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BACKGROUND AND MAIN BODY: Pharmacokinetics (PK) and pharmacodynamics (PD) are central concepts to guide the dosage and administration of drug therapies and are essential to consider for both healthcare professionals and researchers in therapeutic planning and drug discovery. PK/PD properties of a drug significantly influence variability in response to treatment, including therapeutic failure or excessive medication-related harm. Furthermore, suboptimal PK properties constitute a significant barrier to further development for some candidate treatments in drug discovery. This article describes how extracellular vesicles (EVs) affect different aspects of PK and PD of medications and their potential to modulate PK and PD properties to address problematic PK/PD profiles of drugs. We reviewed EVs' intrinsic effects on cell behaviours and medication responses. We also described how surface and cargo modifications can enhance EV functionalities and enable them as adjuvants to optimise the PK/PD profile of conventional medications. Furthermore, we demonstrated that various bioengineering strategies can be used to modify the properties of EVs, hence enhancing their potential to modulate PK and PD profile of medications. CONCLUSION: This review uncovers the critical role of EVs in PK and PD modulation and motivates further research and the development of assays to unfold EVs' full potential in solving PK and PD-related problems. However, while we have shown that EVs play a vital role in modulating PK and PD properties of medications, we postulated that it is essential to define the context of use when designing and utilising EVs in pharmaceutical and medical applications. HIGHLIGHTS: Existing solutions for pharmacokinetics and pharmacodynamics modulation are limited. Extracellular vesicles can optimise pharmacokinetics as a drug delivery vehicle. Biogenesis and administration of extracellular vesicles can signal cell response. The pharmaceutical potential of extracellular vesicles can be enhanced by surface and cargo bioengineering. When using extracellular vesicles as modulators of pharmacokinetics and pharmacodynamics, the 'context of use' must be considered.
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Vesículas Extracelulares , Vesículas Extracelulares/efeitos dos fármacos , Humanos , FarmacocinéticaRESUMO
OBJECTIVES: To investigate the current literature on healthcare policies and cost analyses around international Voluntary Assisted Dying (VAD) laws. The study design is a mapping literature review following Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses (PRISMA) guidelines. METHODS: Original research articles published between January 1990 to March 2023, investigating the financial cost and healthcare budget effect of VAD laws internationally. Citations were screened for relevance and eligibility, and any non-full-text research that did not explore cost analysis was excluded. The following data sources were screened: MEDLINE, PubMed, EMBASE, CINAHL and any relevant international health authority annual reports were also reviewed. RESULTS: Of the 2790 screened articles, eight studies met the inclusion criteria and three were included in the mapping review. The reviewed studies included prospective studies, two Canadian and one US. Only one of the Canadian studies provided a cost analysis using data from current VAD laws. All three studies showed VAD laws would reduce healthcare spending, with the US approximating $627million in 1995. Canada approximating $17.1 to $77.1million in 2017 and $86.9 to $149.0million in 2021, overall, leading to an average percentage reduction in costs of approximately 87% compared to original costs of end-of-life care. CONCLUSION: This review identifies a scarcity in cost-analysis literature and provides a summary of the latest international VAD laws, from which a potential cost reduction is apparent. The absence of retrospectively collated financial VAD data highlights a need for future research to inform policymakers of the economic factors affecting current policies with a need for annual fiscal reports and to optimise future legislative frameworks internationally.
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BACKGROUND AND OBJECTIVE: Although paracetamol (acetaminophen) combined with other analgesics can reduce pain intensity in some pain conditions, its effectiveness in managing low back pain and osteoarthritis is unclear. This systematic review investigated whether paracetamol combination therapy is more effective and safer than monotherapy or placebo in low back pain and osteoarthritis. METHODS: Online database searches were conducted for randomised trials that evaluated paracetamol combined with another analgesic compared to a placebo or the non-paracetamol ingredient in the combination (monotherapy) in low back pain and osteoarthritis. The primary outcome was a change in pain. Secondary outcomes were (serious) adverse events, changes in disability and quality of life. Follow-up was immediate (≤ 2 weeks), short (> 2 weeks but ≤ 3 months), intermediate (> 3 months but < 12 months) or long term (≥ 12 months). A random-effects meta-analysis was conducted. Risk of bias was assessed using the original Cochrane tool, and quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Twenty-two studies were included. Pain was reduced with oral paracetamol plus a non-steroidal anti-inflammatory drug (NSAID) at immediate term in low back pain (paracetamol plus ibuprofen vs ibuprofen [mean difference (MD) - 6.2, 95% confidence interval (CI) -10.4 to -2.0, moderate evidence]) and in osteoarthritis (paracetamol plus aceclofenac vs aceclofenac [MD - 4.7, 95% CI - 8.3 to - 1.2, moderate certainty evidence] and paracetamol plus etodolac vs etodolac [MD - 15.1, 95% CI - 18.5 to - 11.8; moderate certainty evidence]). Paracetamol plus oral tramadol reduced pain compared with placebo at intermediate term for low back pain (MD - 11.7, 95% CI - 19.2 to - 4.3; very low certainty evidence) and osteoarthritis (MD - 6.8, 95% CI - 12.7 to -0.9; moderate certainty evidence). Disability scores improved in half the comparisons. Quality of life was infrequently measured. All paracetamol plus NSAID combinations did not increase the risk of adverse events compared to NSAID monotherapy. CONCLUSIONS: Low-to-moderate quality evidence supports the oral use of some paracetamol plus NSAID combinations for short-term pain relief with no increased risk of harm for low back pain and osteoarthritis compared to its non-paracetamol monotherapy comparator.
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Acetaminofen , Analgésicos não Narcóticos , Anti-Inflamatórios não Esteroides , Quimioterapia Combinada , Dor Lombar , Osteoartrite , Acetaminofen/uso terapêutico , Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Humanos , Osteoartrite/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Analgésicos não Narcóticos/uso terapêutico , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/efeitos adversos , Dor Lombar/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Qualidade de Vida , Ibuprofeno/administração & dosagem , Ibuprofeno/uso terapêutico , Ibuprofeno/efeitos adversos , Dor nas Costas/tratamento farmacológicoRESUMO
The duration of treatment for which a physician may prescribe a medicine, 'prescription duration', is often dispensed at the pharmacy on multiple occasions of shorter time periods, 'dispensing duration'. These durations vary significantly between and within countries. In Australia, the quantity of medication supplied at each dispensing has recently been extended from 30 to 60 days for a selection of medicines used for chronic health conditions, such as diabetes and hypertension. Dispensing durations vary between countries, with 30, 60 or 90 days being the most common-with 90 days aligning with the recommendation of the 2023 Global Report on Hypertension from the World Health Organization. The full impact of shorter vs longer prescription durations on health costs and outcomes is unknown, but current evidence suggests that 90-day dispensing could reduce costs and improve patient convenience and adherence. More rigorous research is needed.
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Anti-Hipertensivos , Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Austrália , Doença Crônica/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Política de Saúde , Prescrições de Medicamentos/estatística & dados numéricosRESUMO
BACKGROUND: Multimodal analgesia regimens are recommended for the postoperative period after hip and knee replacement surgeries. However, there are no data on practice patterns for analgesic use in the immediate postoperative period after hip and knee replacements in Australia. OBJECTIVES: To describe analgesic prescribing patterns in the inpatient postoperative phase for patients undergoing hip and knee replacement. METHODS: Retrospective study of electronic medical record data from two major hospitals in Sydney, Australia. We identified analgesic medication prescriptions for all patients aged 18 years and older who underwent hip or knee replacement surgery in 2019. We extracted data on pain medications prescribed while in the ward up until discharge. These were grouped into distinct categories based on the Anatomical Therapeutic Chemical classification. We described the frequency (%) of pain medications used by category and computed the average oral morphine equivalent daily dose (OMEDD) during hospitalisation. RESULTS: We identified 1282 surgeries in 1225 patients. Patients had a mean (SD) age of 69 (11.8) years; most (57.1%) were female. Over 99% of patients were prescribed opioid analgesics and paracetamol during their hospital stay. Most patients (61.4%) were managed with paracetamol and opioids only. The most common prescribed opioid was oxycodone (87.3% of patients). Only 19% of patients were prescribed nonsteroidal anti-inflammatories (NSAIDs). The median (IQR) average daily OMEDD was 50.2 mg (30.3-77.9). CONCLUSION: We identified high use of opioids analgesics as the main strategies for pain control after hip and knee replacement in hospital. Other analgesics were much less frequently used, such as NSAIDs, and always in combination with opioids and paracetamol.
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Analgésicos Opioides , Cervicalgia , Humanos , Cervicalgia/tratamento farmacológico , Cervicalgia/etiologia , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Dor nas Costas/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.
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Bussulfano , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Humanos , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Bussulfano/farmacocinética , Bussulfano/administração & dosagem , Condicionamento Pré-Transplante/métodos , Masculino , Transplante de Células-Tronco Hematopoéticas/métodos , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Resultado do Tratamento , Estudos Retrospectivos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vidarabina/administração & dosagem , Tiotepa/uso terapêutico , Tiotepa/administração & dosagem , Tiotepa/farmacocinética , Intervalo Livre de Doença , Seguimentos , Doenças Hematológicas/terapia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/administração & dosagemRESUMO
Background: Conscientious objection (CO) in healthcare is a controversial topic. Some perceive CO as freedom of conscience, others believe their professional duty-of-care overrides personal-perspectives. There is a paucity of literature pertaining to pharmacists' perspectives on CO. Aim: To explore Australian pharmacists' decision-making in complex scenarios around CO and reasons for their choices. Method: A cross-sectional, qualitative questionnaire of pharmacists' perspectives on CO. Vignette-based questions were about scenarios related to medical termination, emergency contraception, IVF surrogacy for a same-sex couple and Voluntary Assisted Dying (VAD) Results: Approximately half of participants (n = 223) believed pharmacists have the right to CO and most agreed to supply prescriptions across all vignettes. However, those who chose not to supply (n = 20.9%), believed it justifiable, even at the risk of patients failing to access treatment. Strong self-reported religiosity had a statistically significant relationship with decisions not to supply for 3 of 4 vignettes. Three emergent themes included: ethical considerations, the role of the pharmacist and training and guidance. Conclusion: This exploratory study revealed perspectives of Australian pharmacists about a lack of guidance around CO in pharmacy. Findings highlighted the need for future research to investigate and develop further training and professional frameworks articulating steps to guide pharmacists around CO.
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BACKGROUND: Exercise buddies (people to exercise together with) might support people with low back pain (LBP) to become active. However, involving buddies in randomised controlled trials (RCT) might challenge recruitment, data collection and follow-up. OBJECTIVES: To explore the feasibility of the intervention, recruitment and data collection approaches and potential effects of a health coaching intervention (focused on physical activity) with or without exercise buddies' support on physical activity of people with chronic LBP versus usual discharge care. DESIGN: Feasibility and pilot RCT. METHODS: Adults (n = 30) discharged from LBP treatment were randomised to the Buddy-Assisted (health coaching intervention with exercise buddy's support), Individual-Only (health coaching only), or usual care groups. Data were collected at baseline, three and six months. The feasibility of trial's procedures was assessed through recruitment rate (acceptable if >70%), data completion rate (acceptable if ≤ 20% missing data), and follow-up rate (successful if ≥ 85%). The intervention's acceptability was assessed via feedback questionnaires. Preliminary effects on physical activity and other outcomes were also explored. RESULTS: Recruitment and baseline data completion were acceptable. However, data collection and follow-up rates post-randomisation were not. 85% of the Buddy-Assisted Group believed the buddies helped them to increase physical activity and would recommend the intervention. 70% of the Individual-Only and Control groups believed exercise buddies would help them to become further active. CONCLUSION: The data collection and follow-up approaches were not successful and need amending before a large-scale RCT. Nonetheless, the buddy-assisted intervention was well-accepted. A future RCT will focus on differences in clinical outcomes. TRIAL REGISTRATION: The study was registered at the Australian New Zealand Clinical Trial Registry (ACTRN12620001118998).
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Terapia por Exercício , Estudos de Viabilidade , Dor Lombar , Humanos , Dor Lombar/terapia , Dor Lombar/psicologia , Masculino , Feminino , Projetos Piloto , Adulto , Pessoa de Meia-Idade , Terapia por Exercício/métodos , Exercício Físico , Tutoria/métodos , Dor Crônica/terapia , Dor Crônica/psicologiaRESUMO
INTRODUCTION: Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. OBJECTIVES: To evaluate the concentration-efficacy relationship, concentration-toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. METHODS: We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0-18â
years. Review articles, case series of
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Anfotericina B , Antifúngicos , Monitoramento de Medicamentos , Humanos , Anfotericina B/farmacocinética , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Criança , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Pré-Escolar , Adolescente , Lactente , Recém-Nascido , Aspergilose/tratamento farmacológico , Testes de Sensibilidade MicrobianaRESUMO
OBJECTIVES: Therapeutic drug monitoring allows personalized dosing of chemotherapy, but is not well established for capecitabine. The aim of this study was to compare the concentrations of capecitabine and its metabolites obtained simultaneously by microsampling with plasma sampling and their acceptability to patients. METHODS: Adults taking capecitabine for cancer had paired (duplicate) microsampling at steady state (hour 2 post dose) using Mitra® devices and venous blood samples for analysis. Capecitabine and metabolites were measured using a validated mass spectrometry assay. Correlation between the sampling methods was determined. Patients' preferences were elicited using a Likert numeric rating scale and pain by a Visual Analog Scale (range, 0-10). KEY FINDINGS: Capecitabine concentrations from 10 patients (60 paired samples) by microsampling and plasma sampling were highly correlated (Pearson correlation: 0.97, Coefficients of determination: 0.94, P < 0.0001). Capecitabine concentrations in capillary sampling were consistently lower than the paired plasma concentration (median capecitabine capillary/plasma concentration ratio = 2851/3846 µg/l 75%). The agreement between sampling matrices showed a 28% bias (95% Cl, 4.02-52.00). Participant ratings showed microsampling was the preferred method by all 10 patients. Most participants reported no pain with microsampling (median 0, range 0-1). CONCLUSION: Capecitabine concentration measured by microsampling and plasma sampling were highly correlated, but consistently lower in microsampling. Microsampling was the preferred method with minimal pain.
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Coleta de Amostras Sanguíneas , Monitoramento de Medicamentos , Adulto , Humanos , Projetos Piloto , Capecitabina , Coleta de Amostras Sanguíneas/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , DorRESUMO
Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.
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Analgésicos Opioides , Dor do Câncer , Humanos , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Dor Nociceptiva/tratamento farmacológico , Neoplasias/complicações , Manejo da Dor/métodosRESUMO
INTRODUCTION: Understanding what the most effective and safe non-steroidal anti-inflammatory drug (NSAID) is for managing osteoarthritis (OA) is complicated. OA is prevalent worldwide and people living with OA commonly have multiple comorbidities. The efficacy and safety of NSAIDs in a patient are influenced by their intrinsic and extrinsic factors. Current guidelines recommend the lowest dose for the shortest duration, monitoring patients for risk factors and comorbidities but generally do not specify, which NSAID is most suitable for a patient with specific comorbidities. AREAS COVERED: This paper looks at the mechanism of action of all NSAIDs and reviews the current literature concerning their safety in patients with and without comorbidities. Relevant publications were identified by searching PubMed and Cochrane Library using key terms. The search was conducted from inception to 18 July 2023 and included results published before 18 July 2023. The search results and their references were then manually reviewed. EXPERT OPINION: In the paper, we determine whether the current practice of 'lowest dose for shortest duration' is in fact the best approach for prescribing NSAIDs and identify which NSAIDs are most suitable given a patient's risk factors and comorbidities. Our aim is to help guide health professionals in recommending the most suitable NSAID for each patient.
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Anti-Inflamatórios não Esteroides , Osteoartrite , Humanos , Anti-Inflamatórios não Esteroides/efeitos adversos , Osteoartrite/tratamento farmacológico , Osteoartrite/induzido quimicamente , Comorbidade , Fatores de RiscoRESUMO
PURPOSE: The primary objective was to determine the proportion of hospitals that administered norepinephrine peripheral vasopressor infusions (PVIs) in critically ill adult patients. Secondary objectives were to describe how norepinephrine is used such as the maximum duration, infusion rate and concentration, and to determine the most common first-line PVI used by country. MATERIALS AND METHODS: An international multi-centre cross-sectional survey study was conducted in adult intensive care units in Australia, US, UK, Canada, and Saudi Arabia. RESULTS: Critical care pharmacists from 132 institutions responded to the survey. Norepinephrine PVIs were utilised in 86% of institutions (n = 113/132). The median maximum duration of norepinephrine PVIs was 24 h (IQR 24-24) (n = 57/113). The most common maximum norepinephrine PVI rate was between 11 and 20 µg/min (n = 16/113). The most common maximum norepinephrine PVI concentration was 16 µg/mL (n = 60/113). Half of the institutions had a preference to administer another PVI over norepinephrine as a first-line agent (n = 66/132). The most common alternative PVI used by country was: US (phenylephrine 41%, n = 37/90), Canada (dopamine 31%, n = 5/16), UK (metaraminol 82%, n = 9/11), and Australia (metaraminol 89%, n = 8/9). CONCLUSIONS: There is variability in clinical practice regarding PVI administration in critically ill adult patients dependent on drug availability and local institutional recommendations.
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Metaraminol , Farmácia , Adulto , Humanos , Estado Terminal , Estudos Transversais , Vasoconstritores/uso terapêutico , Norepinefrina/uso terapêutico , Cuidados CríticosRESUMO
BACKGROUND: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. METHODS: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). FINDINGS: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI -0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). INTERPRETATION: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. FUNDING: National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and SafeWork SA.
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Dor Aguda , Analgesia , Dor Lombar , Adulto , Humanos , Masculino , Feminino , Adolescente , Analgésicos Opioides/efeitos adversos , Oxicodona/efeitos adversos , Dor Lombar/tratamento farmacológico , Cervicalgia/tratamento farmacológico , Austrália , Dor Aguda/tratamento farmacológicoRESUMO
OBJECTIVES: Annona muricata, also known as graviola, is traditionally used for the treatment of a range of disorders including cancer. Interest in A. muricata use has increased in recent years. This study investigated the quality and safety of a selection of commercially available A. muricata leaf products. METHODS: Seven commercially available products were purchased via online shopping sites. Each product was assessed for quality indicators including weight variation, quantification of the bioactive constituent annonacin, presence of annonaceous acetogenins and contaminants. The samples were evaluated by thin-layer chromatography, high-performance liquid chromatography, liquid chromatography-mass spectroscopy, low-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Microbial analysis was carried out in accordance with the British Pharmacopoeia. Heavy metals were analysed by inductive coupled plasma mass spectrometry. KEY FINDINGS: Of the seven products analysed, one product contained less than half of the content stated on the label. The labelled dosage recommendation varied between products. There was a high variation in annonacin concentration (1.05-3.09 mg/g) and the presence of annonaceous acetogenins. One of the products was found to have a total aerobic microbial count above the United States Pharmacopoeia limit. CONCLUSIONS: The variation in the indicators of quality and safety of commercially available A. muricata leaf products tested have implications for clinicians and people living with cancer who use these herbal products.
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Annona , Neoplasias , Humanos , Acetogeninas/análise , Acetogeninas/química , Annona/química , Folhas de Planta/química , Extratos Vegetais/análiseRESUMO
We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady-state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUCss , Css,min and Css,max for patients with CML (n = 68) from a real-world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal-Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC0-24,ss 51.2 vs. 42.7 µg h mL-1 , p < 0.05; Css,min 1.1 vs. 0.9 µg mL-1 , p < 0.05; Css,max 3.4 vs. 2.8 µg mL-1 , p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC0-24,ss 56.1 vs. 45.9 µg h mL-1 , p < 0.05; Css,min 1.2 vs. 1.0 µg mL-1 , p < 0.05; Css,max 3.7 vs. 3.0 µg mL-1 , p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α1 -acid glycoprotein concentrations, liver and kidney function) and medication-related factors (dose, concomitant CYP2C8 modulators) contributing to the inter-individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/farmacocinética , Citocromo P-450 CYP2C8 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Citocromo P-450 CYP3ARESUMO
PURPOSE: To determine: (1) the smallest change in function patients would need to see following a self-management intervention for low back pain (LBP) to consider it worthwhile; (2) the association between patient-related factors and the magnitude of the smallest worthwhile change. METHODS: A cross-sectional analysis of 212 participants of the TEXT4myBACK randomised trial was conducted. At baseline, participants nominated the smallest change in function (0-30 scale) following a self-management program they would need to reach to consider it worthwhile. A multivariate regression model estimated the effects of demographic, comorbidities, lifestyle and LBP-related factors on the smallest worthwhile change estimates. RESULTS: On average, people with LBP need to experience an improvement of at least 9.4 points (SD: 5.7) in function to consider a self-management intervention worthwhile. Only baseline function severity was significantly associated with the smallest worthwhile estimate (-0.60; 95%CI - 0.76, - 0.44). CONCLUSION: On average, an improvement of 9.4 points (or 31%) in function is considered by people with LBP as the smallest change that makes self-management worthwhile. Those with lower levels of function needed to experience greater improvements.