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Thesis (M.S.)--Rutgers University, 2007. / "Graduate Program in Nutritional Sciences." Includes bibliographical references (p. 38-45).

Thesis (M.S.)--Rochester Institute of Technology, 1981. / Typescript. Includes bibliographical references (leaves 83-84).

Quinacainol, 1-[2-(1,1-dimethylethyl)-4-quinolyl]-3-(4-piperidyl)-1-propanol is a class I antiarrhythmic agent provisionally subclassified as Ic. Studies were carried out in order to (1) determine the actions of quinacainol in acute myocardial ischæmia, (2) ascertain the mechanism(s) responsible for these actions, and (3) ascertain the appropriateness of its subclassification. Toxicological, hæmodynamic, and ECG effects in chronically prepared conscious rats were determined following administration of 1, 2, 4, or 8 mg/kg of quinacainol given i.v. over 10 minutes on alternate days. Toxicity referable to the heart was seen at doses of 8 mg/kg and above. In rats given 8 or 16 mgkg, arrhythmias occurred. Quinacainol had no major effects on blood pressure, unlike most class I antiarrhythmics, but lowered heart rate (not statistically significantly) and prolonged P-R interval and QRS duration. In an attempt to protect against ischæmic arrhythmias, doses of 2 mg/kg and 4 mg/kg were given. The high dose gave the best protection. It reduced the incidence of ventricular tachycardia (VT) from a control value of 80% to 30%, and reduced the incidence of ventricular fibrillation (VF) from a control value of 60% to 10%. An increase in the incidence of premature ventricular contractions was seen at both doses. Blood pressure was not adversely effected although slight bradycardic effects as well as prolongation of the P-R interval were seen at both doses. Both doses reduced S-T segment and delayed onset of elevation of S-T segment and R-wave which were induced by coronary occlusion. Sensitivity to electrical stimulation was tested in pentobarbital anæsthetised rats using ventricular electrodes. Doses of 0.5, 1, 2, and 4 mg/kg were given cumulatively as a 10 min infusion every 25 min. Quinacainol did not affect QRS duration or the Q-Tc interval but dose-dependently widened P-R interval when compared to pretreatment. Quinacainol dose-dependently increased threshold current, threshold duration, and ventricular fibrillation threshold. In addition, quinacainol elevated effective refractory period while decreasing maximum following frequency. Open-chest rats under pentobarbital anæsthesia were used to record the effects of quinacainol on epicardial intracellular potentials. Recordings were made by conventional microelectrode techniques before and after cumulative doses of 0.5, 1, 2, 4, and 8 mg/kg i.v. Quinacainol dose-dependently reduced phase zero of the action potential (AP) and AP height but did not influence other phases of the AP (with the exception of prolonging repolarization at the highest dose); actions indicative of class Ic. Effects of quinacainol on isolated rat hearts were assessed using a modified Langendorff heart preparation and were compared with those of tetrodotoxin (TTX). Quinacainol widened the P-R interval and QRS duration without having major effect on the Q-Tc interval. In addition it slowed the sinus beating rate. Quinacainol was more potent than TTX. All findings indicated that quinacainol is a potent antiarrhythmic agent with Na⁺channel blocking properties. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The structural and functional consequences of the interaction of various antiarrhythmics with human erythrocyte membranes, guinea pig brain synap-tosomes and myocardial sarcolemmal membranes were studied at drug concentrations affecting the stability of intact erythrocytes to hypotonic lysis. It was assumed that such stabilization might bear some molecular resemblance to the electrical stabilizing properties of these drugs in excitable tissues. Membrane perturbational actions of these drugs were measured in terms of the specific incorporation of the chromophoric probes, 5,51-dithio-bis-(2-nitrobenzoic acid) (DTNB) and trinitrobenzenesulfonic acid (TNBS) into membrane sulfhydryl and amino groups respectively. Most drugs tested, including lidocaine, quinidine, the verapamil analogue D-600 and the quaternary analogues QX 572 and pranolium, exhibited a concentration-dependent stimulation of DTNB and TNBS incorporation. At drug concentrations producing erythrocyte stabilization, the protein perturbational properties of quinidine, lidocaine, D-600 and QX 572 as viewed in terms of DTNB labelling were equivalent while differences were apparent with quinidine, D-600 and lidocaine at high concentrations in the destabilizing range. Most agents, with the exception of pranolium, showed a similar pattern of DTNB incorporation in brain synaptic membranes as in erythrocytes. Studies of the incorporation of TNBS into erythrocyte membranes indicated that antiarrhythmics induce greater structural alterations in membrane phospholipids as compared with membrane proteins. Bretylium and practolol, two substances with minimal direct cardiodepressant properties, did not enhance DTNB or TNBS incorporations into erythrocyte membranes, although both agents, especially practolol, possessed marked antihemolytic properties. It appeared, therefore, that the membrane perturbational actions of antiarrhythmics as analyzed here by means of group-specific chemical probes are a better index of their direct myocardial membrane actions than erythrocyte stabilization. The functional consequences of drug-membrane interaction as reflected in the inhibition of membrane-associated enzymes by antiarrhythmics were shown to be critically dependent on the drug and membrane in question. The activity of erythrocyte membrane ouabain-sensitive K+-stimulated p-nitrophenyl-phosphatase (K+-NPPase) was more readily inhibited than that of Mg++-independent and Mg++-stimulated NPPase by most drugs examined. In myocardial sarcolemmal membranes, lidocaine was stimulatory to the K+-NPPase whereas all other agents exhibited stimulatory actions only at the lowest drug concentrations. The Ca++-ATPase system in the erythrocyte membrane was also inhibited by antiarrhythmics with propranolol, pranolium and lidocaine showing a relatively higher degree of inhibition of the high Ca++ affinity component while quinidine and D-600 exerted equal inhibitory actions on both high and low Ca++ affinity components of the enzyme. A comparison of the perturbational actions of antiarrhythmics in isolated erythrocyte membranes, in the membranes of the intact erythrocyte and in brain synaptic membranes was made by analyzing the effects of drugs on the activity of the membrane acetylcholinesterase present in these preparations. Inhibitory actions of all drugs tested were comparable in both intact and isolated erythrocyte membranes but differed in the excitable tissue membrane. The nature of the inhibition exerted by the antiarrhythmics on acetylcholinesterase of intact erythrocytes was of a mixed type for most drugs except practolol which inhibited non-competitively. The transmembrane chloride gradient had no influence on the inhibition by bretylium, lidocaine and D-600 of the acetylcholinesterase activity of the intact cells but the inhibition produced by quinidine and propranolol was enhanced when erythrocytes were suspended in a low chloride medium. The foregoing results, therefore, indicate that the membrane perturbational actions of antiarrhythmics vary with the agent in question and with the particular membrane system. It is suggested that the molecular mechanisms by which these drugs alter cardiac automaticity may not be identical and may differ in various regions of the myocardium. This in turn may underlie the differing spectra of clinical effectiveness exhibited by these pharmacological agents. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Tocainide carbamoyl ester glucuronlde (TOCG) (R-NHCO.O-GA) is a major metabolite of tocainide (TonocardR). The structure of TOCG was first proposed by Elvin (35) based on the structure of 3-(2,6-xylyl)-5-methylhydantoln, a base hydrolyzed product of TOCG in urine. Due to the presence of two carbonyl groups on the hydantoin ring, TOCG was proposed to arrive from a novel metabolic pathway involving the addition of carbon dioxide to the terminal nitrogen of tocainlde followed by glucuronic acid conjugation. With the initial intention of carrying out a bioavailability study of tocainide using a deuterated pseudoracemic sample, the stereospecific synthesis of R(-)- and S(+)-trideuterated tocainide was attempted through two synthetic approaches. This thesis describes a chemical reaction between tocainide and urea, a second pathway which leads to the formation of 3-(2,6-xylyl)-5-methylhydantoin through a tocainide ureide intermediate. With this observation, a tocainide N-ureide glucuronide structure (R-NHCO.NH-GA) was proposed for TOCG in support of the theory that an in vivo reaction between tocainide and urea may have resulted a tocainide N-ureide which can be further conjugated with glucuronic acid. Attempts were made to assign the correct structure of TOCG by identification of the theoretical tocainide carbamic acid (based on Elvln's proposed structure) or the tocainide N-ureide intermediate in urine. This thesis also describes the preparative HPLC isolation and the structural characterization of this novel glucuronic acid conjugate. Evidence obtained as proof for the identity of TOCG as a conjugate was obtained from acid hydrolysis, basic hydrolysis, beta-glucuronidase hydrolysis, with or without the presence of sacchro-1,4-lactone, and a naphthoresorcinol color test. Structural evidence for the carbamoyl ester linkage of TOCG was obtained from proton-NMR and FAB analysis. The 400-MHz proton NMR data of the isolated glucuronide provided partial evidence for the intact structure of TOCG. In FAB analysis, the [M+1] ion adduct at m/z 413, [M+Na] at m/z 435, and [M-H+2Na] at m/z 457 have provided positive evidence for the molecular ion of TOCG at m/z 412 in favor of the carbamoyl ester structure. In addition to the hydrolysis of TOCG at pH > 12 to the hydantoin, this hydantoin was found to also undergo spontaneous first-order hydrolysis at pH > 12. To assay the levels of TOCG in urine as the hydantoin, a set of accurately timed calibration samples were employed in an assay protocol to take Into account the spontaneous hydrolysis of the hydantoin. Based on this analytical approach, the levels of TOCG were determined in three subjects both after an IV and oral dose of 200 mg tocainide HC1. The urinary excretion half-lives of TOCG of 13.86 hours and 13.33 hours, after an IV and oral dose respectively, were found to agree with literature values. / Pharmaceutical Sciences, Faculty of / Graduate

The stereo-chemistry, structure activity relationships and the metabolism of the anorectic drug, diethylpropion hydrochloride, have been reviewed briefly, together with the analytical methods for the determination of this drug and its metabolites in biological fluids. In addition, the physico-chemical properties, mode of action, pharmacology and uses of the metabolites have been presented. A comprehensive review on general principles of salivary excretion of drugs and their therapeutic drug monitoring in saliva with relevant published data on saliva/plasma drug concentration relationships has been outlined. Sensitive and specific assay procedures, based on gas-liquid chromatography for the identification, separation and determination of diethylpropion and its two major metabolites i.e. ethylaminopropiophenone (11) and diethylnorpseudoephedrine (IV) in aqueous and biological fluids, have been developed. These methods were used to study the urinary excreUon as well as saliva and plasma levels of the two major metabolites and, where possible, the unchanged drug, in man. Sustained release pellets with diffusion rate-controlled membranes were employed to control the rate of input into the body by oral or rectal route of administration. Urinary excretion data and plasma levels of metabolites 11 and IV in volunteers, where the urine was controlled at an acidic pH, were used for the evaluation of the bioavailabilities of different dosage forms of diethylpropion hydrochloride. The concentrations of metabolites 11 and IV were also measured in saliva and in plasma after administration of the drug in different doses and dosage forms: relationships between saliva and plasma concentrations (S/P) and between urinary excretion rates and plasma concentrations (U/P) were developed for each of the two metabolites during plateau levels after oral administration of the sustained release pellets (Lot R 7773). The potential use of salivary excretion of the metabolites as an index to monitor their plasma levels and bioavailabilities, was examined. The distinct advantage of using a subdivided controlled release system (i. .e. sustained release pellets) to a single unit sustained release tablet (erosion-core type) in relation to influence of the physical presence of food on the rate and extent of absorption has been demons t rated . It was found that the route of administration (oral or rectal) did not significantly affect the bioavailability of the sustained release pellets. The study also involved the investigation of the release of the drug from the pellets. Because the release control step was diffusion, no significant influences on dissolution rates were observed with the use of different dissolution test models and agitation intensities. The influence of the concentration and composition (presence of cations viz. Na+ and K+ i~r anions viz . phosphate and borate) of the dissolution medium on the release of the drug from sustained release pellets, was also studied. Any potential changes in the dissolution pattern on storage of the pellets under different conditions (4°C, room temperature and 37°C) ovrr, a period of at least one year, were investigated. The in vitro and in vivo correlations of two lots of sustained release pellets, each exhibiting different dissolution profiles, and administered rectally and orally, were developed: the in vitro data on the free drug were related to the sum of the urinary excretion data of metabolites II and IV. An attempt to use an empirical approach to predict urinary excretion rate profiles of metabolite II after oral administration of the sustained release pellets, was promising; the calculated profiles were reasonably comparable with those of in vivo studies. However, the complete validity of such equations needs further investigations. / Thesis (Ph.D.)-University of Durban-Westville, 1984.

Mephenoxalone is a mild central nervous system depressant with activity resembling that of meprobamate. Since its introduction in 1961 mephenoxalone has been used as an anxiolytic and as a muscle relaxant, although the latter effect is weak. Preliminary studies on the absorption and disposition of mephenoxalone have been conducted in beagle dogs but no pharmacokinetic data from human studies have been reported, except for a single study in which the biotransformation products present in human urine were identified. Methods presently available for the determination of mephenoxalone in biological fluids lack the sensitivity, specificity and precision required for detailed pharmacokinetic studies. In this study, a rapid, sensitive, precise reverse-phase high-performance liquid chromatographic method with ultraviolet detection at 200nm was employed for the determination of mephenoxalone in biological fluids. Serum and urine samples were prepared for chromatographic analysis using simple liquid-liquid extraction techniques. The application of the assay to pharmacokinetic studies in humans is presented. After administration of a single oral dose of 400mg mephenoxalone dispersed in 150ml water to six young, healthy volunteers, the compound was rapidly absorbed with the peak concentration of 8μg/ml occurring after about 1 hour. The elimination half-life was approximately 3 hours. The drug was extensively metabolized with only about 1 percent of the administered dose being excreted unchanged in the urine after 24 hours. The bioavailability of a newly developed mephenoxalone-containing tablet was also investigated. The drug was absorbed more rapidly from the tablet than from the dispersed dose. This was attributed to a shorter in vivo dissolution time on the basis of in vitro tests, but this effect is not expected to be clinically significant. In addition, two human urinary metabolites of mephenoxalone were identified as unconjugated hydroxylated derivatives using thermospray HPLC-mass spectrometry. The plasma protein-binding properties of mephenoxalone were also investigated.

The pineal gland has become the subject of considerable investigation as it provides a productive experimental model for studying circadian rhythms and regulation of end organs. In the rat, the pineal gland provides a convenient model for investigating the noradrenergic receptor system and the effects of various drugs on this system. The effect of appetite suppressants on the rat pineal gland function is described. Appetite suppressants increase melatonin synthesis in organ cultures of rat pineal glands. This effect appears to be mediated by noradrenaline acting on β-adrenoceptors on the pinealocyte membrane. When β-adrenoceptors are blocked, the appetite suppressant-induced rise in melatonin synthesis is prevented. Depletion of noradrenaline in sympathetic nerve terminals also prevented the appetite suppressant-induced rise in melatonin synthesis. Activation of β-adrenoceptors is followed by a rise in N-acetyltransferase activity via a cyclic adenosine monophosphate second messenger system. The effect of appetite suppressants on the activity of liver tryptophan pyrrolase was also investigated. The activity of this enzyme is an important determinant of tryptophan availability to the brain and consequently of brain serotonin levels. The results show that appetite suppressants inhibit both holoenzyme and total enzyme activities of tryptophan pyrrolase. This finding suggests that appetite suppressants may act by inhibiting tryptophan pyrrolase activity thereby increasing brain serotonin, a phenomenon known to be associated with anorexia. There are two possible mechanisms by which appetite suppressants inhibit tryptophan pyrrolase activity. Firstly, these agents, being drugs of dependence, may increase liver NADPH concentrations which inhibit pyrrolase activity. Secondly, appetite suppressants may act on the pineal gland to stimulate melatonin synthesis. Melatonin inhibits pyrrolase activity in a dose-dependent manner. This inhibition will elevate plasma tryptophan levels which result in a rise in brain serotonin synthesis. The present study suggests a possible relationship between the pineal gland and appetite centres in the hypothalamus. Melatonin may have a direct effect on appetite centres since food restriction is associated with an increased melatonin binding in the hypothalamus. If this possible relationship can be extended, melatonin can open new possibilities for the control of food intake and consequently, of pathological obesity.

The high rise in the population suffering from depression depicts the need for improved and highly effective treatment options for this condition. Efforts to develop existing drugs into user-friendly dosage forms with a number of advantages in major depressive states, including but not limited to: sustained drug release, reduced drug dosing frequency, improved tolerance and adherence, suitability for use in diverse populations and different treatment scenarios, as well as less central nervous system side effects are required. One such non-invasive drug delivery route that could provide the aforementioned benefits in the treatment of depression is the transdermal route. A number of conventional and emerging transdermal delivery strategies have been investigated for some potent antidepressants and results depict the potential of this route as a viable means for systemic delivery of therapeutically relevant doses of the tested agents, with Emsam®, the commercially available patch of selegiline, being an evidence for the same. The investigated approaches include the formulation of transdermal patches, use of vesicular drug carriers, pro-drug approach, microemulsification, chemical as well as physical enhancement technologies. This review provides a comprehensive account of the rationale, developments made till date, scope and future prospects of delivering antidepressants via the transdermal1 route of administration.