Choice Consistency in Discrete Choice Experiments: Does Numeracy Skill Matter?

OBJECTIVES: This study investigated the relationship between numeracy skills (NS) and choice consistency in discrete choice experiments (DCEs). METHODS: A DCE was conducted to explore patients' preferences for kidney transplantation in Italy. Patients completed the DCE and answered 3-item numeracy questions. A heteroskedastic multinomial logit model was used to investigate the effect of numeracy on choice consistency. RESULTS: Higher NS were associated with greater choice consistency, increasing the scale to 1.63 (P < .001), 1.39 (P < .001), and 1.18 (P < .001) for patients answering 3 of 3, 2 of 3, and 1 of 3 questions correctly, respectively, compared with those with no correct answers. This corresponded to 63%, 39%, and 18% more consistent choices, respectively. Accounting for choice consistency resulted in varying willingness-to-wait (WTW) estimates for kidney transplant attributes. Patients with the lowest numeracy (0/3) were willing to wait approximately 42 months [95% CI: 29.37, 54.68] for standard infectious risk, compared with 33 months [95% CI: 28.48, 38.09] for 1 of 3, 28 months [95% CI: 25.13, 30.32] for 2 of 3, and 24 months [95% CI: 20.51, 27.25] for 3 of 3 correct answers. However, WTW differences for an additional year of graft survival and neoplastic risk were not statistically significant across numeracy levels. Supplementary analyses of 2 additional DCEs on COVID-19 vaccinations and rheumatoid arthritis, conducted online, supported these findings: higher NS were associated with more consistent choices across different disease contexts and survey formats. CONCLUSIONS: The findings suggested that combining patients with varying NS could bias WTW estimates, highlighting the need to consider numeracy in DCE data analysis and interpretation.

Keeping an eye on cost: What can eye tracking tell us about attention to cost information in discrete choice experiments?

Concern has been expressed about including a cost attribute within discrete choice experiments (DCEs) when individuals do not have to pay at the point of consumption. We use eye tracking to investigate attention to cost when valuing publicly financed health care. One-hundred and four individuals completed a DCE concerned with preferences for UK general practitioner appointments: 51 responded to a DCE with cost included and 53 to the same DCE without cost. Eye-movements were tracked whilst respondents completed the DCE. We assessed if respondents pay attention to cost. We then compare fixation time (FT) on attributes, eye movement patterns and mental effort across the experimental groups. Results are encouraging for the inclusion of cost in DCEs valuing publicly provided healthcare. Most respondents gave visual attention to the cost attribute most of the time. Average FT on multi-attribute tasks increased by 44% in the cost DCE, with attention to non-monetary attributes increasing by 22%. Including cost led to more structured decision-making and did not increase mental effort. Acceptability of the cost attribute and difficulty of choice tasks were predictors of cost information processing, highlighting the importance of both motivating the cost attribute and considering difficulty of the tasks when developing DCEs.

Health workforce supply, needs and financial feasibility in Lesotho: a labour market analysis.

BACKGROUND: The Government of Lesotho has prioritised health investment that aims to improve the health and socioeconomic development of the country, including the scaling up of the health workforce (HWF) training and improving their working conditions. Following a health labour market analysis, the paper highlights the available stock of health workers in Lesotho's health labour market, 10-year projected supply versus needs and the financial implications. METHODS: Multiple complementary approaches were used to collect data and analyse the HWF situation and labour market dynamics. These included a scooping assessment, desk review, triangulation of different data sources for descriptive analysis and modelling of the HWF supply, need and financial space. FINDINGS: Lesotho had about 20 942 active health workers across 18 health occupations in 2020, mostly community health workers (69%), nurses and midwives (17.9%), while medical practitioners were 2%. Almost one out of three professional nurses and midwives (28.43%) were unemployed, and nearly 20% of associate nurse professionals, 13.26% of pharmacy technicians and 24.91% of laboratory technicians were also unemployed. There were 20.73 doctors, nurses and midwives per 10 000 population in Lesotho, and this could potentially increase to a density of 31.49 doctors, nurses and midwives per 10 000 population by 2030 compared with a need of 46.72 per 10 000 population by 2030 based on projected health service needs using disease burden and evolving population size and demographics. The existing stock of health workers covered only 47% of the needs and could improve to 55% in 2030. The financial space for the HWF employment was roughly US$40.94 million in 2020, increasing to about US$66.69 million by 2030. In comparison, the cost of employing all health workers already in the supply pipeline (in addition to the currently employed ones) was estimated to be US$61.48 million but could reach US$104.24 million by 2030. Thus, a 33% gap is apparent between the financial space and what is required to guarantee employment for all health workers in the supply pipeline. CONCLUSION: Lesotho's HWF stock falls short of its population health need by 53%. The unemployment of some cadres is, however, apparent. Addressing the need requires increasing the HWF budget by at least 12.3% annually up to 2030 or prioritising at least 33% of its recurrent health expenditure to the HWF.

Public acceptability of non-pharmaceutical interventions to control a pandemic in the UK: a discrete choice experiment.

OBJECTIVE: To understand how individuals trade off between features of non-pharmaceutical interventions (eg, lockdowns) to control a pandemic across the four nations of the UK. DESIGN: A survey that included a discrete choice experiment. The survey design was informed using policy documents, social media analysis and input from remote think-aloud interviews with members of the public (n=23). SETTING: A nationwide survey across the four nations of the UK using an online panel between 29 October and 12 December 2020. PARTICIPANTS: Individuals who are over 18 years old. A total of 4120 adults completed the survey (1112 in England, 848 in Northern Ireland, 1143 in Scotland and 1098 in Wales). PRIMARY OUTCOME MEASURE: Adult's preferences for, and trade-offs between, type of lockdown restrictions, length of lockdown, postponement of routine healthcare, excess deaths, impact on the ability to buy things and unemployment. RESULTS: The majority of adults are willing to accept higher excess deaths if this means lockdowns that are less strict, shorter and do not postpone routine healthcare. On average, respondents in England were willing to accept a higher increase in excess deaths to have less strict lockdown restrictions introduced compared with Scotland, Northern Ireland and Wales, respectively. In all four countries, one out of five respondents were willing to reduce excess deaths at all costs. CONCLUSIONS: The majority of the UK population is willing to accept the increase in excess deaths associated with introducing less strict lockdown restrictions. The acceptability of different restriction scenarios varies according to the features of the lockdown and across countries. Governments can use information about trade-off preferences to inform the introduction of different lockdown restriction levels and design compensation policies that maximise societal welfare.

A Systematic Review of Patients' Values, Preferences, and Expectations for the Treatment of Metastatic Prostate Cancer.

CONTEXT: Advances in systemic agents have increased overall survival for men diagnosed with metastatic prostate cancer. Additional cytoreductive prostate treatments and metastasis-directed therapies are under evaluation. These confer toxicity but may offer incremental survival benefits. Thus, an understanding of patients' values and treatment preferences is important for counselling, decision-making, and guideline development. OBJECTIVE: To perform a systematic review of patients' values, preferences, and expectations regarding treatment of metastatic prostate cancer. EVIDENCE ACQUISITION: The MEDLINE, Embase, and CINAHL databases were systematically searched for qualitative and preference elucidation studies reporting on patients' preferences for treatment of metastatic prostate cancer. Certainty of evidence was assessed using Grading of Recommendation, Assessment, Development and Evaluation (GRADE) or GRADE Confidence in the Evidence from Reviews of Qualitative Research (CERQual). The protocol was registered on PROSPERO as CRD42020201420. EVIDENCE SYNTHESIS: A total of 1491 participants from 15 studies met the prespecified eligibility for inclusion. The study designs included were discrete choice experiments (n = 5), mixed methods (n = 3), and qualitative methods (n = 7). Disease states reported per study were: metastatic castration-resistant prostate cancer in nine studies (60.0%), metastatic hormone-sensitive prostate cancer in two studies (13.3%), and a mixed cohort in four studies (26.6%). In quantitative preference elicitation studies, patients consistently valued treatment effectiveness and delay in time to symptoms as the two top-ranked treatment attributes (low or very low certainty). Patients were willing to trade off treatment-related toxicity for potential oncological benefits (low certainty). In qualitative studies, thematic analysis revealed cancer progression and/or survival, pain, and fatigue as key components in treatment decisions (low or very low certainty). Patients continue to value oncological benefits in making decisions on treatments under qualitative assessment. CONCLUSIONS: There is limited understanding of how patients make treatment and trade-off decisions following a diagnosis of metastatic prostate cancer. For appropriate investment in emerging cytoreductive local tumour and metastasis-directed therapies, we should seek to better understand how this cohort weighs the oncological benefits against the risks. PATIENT SUMMARY: We looked at how men with advanced (metastatic) prostate cancer make treatment decisions. We found that little is known about patients' preferences for current and proposed new treatments. Further studies are required to understand how patients make decisions to help guide the integration of new treatments into the standard of care.

The role of solar energy and eco-innovation in reducing environmental degradation in China: Evidence from QARDL approach.

In the past decade, researchers have shifted their interests to explore different ways to mitigate environmental degradation. In that context, the present study explores the role of solar energy and eco-innovation in reducing environmental degradation in China. The study utilized data for the period 1990-2018 and applied the latest available econometric technique, a quantile autoregressive distributed lag model, to determine the impacts of solar energy and eco-innovation on improving China's environmental quality. According to the empirical results, in the long term, solar energy is negatively and significantly associated with CO2 emissions at higher quantiles. Eco-innovation has proven to be the most important channel to mitigate CO2 emissions in China. Eco-innovation is exerting a negative and significant influence on CO2 emissions at all quantiles in the long term. In addition, the population size is causing CO2 emissions to surge significantly at lower quantiles. The empirical analysis reveals that per capita income (PI) is positively associated with CO2 emissions at all quantiles, but it is significant only at higher quantiles in China. We found evidence of unidirectional causality for eco-innovation to CO2 emissions and solar energy to CO2 emissions. However, for population and CO2 emissions, per capita income, and CO2 emissions, we found bidirectional causality. As indicated by our empirical results, solar energy and eco-innovation are the two most effective channels to control CO2 emissions in China. Therefore, policies based on the promotion of eco-innovation and the initiation of new solar energy projects can control emissions and improve environmental quality in China. Integr Environ Assess Manag 2022;18:555-571. © 2021 SETAC.

Metastatic prostate cancer men's attitudes towards treatment of the local tumour and metastasis evaluative research (IP5-MATTER): protocol for a prospective, multicentre discrete choice experiment study.

INTRODUCTION: Systemic therapy with androgen deprivation therapy (ADT) and intensification with agents such as docetaxel, abiraterone acetate and enzalutamide has resulted in improved overall survival in men with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC). Novel local cytoreductive treatments and metastasis-directed therapy are now being evaluated. Such interventions may provide added survival benefit or delay the requirement for further systemic agents and associated toxicity but can confer additional harm. Understanding men's preferences for treatment options in this disease state is crucial for patients, clinicians, carers and future healthcare service providers. METHODS: Using a prospective, multicentre discrete choice experiment (DCE), we aim to determine the attributes associated with treatment that are most important to men with mHSPC. Furthermore, we plan to determine men's preferences for, and trade-offs between, the attributes (survival and side effects) of different treatment options including systemic therapy, local cytoreductive approaches (external beam radiotherapy, cytoreductive radical prostatectomy or minimally invasive ablative therapy) and metastases-directed therapies (metastasectomy or stereotactic ablative body radiotherapy). All men with newly diagnosed mHSPC within 4 months of commencing ADT and WHO performance status 0-2 are eligible. Men who have previously consented to a cytoreductive treatment or have developed castrate-resistant disease will be excluded. This study includes a qualitative analysis component, with patients (n=15) and healthcare professionals (n=5), to identify and define the key attributes associated with treatment options that would warrant trade-off evaluation in a DCE. The main phase component planned recruitment is 300 patients over 1 year, commencing in January 2021, with planned study completion in March 2022. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Health Research Authority East of England, Cambridgeshire and Hertfordshire Research Ethics Committee (Reference: 20/EE/0194). Project information will be reported on the publicly available Imperial College London website and the Heath Economics Research Unit (HERU website including the HERU Blog). We will use the social media accounts of IP5-MATTER, Imperial Prostate London, HERU and the individual researchers to disseminate key findings following publication. Findings from the study will be presented at national/international conferences and peer-reviewed journals. Authorship policy will follow the recommendations of the International Committee of Medical Journal Editors. TRIAL REGISTRATION NUMBER: NCT04590976.

Weighting or aggregating? Investigating information processing in multi-attribute choices.

Multi-attribute choices are commonly analyzed in economics to value goods and services. Analysis assumes individuals consider all attributes, making trade-offs between them. Such decision-making is cognitively demanding, often triggering alternative decision rules. We develop a new model where individuals aggregate multi-attribute information into meta-attributes. Applying our model to a choice experiment (CE) dataset, accounting for attribute aggregation (AA) improves model fit. The probability of adopting AA is greater for: homogenous attribute information; participants who had shorter response time and failed the dominance test; and for later located choices. Accounting for AA has implications for welfare estimates. Our results underline the importance of accounting for information processing rules when modelling multi-attribute choices.

To pay or not to pay? Cost information processing in the valuation of publicly funded healthcare.

Discrete choice experiments (DCEs) commonly include a monetary attribute. This enables willingness to pay (WTP), a monetary measure of benefit, to be estimated for non-monetary attributes. There has been concern that the inclusion of a cost attribute challenges the credibility of the experiment when valuing publicly funded healthcare systems. However, very little research has explored this issue. Using a UK sample, we allocated participants across two versions of a DCE: one including a cost attribute and the other excluding a cost attribute. The DCE was identical in all other respects. We find no significant difference in response time across the two surveys, monotonicity was higher for the COST DCE and cost was stated as the most commonly ignored attribute in the COST DCE. Whilst the inclusion of a cost attribute did not alter the structure of preferences, it resulted in a lower level of choice consistency. Using an unrestricted latent class model, we find evidence of a credibility effect: respondents with experience of paying for health services and who perceive the choices as realistic are less likely to ignore cost. Further, respondents with a higher response time are less likely to be cost minimisers. Results are robust across different model specifications and choice formats. DCE practitioners should give due consideration to cost credibility when including a cost attribute, ensuring participants engage with the cost attribute. Ways to do this are suggested, including careful motivation of the cost attribute, consideration to the appropriate payment vehicle and careful consideration to the cost attribute when developing and piloting the survey. Failure to do this will result in an invalid willingness to pay estimates and thus policy recommendations.

The COVID-19 pandemic in Italy: Policy and technology impact on health and non-health outcomes.

BACKGROUND: Italy was the first Western country to experience a major coronavirus outbreak and consequently faced large-scale health and socio-economic challenges. The Italian government enforced a wide set of homogeneous interventions nationally, despite the differing incidences of the virus throughout the country. OBJECTIVE: The paper aims to analyse the policies implemented by the government and their impact on health and non-health outcomes considering both scaling-up and scaling-down interventions. METHODS: To categorise the policy interventions, we rely on the comparative and conceptual framework developed by Moy et al. (2020). We investigate the impact of policies on the daily reported number of deaths, case fatality rate, confirmation rate, intensive care unit saturation, and financial and job market indicators across the three major geographical areas of Italy (North, Centre, and South). Qualitative and quantitative data are gathered from mixed sources: Italian national and regional institutions, National Health Research and international organisations. Our analysis contributes to the literature on the COVID-19 pandemic by comparing policy interventions and their outcomes. RESULTS: Our findings suggest that the strictness and timing of containment and prevention measures played a prominent role in tackling the pandemic, both from a health and economic perspective. Technological interventions played a marginal role due to the inadequacy of protocols and the delay of their implementation. CONCLUSIONS: Future government interventions should be informed by evidence-based decision making to balance, the benefits arising from the timing and stringency of the interventions against the adverse social and economic cost, both in the short and long term.

The role of heterogeneity of patients' preferences in kidney transplantation.

We elicit time and risk preferences for kidney transplantation from the entire population of patients of the largest Italian transplant centre using a discrete choice experiment (DCE). We measure patients' willingness-to-wait (WTW) for receiving a kidney with one-year longer expected graft survival, or a low risk of complication. Using a mixed logit in WTW-space model, we find heterogeneity in patients' preferences. Our model allows WTW to vary with patients' age and duration of dialysis. The results suggest that WTW correlates with age and duration of dialysis, and that accounting for patients' preferences in the design of kidney allocation protocols could increase their welfare. The implication for transplant practice is that eliciting patients' preferences could help in the allocation of "non-ideal" kidneys.

Understanding public preferences and trade-offs for government responses during a pandemic: a protocol for a discrete choice experiment in the UK.

INTRODUCTION: Social distancing and lockdown measures are among the main government responses to the COVID-19 pandemic. These measures aim to limit the COVID-19 infection rate and reduce the mortality rate of COVID-19. Given we are likely to see local lockdowns until a treatment or vaccine for COVID-19 is available, and their effectiveness depends on public acceptability, it is important to understand public preference for government responses. METHODS AND ANALYSIS: Using a discrete choice experiment (DCE), this study will investigate the public's preferences for pandemic responses in the UK. Attributes (and levels) are based on: (1) lockdown measures described in policy documents; (2) literature on preferences for lockdown measures and (3) a social media analysis. Attributes include: lockdown type; lockdown length; postponement of usual non-urgent medical care; number of excess deaths; number of infections; impact on household spending and job losses. We will prepilot the DCE using virtual think aloud interviews with respondents recruited via Facebook. We will collect preference data using an online survey of 4000 individuals from across the four UK countries (1000 per country). We will estimate the relative importance of the attributes, and the trade-offs individuals are willing to make between attributes. We will test if respondents' preferences differ based on moral attitudes (using the Moral Foundation Questionnaire), socioeconomic circumstances (age, education, economic insecurity, health status), country of residence and experience of COVID-19. ETHICS AND DISSEMINATION: The University of Aberdeen's College Ethics Research Board (CERB) has approved the study (reference: CERB/2020/6/1974). We will seek CERB approval for major changes from the developmental and pilot work. Peer-reviewed papers will be submitted, and results will be presented at public health and health economic conferences nationally and internationally. A lay summary will be published on the Health Economics Research Unit blog.

Assessment of Nutrition Competency of Graduating Agriculture Students in Ethiopia: A Cross-sectional Study.

OBJECTIVE: To assess the level of nutrition-sensitive agriculture competencies of graduating midlevel animal and plant sciences students in Ethiopia and identify factors associated with the attainment of competencies. DESIGN: A cross-sectional study design using structured skills observation checklists, objective written questions, and structured questionnaires was employed. SETTING: Two agriculture technical vocational education and training colleges in the 2 regions of Ethiopia. PARTICIPANTS: A total of 145 students were selected using stratified random sampling techniques from a population of 808 students with the response rate of 93%. MAIN OUTCOME MEASURES: Nutrition-sensitive agriculture competency (knowledge and skills attributes) of graduating students. ANALYSIS: Bivariate and multivariable statistical analyses were used to examine the association between the variables of students' gender, age, department, institutional ownership, and perception of learning environment and their performance in nutrition competency. RESULTS: Combined scores showed that 49% of students demonstrated mastery of nutrition competencies. Gender and institutional ownership were associated with the performance of students (P < .001); male students and students at a federal institution performed better. CONCLUSIONS AND IMPLICATIONS: The study showed low performance of students in nutrition competency and suggested the need for strengthening the curriculum, building tutors' capacity, and providing additional support to female students and regional colleges.

Polio outbreak response in Ethiopia.

BACKGROUND: Ethiopia had been polio-free for almost four years until December 2004. However, between December 2004 and February 2006, 24 children were paralysed as a result of infection with wild poliovirus imported from the neighbouring country of Sudan. In response, the country has attempted to document the impact of various response measures on the containment of wild poliovirus transmission. OBJECTIVES: This study aims at systematic and epidemiological assessment of the extent of the outbreak, its determinants, and the lessons learned as well as the implications for future control strategies to interrupt wild poliovirus transmission. DESIGN: A cross-sectional study design with qualitative and quantitative data collection approaches was used to conduct the epidemiologic assessment. SUBJECTS: All confirmed wild poliovirus cases, and reported acute flaccid paralysis cases in close proximity to the confirmed polio cases were the study subjects. Child caretakers and health service providers were interviewed as part of the investigation. RESULTS: Between December 2004 and February 2006, eight children from Tigray Regional State, nine children from Amhara Regional State and seven children from Oromia Regional State were paralysed as a result of infection with wild poliovirus type 1. Genetic sequencing demonstrated two separate importations to Ethiopia. Risk factors that may have facilitated spread of the outbreak within the country included gaps in vaccination coverage and interruption of the cold chain system, gaps in acute flaccid paralysis surveillance performance, high population mobility, poor environmental sanitation, crowded living conditions and unsafe drinking water. In response to the outbreak, Ethiopia conducted detailed outbreak investigations within two days of confirmation of the index cases. Large-scale, house-to-house vaccination campaigns were also implemented. As a result, the three regions interrupted the wild poliovirus transmission within the regions within one year of confirmation of the index case. CONCLUSION: Outbreak response activities were successful in interrupting the imported wild poliovirus transmission in Tigray, Amhara and Oromia Regional States of Ethiopia within a one-year period of time. In Ethiopia, programme strategies should be intensified to contain further spread and prevent future importation of wild poliovirus. Large-scale immunisation campaigns should reach every child, including those isolated by geography, poverty and security.

Intralobar nephroblastematosis: precursor lesions of nephroblastoma in the Sprague-Dawley rat.

Precursor lesions of spontaneous nephroblastoma (NB) in rats are here characterized for the first time, with a description of the progression of the tumor in prenatal, postnatal, and adult Sprague-Dawley rats (Upj:TUC[SD]spf.nb), which are genetically predisposed to the tumor. NB in the rat starts as a focal or multifocal interstitial accumulation of intensely basophilic immature (blastema) cells, invariably located in the deep renal cortex. Precursor lesions of NB (designated intralobar nephroblastematosis) and the early tumor do not overtly disrupt the overall structural organization and integrity of the kidney. However, with increasing size and neoplastic transformation, these lesions trap, compress, and displace/replace the existing renal tubules. Nephroblastematous foci occurred in one or both kidneys in tumor-bearing or non-tumor-bearing kidneys and in young and old rats. Like the precursor lesions, the early tumors in rats as young as 6 weeks of age were located in the inner cortex. Well-developed NB was comprised of blastema cells arranged in dense sheets or in ductular structures surrounded by mantles of blastema cells supported by varying amounts of fibromatous stroma. The stroma in one rat was hemangiosarcomatous (triphasic Wilms' tumor). Tumor cells were slightly pleomorphic and had varying amounts of granular cytoplasm with sparse organelles and showed junctional complexes and basal laminae whose frequency apparently depended upon whether the blastema cell tended to differentiate to epithelial or mesenchymal cells. NB in the rat was morphologically similar to immature pre- and postnatal kidneys, regardless of whether it occurred in young or old rats. The deep cortical location and interstitial infiltrative characteristics of precursor lesions of NB in the rat were analogous to intralobar nephrogenic rests, a variant of the precursor to Wilms' tumor in children.

Venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats following intravenous administration of a novel supersaturated submicron lipid emulsion.

PURPOSE: To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. METHODS: Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography. RESULTS: Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V(ss), (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. CONCLUSIONS: Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.

Relationship between serum concentrations, hemodynamic effects, and cardiovascular lesions in dogs treated with minoxidil.

The threshold hemodynamic changes associated with the cardiovascular (CV) toxicity of minoxidil (MNX) in the dog, characterized by subendocardial necrosis, right atrial hemorrhagic lesions, and coronary vascular medial hemorrhage and necrosis, have not been defined. To determine the relationship between serum concentration, hemodynamic effects [heart rate (HR) and mean arterial pressure (MAP)] and CV toxicity, groups of female Beagle dogs were treated with a continuous iv infusion of dextrose (control) or 0.05, 0.14, 0.43, 1.44, or 4.32 mg/kg/day of MNX for 3 days. Serum concentration of free MNX increased in a dose-related manner and reached steady state within 4 hr after the initiation of infusion. There was a time-dependent, apparently dose-related increase in HR at all doses. MAP was decreased at > or = 0.14 mg/kg/day in a time- and dose-related manner. The doses or steady-state serum concentrations of MNX that showed no significant hemodynamic effects and CV toxicity were approximately 0.05 mg/kg or 3.0 +/- 0.6 ng/ml and 0.14 mg/kg or 7.3 +/- 2.0 ng/ ml, respectively. CV toxicity occurred at a serum concentration of 16.6 +/- 1.9 ng/ml where HR was increased by 65 +/- 11 beats/min and MAP was decreased by 34 +/- 2 mm Hg. A serum concentration of 7.3 +/- 2 ng/ml of MNX that increased HR by 47 +/- 14 beats/min and decreased MAP by 17 +/- 8 mm Hg was not associated with CV toxicity. This study suggests that the threshold hemodynamic effects associated with the CV toxicity of MNX in the dog are a function of an increase in HR by at least 55 beats/min and a decrease in MAP by at least 30 mm Hg. In conclusion, the safety margin of drugs like MNX, where the mechanisms of toxicity are known to be related to their pharmacologic effects, should be based on the ratio of the pharmacokinetically and metabolically adjusted dose/serum concentration of the drug that evokes comparable pharmacologic effects in the animal model and humans rather than on the ratio of the nontoxic dose/serum concentration in animals to the efficacious dose in humans.

Heritable nephroblastoma (Wilms' tumor) in the Upjohn Sprague Dawley rat.

There has been no satisfactory animal model for hereditary nephroblastoma (NB; Wilms' tumor), the most common malignant renal tumor in children. A rat subline with a high incidence of NB, designated Upj:TUC(SD)spf.nb, was established from tumor-bearing Upjohn Sprague Dawley (Upj:TUC[SD]spf) stock rats by inbreeding. Incidence of NB was increased from 2.2% (1/46) to 33.0% (4/12) in males and from 10.0% (5/50) to 58.3% (7/12) in females through four successive generations of sister-to-brother mating. The overall incidence of NB-6.5% (14/214) in males and 21.6% (49/227) in females-was over 150-fold higher than the incidence of the tumor in other strains of rats. Of the 63 tumors, 47 (75%) developed at 4 to 12 months of age, and 32 (51%) developed at 7 to 9 months of age. Twelve of the tumors (19%) were bilateral, and in four rats (6.3%) the tumor was triphasic Wilms' tumor. Five of the tumors invaded the adjoining abdominal organs; none metastasized to distant organs. The tumor was consistently transplanted to syngeneic rats through 10 successive passages. The transplanted tumor, as the primary tumor, was composed of blastemoepithelial cells. The Upj:TUC(SD) spf.nb rat with a high incidence of NB, established at the Upjohn Company and donated to the Cleveland Clinic, may be an appropriate animal model for NB (Wilms' tumor) in children.

The pharmacologic basis of the cardiovascular toxicity of minoxidil in the dog.

Minoxidil (MNX), like several other vasoactive drugs, causes cardiovascular toxicity in dogs by undetermined mechanisms. We studied the mechanism of cardiovascular toxicity of MNX [an adenosine triphosphate (ATP)-sensitive potassium channel opener] by blocking its pharmacologic effects with glyburide (an ATP-sensitive potassium channel blocker) in groups of 5 female beagle dogs treated orally for 2 days with 1.0 mg/kg/day of MNX alone or with glyburide given in 5 or 6 divided doses of 300 mg/kg at 2 hr before and after each dose of MNX and at 3-6-hr intervals thereafter. A third group of 5 dogs received glyburide alone in the same dosing regimen as in the combination group. Mean arterial pressure (MAP), heart rate (HR), the pharmacokinetics of MNX, and gross and microscopic changes in the heart were evaluated. Glyburide did not influence the pharmacokinetics of MNX but prevented or markedly attenuated the MNX-induced cardiovascular lesions (right atrial hemorrhagic lesions, subendocardial necrosis, or coronary arteritis) occurred in dogs whose MNX-induced hemodynamic effects were effectively blocked by glyburide. In conclusion, the cardiovascular toxicity of MNX in dogs is not caused by a direct toxic effect of MNX on the heart but apparently is related to the exaggerated pharmacologic/profound hemodynamic effects it elicits in the dog.