ACE Inhibitors - Evaluation of Disposition Characteristics and Concentration Effect Relationships

Extensive study of the active site of angiotensin converting enzyme (ACE) has led to the development of specific inhibitors which are now successfully used in the treatment of hypertension and cardiac failure. The work carried out within this thesis has been concerned with the evaluation of the disposition characteristics of the ACE inhibitors and their concentration effect relationships. Characterisation of the pharmacokinetics of any compound is dependent upon the availability of accurate, precise, sensitive and specific assay methodology. Three groups of methods have been compared within this thesis, two different methods to measure plasma ACE activity, three methods to measure plasma enalaprilat levels and three methods to measure plasma benazeprilat levels. The methods to measure plasma ACE activity yielded results in good agreement. One of the three methods to measure plasma enalaprilat levels gave results that were significantly lower than the remaining two methods. No obvious explanation could be found for this. Of the three methods to measure benazeprilat, the specific method gave significantly lower results than the two non specific methods, the possible existence of unstable glucuronides contributing to the discrepancy between the methods. These results highlight the need to know the specificity of any assay technique being used. The concentration effect relationship of two different series of ACE inhibitors was assessed in plasma from individual rabbits and volunteers. Differences were found in both the rank order of potency of the compounds between rabbit and man, and also, there were significant differences in the potency of single compounds between rabbit and man. These differences may reflect variations in the tertiary structure of ACE between rabbit and man and indicate that different doses would be needed to obtain the same degree of ACE inhibition. The in vivo/in vitro relationship for plasma ACE inhibition was assessed for perindoprilat and quinaprilat. For both compounds the in vivo values were significantly lower than those found in vitro, indicating greater inhibition of ACE in vivo. Any calculations based upon the in vitro values would overestimate the amount of drug needed to elicit the same response in vivo. The third group of in vitro studies examined the effect of the presence of parent compound on the in vitro potency of the metabolite. In vitro dose response curves for five metabolites were characterised in the presence and absence of parent compound. The presence of parent compound brought about a significant decrease in potency for S-10211 (the active metabolite of S-9650) and quinaprilat in rabbit, and for enalaprilat and perindoprilat in man. The decrease in potency seen for some of the metabolites studied may be due to the parent compound binding to a second active site sequence on the ACE molecule where it causes steric hindrance but not ACE inhibition. The rabbit was used as a model to characterise the effect of saturation of ACE binding sites on the pharmacokinetics of radiolabelled spiraprilat. Rabbits were pretreated with either placebo or unlabelled spiraprilat and the pharmacokinetics of a tracer radiolabelled intravenous dose of spiraprilat characterised. The pharmacokinetics of radiolabelled spiraprilat were best described by a three compartment model with a terminal elimination half life of the order of 2.5 hours. The effect of saturation of plasma and tissue ACE binding sites caused an increase in the rate of elimination during the second phase, the effect was small and did not contribute to a change in total clearance of the radiolabelled dose. Despite higher plasma ACE activity values in rabbit, the long terminal half life, a characteristic feature of ACE inhibitor drugs in man, was not observed in rabbit for radiolabelled spiraprilat. Thus, the rabbit would appear not to be a good model for the disposition of ACE inhibitors in man. The pharmacokinetics of enalaprilat, formed after an oral dose of enalapril, were characterised in the presence and absence of saturated plasma and tissue ACE binding sites. Captopril was the agent used to saturate ACE binding sites. Eight volunteers received a single 10mg dose of enalapril. A washout period ensued then the volunteers were pretreated with captopril, 50mg twice daily, followed by a second 10mg dose of enalapril. Analysis of enalaprilat pharmacokinetics revealed no differences in the presence and absence of captopril. Analysis of the plasma ACE activity data indicated that induction of plasma ACE had occurred during the pretreatment with captopril. Thus, the lack of any detectable change in enalaprilat pharmacokinetics could have been due to the induction of ACE by pretreatment with captopril

Hypertension may be the most important component of hyperdynamic therapy in cerebral vasospasm

Although hyperdynamic therapy is an accepted method of treatment of patients with symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage, it remains unproven in large scale trials and controlled studies. Furthermore, methods of hyperdynamic therapy and specific endpoints vary widely. A systematic review of clinical trials of the various techniques of hyperdynamic therapy and their effects on cerebral blood flow found only 11 studies suitable for analysis. Although controlled trials are lacking, there is some evidence to suggest that hypertension is the most promising component of hyperdynamic therapy. These findings support a future randomized trial of induced hypertension in patients with symptomatic cerebral vasospasm

Good jobs, bad jobs, and trade liberalization

Globalization threatens "good jobs at good wages", according to overwhelming public sentiment. Yet professional discussion often rules out such concerns a priori. We instead offer a framework to interpret and address these concerns. We develop a model in which monopolistically competitive firms pay efficiency wages, and these firms differ in both their technical capability and their monitoring ability. Heterogeneity in the ability of firms to monitor effort leads to different wages for identical workers - good jobs and bad jobs - as well as equilibrium unemployment. Wage heterogeneity combines with differences in technical capability to generate an equilibrium size distribution of firms. As in Melitz (2003), trade liberalization increases aggregate efficiency through a firm selection effect. This efficiency-enhancing selection effect, however, puts pressure on many "good jobs", in the sense that the high-wage jobs at any level of technical capability are the least likely to survive trade liberalization. In a central case, trade raises the average real wage but leads to a loss of many "good jobs" and to a steady-state increase in unemployment

Do horizontal relationships matter to production and operations managers?

This paper shifts the focus of production, operations and supply chain management business relationships from the vertical to the horizontal side and calls for more research on this issue. The main intent is to provide managerially oriented arguments regarding the linkages between the achievement of operations-related goals and decisions related to horizontal business relationships. Specifically, we address the following research question: Does a linkage exist between production and operations objectives and the decisions a company makes about horizontal agreements, particularly horizontal governance mode choice? To answer this research question, we develop literature-based hypotheses and collect data from 4316 agreements of mergers and acquisitions and alliances and joint venture announced and completed between 2000 and 2010 by 88 of the first 100-ranked members of the Fortune 500 in the year 2000. We then test the hypotheses through a binary logistic regression model. This study brings interesting results and findings in terms of how and why production management considerations should play a crucial role in the type of strategic decisions that are usually reserved for finance and strategy managers. Operations managers should be fully involved in such decisions if they are to be well acquainted about how their choices impact on operational objectives

Intelligent automated control of robotic systems for environmental restoration

The US Department of Energy`s Office of Technology Development (OTD) has sponsored the development of the Generic Intelligent System Controller (GISC) for application to remote system control. Of primary interest to the OTD is the development of technologies which result in faster, safer, and cheaper cleanup of hazardous waste sites than possible using conventional approaches. The objective of the GISC development project is to support these goals by developing a modular robotics control approach which reduces the time and cost of development by allowing reuse of control system software and uses computer models to improve the safety of remote site cleanup while reducing the time and life cycle costs

Assessing Rat Forelimb and Hindlimb Motor Unit Connectivity as Objective and Robust Biomarkers of Spinal Motor Neuron Function

Sensitive and objective biomarkers of neuronal injury, degeneration, and regeneration can help facilitate translation of experimental findings into clinical testing. Whereas measures of upper motor neuron connectivity have been readily established, functional assessments of lower motor neuron (LMN) innervation of forelimb muscles are lacking. Compound muscle action potential (CMAP) and motor unit (MU) number estimation (MUNE) are well-established methods that allow longitudinal MU integrity monitoring in patients. In analogy we refined CMAP and MUNE methods for assessing spinal MU input in the rat forelimb and hindlimb. Repeated CMAP and MUNE recordings are robust (coefficients of variability: 4.5–11.3%), and MUNE measurements from forelimb wrist flexor muscles (415 ± 8 [SEM]) align with back-traced anatomical LMN counts (336 ± 16 [SEM]). For disease validation, cross-sectional blinded electrophysiological and muscle contractility measurements were obtained in a cohort of G93A SOD1 mutant overexpressing rats and compared with controls. Longitudinal assessment of mutant animals demonstrated progressive motor unit decline in the hindlimb to a greater extent than the forelimb. Hindlimb CMAP and MUNE demonstrated strong correlations with plantarflexion muscle contractility. Cross-species assessment of upper/fore- limb and lower/hind- limb motor units using objective electrophysiological CMAP and MUNE values as biomarkers will guide and improve bi-directional translation

HLA-Associated viral mutations are common in human immunodeficiency virus type 1 elite controllers

Elite controllers (EC) of human immunodeficiency virus type 1 (HTV-1) maintain viremia below the limit of detection without antiretroviral treatment. Virus-specific cytotoxic CD8+ T lymphocytes are believed to play a crucial role in viral containment, but the degree of immune imprinting and compensatory mutations in EC is unclear. We obtained plasma gag, pol, and nef sequences from HLA-diverse subjects and found that 30 to 40% of the predefined HLA-associated polymorphic sites show evidence of immune selection pressure in EC., compared to approximately 50% of the sites in chronic progressors. These data indicate ongoing viral replication and escape from cytotoxic T lymphocytes are present even in strictly controlled HTV-1 infection

A third dimension in the mirror? How senior managers design products and organizations

Individual CEO characteristics may affect architectural choices through the application of managerial discretion. Systems such as organizations and their products are not purely driven toward modularity because of external forces. Individual CEO characteristics may constitute an additional dimension to established mirroring considerations that impacts both the choice of architecture and the correspondence between product and organization architectures