Duloxetina/sangue , Espectrometria de Massas em Tandem , Adolescente , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/normas , Cloridrato de Duloxetina/administração & dosagem , Cloridrato de Duloxetina/farmacocinética , Cloridrato de Duloxetina/normas , Glucuronídeos/química , Meia-Vida , Humanos , Controle de Qualidade , Curva ROC , Espectrometria de Massas em Tandem/normas , Equivalência Terapêutica , Adulto JovemRESUMO
A simple, fast and sensitive LC-MS/MS method was developed to quantify terazosin in human plasma. The mobile phase consisted of acetonitrile-0.1% (v/v) formic acid (70:30, v/v). Prazosin was used as internal standard (IS). As deproteinization agent, acetonitrile produced a clean sample. A higher response intensity with more symmetrical peak was obtained using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7 µm) compared with Kinetex XB-C18 (100 × 2.1 mm, 2.6 µm) column. The response of terazosin and IS were approximately two times in citrate phosphate dextrose (CPD) plasma compared with dipotassium ethylenediaminetetraacetic acid (K2EDTA) plasma. Plasma calibration curve was linear from 1.0 to 100.0 ng/mL, with coefficient of determination r2 ≥ 0.99. The within-run and between-run precision values (CV, %) were <5.2% and <7.8%, while accuracy values were 102.8-112.7% and 103.4-112.2%. The extended run accuracy was 98.6-102.8% and precision (CV, %) 4.3-10.4%. The recovery of analyte was >98% and IS >94%. Terazosin in plasma kept at benchtop was stable for 24 h, in autosampler tray for 48 h, in instrumentation room for 48 h, for 7 freeze-thaw cycles and in freezer for 140 days. Terazosin and IS stock standard solutions were stable for 140 days at room temperature and in the chiller. The high throughput method was successfully utilized to measure 935 samples in a bioequivalence study of terazosin.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Prazosina/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Administração Oral , Adolescente , Adulto , Estudos Cross-Over , Ensaios de Triagem em Larga Escala , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Prazosina/administração & dosagem , Prazosina/sangue , Prazosina/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Equivalência Terapêutica , Adulto JovemRESUMO
OBJECTIVE: The aim of the study was to develop a simple, highthroughput and sensitive LC-MS/MS method and apply to a bioequivalence study of montelukast, a light sensitive drug. METHOD: The effects of organic modifiers in mobile phase, protein precipitation agent to plasma sample ratio, and light on montelukast stability in unprocessed and processed human plasma, were evaluated. Validation was conducted in accordance with European Medicines Agency Guideline on bioanalytical method validation. RESULTS: No interference peak was observed when acetonitrile was used as an organic modifier. Acetonitrile to plasma ratio of 4:1 produced clean plasma sample. Approximately 3 % of cis isomer was detected in unprocessed plasma samples while 21 % of cis isomer was detected in processed plasma samples after exposing to fluorescent light for 24h. The standard calibration curve was linear over 3.00-1200.00 ng/mL. All method validation parameters were within the acceptance criteria. CONCLUSION: The validated method was successfully applied to a bioequivalence study of two montelukast formulations involving 24 healthy Malaysian volunteers. The light stability of a light sensitive drug in unprocessed and processed human plasma samples should be studied prior to pharmacokinetic/bioequivalence studies. Measures could then be taken to protect the analyte in human plasma from light degradation.
Assuntos
Acetatos/farmacologia , Ciclopropanos/farmacologia , Preparações Farmacêuticas , Quinolinas/farmacologia , Sulfetos/farmacologia , Espectrometria de Massas em Tandem , Acetatos/química , Cromatografia Líquida , Ciclopropanos/química , Humanos , Quinolinas/química , Reprodutibilidade dos Testes , Sulfetos/química , Equivalência TerapêuticaRESUMO
A simple, rapid, sensitive, and reproducible LC-MS/MS method was developed for simultaneous quantification of flavoxate and 3-methyl-flavone-8-carboxylic (MFCA) in human plasma, using diphenhydramine HCl as internal standard (IS). The chromatographic separation was achieved using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7 µm) fitted with UHPLC Guard Poroshell 120 EC-C18 (5 × 2.1 mmID, 2.7 µm). The mobile phase consisted of 0.1 % v/v formic acid and acetonitrile (30:70, v/v) run at a flow rate of 0.40 mL/min. The standard calibration curve was linear over the concentration range of 2.00 - 2,000.31 ng/mL and 240.00 - 24,000.04 ng/mL for flavoxate and MFCA. For flavoxate and MFCA, the within-run precision was 0.81-6.67 % and 1.68-4.37 %, while accuracy was 100.21-108.25 % and 103.99-110.28 %. The between-run precision was 2.01-9.14 % and 2.31-11.11 %, and accuracy was 96.09-103.33 % and 102.37-109.52 %. The extended run precision was 7.78-11.04 % and 2.22-3.33 %, while accuracy was 100.72-101.88 % and 102.34-105.60 %. Flavoxate and MFCA in plasma were stable 4 h at bench top (short term), 24 h in autosampler and instrumentation room (post-preparative), after 7 freeze-thaw cycles, and 89 days in the freezer. Both analytes and IS stock solutions were stable for 31 days when kept at room temperature (25 ± 4 °C) and refrigerated (2-8 °C). The validated method was successfully applied to a bioequivalence study of two flavoxate formulations involving 24 healthy volunteers.
Assuntos
Flavoxato , Espectrometria de Massas em Tandem , Ácidos Carboxílicos , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Equivalência TerapêuticaRESUMO
A simple, rapid, sensitive, and reproducible liquid chromatography-tandem mass spectrometry method was developed to determine sitagliptin in human plasma. Diphenhydramine HCl was used as internal standard (IS). The chromatographic separation was achieved using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7) fitted with UHPLC Guard Poroshell 120 EC-C18 (5 × 2.1mmID, 2.7 µm). The mobile phase consisted of 0.1% v/v formic acid and methanol (45:55, v/v) run at a flow rate of 0.45 mL/min at 30 °C. Methanol produced relatively cleaner plasma sample as deproteinization agent. Polytetrafluoroethylene membrane was preferred over nylon membrane as the former produced clear plasma samples. The standard calibration curve was linear over the concentration range of 5-500.03 ng/mL. The within-run precision was 0.53-7.12% and accuracy 87.09-105.05%. The between-run precision was 4.74-11.68% and accuracy 95.02-97.36%. The extended run precision was 3.60-6.88% and accuracy 93.18-95.82%. The recovery of analyte and IS was consistent. Sitagliptin in plasma was stable at benchtop (short term) for 24 h, in autosampler tray for 48 h, in instrumentation room for 48 h (post-preparative), after 7 freeze-thaw cycles (-20 ± 10 °C), and 62 days in the freezer (-20 ± 10 °C). Both sitagliptin (analyte) and IS stock solutions were stable for 62 days when kept at room temperature (25 ± 4 °C) and in chiller (2-8 °C). The validated method was successfully applied to a bioequivalence study of two sitagliptin formulations involving 26 healthy Malaysian volunteers.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fosfato de Sitagliptina/sangue , Fosfato de Sitagliptina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fosfato de Sitagliptina/química , Equivalência Terapêutica , Adulto JovemRESUMO
Even though many GyrB and ParE inhibitors have been reported in the literature, few possess activity against Gram-negative bacteria. This is primarily due to limited permeability across Gram-negative bacterial membrane as well as bacterial efflux mechanisms. Permeability of compounds across Gram-negative bacterial membranes depends on many factors including physicochemical properties of the inhibitors. Herein, we show the optimization of pyridylureas leading to compounds with potent activity against Gram-negative bacterial species such as P.aeruginosa, E.coli and A.baumannii.