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An investigation of chlorbutol in ophthalmic and parenteral solutions

  • Authors: Summers, Robert Stanley
  • Date: 1967
  • Subjects: Parenteral solutions , Solutions (Pharmacy) , Ocular pharmacology
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3842 , http://hdl.handle.net/10962/d1007694 , Parenteral solutions , Solutions (Pharmacy) , Ocular pharmacology
  • Description: From Introduction Chlorbutol , which is tri-chlor-tertiary-butanol, was first prepared by Willgerodt in 1886 (1). The reaction he used for its preparation is still used today, though slightly modified (2)(3)(4), and is suggested by its original name "acetone-chloroform". The substance was prepared by adding solid potassium hydroxide to a cold mixture of acetone and chloroform (5 ). Chlorbutol is a derivative of the trichlorinated derivative of methane, and its formation may best be described by the use of structural formulae.
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  • Date Issued: 1967

The phytochemistry of several South African aloe species

  • Authors: McCarthy, Terence John
  • Date: 1967
  • Subjects: Botanical chemistry Aloe -- Research -- South Africa Aloe -- Analysis Medicinal plants -- Research -- South Africa Drugs -- Research Chromatographic analysis
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3836 , http://hdl.handle.net/10962/d1007621
  • Description: Introduction: Despite the tremendous advances made with regard to synthetic organic medicinals within the last two decades, heavy reliance is still placed on plant products. This is especially true of the anthracene derivatives used medicinally as purgatives, and which are derived principally from senna, cascara, rhubarb, frangula and aloes. While particular attention has been paid to the chemistry of the former group in recent years, aloes has been largely neglected, possibly due to the fact that the Aloe species are confined largely to areas where extensive research facilities are lacking, such as Africa , India and the West Indies. Thus research in Europe has been confined largely to the lump aloes of commerce, derived from relatively few species. In 1953 a comprehensive report by Hodge (103) appeared on "The Drug Aloes of Commerce, with Special Reference to the Cape Species". Hodge observed that South Africa abounds in species just as abundant as A.ferox, (which is the prime source of Cape aloes), and advised that a systematic chemical survey might show certain of these to be not only higher yielders of bitter aloetic juice but also sources of a superior drug product. Consequently an investigation along these lines is presented here, and it is observed that several species apart from A.ferox not only contain aloin, but also yield a large volume of aloetic juice. Only pharmacologic studies can reveal if the juice of these species is as safe as that of A.ferox, but without doubt they could be used for the extraction of crystalline aloin. Concurrently, the distribution of the Aloe resins, said by some to be purgative themselves, has been studied. The investigation has revealed that the structurally similar compound homonataloin enjoys an equally wide distribution as aloin. However, almost invariably it is confined to small species yielding little aloetic juice, apart from which nothing is known regarding its pharmacologic properties. It is interesting to note that the resin distribution in the homonataloin-containing species is very similar to that of the aloin-containing species, but differs widely from. that of the species containing neither of these principles. Apart from aloin and homonataloin, aloinoside and chrysophanol also occur in Aloe species, and together with the resins, these indicate that when all the South African Aloe species have been investigated, they may well be of chemotaxonomic value. Within the comparatively short space of the last decade some work has been performed on aspects of the metabolism of such anthracene-containing species as Rheum, Rhamnus and Rumex. These investigations have shown that the anthracene derivatives are not merely waste products, but perform definite metabolic functions. The latter portion of this work has been devoted to this relatively neglected aspect of the Aloe species.
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  • Date Issued: 1967

An investigation into chemical and biological assays of new compounds from aloes

  • Authors: Mapp, R K
  • Date: 1969
  • Subjects: Medicinal plants -- Research -- South Africa , Botanical chemistry , Aloe -- Analysis , Aloe -- Research -- South Africa , Aloe , Aloin
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3850 , http://hdl.handle.net/10962/d1012830
  • Description: The drug aloes has been known since earliest times and is mentioned in the Ebers papyrus of circa 1,500 B.C. Alexander the Great is reported to have sent a commission to Socotra to investigate the aloes grown there. The chemical composition of aloes is complex, and being of plant origin, subject to variation. Both the complexity of the chemical constituents and their biological variation has resulted in a very large volume of conflicting material being published on this drug export. Since aloes is used as a purgative for both human and veterinary use, it is obviously important that the dosage and consequently the active constituents, should comply to an accurate means of standardisation. To date, despite extensive world wide research into this drug such standardisation has not been achieved. Even the methods used for the assay of the principal constituent, aloin, vary considerably in their results, and to complicate matters new chemical principles have been isolated from aloes in recent years. Consequently the purpose of this work has been to investigate the main chemical assay methods currently in use, and to determine which was the most accurate, and why discrepancies occurred in the selected assay methods. furthermore the results obtained by chemical assay have been compared with those obtained by biological assay in an attempt to correlate aloin content with purgative activity. Newly isolated compounds have been investigated biologically for the first time, and the biological assays of the resinous, glycosidal and other compounds of aloes have been performed. Intro. p.1-2.
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  • Date Issued: 1969

A gas chromatographic study of oils from some Agathosma species (family Rutaceae)

  • Authors: Persicaner, Peter Henry Robert
  • Date: 1972 , 2013-11-13
  • Subjects: Rutaceae , Rutaceae -- Therapeutic use , Gas chromatography
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3837 , http://hdl.handle.net/10962/d1007634 , Rutaceae , Rutaceae -- Therapeutic use , Gas chromatography
  • Description: From Introduction: Buchu leaf is a very widely used household medicine in South Africa, and is usually administered in the form of a brandy tincture or a vinegar, known as "buchu brandy" and "buchu vinegar" respectively. These preparations have a great reputation in curing diseases of the kidney and urinary tract, and in addition are employed as local applications to bruises, and for the relief of rheumatic pains. We owe its introduction into medicine to the Hottentot, who gave the name "buchu" or "bookoo" to any aromatic herb or shrub which they found suitable for use as a dusting powder.
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  • Date Issued: 1972

Interactions between steroidal anti-inflammatory agents and collagen

  • Authors: Kanfer, Isadore
  • Date: 1975
  • Subjects: Anti-inflammatory agents Collagen
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3849 , http://hdl.handle.net/10962/d1012620
  • Description: Much research has been done on the formation of fibrils from solutions of soluble collagen in vitro in order to gain some knowledge of the mechanisms which may occur in vivo. The in vitro formation of fibres from solutions of collagen has been shown to be extremely sensitive to the nature of the solution environment and the presence of added chemical compounds, and thus constitutes an interesting system for the study of collagen-small molecule inter actions. The present study is concerned with the effects of various corticosteroid drugs, used medicinally as anti-inflammatory agents, on collagen in solution. As these corticosteroids are administered to reduce inflammation in conditions such as rheumatoid arthritis and a host of other pathological conditions in which collagen is implicated, this work has been undertaken in order to establish and charac teri ze any binding mechanisms which may be involved. Furthermore, the corticosteroid drugs available commercially in pure form as the free base or as the water-soluble ester salts offer an interesting range of structural and stereochemical variants for the study of their reaction with a complex and biologically important protein molecule such as collagen. A great deal of research on drug- protein interactions (Goldstein, 1949; Meyer and Guttman, 1968a) and more specifically, steroid-protein interactions have been reported over the years (Daughaday, 1959; Sandberg et al., 1966; Villee and Engel, 1961; Westphal , 1971). Comprehensive reports, however, on steroid-collagen interactions in vitro are conspicuously absent from modern scientific literature although relatively superficial accounts have been published (Menczel and Maibach, 1972; Eik-Nes et al., 1954). Although work involving the above has appeared relating specifically to the effects of steroids on collagen biosynthesis both in vivo and in vitro there have been minimal accounts of steroid-collagen interactions tailored to characterize the binding at the molecular level. The effect of corticosteroids on the metabolism of connective tissue has also received special attention (Asboe-Hansen, 1959; Kivirikko, 1953; Nakagawa and Tsurufuji, 1972). Recently, Uitto et al. (1972) reported the effects of several anti-inflammatory corticosteroids on collagen biosynthesis in vitro, whilst Aalto and Kulonen (1972) reported the effects of several antirheumatic drugs on the synthesis of collagen and other proteins in vitro. The interactions between collagen and certain drugs has also been briefly reviewed (Chvapil, 1967). Much data also exists on the binding of a wide range of small molecules and ions with serum albumin (Steinhardt and Reynolds, 1969; Scatchard, 1949; Klotz, 1950). Serum albumin, being specialized for a very general transport function and apparently designed for the purpose of combining with a large range of small molecules, has a proportion of possible reactive sites 'buried' within the molecule itself because of its folded conformation. In addition, serum albumin shows a high degree of cooperative binding in contrast to collagen. The latter molecule, with its larger molecular size and weight is specialized for a biologically structural function and has a higher proportion of possible reactive sites which appear relatively more accessible to ligands. A study of the interactions between corticosteroids and collagen thus provides the opportunity to investigate a protein which is very different from the much studied serum albumin. Because of the limited information available regarding the interaction of steroid drugs and collagen at the molecular level, studies of this nature are relevant to the understanding of the mode of action of steroid compounds which are such an important group of therapeutic substances used in modern medicine.
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  • Date Issued: 1975

A study of the rabbit eye test system to determine the activity of acidic non-steroidal anti-inflammatory agents

  • Authors: Wiseman, Ian Charles
  • Date: 1977
  • Subjects: Nonsteroidal anti-inflammatory agents , Anti-inflammatory agents
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3855 , http://hdl.handle.net/10962/d1013276
  • Description: From introduction : "Inflammation per se, has been defined sufficiently to permit a rational approach to the search for drugs that modify this process, but satisfactory animal models for most rheumatoid diseases are not available". (Swingle 1974) In the search for new meaningful procedures for the detection and evaluation of anti-inflammatory drugs, the rabbit eye as a test system was studied.
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  • Date Issued: 1977

The in vivo and quantitative assessment of topical corticosteroid formulations

The study of the metabolism of phenylbutazone (4-butyl-1,2 -diphenylpyrazolidine - 3,5 - dione) in rats

  • Authors: Alexander, Dorothy Mary
  • Date: 1978 , 2013-10-18
  • Subjects: Drugs -- Metabolism , Phenylbutazone
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3832 , http://hdl.handle.net/10962/d1007468 , Drugs -- Metabolism , Phenylbutazone
  • Description: In this study the metabolism of the anti-arthritic drug, phenylbutazone, was investigated in female Wistar rats, and the results compared with those of other workers in this field. Two interrelated projects were undertaken. The first covered the pattern of excretion, isolation and characterisation of the metabolites and decomposition products of phenylbutazone in rats dosed post-orally with the drug. It was found that the major route of excretion was via the urine and over 50% of the administered dose was excreted in the first 24 hours by this route. A small percentage of the dose was excreted in the faeces. The following compounds were identified using chromatographic and autoradiographic techniques: p-Hydroxy derivative of phenylbutazone γ-Hydroxy derivative of phenylbutazone in both its molecular forms (ring lactone and straight chain hydroxyl) 4-Hydroxy derivative of phenylbutazone p-γ-Dihydroxy derivative of phenylbutazone p-4-Dihydroxy derivative of phenylbutazone Hydrolysable conjugates (possibly glucuronides) Water soluble non-hydrolysable conjugates. The second project dealt with the quantitation of the water insoluble compounds isolated in the initial work. Using a unique technique, combining inverse isotope dilution assay and spectrophotometric analysis, it was found that the major metabolite was the γ-hydroxy derivative of phenylbutazone, present in both its molecular forms. Oxyphenbutazone was a minor metabolite and the p-γ-dihydroxy derivative of phenylbutazone was present only in very low concentration. These results did not conform with those of previous workers in this field who reported the γ-hydroxy derivative of phenylbutazone, in one molecular form only, as the major metabolite and the dihydroxy derivative as the second metabolite with a higher concentration in the urine than oxyphenbutazone. This disparity could be due to the fact that these workers took no account of the presence of the two molecular forms of the γ-hydroxy derivative of phenylbutazone with their different polarities and different Rf values. The present study showed that the straight chain hydroxyl isomer was probably mistakenly identified as the p-γ-dihydroxy derivative of phenylbutazone. This theory is supported by the fact that the percentage dose recovered by the previous workers of the γ-hydroxy and p-γ-dihydroxy derivatives together equalled the percentage dose recovered in this study of the two molecular forms of the γ-hydroxy derivative. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
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  • Date Issued: 1978

Adreno-active substances and the pineal gland

  • Authors: Midlane, Graham Wallace
  • Date: 1979
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3738 , http://hdl.handle.net/10962/d1001530
  • Description: The pineal gland, a biochemically very active neuroendocrine transducer which is innervated by the sympathetic nervous system, was used in vivo to evaluate the effect of different þ-adrenoceptor agonists and antagonists on pineal enzyme levels. Hydroxyindole-O-methyltransferase (HIOMT), an enzyme with a circadian activity and unknown control was not significantly affected by these drugs. The activity of serotonin N-acetyltransferase, another pineal enzyme with a greater amplitude of circadian rhythmicity and which is under noradrenergic neural control, the degree of blockade depending on the selectivity and affinity of the agent used. An attempt was also made to alter the oestrous cycle of the rat by dosing with þ-active substances. Only propranolol had any effect on the oestrous cycle. It was not possible to establish an absolute link between the alteration in pineal enzyme activity and an influence on the oestrous cycle. It was concluded that the pineal enzyme studies are useful pharmacological means for evaluating þ-active substances
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  • Date Issued: 1979

Aspects of the bioavailability of topical corticosteroid formulations

  • Authors: Magnus, Ashley Denis
  • Date: 1979
  • Subjects: Adrenocortical hormones , Dermatopharmacology , Dermatologic agents , Transdermal medication
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3724 , http://hdl.handle.net/10962/d1001458
  • Description: Two possible variables of the McKenzie/Stoughton blanching assay, namely amount applied to the test site and occlusion time have been investigated. Subsequently, two topical steroid preparations, Synalar cream (0,025% fluocinolone acetonide) and Betnovate cream (0,1% betamethasone 17- valerate) were extemporaneously diluted with five and six placebo bases respectively. Taking cognizance of the two possible variables, these diluted preparations were assessed in vivo using a modified version of the McKenzie/Stoughton blanching assay for blanching activity over a 14 month period. It was found that the base E45, which is slightly alkali, had the greatest effect on both preparations. In the case of betamethasone 17-valerate this base caused the conversion to the less active isomer, betamethasone 21-valerate whereas at the end of the 14 month test period it was found that the Synalar/E45 dilution contained no fluocinolone acetonide. Quantitative analysis of all the diluted preparations by high performance liquid chromatography using a reverse-phase system was performed. The data obtained from the systematic studies of the effects of varying concentrations and occlusion times were presented at the Eleventh National Congress of the South African Pharmacological Society
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  • Date Issued: 1979

Synthesis and reactions of sugar chlorosulphates

  • Authors: Naidoo, Nadasen Thargarajan
  • Date: 1980
  • Subjects: Sugar -- Synthesis , Chemical reactions
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3734 , http://hdl.handle.net/10962/d1001522
  • Description: Sugar chlorosulphates of furanoid and pyranoid derivatives bearing chlorosulphonyloxy groups at primary and secondary positions, were synthesized and examined mainly with a view to determine their extent of reactivity in terms of nucleophilic substitution reactions, especially with azide. Inversion of configuration occurred at reactive chiral centres, whereas intermediate azidosulphonyloxy derivatives (azidosulphates) were formed via S-Cℓ bond fission of the chlorosulphonyloxy group at less reactive primary or secondary centres, e.g. 1,2:3,4-diO̲isopropyl idene-α-D-galactopyranose 6-azidosulphate, 1,2-O̲isopropylidenea- D-xylofuranose 3-azidosulphate and 1,2:5,6-di-O̲-isopropyl idene-α-Dglucofuranose 3-azidosulphate. 1,2:3,4-Di-O̲-isopropylidene-α-Dgalactopyranose 6-azidosulphate ultimately afforded the 6-azidodeoxy derivative probably by an SN2 mechanism. Some SNi characteristics were,however, evident when substitution occurred at a reactive primary centre (e.g. methyl 2,3,4-tri-O̲-methyla- D-glucopyranoside 6-chlorosulphate), as the 6-azidodeoxy derivative obtained, appeared to be contaminated with a trace amount of the corresponding 6-chlorodeoxy sugar, which had presumably formed via an internal SNi mechanism, while no intermediate azidosulphonyloxy derivative was isolated. In another study, the reaction pathways for the synthesis of benzylated chlorodeoxy sugars having potential biological properties as exemplified by the multivalent drug, tribenoside, were also investigated
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  • Date Issued: 1980

The evaluation of melatonin as a possible antidepressive

  • Authors: Skene, Debra Jean
  • Date: 1980
  • Subjects: Melatonin , Antidepressants
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3728 , http://hdl.handle.net/10962/d1001465
  • Description: Melatonin, a hormone of the pineal gland, was evaluated in a variety of animal models of depression. Measurements of the frog righting reflex and rat locomotor activity showed that low doses of melatonin have a serotonin-like potentiating effect following monoamine oxidase inhibition. High doses of melatonin caused a reduction in the duration of rat immobility in the Porsolt model of depression and exerted a chlorpromazine-like effect on conditioned avoidance behaviour. In view of the indoleamine hypothesis of depressive disorders, the possibility of melatonin being a potential antidepressive is discussed and it is concluded that melatonin might be useful in the treatment of "agitated" depressions
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  • Date Issued: 1980

A study of the interactions between phenytoin and pharmaceutical antacids, excipients and adsorbents

  • Authors: Gilbert, Peter John
  • Date: 1981 , 2013-03-14
  • Subjects: Phenytoin , Antacids
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3821 , http://hdl.handle.net/10962/d1004935 , Phenytoin , Antacids
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  • Date Issued: 1981

The comparative bioavailability and in vitro assessment of solid oral dosage forms of paracetamol

  • Authors: Braae, Karen
  • Date: 1981 , 2013-04-02
  • Subjects: Acetaminophen , Bioavailability , Drugs -- Bioavailability , Drugs -- Dosage forms , Analysis of variance
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3827 , http://hdl.handle.net/10962/d1006288 , Acetaminophen , Bioavailability , Drugs -- Bioavailability , Drugs -- Dosage forms , Analysis of variance
  • Description: The dissolution profiles of eight lots of paracetamol tablets representing seven different tablet brands are determined in a USP rotating basket assembly and a stationary basket-rotating paddle apparatus. The in vitro data are expressed in terms of dissolution parameters and inter-tablet differences are assessed statistically using analysis of variance (ANOVA) and the Scheffe test. Highly significant differences are observed between a number of the tablets at the 95% confidence level. Representative tablets from the dissolution rate study and a control dose of paracetamol dissolved in water are subsequently investigated in a 4 x 4 latin square design bioavailability trial. Serum and urine samples are collected and assayed for paracetamol alone (serum) and together with its metabolites (urine) by means of high pressure liquid chromatography. The in vivo data are expressed in terms of bioavailability parameters and differences between the test doses are assessed by means of ANOVA. No significant differences are observed between the dosage forms at the 95% confidence level.
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  • Date Issued: 1981

The study of the potentiation of anticholinergic side effects of tricyclic antidepressives by female sex steroids

  • Authors: Kok, Eric Charl
  • Date: 1981
  • Subjects: Antidepressants , Steroid hormones
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3822 , http://hdl.handle.net/10962/d1005623 , Antidepressants , Steroid hormones
  • Description: It has been recorded that women respond to tricyclic antidepressives with a greater incidence of anticholinergic side effects than men do, particularly women taking an exogenous source of oestrogen. The aim of this study was to investigate the influence that ethinyl oestradiol and Premarin© had on the metabolism of a number of tricyclic antidepressives, and also the influence they had on the binding ability of microsomes to imipramine. Rat hepatocyctes and microsomes were used. Detection techniques used were High Pressure Liquid Chromatography and Spectrophotometry respectively. In addition to these studies, a study of the anticholinergic activity of Nomifensine, tricyclic antidepressives and their derivatives was performed on a rat jujenum. Results conclusively showed that ethinyl oestradiol had a marked influence on the metabolism of the tricyclic antidepressives studied. Premarin© had Iittle, if any influence. However, both ethinyl oestradiol and Premarin© affected the binding of microsomes to imipramine, but ethinyl oestradiol had the greater effect. The parent compound in each case exhibited a higher pAZ value. Results indicate that a possible explanation for the increased anticholinergic side effect is due to an inhibition of the metabolism of the tricyclic antidepressives by oestrogen.
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  • Date Issued: 1981

Reaction of carbohydrates with the sulphuryl chloride-N, N-dimethyl formamide reagent

  • Authors: Mabusela, Wilfred Thozamile
  • Date: 1982
  • Subjects: Chemical reactions Carbohydrates
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3731 , http://hdl.handle.net/10962/d1001470
  • Description: An investigation of the reaction of the sulphuryl chloride-N, N-dimethyl formamide reagent with several carbohydrate compounds, containing free hydroxyl groups, was undertaken, mainly with the view of looking at substitution of the hydroxyl groups with chlorine atoms. The reaction was found to lead to substitution of both primary and secondary hydroxyl groups with chlorine, with inversion of configuration in the latter case. The reagent was further found to effect formylation and chlorosulphation of secondary hydroxyl groups, where nucleophilic substitution by a chlorine was not favourable. Studies involving the methyl pentopyranosides, showed that the reagent was particularly useful in the chlorosulphation and chlorination of sugars, compared with the hexopyranosides.
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  • Date Issued: 1982

Synthesis and reactions of sugar chlorosulphates

  • Authors: Glass, Beverley Dawn
  • Date: 1982
  • Subjects: Chemical reactions Sugar -- Synthesis
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3826 , http://hdl.handle.net/10962/d1006145
  • Description: Summary: Partially chlorosulphated derivatives were synthesised for the purpose of examining the reactions of the chlorosulphonyloxy group in the presence of free hydroxyl groups. The behaviour of the chlorosulphonyloxy group was investigated under acidic conditions. Since sterically favoured chlorosulphonyloxy groups undergo facile replacement by chlorine to form chlorodeoxy sugars, some compounds possessing chlorosulphonyloxy groups which,due to polar and steric effects are not replaced by chloride,were investigated with a view to possible activation of the unfavourable centres towards nucleophilic substitution, thereby making available previously inaccessible chlorodeoxy sugars.
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  • Date Issued: 1982

Aspects of prostacyclin in experimental hypertension

  • Authors: Botha, Julia Hilary
  • Date: 1983
  • Subjects: Prostacyclin Prostaglandins Prostaglandin endoperoxides Thromboxanes Hypertension
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3825 , http://hdl.handle.net/10962/d1006109
  • Description: A new prostaglandin - prostaglandin X (later renamed prostacyclin or prostaglandin I₂ (PGI₂)), was discovered by Moncada, Gryglewski, Bunting and Vane in 1976. This unstable substance was shown to be produced by vascular tissue and to be a vasodilator and the most potent endogenous inhibitor of platelet aggregation known. Because of its properties, it appeared that a lack of it may be related to the development and or maintenance of hypertension, a disorder featuring vasoconstriction and an increased tendency to arterial thrombosis. The present studies aimed to investigate this possibility using a rat model. A bioassay for prostacyclin was first perfected. This consisted of a modification of the method used by Moncada, Higgs and Vane (1977): PGI₂ released by rat aortic strips, during incubation in tris buffer, was measured by assessing the ability of the incubate to inhibit adenosine diphosphate induced aggregation of human platelets, as compared to the inhibitory effect of standard prostacyclin sodium salt. The specificity of the assay for the detection of PGI₂ was tested. The abil ity of hypertensive rat aorta to release prostacycl in was investigated in two studies. The first compared aortas of Wistar rats of the New Zealand genetically hypertensive strain (GH) with those of matched normotensive Wistar controls. In the second study, hypertension was induced by wrappi ng the ri ght kidney with surgical silk and removing the contralateral kidney. Ten weeks later, aortic generation of prostacyclin by these animals was compared with that of matched sham controls which had received identical surgical manipulation but for the application of silk to the right kidney. Contrary to expectation, in both forms of hypertension, aortas of the rats with elevated pressure produced consistently more prostacyclin than those of matched controls. In order to discover more about the relationship between elevated pressure and elevated PGI₂ production, the effect of pressure reduction with hypotensive agents on the ability of GH rat aortas to produce prostacyclin, was investigated. After pressure had been controlled within normal range for one week (achieved by oral administration of furosemide, dihydralazine and reserpine for one month), aortic PGI₂ was reduced in comparison with matched GH controls. However, the reduction was not consistent and statistical significance was not reached. Because it was subsequently reported by other workers, that some of the hypotensive agents which had been employed may effect prostaglandin levels per se, no conclusions could be drawn from this study as to any possible direct relationships between pressure and aortic prostacyclin generating capacity. A further means of reducing elevated pressure (which had no inherent effect on prostaglandin levels) was thus sought. A mechanical method was eventually selected, application of a silver clip to the aortas of GH rats, just below the diaphragm, producing an immediate reduction in pressure distal to the constriction. Eighteen hours with later, PGI₂ production by these distal aortas those of matched sham GH controls and was was compared found to be consistently reduced. These results indicate that the ability to produce PGI₂ may be influenced by prior local pressure changes and that the increased capacity of hypertensive rat aortas to generate prostacyclin may be related to the increased mechanical transmural stress consequent on elevated pressure. Since haemostatic balance must be influenced not only by vascular PGI₂ generation but also by platelet sensitivity to PGI₂, the response of GH platelets to the anti-aggregatory effect of prostacyc1in was also investigated. As it had been shown by Sinzinger, Si1berbauer, Horsch and Gall (1981) that intra-arterial infusion of PGI₂ in humans decreased platelet sensitivity to the substance, the possibility existed that platelet sensitivity in hypertension might be reduced. This hypothesis was, however, invalidated as the sensitivity of GH platelets to the anti-aggregatory effect of PGI₂ was almost identical to that of normotensive controls. The shortcomings of the methodology and the possible importance of these findings in the hypertensive animal are discussed. The idea that elevated PGI₂ in hypertension may play a protective role both with respect to platelet aggregation and in attenuating further pressure rises is considered. It is finally suggested that it will be possible to draw more accurate conclusions as to the meaning of the increased PGI₂ generation in hypertension (both in relation to vascular tone and platelet function) only when details of production of, and sensitivity to, thromboxane A₂ are known. Thromboxane A₂ (TXA₂) is a vasoconstrictor and promotor of aggregation (Hamberg, Svensson and Samuelson, 1975) and it may be that, despite elevated vascular PGI₂ generation, the TXA₂/PGI₂ balance is still tipped in favour of vasoconstriction and platelet aggregation in hypertension.
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  • Date Issued: 1983

Effect of anticonvulsant agents on pineal gland indole metabolism

  • Authors: Morton, Dougal John
  • Date: 1983
  • Subjects: Pineal gland -- Metabolism Anticonvulsants
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3844 , http://hdl.handle.net/10962/d1009518
  • Description: Preface: The general indications that the pineal gland might be involved in homeostasis, and more specifically the evidence suggesting a role in amelioration of seizure states warranted further investigation . No reports had examined a possible link between anticonvulsant drug administration and pineal gland function, and few enabled any type of presumption to be made as to possible effects. This study was an attempt to evaluate in which ways anticonvulsant drugs might alter pineal gland indole metabolism, with a view to increasing understanding of the role of the pineal in modulation of epileptic discharges. In order to make the study as meaningful as possible extensive preliminary investigations were necessary. Pharmacokinetic determinations gave an indication of tissue concentrations of the drugs, which could then be related to observed effects. As far as possible, where existing information was lacking, the catalytic behaviour of the various enzymes was characterised in order to explain any observed effects at a molecular level. An attempt was also made to characterise the regulatory mechanisms controlling indole metabolism, again in order to define the pharmacological effects exerted by the drugs used. The complexity of the system made it impossible to suggest a single uniform regulatory hypothesis, although some significant observations were made. Finally, the studies involving the anticonvulsant drugs were conducted on intact animals, isolated organs and individual enzymes in an attempt to determine whether the observed effects were occuring at a molecular, local or central level.
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  • Date Issued: 1983

The effect of tricyclic antidepressant drugs on the uptake and metabolism of serotonin by the pineal gland in organ culture

  • Authors: Pillay, Manoranjenni
  • Date: 1983 , 2013-04-05
  • Subjects: Antidepressants , Pineal gland -- Metabolsim , Serotonin
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3828 , http://hdl.handle.net/10962/d1007053 , Antidepressants , Pineal gland -- Metabolsim , Serotonin
  • Description: The effect of tricyclic antidepressants (TADs) on a variety of pineal functions was assessed. TADs affected the uptake of ³H-5HT into bovine pineal slices within a particular concentration range of these drugs, DESI, CLOMI and IMI appeared to inhibit uptake slightly, within a limited concentration range. Surprisingly, DESI appeared to be a relatively potent 5HT uptake inhibitor. The 5-HT re-uptake system in the pineal probably differes from that in brain tissue. TADs had a marked effect on the metabolism of ³H-5HT in the rat pineal, in an organ culture system, MEL and N-acetylserotonin synthesis increased for the first 11 days and thereafter a slight decrease was observed. HTOH and HIAA also showed an initial increase followed by a slight decrease in synthesis. The synthesis of MTOH and MIAA was decreased. The possibility that TADs could affect HIOMT and SNAT synthesis and thereby change the metabolic pattern of 5-HT was investigated. TADs appeared to stimulate SNAT initially and thereafter a slight decrease from peak activity was observed. This is probably due to stimulation followed by development of subsensitivity of β-receptors, HIOMT activity also appeared to be affected by TADs. The existence of two types of HIOMT is suggested. There is a possibility that these changes in the metabolism of 5-HT could be implicated in the mechanism of action of TADs. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
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  • Date Issued: 1983
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