Oral docetaxel plus encequidar - A pharmacokinetic model and evaluation against IV docetaxel.

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.

Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study.

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.

Pharmacokinetics in Penguins Compared to Other Avian Species: A Review of Enrofloxacin and Voriconazole.

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.

Pharmacists in zoos? A qualitative study investigating the potential for pharmacist involvement in wildlife health care in Aotearoa, New Zealand.

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.

A Survey of Neonatal Nurses on Mydriatic Regimens Used in Neonatal Retinopathy of Prematurity Eye Examinations.

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.

Effectiveness of patient decision aids in women considering psychotropic medication use during pregnancy: a literature review.

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.

Formulation of a Semisolid Emulsion Containing Leptospermum scoparium Essential Oil and Evaluation of In Vitro Antimicrobial and Antibiofilm Efficacy.

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 1 : 3 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.

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review.

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.

AgNP/Alginate Nanocomposite hydrogel for antimicrobial and antibiofilm applications.

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.

Monitoring the use of dabigatran etexilate for stroke prevention: compliance with renal function guidelines.

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.

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study.

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.

Ascending-Dose Study of Controlled-Release Ketamine Tablets in Healthy Volunteers: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability.

Parenteral ketamine has fast-onset antidepressant and antianxiety effects; however, it causes dissociation, hypertension, and tachycardia shortly after dosing. Ketamine's antidepressant effects may be due to active metabolites rather than to ketamine itself. We hypothesized that oral controlled-release ketamine tablets would improve safety and tolerability compared with injected ketamine by reducing peak ketamine exposures compared with dosing by injection. In this randomized, placebo-controlled ascending-dose study, ketamine doses of 60, 120, or 240 mg or matching placebo (single dose followed by every-12-hours dosing for 5 doses) were given to 24 healthy volunteers. Pharmacokinetics, pharmacodynamics (brain-derived neurotropic factor), adverse events, and vital signs were assessed up to 72 hours. Drug release occurred over ∼10 hours, with most drug substance present as norketamine (∼90%). Area under the concentration-time curve and peak concentration were dose proportional. Elimination half-life was prolonged (7-9 hours) compared with published data from immediate-release oral formulations. There were no changes in blood pressure or heart rate after any dose. Mild dissociation was reported after 240 mg but not lower doses; mean dissociation ratings in this group were minimal (1-2/76). There were no clinically significant changes in ECGs or safety laboratory tests at any time. Compared with injected ketamine, oral controlled-release ketamine tablets did not increase blood pressure or heart rate, and only at doses of 240 mg was dissociation of mild intensity reported. Reducing and delaying ketamine peak concentration by oral dosing with controlled-release ketamine tablets improve this drug's tolerability for patients with depression/anxiety.

Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study.

BACKGROUND: We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders. AIMS: The purpose of this study was to replicate our earlier report about ketamine's anxiolytic activity, using a more robust study design. METHODS: This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations. RESULTS: Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments. CONCLUSIONS: Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.

Exposure Response Supports Therapeutic Drug Monitoring for Dabigatran Etexilate in Patients with Atrial Fibrillation.

Background Dabigatran etexilate has become widely used for the prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF). Currently, there is limited information in real-world patients relating to dabigatran etexilate exposure and response. Methods This retrospective cohort study used administrative health data for NVAF patients dispensed dabigatran etexilate between July 1, 2011 and December 31, 2015. Outcomes of cerebrovascular accident (CVA), systemic embolism, and hemorrhage were extracted. Simulated pharmacokinetic parameters were obtained using a published population pharmacokinetic model of dabigatran etexilate. Area under the curve calculated for a 24-hour period at steady state (AUC ss ), the exposure parameter, was derived using these simulations and the dosing data and the exposure-response relationship were investigated. The risk of adverse outcomes at AUC ss quartiles was compared using Poisson regression and expressed using incidence rate ratios (95% confidence interval) adjusted for known potential confounders. Results In total, 2,660 NVAF patients had been dispensed dabigatran etexilate. For these patients there was a decreased risk of hemorrhage (0.51, 0.32-0.79) when dabigatran AUC ss was in the second quartile range of 1.70 to 1.96 mg h/L and thromboembolism/CVA (0.34, 0.16-0.76) when in the third quartile range of 1.97 to 2.26 mg h/L. An increased risk of hemorrhage (1.68, 1.18-2.38) was observed when AUC ss was in the fourth quartile range of 2.27 to 12.76 mg h/L. Conclusion An exposure-response relationship for dabigatran etexilate was described, where the most effective response was observed when AUC ss was in the range of 1.70 to 2.26 mg h/L. Hence, it is feasible to develop guidance for optimal dosing to improve outcomes for patients with NVAF.

The effect of route of administration on the enantioselective pharmacokinetics of ketamine and norketamine in rats.

BACKGROUND: Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration. AIMS: To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration. METHODS: Plasma from conscious non-anaesthetised rats was collected following administration of ketamine by either subcutaneous (SC), intramuscular (IM), intravenous infusion (IVI) or intravenous bolus (IVB) routes of administration. Concentrations of the enantiomers of ketamine and norketamine were determined by LC/MS. RESULTS: Administration by the SC, IM and IVI routes produced an overall similar drug exposure. In contrast, administration by the IVB route produced approximately 15-fold higher peak plasma concentrations for the enantiomers of ketamine and an approximately four-fold lower AUC for the enantiomers of norketamine. CONCLUSIONS: Route of administration can significantly influence ketamine and norketamine exposures. These differences may influence safety and tolerability, and potentially drug efficacy in humans. This knowledge adds to current research into the optimisation of the use of ketamine for the treatment of depression.

Service provision in the wake of a new funding model for community pharmacy.

BACKGROUND: Recently, New Zealand has taken a system wide approach providing the biggest reform to New Zealand community pharmacy for 70 years with the aim of providing more clinically orientated patient centred services through a new funding model. The aim of this study was to understand the types of services offered in New Zealand community pharmacies since introduction of the new funding model, what the barriers are to providing these services. METHOD: A survey of all community pharmacies were undertaken between August, 2014 and February, 2015. Basic descriptive statistics were completed and group comparisons were made using the chi squared test with significance set at p < 0.05. RESULTS: 528 responses were received. Education and advice on prescription and non-prescription medicines were the two top listed services provided. There were no significant differences in service provision between rural and metro based pharmacies. Many pharmacies were considering introducing new patient centred services. Four of the top ten frequently provided services have no public funding attached. Costs and staff availability are the most common barriers to undertake services, more predominantly in patient centred services. CONCLUSION: This study was the first to provide an evaluation of service provision in response to a new funding model for New Zealand Community Pharmacies. A broad range of services are being undertaken in New Zealand community pharmacies including patient-centred services. A number of barriers to service provision were identified. This study provides a baseline for the current levels of service provision upon which future studies can compare to and evaluate any changes in service provision with differing funding models going forward.

Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders.

OBJECTIVE: In this maintenance treatment study, we sought to evaluate the effect on anxiety ratings, safety and tolerability of 3 months of weekly ketamine in 20 patients with treatment-refractory DSM IV generalised anxiety disorder (GAD) and/or social anxiety disorder (SAD), and subsequent assessment of remission post-treatment. METHODS: This was an uncontrolled open-label study in 20 patients who had been responders in an ascending dose ketamine study. The study was undertaken in a university clinic. Patients received one or two weekly ketamine doses of 1 mg/kg injected subcutaneously for 3 months. Data were collected from December 2015-June 2017. RESULTS: There were 10 women (50%) and 10 men (50%); 15 patients (75%) met criteria for GAD and 18 (90%) for SAD. One hour after dosing, Fear Questionnaire ratings decreased by ~50%, as did Hamilton Anxiety ratings. Clinician Administered Dissociative States Scale mean scores declined over time, from 20 points at week 1 to 8.8 points at week 14. Compared with pre-dose values, mean systolic and diastolic blood pressure increased by ~10 mm Hg at 30 min. The most common adverse events were nausea, dizziness and blurred vision. Of the 20 patients, 18 reported improved social functioning and/or work functioning during maintenance treatment. CONCLUSIONS: Weekly ketamine dosing was safe and well tolerated, and post-dose dissociative symptoms tended to reduce after repeated dosing. Patients reported marked improvements in functionality and in their personal lives. Maintenance ketamine may be a therapeutic alternative for patients with treatment refractory GAD/SAD. TRIAL REGISTRATION: http://www.anzctr.org.au/ACTRN12615000617561.

The influence of patient variables on insulin total daily dose in paediatric inpatients with new onset type 1 diabetes mellitus.

PURPOSE: Insulin dose requirements at new diagnosis of type 1 diabetes mellitus (T1DM) vary widely. Current guidelines recommend an initial total daily dose (TDD) ranging from 0.5 to 1.0 IU/kg/day. It often takes several days of frequent dose adjustments before an optimal insulin dose is achieved. The aim of this study was to identify the influence of patient variables on the dose-requirement of insulin in newly diagnosed children with T1DM. METHODS: A retrospective chart review of children (≤ 18 years old) admitted to hospital between 2010 and 2016 due to new onset T1DM was undertaken. Demographic, clinical, insulin dosing, and laboratory data were recorded. The influence of patient characteristics on insulin TDD was analysed statistically by performing univariate and multivariate linear regression analyses. RESULTS: Complete clinical records for 70 patients were available for analysis. The median insulin TDD on first day of admission was 21 (4.5 to 75 units) and that on the day before discharge was 27 (5.5 to 124 units). In the multivariate regression analysis, body size (total body weight and fat-free mass), glycated haemoglobin (HbA1C), and blood ketone concentration were found to be significant predictors of optimal insulin TDD (p < 0.05). CONCLUSION: In addition to body size, HbA1c and ketone concentrations are useful in calculating initial TDD in newly diagnosed children with T1DM. This could potentially decrease the number of days needed to reach a stable dose and result in improved early glycaemic control.