The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Violence against women and against children are human rights violations with lasting harms to survivors and societies at large. Intimate partner violence (IPV) and sexual violence against children (SVAC) are two major forms of such abuse. Despite their wide-reaching effects on individual and community health, these risk factors have not been adequately prioritised as key drivers of global health burden. Comprehensive x§and reliable estimates of the comparative health burden of IPV and SVAC are urgently needed to inform investments in prevention and support for survivors at both national and global levels. We estimated the prevalence and attributable burden of IPV among females and SVAC among males and females for 204 countries and territories, by age and sex, from 1990 to 2023, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2023. We searched several global databases for data on self-reported exposure to IPV and SVAC and undertook a systematic review to identify the health outcomes associated with each of these risk factors. We modelled IPV and SVAC prevalence using spatiotemporal Gaussian process regression, applying data adjustments to account for measurement heterogeneity. We employed burden-of-proof methodology to estimate relative risks for outcomes associated with IPV and SVAC. These estimates informed the calculation of population attributable fractions, which were then used to quantify disability-adjusted life-years (DALYs) attributable to each risk factor. Globally, in 2023, we estimated that 608 million (95% uncertainty interval 518-724) females aged 15 years and older had ever been exposed to IPV, and 1·01 billion (0·764-1·48) individuals aged 15 years and older had experienced sexual violence during childhood. 18·5 million (8·74-30·0) DALYs were attributed to IPV among females and 32·2 million (16·4-52·5) DALYs were attributed to SVAC among males and females in 2023. IPV and SVAC were among the top contributors to the global disease burden in 2023, particularly among females aged 15-49 years, ranking as the fourth and fifth leading risk factors, respectively, for DALYs in this group. Among the eight health outcomes found to be associated with IPV, anxiety disorders and major depressive disorder were the leading causes of IPV-attributed DALYs, accounting for 5·43 million (-1·25 to 14·6) and 3·96 million (1·71 to 6·92) DALYs in 2023, respectively. SVAC was associated with 14 health outcomes, including mental health disorder, substance use disorder, and chronic and infectious disease outcomes. Self-harm and schizophrenia were the leading causes of SVAC-attributed burden, with SVAC accounting for 6·71 million (2·00 to 12·7) DALYs due to self-harm and 4·15 million (-1·92 to 13·1) DALYs due to schizophrenia in 2023. IPV and SVAC are substantial contributors to global health burden, and their health consequences span a variety of individual health outcomes. Importantly, mental health disorders account for the greatest share of disease burden among survivors. Investing in prevention of these avoidable risk factors has the potential to avert millions of DALYs and considerable premature mortality each year. Our findings represent strong evidence for global and national leaders to elevate IPV and SVAC among public health priorities. Sustained investments are needed to prevent IPV and SVAC and to implement interventions focused on supporting the complex social and health needs of survivors. Gates Foundation.
According to the European Association of Establishments for Veterinary Education (EAEVE), a graduate of veterinary medicine should be able to prescribe and dispense "medicines correctly and responsibly in accordance with legislation and latest guidance" (2019). In Germany, veterinarians can dispense drugs from their in-practice pharmacy, which makes dispensing and compounding a higher educational priority than in other EU member states. This report describes recent efforts to improve the teaching of relevant first-day skills in compounding and prescribing through active learning approaches such as blended learning and online learning resources, including flipped classroom settings and cloud-based documents to practice prescribing at one of the German Schools of Veterinary Medicine. We assessed how the introduction of blended and case-based learning and quizzes impacted learning outcomes and grades over the last 5 years, from 2019 to 2023. This timeframe included regular pre-pandemic teaching operations, remote teaching during the pandemic, and a return to in-person classes. Pandemic online teaching did not lead to worse outcomes in practical or theoretical knowledge; online tutorials for compounding improved student performance significantly during the pandemic, though performance declined after returning to in-person teaching until quiz-based extra points were introduced in 2023. Doubling prescription seminar time did not improve outcomes in 2020, but introducing a cloud-based prescription exercise in 2021 led to better results, and overall grades in pharmaceutical and narcotics law have significantly improved since 2020. Novel tools for blended and case-based learning improved all outcomes significantly and were positively evaluated by the students.
Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.
Adverse drug event (ADE) reports submitted by veterinary professionals are essential for monitoring the safety and efficacy of marketed veterinary products. Despite this, the majority of veterinary ADEs are not reported. Further education on the topic of pharmacovigilance has been widely explored in human healthcare as a potential facilitator for reporting. To guide design of an enhanced pharmacovigilance curriculum for veterinary professionals, a better understanding of student veterinary professional pharmacovigilance training is required. Therefore, we investigated the current UK pharmacovigilance curriculum through a survey of veterinary educators. In total, there were 17 responses from UK-based training providers, six relating to undergraduate veterinary surgeon training and 11 relating to training in veterinary nursing. All students received some pharmacovigilance training, which appeared to be largely didactic in nature. A total of 29.4% of respondents indicated that students are provided the opportunity to submit a practice ADE report. Exploration of the knowledge, attitudes, and perceptions of students with regards to this training would be useful in assessing quality and opportunities for enhancement. Development of shared resources which provide students with access to 'real world' examples of ADEs would support development of practical skills in identifying, managing, and reporting ADEs.
Ceftiofur is a third-generation cephalosporin widely used in veterinary medicine; however, pharmacokinetic data in rabbits remain limited. This study aimed to characterize the pharmacokinetics of ceftiofur in rabbits following single intravenous (IV) and intramuscular (IM) administration and to evaluate its potential antibacterial efficacy using pharmacokinetic/pharmacodynamic (PK/PD) indices. Ceftiofur was administered at a dose of 2 mg/kg body weight (BW) via IV and IM routes. Plasma ceftiofur-related concentrations (expressed as desfuroylceftiofur acetamide, DCA) were quantified using a validated analytical method, and pharmacokinetic parameters were determined by noncompartmental analysis. Following IM administration, ceftiofur was rapidly absorbed, with a median time to peak concentration (Tmax) of 2 h and a high absolute bioavailability (88.72%). The drug exhibited moderate distribution, with a volume of distribution (VZ) of 1.93 L/kg and a steady-state volume of distribution (VSS) of 0.85 L/kg, and was eliminated slowly, with a systemic clearance of 0.083 L/h/kg. The mean residence time (MRT; 9.95 h) after IM administration was not longer than that observed after IV administration (10.34 h), precluding reliable estimation of the absorption half-life. Based on PK/PD analysis assuming a minimum inhibitory concentration (MIC) of ≤ 1.0 μg/mL, the calculated time above MIC (T > MIC) values following single IV and IM administration were approximately 4 and 5 h, respectively. These results indicate that although ceftiofur is rapidly and extensively absorbed in rabbits, a single IV or IM dose of 2 mg/kg BW may be insufficient to achieve effective exposure against bacterial pathogens with MIC values ≥ 1.0 μg/mL.
Misconceptions in pharmacology can undermine learning and compromise both clinical and scientific reasoning, yet few validated tools exist to identify them. Consequently, we developed and validated the Pharmacology Concept Inventory (PCI), which can be used to identify misconceptions, assess learning gains, and evaluate teaching effectiveness. This PCI was designed based on the IUPHAR-Education Section (IUPHAR-Ed) Core Concepts of Pharmacology Project, addressing eight core concepts: drug efficacy, drug-target interaction, steady-state concentration, structure-activity relationship, drug tolerance, drug bioavailability, volume of distribution, and drug clearance. A triangulated design strategy integrated theoretical frameworks, expert review, and student perspectives. Experts examined quality, content validity, and cognitive alignment. The pilot PCI was then administered to a student cohort to evaluate its psychometric properties, providing preliminary evidence for further refinement. Item-level content validity indices ranged from 0.67 to 1.00, with a scale-level average of 0.93. Seventy students completed the pilot survey, leading to the exclusion of items with low discrimination and reliability. Items on drug-target interaction were removed due to consistently poor performance. The final PCI included 26 items covering seven concepts, with strong discrimination indices (0.36-0.75) and difficulty indices (0.26-0.71). Internal consistency was high (Cronbach's alpha = 0.91), and concept-level reliability ranged from 0.64 to 0.85. The PCI provides strong evidence for identifying misconceptions and assessing learning outcomes through a pre-post-test approach. Although the PCI currently addresses only a subset of concepts, continued refinements informed by surveys and interviews will enhance its utility and expand its scope for concept-based learning and curriculum evaluation.
Veterinary graduates must be prepared to educate clients about medications and supplements. We surveyed 1955 Dog Aging Project newsletter recipients and 40 final-year veterinary students at Texas A&M College of Veterinary Medicine and Biomedical Sciences on their perceptions about medications and supplements. Respondents indicated whether each of 13 attributes applied to medications, supplements, neither, both, or "I'm not sure." Frequency of responses by newsletter recipient respondents versus student respondents, respectively, were evaluated. We observed differences in the majority response for: (1) target a specific ailment (51% for newsletter recipients versus 62% for students, respectively); (2) target a specific condition (54% vs. 40%); (3) promote health and wellness (51% vs. 38%); (4) prevent worsening of a condition (60% vs. 72%); (5) are added to food (58% vs. 80%); (6) are recommended by a veterinarian (58% vs. 82%); (7) are covered by pet insurance (57% vs. 80%); and (8) are given to the animal long term or lifelong (55% vs. 72%). The overall distribution of responses was statistically significantly different between groups for three attributes: added to food (p < 0.001); recommended by a veterinarian (p = 0.005); and covered by pet insurance (p < 0.001). While a majority of both groups recognized that only medications are tested and approved by the Food and Drug Administration (FDA), 15% of final-year veterinary students indicated that they thought both supplements and medications are FDA regulated, which suggests an important educational gap.
At the Texas A&M University College of Veterinary Medicine (TAMU-CVM), the veterinary pharmacology faculty and library faculty have collaborated to teach aspects of Evidence-Based Veterinary Medicine (EBVM) since 2010. These skills are integral to drug and therapeutic decision-making and are required for veterinary graduate Day-One competency. Herein, we explain the progression of incorporation of EBVM teaching at TAMU-CVM to make clear that the development of teaching and assessment activities did not occur as a single design exercise, but rather in an iterative and reflective manner over several years. We describe the courses in which we have one or more lecture or laboratory sessions focused on scaffolding the skills of EBVM across 3 semesters, including the skills of writing clinical questions, searching the biomedical literature for evidence, critically appraising the evidence, and then applying the evidence to answer the clinical question to make a clinical recommendation. We share the specific contributions of the librarians and the pharmacologist in creating opportunities for students to develop the competencies of EBVM.
Cranberry and cranberry extracts are available for treatment or prevention of urinary tract disease in dogs and cats, but guidance regarding their use is lacking. The objectives were to identify and assess literature pertaining to the efficacy of cranberry and cranberry extract supplementation for prevention and treatment of bacterial cystitis and subclinical bacteriuria in dogs and cats. A systematic review was performed, and three studies involving a total of 122 animals (106 dogs and 16 cats) were identified. No studies reported statistically significant or numerical impacts of treatment. Two studies were deemed at high risk of bias, and one was deemed at low risk. Certainty of evidence was low to very low. The small number of studies, small sample sizes, data from those studies, and low certainty of evidence preclude confident assessment of the role of cranberry for the prevention or treatment of infectious urinary tract disease in dogs and cats.
Veterinary students often find it difficult to select antimicrobial drugs for patients, likely because it requires them to consider multiple factors and there are frequently several possible options with a lack of a defined "correct or incorrect" choice. Our goal was to develop a teaching tool to engage the students through the decision-making processes associated with antimicrobial drug selection in cats and dogs, designed to align with the CBVE competency of explaining a justification. We developed a series of small animal case vignettes with a set of antimicrobial choices. The students use a visual analogue scale (VAS) to indicate the relative safety and/or efficacy of the drug in question; they also provide a written justification for their selection. Student responses are anonymized and downloaded for instructor review. The instructor categorizes the frequency of selections according to the labeled quartiles and displays the results as a bar graph during the classroom session and selects some written justifications for the class to view as a group. Practical considerations for tool implementation include considerations of the curriculum, time spent reviewing individual answers, and the tool's utility as a supplementary aid to foster more student discourse about topics in pharmacology. Overall, the VAS tool has the potential to aid in generating discussion in clinical contexts where there is not a single best answer.
Tapentadol is a dual mechanism analgesic utilizing both μ-opioid receptor (MOR) agonism and norepinephrine reuptake inhibition (NRI). This study evaluated the pharmacokinetics and pharmacodynamics of tapentadol as a potential analgesic with the goal of treating pain in horses. Pharmacokinetics of both tapentadol and tapentadol-O-glucuronide were elucidated. Six horses received three separate escalating single oral doses (1, 3, and 5 mg/kg) and a single intravenous (0.32 mg/kg) dose of tapentadol in a four-period sequential design. Concentrations of tapentadol and tapentadol-O-glucuronide were determined using liquid chromatography-tandem mass spectrometry. The maximum concentrations (mean ± SD) in plasma following administration of 1, 3, 5 mg/kg oral tapentadol were 7.98 ± 6.95, 39.8 ± 53.8, and 210.6 ± 234.4 ng/mL at 0.75, 0.63, and 0.38 h, respectively. Maximum plasma concentration (mean ± SD) after a single 0.32 mg/kg IV dose was 339.2 ± 83.5 ng/mL. The maximum concentrations of tapentadol-O-glucuronide following single 1, 3, and 5 mg/kg oral doses and a single 0.32 mg/kg IV dose of tapentadol were 532.6 ± 171.4, 1169.4 ± 345.4, 1559.5 ± 574.6, and 226.4 ± 51.5 ng/mL at times 6.0, 6.0, 7.0, and 0.5 h. Tapentadol was well-tolerated at all doses.
Equine protozoal myeloencephalitis can cause acute infections with rapid onset of neurologic signs, necessitating immediate empiric therapy with antiprotozoal medication. The objective of the study was to identify when concentrations of diclazuril reached the MIC of Sarcocystis neurona in CSF (1 ng/mL) of healthy adult horses after a single oral dose. Six healthy adult horses were used. Blood and CSF were collected from indwelling intravenous jugular catheters and intrathecal catheters in the lumbosacral space prior to drug administration and then at 1-, 4-, 8-, 12-, 16-, 24-, 48-, 72-, 96-, 120-, 144-, 168-, and 192-h post-administration of a 1 mg/kg dose of pelleted diclazuril administered by mouth in 8 oz of sweet feed. Samples were centrifuged then plasma and CSF supernatant were separated and frozen at -80°C until analysis. Diclazuril concentrations were analyzed with a liquid chromatography-mass spectrometer assay developed specifically for this study. Plasma concentrations of diclazuril peaked at 48 h with a mean concentration of 395.6 ± 109.4 ng/mL. CSF concentrations of diclazuril peaked at 24 h (mean concentration 9.0 ± 5.4 ng/mL) but achieved the MIC of S. neurona 12 h after administration (mean concentration 2.6 ± 1.8 ng/mL) and remained above MIC for the duration of the sampling period. In conclusion, pelleted diclazuril at 1 mg/kg reaches concentrations in the CSF above the MIC for S. neurona in healthy horses 12 h after a single oral dose.
The purpose of this study was to evaluate the pharmacokinetic profile of ondansetron following intravenous (IV) and subcutaneous (SC) administration in five healthy adult female Beagles. Dogs were administered ondansetron at 0.5 mg/kg IV and SC in a randomized crossover design. On day 0 ondansetron was administered either IV (OV group) or SC (OS group), and 7 days later administered via the opposite route. Plasma samples were collected, and heart and respiratory rates, and rectal temperature were recorded over an 8 h period. Ondansetron concentrations were quantified using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was performed using commercially available software. Median (min-max) peak plasma concentration following OS was 84.6 (56.0-326.1) ng/mL, which occurred at the first sampled time point of 0.25 (0.25-0.5) h. The terminal half-life was longer in the OS versus the OV group. Bioavailability of ondansetron in the OS group was 84.6 (51.2-132.6)%. Ondansetron administered SC at 0.5 mg/kg to adult healthy dogs has a similar bioavailability and a longer duration of action compared to the IV route of administration. Future pharmacokinetic and pharmacodynamic clinical studies should be performed in dogs utilizing the SC route of administration of ondansetron.
Allergic rhinitis (AR) impacts quality of life, work and school productivity. Over the last years, an important body of evidence resulting from mHealth data has led to a better understanding of AR. Such advances have motivated an EAACI-endorsed update of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (ARIA 2024-2025). This manuscript presents the ARIA 2024-2025 recommendations for intranasal treatments, one of the mainstays for AR management. The ARIA 2024-2025 guideline panel issued recommendations following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework. Several sources of evidence were used to inform panel judgments and recommendations, including systematic reviews, evaluation of mHealth and pharmacovigilance data, as well as a survey of experts on costs. Eleven guideline questions concerning intranasal treatments for AR were prioritized, leading to recommendations. Overall, these questions concern the choice between different classes of intranasal medications-most notably, intranasal corticosteroids (INCS), antihistamines (INAH), fixed combinations of INAH+INCS and decongestants-or between different individual medications within each class. Four questions had not been evaluated in previous ARIA guidelines, while for the other three there was a change in the strength or directionality of recommendations. Overall, recommendations point to the suggested use of INAH+INCS over INAH or INCS and INCS over INAH. This ARIA 2024-2025 article supports patients, their caregivers, and healthcare professionals in choosing an intranasal treatment. However, decisions on AR treatment should consider the clinical variability of the disease, patients' values, and the affordability of medications.
Meropenem is a carbapenem antibiotic used infrequently in veterinary medicine. However, antimicrobial susceptibility testing standards are needed to monitor for resistance caused by carbapenem resistant Enterobacterales (CRE). The Clinical and Laboratory Standards Institute (CLSI) does not have veterinary-specific carbapenem breakpoints for testing bacteria isolated from animals. Our objective was to correct this deficiency and propose clinical antimicrobial susceptibility testing breakpoints for consideration by clinical laboratories, standard-setting organizations, and for monitoring and surveillance programs. We collected pharmacokinetic data from published studies, which were entered into a forecasting program to perform 10,000 Monte Carlo Simulation using a range of dosages considered for administration of meropenem to dogs. Our target for the simulations was a 90% Probability of Target Attainment (PTA) to reach a time-above-MIC for the unbound fraction of the drug (f T > MIC) for at least 40% of the dosing interval. Our results showed that this target can be met for a MIC of ≤ 1 μg/mL (Enterobacterales) with a dose of 20-30 mg/kg IV every 8 h or 10 mg/kg every 6 h. For a one-step higher dilution of ≤ 2 μg/mL (Pseudomonas aeruginosa), a dose of 20-30 mg/kg every 6 h is needed. Therefore, we propose new clinical MIC breakpoints for antimicrobial susceptibility testing these bacteria isolated from dogs of ≤ 1, 2, and ≥ 4 μg/mL for the Susceptible, Intermediate, and Resistant category, respectively, for testing bacteria of the Enterobacterales, and values of ≤ 2, 4, and ≥ 8 μg/mL, respectively, for testing P. aeruginosa.
Medetomidine, an α₂-adrenergic agonist, is widely used as a sedative in horses. While its pharmacological effects are established, limited data exist on elimination of its metabolites, 3'-hydroxy medetomidine (HMD) and 3'-carboxy medetomidine (CMD), which are of regulatory interest. HMD is currently targeted in plasma and urine under International Screening Limits (ISLs) established by the International Federation of Horseracing Authorities (IFHA). In this study, seven Thoroughbreds received 6.3 μg/kg of medetomidine intravenously. Blood and urine were collected for 96 h and analyzed by LC-MS/MS after solid-phase extraction with and without enzymatic hydrolysis. Parent drug was detectable in plasma up to 4 h but absent in urine. HMD was quantifiable in plasma to 48 h and urine to 72 h, while CMD, with a distinct profile, was measurable in plasma to 32 h and urine to 72 h. Based on the ISLs, the detection times (DTs) for both plasma and urine were 48 h. Pharmacokinetic modeling estimated clearance at 2.15 L/h/kg and steady-state distribution volume at 1.90 L/kg. These findings show rapid clearance of medetomidine and extended metabolite excretion. The DT of HMD aligns with loss of pharmacological effect, supporting current ISLs and reinforcing the rationale for targeting HMD, with CMD providing supplementary regulatory insight.
Captive-reared kiwi (Apteryx spp.) chicks commonly suffer from coccidiosis, a parasitic disease that can cause morbidity and mortality in young immune-naive birds. Disease is currently managed in captivity through a combination of preventative husbandry practices and therapeutic treatment with the coccidiocide toltrazuril, for which no safety or pharmacokinetic data is available for kiwi. In this study we attempted to determine the pharmacokinetics of synthetic triazine anticoccidials, toltrazuril and diclazuril, in healthy three-to-four-week-old North Island brown kiwi (Apteryx mantelli) chicks. Birds were given a single oral dose of toltrazuril (25 mg/kg.bw; n = 6) or diclazuril (5 mg/kg.bw; n = 6), and closely monitored for adverse reactions. Serial blood samples were analysed via liquid chromatography-mass spectrometry (LC-MS) to determine the pharmacokinetics of both drugs, including the active metabolite of toltrazuril, toltrazuril sulphone. Pharmacokinetics were ascertained for both drugs in kiwi chicks. The mean (standard deviation) Cmax of diclazuril in plasma was 539.48 ± 169.63 ng/mL with a Tmax of 11.33 ± 1.63 h, while the Cmax for toltrazuril was 5622.16 ± 1997.52 ng/mL with a Tmax of 11.33 ± 1.63 h and Cmax of toltrazuril sulphone 3623.01 ± 1085.71 ng/mL with a Tmax of 96 ± 26.29 h. Mild changes to some biochemical parameters were observed, most notably elevations in uric acid in some toltrazuril-treated birds; however no remarkable clinical changes were observed in any chicks dosed with the drugs trialled.
The pharmacokinetics and pharmacodynamics of betamethasone following intra-articular administration to horses have been described; however, studies characterizing intramuscular administration are lacking. Twenty-four horses received an intramuscular dose of 12 mg betamethasone sodium phosphate/betamethasone acetate. Blood and urine were collected at post administration for up to 408 h. Concentrations of betamethasone were determined using LC-MS/MS and pharmacokinetic parameters determined using a Population PK three-compartment model. The duration of pharmacodynamic effects was assessed by measuring changes in cortisol and inflammatory biomarkers utilizing an ex vivo model. The Cmax, Tmax, and terminal half-life of betamethasone were 6.43 ± 1.70 ng/mL, 0.75 (0.5-2.0 h; median and range), and 30.5 ± 20.4 h, respectively. Covariates were not found to have significant effects on the variability of pharmacokinetic parameters. Based on Monte Carlo simulations, for 1000 horses, a detection time of 23 days is recommended for concentrations to fall below the screening limit of 10 pg/mL in 99% of the population. Urine concentrations were above the limit of quantitation in 2/24 horses at 408 h. Suppression of cortisol lasted for 360 h. Effects on inflammatory biomarker production lasted for a prolonged period. An extended withdrawal time for intramuscular administration prior to competition is warranted.
The misuse and abuse of veterinary anesthetic and analgesic agents pose significant public health risks, particularly with the growing presence of ultrapotent opioids and other anesthetics in the illicit drug trade. In response, there is increasing emphasis on incorporating medication safety training into veterinary curricula. This paper has two main objectives: first, to describe an evidence-based, interprofessional simulation activity designed to raise awareness about the diversion and misuse of veterinary opioids and alpha-2 agonists, while also developing basic life support skills for responding to accidental exposure; second, to propose three veterinary medication safety education sub-competencies aligned with CBVE Domain 4 and proposed discipline-level pharmacology competencies. These are aimed at equipping veterinary students to mitigate human health risks arising from exposure to veterinary medications, especially ultrapotent opioids and alpha-2 agonists.