RESUMEN
INTRODUCTION: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel. METHODS: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay. RESULTS: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at -60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay. CONCLUSION: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience.
RESUMEN
The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. METHODS: A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. RESULTS: The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. CONCLUSION: The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.
Asunto(s)
Administración Intravenosa , Docetaxel , Modelos Biológicos , Docetaxel/farmacocinética , Docetaxel/administración & dosificación , Humanos , Administración Oral , Área Bajo la Curva , Masculino , Simulación por Computador , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Equivalencia Terapéutica , Femenino , Persona de Mediana EdadRESUMEN
BACKGROUND: The N-methyl-D-aspartate antagonist ketamine has rapid onset antidepressant activity in treatment-resistant depression (TRD). AIMS: To evaluate mood rating, safety and tolerability data from patients with TRD treated with ketamine and the psychoactive control fentanyl, as part of a larger study to explore EEG biomarkers associated with mood response. METHODS: We evaluated the efficacy and safety of intramuscular racemic ketamine in 25 patients with TRD, using a double-blind active-controlled randomized crossover design. Ketamine doses were 0.5 and 1 mg/kg, and the psychoactive control was fentanyl 50 mcg, given at weekly intervals. RESULTS/OUTCOMES: Within 1 h of ketamine dosing, patients reported reduced depression and anxiety ratings, which persisted for up to 7 days. A dose-response profile for ketamine was noted for dissociative side effects, adverse events and changes in blood pressure; however, changes in mood ratings were broadly similar for both ketamine doses. Overall, 14/25 patients (56%) were responders (⩾50% reduction at 24 h compared with baseline) for either ketamine dose for the Hospital Anxiety and Depression Scale (HADS), and 18/25 (72%) were responders for the HADS-anxiety scale. After fentanyl, only 1/25 (HADS-depression) and 3/25 (HADS-anxiety) were responders. Ketamine was generally safe and well tolerated in this population. CONCLUSIONS: Our findings add to the literature confirming ketamine's activity against depressive and anxiety symptoms in patients with TRD.
Asunto(s)
Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Ketamina , Humanos , Ketamina/efectos adversos , Trastorno Depresivo Mayor/tratamiento farmacológico , Estudios Cruzados , Antidepresivos/efectos adversos , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Método Doble Ciego , Fentanilo/efectos adversos , Depresión/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Australasia is home to unique and endangered avian species. Drug administration to this group of animal patients for prophylaxis and treatment is challenging from a number of different perspectives. A key limitation for optimal drug dosing in birds is the lack of published pharmacokinetic studies to guide dose requirements. The aim of this review was to systematically investigate published literature on pharmacokinetics in penguin species and compare that with the pharmacokinetics of other avian species with a focus on two drugs: enrofloxacin and voriconazole. The review was conducted following PRISMA guidelines. A systematic literature search was performed in Pubmed, Embase, Scopus, and Web of Science databases. A key finding is that penguin pharmacokinetics differs from other avian species, with weight-adjusted AUC and Cmax values higher than most other avian species (e.g., for enrofloxacin, the AUC in the African penguin is 85.7 µg h/mL, which is more than double the other bird species). Doses for some avian species may be successfully extrapolated from other avian species; however, it appears important to consider factors other than just body weight (e.g., clearance mechanism and drug physicochemical characteristics). Consequently, there is an important need for robust pharmacokinetic data in wildlife species to ensure optimal therapy for this special group of patients. As part of this review, we identify key aspects that should be considered when estimating dose in species for which there is limited pharmacokinetic information available.
Asunto(s)
Spheniscidae , Animales , Voriconazol , EnrofloxacinaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease of 2019 (COVID-19), has caused havoc around the world. While several COVID-19 vaccines and drugs have been authorized for use, these antiviral drugs remain beyond the reach of most low- and middle-income countries. Rapid viral evolution is reducing the efficacy of vaccines and monoclonal antibodies and contributing to the deaths of some fully vaccinated persons. Others with normal immunity may have chosen not to be vaccinated and remain at risk if they contract the infection. Vaccines may not protect some immunodeficient patients from SARS-CoV-2, who are also at increased risk of chronic COVID-19 infection, a dangerous stalemate between the virus and a suboptimal immune response. Intra-host viral evolution could rapidly lead to the selection and dominance of vaccine and monoclonal antibody-resistant clades of SARS-CoV-2. There is thus an urgent need to develop new treatments for COVID-19. The NZACE2-Patari project, comprising modified soluble angiotensin-converting enzyme 2 (ACE2) molecules, seeks to intercept and block SARS-CoV-2 infection of the respiratory mucosa. In vitro data presented here show that soluble wild-type ACE2 molecules retain the ability to effectively block the Spike (S) glycoprotein of SARS-CoV-2 variants including the ancestral Wuhan, delta (B.1.617.2) and omicron (B.1.1.529) strains. This therapeutic strategy may prove effective if implemented early during the nasal phase of the infection and may act synergistically with other antiviral drugs such as Paxlovid to further mitigate disease severity.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Enzima Convertidora de Angiotensina 2 , Vacunas contra la COVID-19 , Peptidil-Dipeptidasa A , Antivirales/uso terapéutico , Antivirales/farmacología , Gravedad del PacienteRESUMEN
INTRODUCTION: Decisions about using psychotropics during pregnancy are complex as risks of untreated illness are balanced against risks of fetal exposure to medication. The objective was to describe perinatal psychotropic dispensing patterns in New Zealand. METHODS: Nationwide data from the New Zealand National Maternity Collection between January 1, 2011 and December 31, 2017 identified 399 715 pregnancies. These were linked with dispensing records to determine the proportion of pregnancies during which at least 1 psychotropic was dispensed. Proportions were calculated separately for each class, year, pregnancy period, and across maternal characteristics. The pattern of dispensing (including discontinuations) was also determined for the 25 841 women who were dispensed at least 1 psychotropic drug prior to pregnancy. RESULTS: From the 399 715 pregnancies in the study cohort, 6.6% were dispensed at least 1 psychotropic during pregnancy. Antidepressants (5.1%) were the most dispensed, followed by hypnotics (1.2%), anxiolytics (0.7%), and antipsychotics (0.7%). From the 25 841 pregnancies during which a psychotropic was dispensed pre-pregnancy, 91% and 90% discontinued hypnotics and anxiolytics respectively, prior to or during pregnancy. This was followed by lithium (71%), antipsychotics (66%), and antidepressants (66%). DISCUSSION: Dispensing of psychotropics during pregnancy occurs in approximately 6.6% of pregnancies in New Zealand. Two-thirds of women (66%) on antidepressants or antipsychotics discontinue dispensing before or during pregnancy. This may have implications for maternal mental health, suggesting there is a need to investigate how healthcare providers and women are making decisions about psychotropic use during pregnancy.
Asunto(s)
Ansiolíticos , Antipsicóticos , Femenino , Humanos , Embarazo , Antipsicóticos/uso terapéutico , Nueva Zelanda/epidemiología , Psicotrópicos/uso terapéutico , Antidepresivos , Hipnóticos y SedantesRESUMEN
BACKGROUND: The importance of wildlife health has been critically emphasized by the current global pandemic. Pharmacists play a valuable role in the health care of companion animals and livestock; however, their involvement in exotic animal health is largely unexplored. OBJECTIVES: This project consulted with zoo vets in New Zealand and investigated their practices around prescribing and dispensing of medicines to explore the opportunities for the involvement of pharmacists. METHODS: A mixed methods approach was used where data were initially collected through an online survey distributed to 26 veterinarians and animal keepers working in zoos, wildlife parks, and sanctuaries. An optional semistructured interview followed the survey. RESULTS: The facilities surveyed housed New Zealand native animal species and 85% also housed exotic animals. Veterinarians dispensed 75% of medicines at their animal facility, whereas the remaining 25% were dispensed by veterinary nurses. On average, 5-10 medications were dispensed at each animal facility per day. Common medicines dispensed were antibiotics, pain relievers, and antifungals. Most respondents felt that they could benefit from working alongside pharmacists in veterinary care. Compounding, access to medicines and identification of tailored formulations were identified as areas where collaboration would be valued. Limitations in the knowledge of pharmacists in animal medicine were distinguished as an area enhancement to assist in collaborative relationships. CONCLUSIONS: There are opportunities for the skills of pharmacists to be incorporated into the care of animals in zoos and wildlife parks in New Zealand. Strengthening the pharmacist-veterinarian relationship can enhance the health outcomes of animals in animal facilities through this interprofessional interaction.
Asunto(s)
Animales Salvajes , Farmacéuticos , Animales , Humanos , Nueva Zelanda , Actitud del Personal de Salud , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To determine if very low dose (VLD, 0.5% phenylephrine, 0.1% cyclopentolate) mydriatic microdrop (approximately 7 µL) administration (up to three doses) is non-inferior to low dose (LD, 1% phenylephrine, 0.2% cyclopentolate) mydriatic microdrop administration for ophthalmologist-determined successful retinopathy of prematurity eye examination (ROPEE). DESIGN: Multicentre, prospective, randomised controlled, non-inferiority clinical trial. SETTING: Four neonatal intensive care units in Aotearoa, New Zealand from October 2019 to September 2021. PATIENTS: Infants with a birth weight less than 1250 g or gestational age less than 30+6 weeks and who required a ROPEE. INTERVENTIONS: The intervention: microdrop (approximately 7 µL) of VLD (0.5% phenylephrine and 0.1% cyclopentolate) to both eyes, or the comparison: microdrop of LD (1% phenylephrine and 0.2% cyclopentolate) to both eyes. Up to three doses could be administered. MAIN OUTCOME MEASURES: The primary outcome measure was an ophthalmologist-determined successful ROPEE. RESULTS: One hundred and fifty preterm infants (LD mean GA=27.4±1.8 weeks, mean birth weight=1011±290 g, VLD mean GA=27.5±1.9 weeks, mean birth weight=1049±281 g,) were randomised. Non-inferiority for successful ROPEE was demonstrated for the VLD group compared with the LD group (VLD successful ROPEE=100%, LD successful ROPEE=100%, 95% CI no continuity correction -0.05 to 0.05) and for Maori (95% CI no continuity correction -0.02 to 0.19). CONCLUSION: VLD microdrops enable safe and effective screening for ROPEE in both Maori and non-Maori preterm infants. TRIAL REGISTRATION NUMBER: ACTRN12619000795190.
Asunto(s)
Ciclopentolato , Retinopatía de la Prematuridad , Lactante , Recién Nacido , Humanos , Ciclopentolato/farmacología , Midriáticos/farmacología , Fenilefrina/farmacología , Recien Nacido Prematuro , Retinopatía de la Prematuridad/diagnóstico , Retinopatía de la Prematuridad/tratamiento farmacológico , Peso al Nacer , Soluciones Oftálmicas/farmacología , Estudios Prospectivos , Pupila , Recién Nacido de muy Bajo PesoRESUMEN
OBJECTIVE: This study was aimed to determine mydriatic regimen(s) used in neonatal units in Aotearoa, New Zealand (NZ), and Australia and to estimate the frequency of adverse drug events following mydriatic administration in preterm neonates. STUDY DESIGN: A cross-sectional survey was sent to neonatal nursing staff listed in the Australian and New Zealand Neonatal Network contact list. Participants were asked to state what mydriatic regimen they use, and to estimate the frequency of adverse drug events when eye drops were administered for retinopathy of prematurity eye examinations (ROPEE). RESULTS: Thirteen different mydriatic regimens were identified; phenylephrine 2.5% and cyclopentolate 0.5% (1 standard drop of each) was the most commonly used regimen. Two of the regimens exceeded adult doses and five regimens included a mydriatic that is equivalent to an adult dose. Following mydriatic instillation, the three most common adverse effects were apnea, tachycardia, and periorbital pallor. CONCLUSION: Low-concentration single-microdrop regimens are currently in use and resulting in successful ROPEE, yet doses exceeding adult doses are in use throughout Aotearoa, NZ, and Australian units. We know from this dataset that neonates are experiencing unwanted and potentially preventable, adverse effects associated with mydriatics, and every effort should be made to minimize this risk. KEY POINTS: · Thirteen different regimens are in use in Aotearoa, NZ, and Australia.. · Three regimens use doses in excess of adult doses.. · Phenylephrine 2.5% and cyclopentolate 0.5% (one standard drop of each) is the most common regimen.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Enfermedades del Prematuro , Enfermeras Neonatales , Retinopatía de la Prematuridad , Humanos , Recién Nacido , Midriáticos/efectos adversos , Ciclopentolato/efectos adversos , Retinopatía de la Prematuridad/diagnóstico , Estudios Transversales , Australia , Fenilefrina/efectos adversosRESUMEN
Background: COVID-19 has caused calamitous health, economic and societal consequences globally. Currently, there is no effective treatment for the infection. Areas covered: We have recently described the NZACE2-Patari project, which seeks to administer modified Angiotensin Converting Enzyme 2 (ACE2) molecules early in the infection to intercept and block SARS-CoV-2 binding to the pulmonary epithelium. Expert opinion: Since the nasopharyngeal mucosa is infected in the first asymptomatic phase of the infection, treatment of the nose is likely to be safe and potentially effective. The intercepted virus will be swallowed and destroyed in the stomach. There is however a limited window of opportunity to alter the trajectory of the infection in an individual patient, which requires access to rapid testing for SARS-CoV-2. The proposed strategy is analogous to passive immunization of viral infections such as measles and may be of particular benefit to immunodeficient and unvaccinated individuals.
Asunto(s)
Enzima Convertidora de Angiotensina 2/administración & dosificación , Antivirales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Nasofaringe/virología , Mucosa Respiratoria/virología , SARS-CoV-2/efectos de los fármacos , Estómago/virología , Administración Intranasal , COVID-19/enzimología , COVID-19/virología , Interacciones Huésped-Patógeno , Humanos , SARS-CoV-2/patogenicidad , Resultado del TratamientoRESUMEN
Women face complicated decisions regarding psychotropic medication use during pregnancy. Patient decision aids (PDAs) could be a valuable tool to assist with decision-making. The objective of this review was to evaluate the effectiveness of PDAs in this population. A systematic search of the literature was conducted using PRISMA guidelines. Three major databases were searched to identify articles published between 2006 and June 2020. Studies were included if they evaluated use of a PDA for women considering medication for mental illness during pregnancy. A total of 4629 titles were returned from the search; however, only three studies met inclusion criteria and were selected for analysis. Two were pilot randomised controlled trials in women considering antidepressant use during pregnancy, and one was a non-randomised study in women considering medication for the treatment of opioid use disorder (OUD). The PDAs had good acceptability across all three studies. The randomised trials assessed knowledge, decisional conflict, depression, and anxiety, with non-significant trends towards reduced decisional conflict and anxiety in the PDA groups. PDAs have the potential to assist women with mental illnesses to make decisions regarding medication use during pregnancy; however, current evidence is too limited to evaluate the effectiveness of PDAs for this population.
Asunto(s)
Antidepresivos , Técnicas de Apoyo para la Decisión , Antidepresivos/uso terapéutico , Toma de Decisiones , Femenino , Humanos , Embarazo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Manuka oil, an essential oil derived from the Leptospermum scoparium, has been traditionally used for wound care and as a topical antibacterial, antifungal, and anti-inflammatory. However, the essential oil is not well retained at mucosal sites, such as the oral cavity, where the benefits of the aforementioned properties could be utilized toward the treatment of persistent biofilms. Within this study, L. scoparium essential oil was incorporated into a semisolid emulsion for improved delivery. The safety profile of L. scoparium essential oil on human gingival fibroblasts was determined via cell viability, cytotoxicity, and caspase activation. The minimal bactericidal concentration of L. scoparium essential oil was determined, and the emulsion's antibiofilm effects visualized using confocal laser scanning microscopy. L. scoparium essential oil demonstrated a lower IC50 (0.02% at 48 h) when compared to the clinical control chlorhexidine (0.002% at 48 h) and displayed lower cumulative cytotoxicity. Higher concentrations of L. scoparium essential oil (≥ 0.1%) at 6 h resulted in higher caspase 3/7 activation, suggesting an apoptotic pathway of cell death. A minimal bactericidal concentration of 0.1% w/w was observed for 6 oral bacteria and 0.01% w/v for Porphyromonas gingivalis. Textural and rheometric analysis indicated increased stability of emulsion with a 1â:â3 ratio of L. scoparium essential oil: Oryza sativa carrier oil. The optimized 5% w/w L. scoparium essential oil emulsion showed increased bactericidal penetrative effects on Streptococci gordonii biofilms compared to oil alone and to chlorhexidine controls. This study has demonstrated the safety, formulation, and antimicrobial activity of L. scoparium essential oil emulsion for potential antibacterial applications at mucosal sites.
Asunto(s)
Leptospermum , Aceites Volátiles , Antibacterianos/farmacología , Biopelículas , Emulsiones , Aceites Volátiles/farmacologíaRESUMEN
AIMS: To determine ifVery low dose mydriatic eye microdrop regimen sufficiently dilates the pupil (above 4.1 mm) compared with the currently used low dose mydriatic eye microdrop regimen.Cardiovascular, gastrointestinal and respiratory adverse effects occur following eye drop instillation. METHODS: Seventeen premature infants were recruited into this prospective, randomised controlled pilot trial in January 2017 to November 2018. Data were collected from the single-centre Neonatal Intensive Care Unit, Dunedin Hospital, New Zealand. The inclusion criteria were birth weight less than 1500 g or gestational age less than 31 weeks, or any premature infant requiring red reflex testing. Infants were randomised to receive either phenylephrine 1% or 0.5% and cyclopentolate 0.2% or 0.1%, 1 microdrop in both eyes. Efficacy outcome measures were pupil size at retinopathy of prematurity eye examination (ROPEE) and ophthalmologist rating of ease of screen. RESULTS: All participants had sufficient pupillary dilation for a successful ROPEE. Ophthalmologists rated the ROPEE as easy for 90% of all examinations. Pupil dilation measurements at the time of examination, mean±SD, 4.8±0.2 (95% CI 4.5 to 5.2) mm for treatment A and 5±0.2 (95%CI 4.6 to 5.4) mm for treatment B (p=0.61). There were no statistically significant differences between the groups for safety data. CONCLUSIONS: Very low dose microdrop administration of phenylephrine and cyclopentolate appears to be effective at sufficiently dilating the neonatal pupil for ROPEEs. Low dose and very low dose microdrop mydriatic regimens may also reduce the risk of unwanted adverse effects associated with these medicines. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (reference ACTRN12616001266459p).
Asunto(s)
Ciclopentolato/administración & dosificación , Midriáticos/administración & dosificación , Fenilefrina/administración & dosificación , Retinopatía de la Prematuridad/diagnóstico , Retinoscopía/métodos , Administración Oftálmica , Ciclopentolato/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Unidades de Cuidado Intensivo Neonatal , Masculino , Midriáticos/efectos adversos , Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/efectos adversos , Fenilefrina/efectos adversos , Proyectos Piloto , Estudios Prospectivos , Pupila/efectos de los fármacosRESUMEN
PURPOSE: Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects. METHODS: This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported Cmax values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman's method. RESULTS: A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine Tmax (r = - 0.87; p < 0.00001 for all). Ketamine Tmax strongly positively correlated with a change in dissociation ratings (r = - 0.96) and change in blood pressure (r = - 0.99; p < 0.00001 for all). CONCLUSION: Ketamine formulations that maximize first pass metabolism and delay Tmax will be better tolerated and safer than formulations which lack those characteristics.
Asunto(s)
Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Ketamina/administración & dosificación , Ketamina/efectos adversos , Antidepresivos/farmacocinética , Trastornos Disociativos/inducido químicamente , Vías de Administración de Medicamentos , Humanos , Hipertensión/inducido químicamente , Ketamina/análogos & derivados , Ketamina/sangre , Ketamina/farmacocinética , Tasa de Depuración MetabólicaRESUMEN
The synthesis and specific surface functionalization of antimicrobial silver nanoparticles (AgNPs) and their incorporation into an alginate hydrogel is described. Divalent cation-mediated ionic crosslinking was used to disperse the AgNPs throughout the gel, made possible by -COO- cross-linking sites provided by the surface-enhanced nanoparticles, inspired by the classic egg-box model crosslinking of calcium alginate. An AgNP concentration, 10-20 µg g-1 increased hygrogel elasticity, viscosity, and shear resistance by 45, 30, and 31% respectively. Cryo-TEM revealed evenly distributed AgNP assemblies of discrete AgNPs throughout the gel matrices. FTIR-ATR indicated AgNPs were involved in alginate carboxylate-Ca2+-COO-AgNP crossbridging, which was not achieved through mixing of AgNPs into preformed gels. Live/dead fluorometric assays determined a minimal bactericidal concentration of 25 µg g-1 Ag for 6 microorganisms. Anti-biofilm assays showed species-dependent cell death of 44 -61%, with limited silver ion release of 0.41% and 1.1% after 7 days for Gram positive and negative bacteria, respectively.
Asunto(s)
Alginatos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Biopelículas/efectos de los fármacos , Hidrogeles/química , Plata/farmacología , Nanopartículas del Metal/química , Nanogeles/químicaRESUMEN
INTRODUCTION Dabigatran etexilate has become widely used in New Zealand, but information relating to when renal function monitoring is being undertaken is lacking. AIM To investigate if clinically appropriate renal function monitoring is being undertaken in New Zealand primary care for stroke prevention in non-valvular atrial fibrillation patients prescribed dabigatran etexilate. METHODS New Zealand non-valvular atrial fibrillation patients' prescription and primary care health data were extracted from national administrative databases for the period 1 July 2011 to 31 December 2015. The proportion of patients who had serum creatinine measurements at close proximity to treatment initiation and 12-months post initiation were assessed with 95% confidence intervals (CIs) and compared with Fisher's exact test. Log-rank tests for univariate analysis (gender, age, ethnicity and deprivation) effects on serum creatinine testing at dabigatran etexilate treatment initiation and 12-months post initiation were performed. RESULTS Overall, 1,948 patients who had been dispensed dabigatran etexilate with available primary care health data were identified. A total of 1,752 (89.9% [CI: 88.5-91.2]) patients had a renal function test at dabigatran etexilate initiation. There were 929 (72.8% [CI: 70.2-75.2]) patients who received ≥1 year supply of dabigatran etexilate and of these 207 (22.3% [CI: 19.6.6-25.1]) had a serum creatinine test 1 year after initiation. Demographic univariate analysis yielded insignificant log-rank tests for association with having serum creatinine measurements, except for Pacific Peoples. DISCUSSION There appears to be sub-optimal adherence to renal function monitoring for non-valvular atrial fibrillation patients who receive more than 12-months' treatment with dabigatran etexilate in New Zealand primary care.
Asunto(s)
Antitrombinas/administración & dosificación , Creatinina/sangre , Dabigatrán/administración & dosificación , Monitoreo de Drogas/métodos , Accidente Cerebrovascular/prevención & control , Anciano , Anciano de 80 o más Años , Antitrombinas/efectos adversos , Dabigatrán/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico , Nueva Zelanda , Atención Primaria de Salud , Insuficiencia Renal/inducido químicamente , Estudios Retrospectivos , Factores SocioeconómicosRESUMEN
BACKGROUND: Ketamine's defining side effects are dissociation and increased blood pressure/heart rate. An oral formulation with delayed absorption could minimize these effects. We recently reported safety and tolerability data for an extended release ketamine tablet in healthy volunteers. METHODS: To assess safety, tolerability, efficacy, and pharmacokinetics of an extended release oral ketamine tablet in patients with treatment-resistant depression/anxiety. This was a multiple dose open-label flexible dose uncontrolled study in seven patients with treatment-resistant depression/anxiety, who had all previously demonstrated mood improvement to subcutaneous ketamine. Assessments included ratings of anxiety, depression and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and brain-derived neurotrophic factor (BDNF) concentrations. RESULTS: Improvements in anxiety and depression ratings occurred gradually over 96 h; all patients had >50% improvements in mood ratings. Ketamine was safe and well tolerated, with no changes in vital signs, and a single brief report of dissociation. Ketamine may induce its own metabolism, as the ratio of norketamine to ketamine increased out to 96 h. Serum BDNF concentrations did not change during the study. CONCLUSION: Ketamine's safety/tolerability may be improved with an extended release oral formulation. Onset of mood improvement is slightly delayed compared with parenteral dosing. These data support the further development of extended release ketamine tablets for treatment of resistant depression and anxiety disorders.
RESUMEN
COVID-19 is a new zoonotic disease caused by the SARS-CoV-2 virus. Since its emergence in Wuhan City, China, the virus has rapidly spread across the globe causing calamitous health, economic and societal consequences. It causes disproportionately severe disease in the elderly and those with co-morbidities, such as hypertension and diabetes. There is currently no proven treatment for COVID-19 and a safe and effective vaccine is at least a year away. The virus gains access to the respiratory epithelium through cell surface angiotensin converting enzyme 2 (ACE2). The receptor binding domain (RBD) of the virus is unlikely to mutate without loss of pathogenicity and thus represents an attractive target for antiviral treatment. Inhaled modified recombinant human ACE2, may bind SARS-CoV-2 and mitigate lung damage. This decoy strategy is unlikely to provoke an adverse immune response and may reduce morbidity and mortality in high-risk groups.