The clinical use of xylazine may result in morbidity and mortality in small ruminants, and it was suspected that exposure to changes in environmental temperature may contribute to these effects. Xylazine hydrochloride was administered intravenously at a dose of 0.1 mg/kg to a group of six indigenous domestic goats with a mean body mass of 28.2 kg. Xylazine was administered at a room temperature of 14°C and relative humidity of 33%, at 24°C and a relative humidity of 55%, and at 34°C with a relative humidity of 65%. The following variables were evaluated: clinical behaviour, cardiopulmonary function, haematology, acid-base balance, plasma glucose and insulin, body temperature, and the pharmacokinetic characteristics of xylazine. Xylazine administration resulted in transient restlessness, followed by sedation, muscle relaxation, and salivation. The onset of these clinical signs was not influenced by environmental conditions. Administration of xylazine resulted in a transient increase in respiratory rate in the 24 and 34°C environments. In the 14°C environment, the respiratory rate decreased significantly (p<0.05) from baseline and continued to decrease for the full duration of the 60 minutes observation period. Heart rate decreased in all three environments, but this decrease was only significant in the 14°C environment for the duration of the observation period. Changes in haemoglobin concentration, haematocrit, red blood cell count and mean red blood cell volume were significantly (p<0.05) different 15 minutes after xylazine administration and continued to be so for the duration of the observation period. Total serum protein changed significantly (p<0.05) in the 24° and 34°C environments from 15 minutes after xylazine administration. The white cell count changed significantly (p<0.05) from 15 minutes after xylazine administration for the duration of the observation period in all three environments. Significant (p<0.05) changes occurred after xylazine administration in acid-base balance and arterial blood gas variables independent of environmental conditions. Arterial pH and the partial pressure of oxygen decreased significantly within 5 minutes of xylazine administration, and the partial pressure of carbon dioxide, total carbon dioxide and base excess increased significantly (p<0.05). Environmental conditions had no observable on plasma glucose and insulin concentration. Significant (p<0.05) changes occurred in all three environments. Environmental conditions had no influence on body temperature in the control (untreated) animals. Following the administration of xylazine, the body temperature of the goats in the 14 and 24°C environments was significantly (p<0.05) lower than that of the goats in the 34°C environment. The maximum decrease in oesophageal temperature of 1.57°C was observed 60 minutes after xy1azine administration to goats maintained in the 14°C environment. Environmental conditions had no influence on all of the pharrnacokinetic parameters of xylazine hydrochloride evaluated. It is concluded that apart from changes in body temperature, changes that occurred in clinical and pharmacokinetic variables after xylazine administration, were independent of the three environmental temperature and humidity conditions. / Thesis (DPhil (Surgery))--University of Pretoria, 1999. / Companion Animal Clinical Studies / unrestricted

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Indiana University-Purdue University Indianapolis (IUPUI) / Drug-Drug Interaction (DDI) is one of the major causes of adverse drug reaction (ADR) and has been demonstrated to threat public health. It causes an estimated 195,000 hospitalizations and 74,000 emergency room visits each year in the USA alone. Current DDI research aims to investigate different scopes of drug interactions: molecular level of pharmacogenetics interaction (PG), pharmacokinetics interaction (PK), and clinical pharmacodynamics consequences (PD). All three types of experiments are important, but they are playing different roles for DDI research. As diverse disciplines and varied studies are involved, interaction evidence is often not available cross all three types of evidence, which create knowledge gaps and these gaps hinder both DDI and pharmacogenetics research. In this dissertation, we proposed to distinguish the three types of DDI evidence (in vitro PK, in vivo PK, and clinical PD studies) and identify all knowledge gaps in experimental evidence for them. This is a collective intelligence effort, whereby a text mining tool will be developed for the large-scale mining and analysis of drug-interaction information such that it can be applied to retrieve, categorize, and extract the information of DDI from published literature available on PubMed. To this end, three tasks will be done in this research work: First, the needed lexica, ontology, and corpora for distinguishing three different types of studies were prepared. Despite the lexica prepared in this work, a comprehensive dictionary for drug metabolites or reaction, which is critical to in vitro PK study, is still lacking in pubic databases. Thus, second, a name entity recognition tool will be proposed to identify drug metabolites and reaction in free text. Third, text mining tools for retrieving DDI articles and extracting DDI evidence are developed. In this work, the knowledge gaps cross all three types of DDI evidence can be identified and the gaps between knowledge of molecular mechanisms underlying DDI and their clinical consequences can be closed with the result of DDI prediction using the retrieved drug gene interaction information such that we can exemplify how the tools and methods can advance DDI pharmacogenetics research. / 2 years

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Introduction :La prévalence de l’obésité, parmi les patients hospitalisés, est en augmentation. Les patients obèses présentent un risque accru de développer des infections nosocomiales par rapport aux individus non-obèses. Parmi les antibiotiques, la classe des β-lactames est la plus utilisée à l’hôpital tant en prophylaxie chirurgicale que pour le traitement des infections. Les recommandations de doses en vigueur sont basées sur des études pharmacocinétiques (PK) effectuées chez des patients non-obèses. Cependant, les patients obèses présentent des altérations physiologiques qui pourraient théoriquement être à l’origine de modifications des paramètres PK de ces antibiotiques. L’utilisation de doses standards d’antibiotiques pourrait avoir comme conséquence des concentrations sériques inadéquates chez ces patients; elles peuvent, dès lors, conduire à des échecs thérapeutiques et/ou favoriser l’émergence de souches résistantes. Objectifs: Ce travail de thèse a pour but d’approfondir les connaissances sur la PK des β-lactames chez les patients obèses présentant des scores de sévérité clinique différents. Patients et Méthodes: Quatre études PK ont été réalisées chez les patients obèses :1) une étude prospective de patients obèses, et non-obèses, ayant reçu de la céfazoline (CFZ) en prophylaxie de chirurgie digestive, 2) une étude préliminaire, prospective incluant uniquement des patients obèses traités pour des infections non sévères par l’un des 4 β-lactames à large spectre (pipéracilline-tazobactam (TZP), ceftazidime/céfépime (CEF), et méropénem (MEM)), 3) une étude prospective, avec groupe contrôle de patients non-obèses, étudiant la PK du TZP donné en traitement d’infections non sévères et 4) une étude rétrospective cas-témoin évaluant la PK de 4 β-lactames à large spectre (TZP, CEF, ou MEM) donnés pour le traitement d’infections sévères aux soins intensifs. Les taux sériques de ces antibiotiques ont été mesurés par chromatographie liquide et corrélés à plusieurs paramètres démographiques, biologiques et hémodynamiques. Résultats: Etude sur CFZ :Soixante-trois patients ont participé à l’étude: parmi ceux-ci, 43 avaient un index de masse corporelle (IMC) ≥ 35 kg/m2, et 22 un poids total ≥ 120 kg. Sur l’ensemble des patients, les concentrations sériques de CFZ étaient adéquates chez 100% des patients à 180 minutes (T180) et chez 64% (40/63) à 240 minutes (T240) après le début de l’infusion de CFZ. Il n’y avait pas de différence significative entre le pourcentage des patients avec des taux sériques adéquats à T240, quel que soit le paramètre utilisé pour la comparaison (IMC ≥ 35 kg/m2 versus IMC < 35 kg/m2, ou poids total ≥ 120 kg versus poids total < 120 kg). Etude préliminaire sur TZP, CEF et MEM: Cinquante-six patients obèses ont été inclus dans l’étude ;14 ont reçu du MEM, 31 du TZP et 11 du CEF. Parmi ces patients, les concentrations sériques adéquates pour traiter une infection à P. aeruginosa ont été atteintes chez 93% des patients traités par MEM, 68% des patients traités par TZP, et 73% des patients traités par CEF. Le volume de distribution (VD) et la clearance totale (CL) des β-lactames étaient augmentés par rapport à des valeurs rapportées dans la littérature chez les patients non-obèses. En effet, plus de 25% des patients présentaient une clearance en créatinine (CrCl) mesurée supérieure à 150 ml/minute, ce facteur étant identifié comme facteur de risque de concentrations sériques insuffisantes. Etude sur TZP: Trente-deux patients (14 non-obèses et 18 obèses) ont été inclus dans l’étude et ont reçu les doses standards de TZP. Une augmentation du VD (25.4 ± 5.6L vs. 21.0 ± 3.9 L, p= 0.018) et de la CL (18.1 ± 4.7 vs. 13.5 ± 40.1, p= 0.007) a été observé chez les patients obèses par rapport aux non-obèses conduisant à des concentrations statistiquement inférieures de TZP libre par rapport aux patients non-obèses. De même, malgré des valeurs de créatinine sérique semblables (0.8 ± 0.3 versus 0.9 ± 0.3 mg/dl, p=0.26), la CrCl mesurée sur des urines de 24h, était significativement plus élévée chez les obèses par rapport aux non-obèses (128 ± 58 vs. 79 ± 26 ml/min, p=0.006). Etude rétrospective cas-témoin sur TZP, CEF, et MEM aux soins intensifs: Quarante-neuf patients obèses et 59 patients non-obèses ont été inclus. Soixante-huit monitoring thérapeutiques ont été effectués chez les patients obèses et comparés à 68 monitoring thérapeutiques effectués chez les patients non-obèses. Après administration des doses standards des β-lactames, 1/3 des patients obèses avait des concentrations sériques insuffisantes pour traiter des infections à P. aeruginosa, et 1/4 de ces patients avait des concentrations sériques excessives, potentiellement toxiques. Par contre, aucune différence statistiquement significative n’a été observée entre les concentrations sériques des β-lactames des patients obèses et non-obèses. Conclusions :Lors de la prophylaxie chirurgicale, l’administration des doses standards de CFZ a montré des concentrations sériques insuffisantes pour assurer une couverture prophylactique adéquate en cas d’intervention chirugicale d’une durée supérieure à 180 minutes. Ni le poids total, ni l’IMC n’a pu identifier les patients qui nécessiteront une dose plus élevée de CFZ. De même, les doses standards des β-lactames à large spectre se sont avérées insuffisantes dans le traitement des infections non sévères et sévères dues à P. aeruginosa chez les patients obèses. En cas d’infections peu sévères, les concentrations sériques, chez ces patients, étaient significativement moindres que chez les patients non-obèses ;ceci étant lié à une augmentation du VD et de la CL des β-lactames. Un facteur de risque majeur retrouvé était une CrCl augmentée chez les patients obèses. Chez les patients avec infections sévères, la PK des β-lactames n’était par contre pas significativement différente entre les patients obèses et non-obèses. Ceci probablement à cause des perturbations déjà importantes de la PK des β-lactames liées à la séverité du sepsis. En conclusion, ces études identifient des perturbations de la PK des β-lactames chez les patients obèses. Parmi celles-ci, l’augmentation de la clearance rénale est un élement déterminant dans l’inadéquation des concentrations sériques. La situation est plus complexe chez les patients obèses aux soins intensifs où d’autres facteurs peuvent encore s’associer et perturber la PK des β-lactames. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

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Commercial pharmacokinetic programs are used to provide clinicians with the tools to predict pharmacokinetic models, estimate pharmacokinetic parameters, and analyze serum data for efficient and consistent drug therapy and, therefore, help clinicians to optimize drug therapy. Many of the commercial programs use different methods of data entry and analysis. In this study, three commercial dosing programs, Kinetidex®, DataKinetics®, and Simkin®, were utilized to evaluate their performance on predicting gentamicin initial dosage regimens and adjusted dosage regimens. The performance of the three programs were compared by measuring the difference in the percentage of the prediction error (PE) as bias and absolute prediction error (APE) as precision using a modified method developed by Sheiner. A clinically significant difference in outcomes was determined to exist if the difference in the calculation of the dosage regimen obtained from the programs as compared to a reference calculated dosage regimen exceeded 1 0 %. A statistically significant difference in the calculation of the dosage regimens obtained from the programs was determined by ANOVA testing (p < 0.05). The results indicated that the Simkin® program had the tendency to overestimate loading doses, and the difference as compared to the reference data was clinically significant. Also the difference observed in calculating loading doses between the Simkin® program and the other two programs was statistically significant. The Kinetidex® program had bias by underestimating daily maintenance doses, and the difference as compared to the reference data was clinically significant. The difference as compared to the reference data for calculating the daily maintenance doses by the DataKinetics® and Simkin® program did not exhibit bias, but the difference was clinically significant. The difference in the performance of predicting daily maintenance doses by the programs was statistically significant in bias but not in precision. The results of computer predicted serum levels versus the measured serum levels indicated that the Kinetidex® program exhibited bias by overestimating the peak and trough concentrations as compared to the other two programs, but there is no statistically significant difference among the programs in precision. In calculating adjusted doses using the measured serum levels, the results obtained from the three programs showed no difference in bias or precision. A comparison of the results of computer-predicted serum levels showed no difference among the programs in bias and precision. In conclusion, the study showed that there was a difference in the predicting ability of the three programs in calculating initial dosage regimens but showed no statistical difference in calculating the total daily-adjusted doses when using patient serum levels.

The development and evaluation of a vancomycin population pharmacokinetic model in children, pre-adolescent, and adolescent patients was performed via non linear mixed effects modeling (NONMEM) in 2 phases. In phase I, a vancomycin population pharmacokinetic model was developed based on data from 200 children (aged 2-17 years) using a two-compartment model. Variables tested for inclusion in the model were serum creatinine (SCR), age (AGE), weight (WT), height (HT), sex (SEX), and body surface area (BSA). Variables were included at the p $ In phase II, the performance of the derived model was evaluated in a naive tested population and then compared to the Schaad, et al. model via prediction error techniques (PE). The predictability of 159 measured concentrations was assessed in 68 new patients. In predicting all concentrations types, the mean prediction error (MPE) with a 95% confidence interval (CI) for both the current study model and Schaad, et al model were: $-$1.42 ($-$3.38, 0.54), and 6.01 (4.46, 7.56) mg/L, respectively. When considering only peaks, a MPE with 95% CI were 1.72 ($-$0.94, 4.38), and 7.61 (5.13, 10.09) mg/L, respectively. Finally, MPE with 95% CI for the troughs were $-$1.45 ($-$3.42, 0.52), and 3.84 (2.98, 4.70) mg/L, respectively. Maintenance dose (MD) tables were designed, based on the relationship of height and serum creatinine to clearance. In addition, a loading dose (LD) was also recommended, which was 5 mg/cm. It is recommended that the current study model be used for dosing the pediatric population while setting an initial target peak of 30 mg/L and a trough of 5-10 mg/L. This should frequently result in optimal serum vancomycin concentrations within the therapeutic window. Individualization of therapy should then be done, once the measured concentrations are available.