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The therapeutic importance of isoniazid metabolism in elderly patients
Get PDFThis is a study of the role of oxygen free radicals in isoniazid induced toxicity and its implications on the safety of isoniazid containing regimens in elderly patients. During isoniazid metabolism, toxic metabolites are produced which, together with isoniazid, may lead to toxicity by mechanism (s) yet unknown. Understanding the mechanism of toxicity is important for effective management and prevention of isoniazid induced toxicity. Elderly patients take priority for this consideration because isoniazid is more toxic in these people. Consequently, "the therapeutic importance of isoniazid metabolism in elderly patients" was found a suitable title for this work. lsoniazid metabolites; acetylisoniazid, monoacetyl-hydrazine and diacetylhydrazine were synthesized and characterized by thin layer chromatography, high performance liquid chromatography (HPLC), ultra-violet absorption spectra and mass spectrometry. Thereafter, these compounds together with hydrazine were used in the subsequent experiments
The first-pass extraction of pindolol in comparison with propranolol in rat liver
Get PDFReports in the literature have shown that in man propranolol has a larger first-pass effect (70%) than pindolol (13%). The aim of this research was to make a direct comparison of first-pass extraction and other pharmacokinetic parameters of these drugs under identical experimental conditions by means of an isolated rat liver perfusion model
Studies of the excretion of aluminium by the kidney and the toxic effects of the element on DNA
Get PDFAluminium is an element of increasing clinical importance. It not only has uses as a medicinal substance but also in recent years it has been shown to be the cause of considerable toxicity, particularly in the setting of chronic renal failure. Diseases that have been shown to be associated with aluminium, or in which it has been implicated, include dialysis dementia, renal osteodystrophy and Alzheimer's disease. This thesis has studied aspects of the interaction between aluminium and the kidney. The work has addressed two major issues. Firstly, a study is described where Malvin's stop-flow technique was used to determine any excretory/absorptive tubular site for Al in the pig kidney. Al was found to be excreted in the distal nephron of the pig kidney. Secondly, the toxic effects of Al in vitro on the DNA of pig kidney cell line LLC-PKl were investigated, in an attempt to elucidate some of the mechanisms of toxic action. DNA synthesis was measured using ³H-TdR incorporation. Over increases of both time (9-72 h) and Al concentration (0.01-8.0 mM), ³H-TdR incorporation was diminished. Effects were evident at concentrations as low as 0.05 mM Al. The production of DNA strand breaks was assessed by the increase in size of cell nucleoids (ie DNA in supercoiled form). Nucleoid size was analyzed in a Epics 753 Fluorescence Activated Cell Sorter interfaced with an MDADSII data acquisition and analysis system. After 90 min incubation with Al (over the concentration range 0.001-32 mM), an increase in nucleoid size was noted at concentrations above 0.05 mM. The data demonstrate that Al exerts an effect on kidney cells in vitro which is expressed as diminished DNA synthesis and production of DNA strand breaks. These effects on DNA may have important long-term implications on various disease states associated with Al toxicity
An electrophoretic study of fetal mouse brain proteins after in vivo exposure to phenytoin and disulfiram
Get PDFAlthough there have been two-dimensional electrophoretic studies on fetal brain tissue (for instance, Yoshida and Takahashi, 1980), the emphasis in most of this work has been on developmental changes in protein expression, and not on the effects that drugs have on fetal brain protein complement. Klose and co-workers (1977) did an early study using two-dimensional gel electrophoresis to determine the effects of various teratogens on whole embryos. No protein changes were found and that line of research was not continued. In this study two-dimensional gel electrophoresis is extensively used, in the belief that the usefulness of this technique to experimental teratology has not been fully evaluated. It is reasonable to suppose that a central nervous system teratogen administered during critical periods of susceptibility will led to perturbations of orderly brain development, and that these perturbations will be reflected as changes to the protein complement. The total brain protein complement of mice that have been exposed to drugs in utero will therefore be analysed, in the hope that any inductions or deletions of proteins as a result of drug exposure may provide a clue to the molecular events underlying drug injury to the fetus
A study of the teratogenicity of diphenylhydantoin and phenobarbitone in the experimental mouse
Get PDFThe aims of the research were to establish whether diphenylhydantoin and phenobarbitone are teratogenic in mice both in vivo and in an in vitro whole embryo culture system, to investigate possible mechanisms of teratogenicity and to examine whether the methods used in this study, may form a basis for developing systems of more extensive drug teratogenicity screening
Determination of the effect of blood testing intervals on bioavailability and bioequivalence assessment of fixed-dose drug combination anti-tuberculosis drugs
No full textIncludes bibliographical references
A study of the antimalarial action of Pyronaridine and its accumulation into Plasmodium falciparum
No full textIncludes abstract.Includes bibliographical references.Pyronaridine (PND), a hydroxyanilino-benzonaphthyridine derivative and also a structural analogue of chloroquine, was synthesized in China in the 1970s as a result of a search for alternative drugs to treat chloroquine-resistant (CQR) Plasmodium falciparum malaria
The pharmacokinetics of ranitidine in patients with chronic duodenal ulceration and in patients with chronic renal failure
Get PDFThe pharmacokinetics of orally administered ranitidine were studied in 10 patients with endoscopically proved duodenal ulceration after a single 150 mg dose and after 4 weeks 1 ranitidine treatment (150 mg twice daily), at which time there was endoscopic evidence of complete ulcer healing. After a single dose the median elimination half-life was 135 minutes and the median area under the curve (AUC) was l 844 ng/ml.hr. Although the maximum concentration after a single dose (Cmax = 365 ng/ml) was significantly different from that after continuous treatment (Cmax = 562 ng/ml) (p 65 ml/min). There appeared to be no significant differences in absorption rate or amount absorbed but the median elimination rate constant was significantly reduced from 0,31 h⁻¹ in controls to 0,14 h⁻¹ in RF (p <0,002) resulting in a two-fold increase in t½ (312 minutes) after a single dose. Cmax did not differ significantly although Cmin and AUC were significantly larger in RF patients (both p <0,002). It is suggested that the dosage of ranitidine be reduced from 150 mg to 75 mg twice daily in severe renal failure although it was not possible to relate half-life, elimination rate constant or AUC directly to creatinine clearance
Design and construction of a laboratory system for neuromuscular stimulation of the lower extremities during cycling
Get PDFFunctional Neuromuscular Stimulation (FNS) is a method by which paralyzed muscles are stimulated electrically in order to produce a useful movement. The design and testing of a laboratory system for the modulated control of the lower extremities during FNS-induced cycling on an exercising device (Paracycle) is described. The system hardware, which is designed around a standard IBM compatible Personal Computer, features six independent stimulation channels. Waveform characteristics such as pulse frequency, width and amplitude are defined as a function of the crank position of the Paracycle for each channel. An extensive software package allows programmability of the waveform parameters and supports the user in the definition of stimulation sequences. The effective performance of the complete FNS-controller/ Paracycle system has been demonstrated during a controlled case study with two paraplegic subjects
Characterisation of Mefloquine accumulation in Plasmodium falciparum
No full textIncludes bibliographical references (leaves 165-180).Mefloquine has been in use for over twenty years and still very little is known about its interaction with Plasmodium falciparum. In 1979, Fitch er al carried out the only other published extensive investigation of mefloquine accumulation, but were not able to demonstrate energy dependent uptake. They later indicated that an energy requirement may be being masked by mefloquine’s ability to bind membrane phospholipids to a large extent (Chevli & Fitch, 1982).Until now no energy requirement for mefloquine accumulation has been uncovered. This thesis investigates the relationship between chloroquine and mefloquine resistance, and characterizes the mechanism of mefloquine accumulation in Plasmodium falciparum. Conditions were established that enabled the amplification of the parasites' contribution to overall mefloquine accumulation in the parasitised erythrocyte. It was found that mefloquine accumulation is stimulated by glucose and is inhibited by the glycolysis inhibitor, iodoacetate, and also by incubation at low temperature. Mefloquine accumulation was also found to be partly dependent on the pH gradient between the acidic food vacuole and the external medium. It has also been determined that mefloquine-resistant Plasmodium falciparum accumulate approximately half the amount of mefloquine than do mefloquine-sensitive parasites. It has been shown that the accumulation of both chloroquine and mefloquine have two components, a high affinity saturable component and a low affinity non-saturable component (Fitch et aI., 1979; Fitch et al., 1974; Bray et al., 1998). The saturable component has been well characterized, but until now the non-saturable component has not been identified. This thesis shows that chloroquine and mefloquine adsorption to synthetic β-haematin and pure isolated haemozoin is non-saturable. It is proposed that the malaria pigment is responsible for the low affinity, non-saturable component of chloroquine and mefloquine accumulation. The effect of chloroquine, mefloquine and artemisinin on haemoglobin levels in parasitised erythrocytes was also measured. Chloroquine caused a buildup in haemoglobin and mefloquine caused a decrease in haemoglobin levels. This adds weight to previously published work (Famin & Ginsburg, 2002) suggesting that chloroquine prevents the degradation of haemoglobin, while mefloquine inhibits the endocytosis of haemoglobin
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