Thesis (M.S.)--Rutgers University, 2008. / "Graduate Program in Pharmaceutical Science." Includes bibliographical references (p. 41-42).

No description available.

Conventional routes of drug administration have several disadvantages. The rate and extent of absorption can vary greatly depending on the drug, its formulation, the presence or absence of food, drug interactions, and the pH of gastrointestinal fluids. Extensive first-pass metabolism can greatly reduce the absorption of many drugs. Better dosage forms or drug delivery mechanisms could minimize some of these problems. The pharmaceutical industry has recognized the need for, and has developed many new, novel drug delivery systems. Drugs that previously experienced diminished effective concentrations due to the first-pass effect may now be given by a novel route. The dosing frequency of many drugs may be reduced when administered by a novel route or site. Transmucosal drug delivery (TMDD) via the buccal mucosa is one site that is suited to rapid drug absorption and systemic delivery. Drugs selected for TMDD must have physiochemical properties that will allow them to penetrate the mucosa and produce therapeutic blood concentrations. This study utilized a buccal patch less than 1.5 cm in length to deliver albuterol and butorphanol-two drugs with dissimilar physiochemical properties. The purpose of this study was to establish pharmacokinetic parameters and the bioavailability of albuterol and butorphanol when administered intravenously and buccally. Three dogs weighing at least 20 kg were studied using a randomized crossover design, each receiving albuterol and butorphanol by buccal and intravenous administration. Blood samples were collected and analyzed using ELISA. Values for pharmacokinetic parameters were analyzed using compartmental and non-compartmental models. For albuterol, extrapolated Cmax and Co after buccal and IV administration were 10.28 ± 2.77 and 57.74 ± 9.04 ng/ml, respectively. Volume of distribution at steady state (Vss) was 2.13 ± 1.30 L/kg and Cl was 4.73 ± 3.91 ml/min/kg. A significant difference existed between the disappearance rate constant of buccal and intravenous albuterol administration. The disappearance half-lives of buccal and IV albuterol were 160.96 ± 24.19 and 364.20 ± 115.20 min, respectively. The bioavailability of buccally administered albuterol was 35%. Maximal concentration (Cmax) and Co after buccal and IV butorphanol administration were 6.66 ± 1.65 and 8.24 ± 5.55 ng/ml, respectively. Volume of distribution at steady state (Vss) was 27.58 ± 10.14 L/kg and Cl was 137.87 ± 19.55 ml/min/kg. The half-life of buccally administered butorphanol was 259.15 ± 33.12 min and the half-life of IV butorphanol was 172.12 ± 94.95 min. The bioavailability of buccally administered butorphanol was 606%. The buccal patch used in this study achieved systemic concentrations for both albuterol and butorphanol. Further studies are needed to determine if therapeutic drug concentrations can be achieved with the buccal patch and if the patch can result in clinical efficacy.

Theophylline is a dimethylated xanthine similar in structure to caffeine which is commonly found in tea, coffee and cola beverages (Hendeles and Weinberger, 1983; Rall, 1985). Clinically, its most important pharmacological action is the ability to relax bronchial smooth muscle throughout the bronchial tree (Persson, 1986). This effect has found extensive use in the treatment of asthma with the drug being recommended as the first line agent for chronic asthma (la/rate et ai, 1986). The observation that both beneficial effects as well as toxicity correlate with serum concentrations and that the drug displays a narrow therapeutic window (Finn et al, 1981; Hendeles and Matthay, 1986) has resulted in the recommendation that theophylline dosing be guided by serum concentration measurements (Hendeles and Weinberger, 1980; Whiting et al, 1984; Fitzpatrick and Moss-Barclay, 1985; Barlow et. al, 1988). However, this recommendation appears to have been largely ignored locally. In 1986, one of the first local Therapeutic Drug Monitoring Clinics for theophylline was established at R K Khan Provincial Hospital in Chatsworth, Durban. Preliminary results from this clinic confirmed the widespread use of standard theophylline dosing regimens and revealed that 68% (n = 44) of patients given these regimens had serum theophylline concentrations below the generally accepted therapeutic range (Pillai and Miller, 1988). Previous studies have assessed the influence of Therapeutic Drug Monitoring programmes in terms of the attainment of 'therapeutic' serum concentrations (Whiting et aI, 1984; Fitzpatrick and Moss-Barclay, 1985). This approach has been criticised and it has been recommended that clinical assessment should be the criterion. The purpose of this study was to investigate the influence of serum concentration monitoring on theophylline utilisation at the R K Khan Hospital in terms of clinical control of asthma symptoms. A secondary purpose of this study was to determine population pharmacokinetic parameters in Indian patients. In order to interpret the serum concentrations and make recommendations on dosage design for individual patients, the Bayesian technique of drug dose optimisation is used (Sheiner et aI, 1972). This technique has been shown to be accurate, precise and easy to use (Sheiner and Beal, 1982; Hurley and McNeil, 1988) particularly with currently available computer software. It has been emphasised, however, that for satisfactory performance of this technique, good initial estimates of the population parameter distributions are important (Whiting et al, 1986). Since this information is not available for the Indian population this study was undertaken. A knowledge of population pharmacokinetics can help one to choose initial dosage, to modify dosage appropriately in response to observed drug levels, to make rational decisions regarding drug regulatory requirements and toinvestigate and elucidate certain research questions in pharmacokinetics (Sheiner, 1984). The NONMEM approach (Sheiner et aI, 1972; 1977), currently the mostsatisfactory method of population pharmacokinetic data analysis is utilised in this study. / Thesis (M.Pharm.)--University of Durban-Westville, 1989.

No description available.

No description available.

Perhexiline maleate was first introduced for the prophylaxis of exertional angina in the 1970s but reports of adverse reactions, including potentially fatal hepatotoxicity, increasingly restricted its application. By 1988 Australia and New Zealand were the only countries permitting its use, limited to the treatment of refractory angina pectoris conditional upon the therapeutic monitoring of patients, due to recognition of the concentration dependent nature of its efficacy and toxicity. An understanding of the extreme interindividual variability in the pharmacokinetics of perhexiline due to metabolism by the polymorphic Cytochrome P450 2D6 (CYP2D6) has prompted a recent resurgence of its use in Australasia and Europe. Perhexiline is a chiral molecule and is administered as a racemic mixture. Prior to the publication of the papers that are the topic of this thesis the characterisation of the clinical pharmacology of the enantiomers of perhexiline had been limited to one pharmacokinetic study that suggested that the (+) enantiomer of perhexiline may display a smaller polymorphic effect in its metabolism than its optical antipode. The four publications that comprise this thesis describe a comprehensive investigation of the pharmacokinetics and metabolism of the enantiomers of perhexiline in extensive and poor metabolisers (EM and PM, respectively) of CYP2D6 in both an in vitro model and clinically. The aim was to determine if the CYP2D6 polymorphism affects the metabolism of (+)-perhexiline significantly less than (-)-perhexiline, such that the inherent variability observed in the pharmacokinetics of the racemic preparation used clinically might be overcome by administration of only (+)-perhexiline. Although both the in vitro and in vivo studies determined that the involvement of CYP2D6 was proportionately greater in the total clearance of (-)- than (+)-perhexiline, the empirical data also demonstrated that the role of CYP2D6 in the metabolism of (+)-perhexiline was simply too pre-eminent for a chiral preparation of this enantiomer to significantly reduce the difference in clearance observed between EM and PM. An unexpected finding was that the enantioselectivity observed in the clinical pharmacokinetics of perhexiline in EM was, in fact, significantly greater in PM. Whilst the enantioselectivity in EM was attributable to metabolism by CYP2D6, the mechanism responsible for this in PM could not be determined, but was postulated to involve enantioselective biliary excretion. Because PM are effectively exposed to greater concentrations of (+)-perhexiline and lower concentrations of (-)-perhexiline, when the relative pharmacodynamic activities of the individual enantiomers have been established therapeutic drug monitoring may be improved by the development of specific enantiomer target concentration ranges in plasma. What is certain is that perhexiline will remain an essential option in the armamentarium for the treatment of refractory angina pectoris and therapeutic drug monitoring will remain obligatory due to the inter- and intra-subject pharmacokinetic variability attributable to the respective polymorphic and saturable metabolism of both enantiomers by CYP2D6. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346638 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008

Perhexiline maleate was first introduced for the prophylaxis of exertional angina in the 1970s but reports of adverse reactions, including potentially fatal hepatotoxicity, increasingly restricted its application. By 1988 Australia and New Zealand were the only countries permitting its use, limited to the treatment of refractory angina pectoris conditional upon the therapeutic monitoring of patients, due to recognition of the concentration dependent nature of its efficacy and toxicity. An understanding of the extreme interindividual variability in the pharmacokinetics of perhexiline due to metabolism by the polymorphic Cytochrome P450 2D6 (CYP2D6) has prompted a recent resurgence of its use in Australasia and Europe. Perhexiline is a chiral molecule and is administered as a racemic mixture. Prior to the publication of the papers that are the topic of this thesis the characterisation of the clinical pharmacology of the enantiomers of perhexiline had been limited to one pharmacokinetic study that suggested that the (+) enantiomer of perhexiline may display a smaller polymorphic effect in its metabolism than its optical antipode. The four publications that comprise this thesis describe a comprehensive investigation of the pharmacokinetics and metabolism of the enantiomers of perhexiline in extensive and poor metabolisers (EM and PM, respectively) of CYP2D6 in both an in vitro model and clinically. The aim was to determine if the CYP2D6 polymorphism affects the metabolism of (+)-perhexiline significantly less than (-)-perhexiline, such that the inherent variability observed in the pharmacokinetics of the racemic preparation used clinically might be overcome by administration of only (+)-perhexiline. Although both the in vitro and in vivo studies determined that the involvement of CYP2D6 was proportionately greater in the total clearance of (-)- than (+)-perhexiline, the empirical data also demonstrated that the role of CYP2D6 in the metabolism of (+)-perhexiline was simply too pre-eminent for a chiral preparation of this enantiomer to significantly reduce the difference in clearance observed between EM and PM. An unexpected finding was that the enantioselectivity observed in the clinical pharmacokinetics of perhexiline in EM was, in fact, significantly greater in PM. Whilst the enantioselectivity in EM was attributable to metabolism by CYP2D6, the mechanism responsible for this in PM could not be determined, but was postulated to involve enantioselective biliary excretion. Because PM are effectively exposed to greater concentrations of (+)-perhexiline and lower concentrations of (-)-perhexiline, when the relative pharmacodynamic activities of the individual enantiomers have been established therapeutic drug monitoring may be improved by the development of specific enantiomer target concentration ranges in plasma. What is certain is that perhexiline will remain an essential option in the armamentarium for the treatment of refractory angina pectoris and therapeutic drug monitoring will remain obligatory due to the inter- and intra-subject pharmacokinetic variability attributable to the respective polymorphic and saturable metabolism of both enantiomers by CYP2D6. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346638 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2001. / Härtill 6 uppsatser.

Diss. (sammanfattning) Uppsala : Univ. / Härtill 6 uppsatser.