Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in the horse.

The aim of the study was to describe the pharmacokinetics and selected pharmacodynamics of intravenous dexmedetomidine in horses. Eight adult horses received 5 µg/kg dexmedetomidine IV. Blood samples were collected before and for 10 h after drug administration to determine dexmedetomidine plasma concentrations. Pharmacokinetic parameters were calculated using noncompartmental analysis. Data from one outlier were excluded from the statistical summary. Behavioral and physiological responses were recorded before and for 6 h after dexmedetomidine administration. Dexmedetomidine concentrations decreased rapidly (elimination half-life of 8.03 ± 0.84 min). Time of last detection varied from 30 to 60 min. Bradycardia was noted at 4 and 10 min after drug administration (26 ± 8 and 29 ± 8 beats/min respectively). Head height decreased by 70% at 4 and 10 min and gradually returned to baseline. Ability to ambulate was decreased for 60 min following drug administration, and mechanical nociceptive threshold was increased during 30 min. Blood glucose peaked at 30 min (134 ± 24 mg/dL) and borborygmi were decreased for the first hour after dexmedetomidine administration. Dexmedetomidine was quickly eliminated as indicated by the rapid decrease in plasma concentrations. Physiological, behavioral, and analgesic effects observed after dexmedetomidine administration were of short duration.

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.

Pharmacokinetic profile in relation to anaesthesia characteristics after a 5% micellar microemulsion of propofol in the horse.

BACKGROUND: To define the pharmacokinetic profile of propofol 5% microemulsion formulation in horses. METHODS: First, propofol was administered as bolus injection (2 mg kg(-1)) to six xylazine-sedated horses. Secondly, after sedation and bolus injection, propofol was maintained with continuous infusion for 3 h [8.1 (sd 3.2) mg kg(-1) h(-1)] to the same six horses. Thirdly, in two horses, a commercial propofol was used for comparison. Response to noxious stimulation was used to evaluate analgesia. Venous blood samples were obtained to measure propofol plasma concentration using liquid chromatography-mass spectrometry analysis. The plasma concentrations were related to the anaesthesia characteristics to determine the ED(50). RESULTS: The pharmacokinetic profile of propofol is best characterized by a non-compartmental model. The mean (confidence interval) for area under plasma concentration-time curve, elimination half-life, mean residence time, and clearance was 41 min microg ml(-1) (+/-7.7), 44.8 min (+/-21.3), 13.7 min (+/-3.2), and 45.8 ml min(-1) kg(-1) (+/-6.5), respectively. Linear regression analysis showed a correlation between plasma concentration and infusion rate (r(2)=0.47). Most propofol infusion rates did not inhibit the response to noxious stimulation and rates above 11.9 mg kg(-1) h(-1) caused involuntary muscle contractions. Better recoveries were associated with lower propofol plasma concentrations. Propofol plasma concentration frequently increased when horses woke from anaesthesia. CONCLUSIONS: Caution is warranted when propofol is used for continuous infusion due to variable kinetics, myoclonal activity, poor analgesia, and less desirable recovery quality.

Plasma concentrations, behavioural and physiological effects following intravenous and intramuscular detomidine in horses.

REASONS FOR PERFORMING STUDY: Detomidine hydrochloride is used to provide sedation, muscle relaxation and analgesia in horses, but a lack of information pertaining to plasma concentration has limited the ability to correlate drug concentration with effect. OBJECTIVES: To build on previous information and assess detomidine for i.v. and i.m. use in horses by simultaneously assessing plasma drug concentrations, physiological parameters and behavioural characteristics. HYPOTHESIS: Systemic effects would be seen following i.m. and i.v. detomidine administration and these effects would be positively correlated with plasma drug concentrations. METHODS: Behavioural (e.g. head position) and physiological (e.g. heart rate) responses were recorded at fixed time points from 4 min to 24 h after i.m. or i.v. detomidine (30 microg/kg bwt) administration to 8 horses. Route of administration was assigned using a balanced crossover design. Blood was sampled at predetermined time points from 0.5 min to 48 h post administration for subsequent detomidine concentration measurements using liquid chromatography-mass spectrometry. Data were summarised as mean +/- s.d. for subsequent analysis of variance for repeated measures. RESULTS: Plasma detomidine concentration peaked earlier (1.5 min vs. 1.5 h) and was significantly higher (105.4 +/- 71.6 ng/ml vs. 6.9 +/- 1.4 ng/ml) after i.v. vs. i.m. administration. Physiological and behavioural changes were of a greater magnitude and observed at earlier time points for i.v. vs. i.m. groups. For example, head position decreased from an average of 116 cm in both groups to a low value 35 +/- 23 cm from the ground 10 min following i.v. detomidine and to 64 +/- 24 cm 60 min after i.m. detomidine. Changes in heart rate followed a similar pattern; low value of 17 beats/min 10 min after i.v. administration and 29 beats/min 30 min after i.m. administration. CONCLUSIONS: Plasma drug concentration and measured effects were correlated positively and varied with route of administration following a single dose of detomidine. POTENTIAL RELEVANCE: Results support a significant influence of route of administration on desirable and undesirable drug effects that influence case management.

Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses.

REASONS FOR PERFORMING STUDY: Detomidine is commonly used i.v. for sedation and analgesia in horses, but the pharmacokinetics and metabolism of this drug have not been well described. OBJECTIVES: To describe the pharmacokinetics of detomidine and its metabolites, 3-hydroxy-detomidine (OH-detomidine) and detomidine 3-carboxylic acid (COOH-detomidine), after i.v. and i.m. administration of a single dose to horses. METHODS: Eight horses were used in a balanced crossover design study. In Phase 1, 4 horses received a single dose of i.v. detomidine, administered 30 microg/kg bwt and 4 a single dose i.m. 30 microg/kg bwt. In Phase 2, treatments were reversed. Plasma detomidine, OH-detomidine and COOH-detomidine were measured at predetermined time points using liquid chromatography-mass spectrometry. RESULTS: Following i.v. administration, detomidine was distributed rapidly and eliminated with a half-life (t1/2(el)) of approximately 30 min. Following i.m. administration, detomidine was distributed and eliminated with t1/2(el) of approximately one hour. Following, i.v. administration, detomidine clearance had a mean, median and range of 12.41, 11.66 and 10.10-18.37 ml/min/kg bwt, respectively. Detomidine had a volume of distribution with the mean, median and range for i.v. administration of 470, 478 and 215-687 ml/kg bwt, respectively. OH-detomidine was detected sooner than COOH-detomidine; however, COOH-detomidine had a much greater area under the curve. CONCLUSIONS AND POTENTIAL RELEVANCE: These pharmacokinetic parameters provide information necessary for determination of peak plasma concentrations and clearance of detomidine in mature horses. The results suggest that, when a longer duration of plasma concentration is warranted, the i.m. route should be considered.

Measles vaccination of infants in a well-vaccinated population.

During outbreaks of measles, measles vaccine is recommended for infants considered to be at risk who are 6 months of age and older. In a prospective trial the serologic response to early measles immunization has been evaluated in 125 infants given monovalent measles vaccine at 6 to 8.5 months of age and measles-mumps-rubella at 15 months. The response to vaccination was measured by plaque reduction neutralization (PRN) assay and enzyme immunoassay. Infants were grouped by the mother's immunization history: natural immunity (n = 60, Group 1); killed followed by live, further attenuated vaccine (n = 22, Group 2); and live, further attenuated vaccine only (n = 43, Group 3). The prevaccination geometric mean titer (GMT) by PRN for Group 1 (GMT = 69) was significantly higher than that of Group 2 (GMT = 18) or 3 (GMT = 13). Seroconversion (4-fold increase in PRN titer) rates after monovalent vaccine were 31, 71 and 76% for Groups 1, 2 and 3, respectively. Seroconversion percentages were higher when measured 6 to 8 weeks after vaccination compared with 4 to 5 weeks. After measles-mumps-rubella > or = 97% of all infants had PRN titers > 120 and were measles IgG-positive by enzyme immunoassay. These data show that as demographics shift to a well-vaccinated maternal population and susceptibility in younger infants, measles vaccination before the currently recommended age will be effective.

Reduced measles immunity in infants in a well-vaccinated population.

The recommended age for measles vaccination is based in part on information gathered when most mothers had natural measles. Nowadays many mothers have received measles vaccine. To assess this change measles antibody neutralization titers (NT) were determined for 278 mother-infant pairs. One hundred sixty-four mothers, born before 1958, likely had had natural measles (Group 1). Sixty mothers received one to three killed plus one attenuated measles vaccination (Group 2) and 54 received 1 attenuated measles vaccination only (Group 3). NT were determined for the mother and for the infant at birth and in the infant during the fourth and sixth months. Group 1 mothers and infants at every age had higher geometric mean NT than those in Groups 2 or 3 (P less than 0.05). By 7 months 65% of Group 1 infants and greater than 90% of Group 2 and 3 infants had an NT less than 1:10. The rate of antibody decay was significantly faster for Group 1 infants (P less than 0.05). Earlier vaccination in the infant should be considered.

Soluble highly coloured phenylboronic acids and their use in glycohemoglobin quantification.

Water soluble dye-phenylboronic acid conjugates (dye-PBAs) possessing strong absorption of visible light are introduced as new reagents for the determination of glycohemoglobin. Their functionality and prospective use are demonstrated in a semi-homogenous glycohemoglobin assay. The assay is based on cis-diol esterification of dye-PBA to glycohemoglobin followed by selective precipitation of hemoglobin from solution, co-precipitating bound dye-PBA. Quantification of the molar "dye-PBA/Hb"-ratio in redissolved precipitates using either absorption or fluorescence spectroscopy, reflects the glycation level of the blood samples used. Future development of the assay principle is illustrated in a filter based assay, collecting the precipitated hemoglobin on a filter followed by reflectometric readings directly on the precipitate. The significance of this work lies first, in the demonstration of a new principle for the determination of glycohemoglobin, and second, as an illustration of the prospective use of water soluble, signal-forming non-immobilised boronic acids in the determination of cis-diol containing analytes.

A Canadian multicentre case-control study of sporadic Escherichia coli 0157:H7 infection.

OBJECTIVE: To evaluate further risk factors for Escherichia coli 0157:H7 infection including consumer preferences related to the consumption of ground beef and the role of person-to-person transmission of this infection. PATIENTS AND METHODS: A case-control study of sporadic E coli 0157:H7 infection was undertaken in five Canadian cites from June to December 1991. One hundred cases of E coli 0157:H7 infection were age- and sex-matched to 200 neighbourhood controls. Cases and controls were interviewed face-to-face to obtain information on potential risk factors for infection and health outcomes. Daycare providers of case and control children were interviewed regarding risk factors for infection at the institutional level. Contacts of cases and controls who reported diarrhea in the seven days before the case onset date were also interviewed about their symptoms and risk factors. RESULTS: All cases had diarrhea during the course of their illness and 90 (90%) reported bloody diarrhea. Four (4%) were reported to have developed hemolytic uremic syndrome; however, there were no fatalities. Sixty-one (61%) of patients were hospitalized. Two variables were associated with infection in the final conditional logistic regression model: eating pink hamburger patties (odds ratio = 12.4, P=0.0001, population attributable fraction =40.2%) and contact with a nonhousehold member suffering from diarrhea (odds ratio = 7.0, P=0.0054, population attributable fraction = 10.3%) in the seven days before illness. Forty per cent of cases and controls who indicated that they prefer well done hamburgers said they would eat a 'pink' hamburger if served to them rather than ask that the hamburger be cooked longer. CONCLUSIONS: Health care workers should remain vigilant in their efforts to educate the public as to the risks associated with the consumption of ground beef that is inadequately cooked, and the importance of personal hygiene in the prevention of enteric illness.

A multi-level approach for investigating socio-economic and agricultural risk factors associated with rates of reported cases of Escherichia coli O157 in humans in Alberta, Canada.

Using negative binomial and multi-level Poisson models, the authors determined the statistical significance of agricultural and socio-economic risk factors for rates of reported disease associated with Escherichia coli O157 in census subdivisions (CSDs) in Alberta, Canada, 2000-2002. Variables relating to population stability, aboriginal composition of the CSDs, and the economic relationship between CSDs and urban centres were significant risk factors. The percentage of individuals living in low-income households was not a statistically significant risk factor for rates of disease. The statistical significance of cattle density, recorded at a higher geographical level, depended on the method used to correct for overdispersion, the number of levels included in the multi-level models, and the choice of using all reported cases or only sporadic cases. Our results highlight the importance of local socio-economic risk factors in determining rates of disease associated with E. coli O157, but their relationship with individual risk factors requires further evaluation.

Epidemiological characteristics of reported sporadic and outbreak cases of E. coli O157 in people from Alberta, Canada (2000-2002): methodological challenges of comparing clustered to unclustered data.

Using multivariable models, we compared whether there were significant differences between reported outbreak and sporadic cases in terms of their sex, age, and mode and site of disease transmission. We also determined the potential role of administrative, temporal, and spatial factors within these models. We compared a variety of approaches to account for clustering of cases in outbreaks including weighted logistic regression, random effects models, general estimating equations, robust variance estimates, and the random selection of one case from each outbreak. Age and mode of transmission were the only epidemiologically and statistically significant covariates in our final models using the above approaches. Weighing observations in a logistic regression model by the inverse of their outbreak size appeared to be a relatively robust and valid means for modelling these data. Some analytical techniques, designed to account for clustering, had difficulty converging or producing realistic measures of association.

The use of randomization tests to assess the degree of similarity in PFGE patterns of E. coli O157 isolates from known outbreaks and statistical space-time clusters.

Using isolates from reported cases of Escherichia coli O157 from Alberta, Canada in 2002, we applied randomization tests to determine if cases associated with an outbreak or statistical space-time cluster had more similar pulsed-field gel electrophoresis patterns, based on Dice coefficients, than expected by chance alone. Within each outbreak and space-time cluster, we assessed the mean, median, 25th percentile, 75th percentile, standard deviation, coefficient of variation, and interquartile range of the Dice coefficients of each pairwise comparison among the isolates. To assess the statistical significance of measures of location (e.g. mean) and variation (e.g. standard deviation) we created randomization distributions using all isolates or only isolates from sporadic cases. We determined that randomization tests are an appropriate tool for evaluating the similarity among isolates from cases that have been linked epidemiologically or statistically. We found little difference between using all cases or only sporadic cases when creating our randomization distributions.

The use of outbreak information in the interpretation of clustering of reported cases of Escherichia coli O157 in space and time in Alberta, Canada, 2000-2002.

We obtained a list of all reported cases of Escherichia coli O157 in Alberta during the 2000-2002 period, and using scan statistics we identified yearly temporal and spatial clusters of reported cases of E. coli O157 during the summer and in southern Alberta. However, the location of the spatial cluster in the south was variable among years. The impact of using both outbreak and sporadic data or only sporadic data on the identification of spatial and temporal clusters was small when analysing individual years, but the difference between spatial clusters was pronounced when scanning the entire study period. We also identified space-time clusters that incorporated known outbreaks, and clusters that were suggestive of undetected outbreaks that we attempted to validate with molecular data. Our results suggest that scan statistics, based on a space-time permutation model, may have a role in outbreak investigation and surveillance programmes by identifying previously undetected outbreaks.

The changing epidemiology of chickenpox in Alberta.

BACKGROUND: Varicella vaccine was licensed in Canada in 1998. The province of Alberta introduced a universal publicly funded varicella vaccination program in 2001. PURPOSE: To describe the epidemiology of non-fatal cases of chickenpox for which publicly funded health services were utilized for the period 1986-2002. METHODS: We used the records of Alberta's universal, publicly funded health care insurance system to identify cases of chickenpox for the period 1986-2002. The earliest dated utilization of a health service for which there was an ICD9-CM code of 052.xx or an IC10-CA code of B01.xx was used as the date of illness onset. Denominators for rates were estimated using mid-year population estimates from the Alberta Health Care Insurance Registry. Age-specific rates were estimated for each year. RESULTS: The crude incidence of chickenpox significantly declined over the period 1994-2002, most steeply after the year 2000. The incidence of chickenpox varied by age group and year and there was evidence of age-group-year interaction. Among those aged 5-19 years, chickenpox incidence began to decline prior to vaccine licensure in Canada. Among those aged less than one year and those aged 1-4 years, the incidence increased until 1999 when a decline began. Over the period 0.8% of cases were hospitalized. CONCLUSION: Chickenpox rates began to decline prior to the introduction of the publicly funded vaccination program; however the declines in rates among the youngest age-groups are consistent with a vaccination program effect.

Units, mg/l or % CDT for detection of harmful alcohol consumption?

Recent studies have demonstrated that the diagnostic performance of CDT measurements is influenced by variations in total transferrin concentration. Improved specificity is obtained with relative values, either %CDT or units CDT per total transferrin concentration. Whether relative or absolute values are used, confirmatory methods by HPLC or IEF should be available, and definition of the CDT values and correlation to HPLC or IEF should be given.

Selective precipitation of human hemoglobin by organic solvents and metal cations.

The interaction of human hemoglobin with several organic solvents and metal cation has been studied in order to obtain selective precipitation of hemoglobin from solution. Alcohols, and preferably the mixture ethanol: butanol added to a final concentration of 8% (v/v) 1-butanol was found to be superior in this respect, giving close to selective precipitation of hemoglobin from whole blood lysates. An equally specific precipitation was achieved by using zinc-chloride in 10-15 molar excess to hemoglobin. Contrary to organic solvents, complex formation with Zn2+ resulted in a reversible precipitation enabling renaturation using strong chelating agents. Specificity of the hemoglobin-precipitating agents was verified by chromatographic and electrophoretic studies. Applications of the presented methods in analytical chemistry and in the isolation and purification of blood proteins are discussed.

Protein-boronic acid conjugates and their binding to low-molecular-mass cis-diols and glycated hemoglobin.

Different methods for covalent linkage of phenylboronic acid (PBA) to structural proteins and enzymes are presented. Protein-PBA conjugates, free in solution or immobilised on magnetizable polymer particles, were tested for their binding of D-sorbitol, D-mannose and glycohemoglobin (GHb). Similarly, alkaline phosphatase-PBA conjugates were used in an attempted enzyme-linked sorbent assay for the detection of GHb. Affinity chromatography on immobilised D-mannose and gel chromatographic studies of protein-PBA complexes with [14C]sorbitol, clearly illustrated a low affinity of the interaction studied. Glycated hemoglobin could not be detected using the enzyme-linked sorbent assay approach. However, GHb was found to be specifically retained on columns filled with protein-PBA-coated particles as affinity matrix, enabling the glycation level of blood samples to be determined.

Hantavirus pulmonary syndrome in northern Alberta, Canada: clinical and laboratory findings for 19 cases.

We reviewed the clinical and laboratory findings for 19 cases of hantavirus pulmonary syndrome (HPS) identified either serologically or by immunohistochemical testing of archival tissue at our tertiary care center. Fever (95%), cough (89%), and dyspnea (89%) were the most common presenting symptoms. The most prevalent presenting signs were respiratory abnormalities (95%) and tachycardia (84%). Common laboratory findings included thrombocytopenia (95%) and leukocytosis (79%). Elevated aspartate aminotransferase and lactate dehydrogenase levels were found in all patients tested. Intubation was required in 58% of the patients, and inotropic support was required in 53%. Our study confirms that serological responses appear early during clinical illness, making the enzyme immunoassay a useful tool for the diagnosis of acute HPS. The mortality (26%) and severity of disease that we observed among patients with HPS appear to be less than those reported elsewhere.

Glycohemoglobin filter assay for doctors' offices based on boronic acid affinity principle.

We present a new filter assay for the determination of glycohemoglobin as a unique application of the boronic acid affinity principle. With the use of a water-soluble blue-colored boronic acid derivative and a specific precipitation method for hemoglobin, total hemoglobin including bound boronic acid is precipitated and collected on a filter strip before quantification. Hemoglobin and boronic acid are quantified by a dual-wave-length reflectometric measurement, and the result is reported directly as percent glycohemoglobin. The test is simple, quick, and designed as a doctors' office test for the monitoring and management of diabetes. The imprecision of the assay is < 4% over the range 3-18% Hb A1c, and the method is linear up to at least 20% Hb A1c. Comparisons with four well-established glycohemoglobin methods yielded correlation coefficients ranging from 0.94 to 0.99, with slopes from 0.94 to 1.01.