Masters Degrees (Pharmaceutical Sciences)

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An assessment of the level of knowledge of diabetics and primary health care providers in a primary health care setting : on diabetes mellitus.
(2006) Moodley, Lushendran Manikum.
Hypoglycaemic and renal effects of a bioactive plant extract in streptozotocin induced diabetic rats.
(2008) Mapanga, Rudo Fiona.
Background: Evidence from our laboratories indicates that triterpene constituents of Syzygium cordatum (Hochst.) [Myrtaceae] crude leaf extracts can be used to treat diabetes mellitus. For the plant derived triterpenes to have further potential in diabetes management, they should, however, additionally alleviate or prevent some of the complications of diabetes mellitus such as impaired kidney function and cardiovascular disorders. Accordingly, this study was designed to isolate the triterpene, oleanolic acid (OA) from S. cordatum leaves and evaluate its effects on blood glucose, renal function and blood pressure in streptozotocin (STZ)-induced diabetic rats. OA was studied because it is the major constituent of many African plant species used in traditional medicine. Materials and Methods S. cordatum crude leaf ethyl acetate solubles (EAS) were obtained after defatting the leaves with hexane followed by dichloromethane before maceration with ethyl acetate. Preliminary experiments indicated that EAS contained triterpenes with hypoglycaemic properties. Solvent extraction and fractionation of EAS yielded mixtures of oleanolic acid/ursolic acid (OA/UA) and methyl maslinate/methyl corosolate. Recrystallisation of the OA/UA mixture using ethanol yielded OA, the structure of which was confirmed by NMR spectroscopy ('H & 13C). Oral glucose tolerance test (OGTT) responses to various doses of OA (40, 80 and 120 mg/kg) were monitored in separate groups of non-diabetic and STZ-induced diabetic rats given a glucose load (0.86 g/kg, p.o.) after an 18-h fast. Rats treated with deionized water (3 ml/kg p.o.), or standard drugs, (insulin, 200 Hg/kg, s.c; metformin, 500 mg/kg, p.o. and glibenclamide, 500 f^g/kg, p.o.) acted as untreated and treated positive controls, respectively. To investigate the possible interaction between OA and standard drugs in lowering blood glucose, OGTT responses were studied in separate groups of animals simultaneously treated with OA at either 40 or 80 mg/kg and insulin (100 or 200 ug/kg, s.c), metformin, (250 or 500 mg/kg, p.o.) or glibenclamide (250 or 500 mg/kg, p.o.). Blood glucose was monitored at 15-min intervals for the first hour, and hourly thereafter for 3 h. Plasma insulin concentrations were measured in separate parallel groups of rats prepared as for OGTT studies to examine whether there was an association between OA treatment and pancreatic insulin secretion. Acute effects of OA on kidney function and mean arterial blood pressure (MAP) were investigated in anaesthetized rats challenged with hypotonic saline after a 3'/2-h equilibration for 4 h consisting of 1 h control, 1XA h treatment and 1 Vi h recovery periods. OA was added to the infusate during the treatment period. Short-term effects of OA were studied in individually-caged rats treated twice daily with OA (80 mg/kg, p.o.) for 5 weeks. Results OA decreased blood glucose concentrations of both non-diabetic and diabetic rats, as did some standard drugs except glibenclamide which did not exhibit any effects in STZ-induced diabetic animals. The blood glucose lowering effects were most potent in STZ-induced rats treated with combined OA and insulin by comparison with all other treatments. Short-term treatment of non-diabetic and STZ-induced diabetic rats with OA alone for 5 weeks decreased blood glucose concentrations, but the reduction in non-diabetic rats was to values that did not achieve statistical significance. Except for non-diabetic rats treated with insulin alone or in combination with OA, plasma insulin concentrations were not altered by treatment in non-diabetic and STZ-induced diabetic animals. Hepatic glycogen concentrations of non-diabetic and STZ-induced diabetic rats were significantly increased by all treatments at the end of 5 weeks. Acute intravenous infusion of OA in anaesthetized rats significantly increased Na+ excretion outputs of non-diabetic and STZ-induced diabetic rats without affecting urine flow, K+ or CI" excretion rates. Similarly, daily OA treatment (80 mg/kg, p.o.) significantly increased Na+ excretion rates of non-diabetic and STZ-induced diabetic rats throughout the 5 week experimental period without affecting urine flow, K+ or CI" excretion rates. By comparison with respective control animals, Short-term administrations of OA significantly (p<0.05) increased GFR of non-diabetic (2.88±0.14 vs 3.71±0.30 ml/min) and STZ-diabetic rats (1.81± 0.32 vs 3.07±0.16 ml/min, n=6 in all groups) with concomitant reduction of plasma creatinine concentrations. Acute and Short-term administrations of OA non-diabetic and STZinduced diabetic rats reduced mean arterial blood pressure by comparison with respective control animals. Discussion The results suggest that S. cordatum leaf derived OA not only has the potential to lower blood glucose in diabetes, but also has beneficial effects on kidney function and blood pressure. We suggest that the hypoglycaemic effects of OA mimic those of metformin as evidenced by the fact that neither of these treatments altered plasma insulin concentration of non-diabetic rats. OA-evoked increases in urinary Na+ outputs of STZ-diabetic rats and elevation of GFR suggest up-regulation of renal function by the triterpene. The findings are of considerable importance because they suggest the hypoglycaemic, renal and hypotensive effects of OA in the management of diabetes mellitus. Conclusion The results demonstrated that the oleanolic acid extracted from S. cordatum leaf has blood glucose-lowering effects comparable to standard anti-diabetic drugs in STZ-induced diabetic rats. Furthermore, OA augmented the hypoglycaemic effects of insulin in STZ-induced diabetic rats. These findings suggest that OA may have beneficial effects on some of the processes that are associated with renal derangement in STZ-induced diabetic rats. The results introduce the first in vivo evidence that OA ameliorates kidney function in STZinduced diabetic rats. Keywords: Renal function; diabetes mellitus; triterpenoids; oleanolic acid, hypoglycaemia
HIV and the metabolic syndrome.
(2008) Bryant, Lynda P.
Abstract not available.
Pharmacological effects of Hypoxis hemerocallidea Fisch. & C. A. Mey. (Hypoxidaceae) Corm ("African Potato") aqueous extract on some mammalian extra-vascular smooth muscles in vitro.
(2009) Nyinawumuntu, Agatha.; Ojewole, John Akanni Oluwole.
Extracts of Hypoxis hemerocallidea corm (African potato) are commonly used by some traditional health practitioners in KwaZulu-Natal Province of South Africa for an array of human ailments. This study was, therefore, undertaken to investigate the GIT spasmolytic, bronchospasmolytic, uterolytic and vasa deferentia relaxant effects of Hypoxis hemerocallidea corm aqueous extract. Respectively, these effects were determined on both naive and spasmogenevoked contractions of the guinea-pig and rat isolated ileum, trachea, uterine horns and the vas deferens in vitro. Healthy, young adult, male and female Dunkin-Hartley guinea-pigs (300-400g) and Wistar rats (250-350g) were used in this study. The isolated tissues were prepared and mounted in Ugo Basile organ-baths under normal physiological conditions. After an equilibration period of 30-45 minutes, the isolated smooth tissue segments were challenged with graded concentrations of Hypoxis hemerocallidea corm aqueous extract, and/or reference drugs. Changes in tension developed by the muscle preparations (relaxations and contractions) were recorded isometrically by means of Ugo Basile's force-displacement transducers and pen-writing 'Gemini' recorders. Relatively low to high concentrations of Hypoxis hemerocallidea corm aqueous extract (APE, 25-400 mg/ml) produced dose-dependent and significant (p<0.05) relaxations of the guinea-pig ileum, and the uterine horns taken from non-pregnant rats, as well as on spasmogenprovoked contractions of stilboesterol-primed, oestrogen-dominated, non-pregnant rats in a concentration-related manner. Potassium chloride (40 mM)-induced contractions of uterine horns, ACh (0.1-3.2 ug/ml)-induced increases in the amplitude of contractions of the guinea-pig ileum, as well as noradrenaline (0.2-1.6 ug/ml)-induced increases in the amplitude of contractions of the male rat isolated vasa diferentia, were significantly (p<0.05-0.001) reduced or abolished by bathapplied APE (25-400 mg/ml). Relatively low to high concentrations of the extract (25-400 mg/ml) caused concentration-dependent increases in the relaxations of the guinea-pig isolated tracheal smooth muscles. Inhibitions of ACh (0.1-3.2 ug/ml)-induced contractions of the guineapig isolated ileum probably suggests possession of antidiarrhoeal activity of APE. Results of this study show pronounced relaxant effects of Hypoxis hemerocallidea corm aqueous extract on guinea-pig vas deferens. The study also lends pharmacological credence to the folkloric, ethnomedical uses of APE as a natural antenatal remedy for threatening abortions, as an antidiarrhoeal remedy, and as a bronchorelaxant. The precise mechanisms of APE action on the smooth muscles could not be established in the present study. However, the uterolytic action of the corm's extract is unlikely to be mediated via ^-adrenoceptor stimulation, but probably mediated through a non-specific spasmolytic mechanism.
A retrospective analysis of subjects who have approved gastro-oesophageal reflux disease (GORD) from a private medical aid fund.
(2006) Suleman, Aisha Bebe.
Abstract not available.
Multipolymeric monolayered mucoadhesive films for drug therapy.
(2007) Perumal, Velisha Ann.; Govender, Thirumala.
The use of the oral cavity membranes as sites of drug administration has been a topic of increasing interest for the past decade. The buccal route, in particular, offers several advantages over the per oral route and may prove to be a viable alternative to other routes for drug delivery, as it bypasses hepatic first pass metabolism, thereby improving the systemic bioavailability of the administered drug. A controlled drug release formulation may further enhance the therapeutic efficacy of a buccal drug delivery system. Propranolol HCI (PHCI), a non-selective p-blocker, primarily advocated in the treatment of hypertension, has a short half-life (3 - 6 hours) and is also subjected to extensive hepatic first-pass metabolism following oral administration, resulting in a low oral bioavailability, therefore rendering it an ideal candidate for buccal drug delivery. For optimal controlled release and mucoadhesivity of a buccal delivery system containing PHCI, the blending of polymers and drug of opposing solubilities may be required for the formation of monolayered films. The aim of this study was therefore to formulate and characterise multipolymeric monolayered mucoadhesive films containing drug and polymer/s of opposing solubilities for the buccal delivery of PHCI. First, preparation parameters for the formation of monolayered multipolymeric films (MMFs) and homopolymeric PHCI films comprising drug and polymer/s of opposing solubilities, i.e. Chitosan (CHT) and Poly(D,L-lactide-co-glycolide) (PLGA) by an emulsification/casting/solvent evaporation method were investigated. MMFs could be prepared at all homogenisation speeds (6000, 9000, 12000, 15000 rpm) and times (1, 5, 15, 25 minutes). The films showed micromatrices embedded in the film matrix due to the inclusion of the PLGA polymer. Increased homogenisation speed and time resulted in a reduction in the size of the micromatrices. Phase separation occurred at temperatures below 20 °C. Emulsifiers employed in the study (Poly(vinylalcohol) (PVA) and Tween 80®) adversely affected the morphology and appearance of the film and were therefore not considered feasible for inclusion in the formulation. The preparation parameters identified for emulsification without phase separation and the subsequent generation of monolayered films, without phase separation during solvent evaporation and drying, were emulsification at 20 °C and homogenisation at 9500 rpm for 15 minutes. It was discovered through preliminary investigations and a comprehensive literature search that the conventional film casting method of film preparation suffered from poor drug content uniformity. To address this problem of non-uniformity, a specially designed silicone-molded tray (SMT) for film casting was prepared and evaluated in terms of enhancing drug content uniformity. These investigations confirmed that the SMT with teflon-coated perspex inserts provided a reproducible method for the preparation of both homopolymeric and multipolymeric (including drug and polymers of similar and opposing solubilities) films that met drug content uniformity requirements (assay values were within 92-107.5%) and also reduced the variability in mucoadhesivity (p=0.2922), drug release [fi values = 92.76, 90.99 and 86.06) and film thickness for all three trays. The final phase of this study involved the identification of a suitable polymeric blend for the preparation of MMFs comprising hydrophilic and hydrophobic polymers for the controlled buccal delivery of PHCI and subsequent characterisation of these films in terms of their physicochemical/mechanical properties. Initial investigations of different polymers for the formation of homopolymeric films showed that the combination of drug and polymer/s of opposing ionic states was not possible due to complexation. PHCI film formation as homopolymeric films was achievable with hydrophilic polymers, Hydroxypropylmethylcellulose (HPMC) and CHT, and hydrophobic polymers, Ethylcellulose (EC) and Eudragit® RSI00 (EUD100). It was also found that combining PHCI, a hydrophilic drug, with a hydrophilic polymer (CHT or HPMC) failed to retard drug release (> 80% at 1 hour), whilst the release of PHCI from a homopolymeric film comprising a hydrophobic polymer (EC or EUD100) was retarded. A PHCIiEUDlOO (1:10) film provided controlled release but was too retarded (< 67% at 8 hours) for the purposes of this study. Hence, the polymeric content of the formulation was altered by the addition of a hydrophilic polymer CHT, to obtain the desired controlled release profile. A PHCI:EUD100:CHT (1:10:0.5) polymeric blend (MMF) was found to be suitable for the controlled release of PHCI and was reproducible in terms of drug content uniformity (p=0.1964), drug release [h values = 83.18; 82.03 and 71.19) and mucoadhesivity (p=0.9971). Drug release followed Higuchi's square-root model (r2=0.9426). Scanning electron microscopy revealed that the addition of CHT to the PHCI:EUD100 (1:10) film formulation rendered it more textured, which contributed to the faster drug release observed with the PHCI:EUD100:CHT (1:10:0.5) MMF. Swelling and erosion studies indicated that maximal swelling of the films occurred after 1 hour and 28.26% of the film eroded during the 8 hour test period. The system also demonstrated acceptable mucoadhesivity and mechanical properties. The surface pH of the films also remained constant at neutral pH throughout the study. The data obtained in this study confirmed the potential of this multipolymeric monolayered film system as a promising candidate for the controlled buccal delivery of PHCI. Key words: Films; Buccal; Multipolymeric; Mucoadhesive; Controlled drug release; Propranolol HCI
Effects of acetylcholine on isolated urinary bladders of normal and streptozotocin-treated diabetic rats.
(2006) Nsabimana, Abdon.; Ojewole, John Akanni Oluwole.
This study was prompted by the inconsistent reports and apparent controversies that exist in the biomedical literature on the responses of diabetic bladder strips to cholinergic nerve stimulation or exogenous administration of muscarinic agonists, especially acetylcholine (ACh), in vitro. In the present study, acetylcholine-induced contractions of urinary bladders isolated from normoglycaemic (normal) and streptozotocin-treated, diabetic Wistar rats were examined under physiological conditions. Mechanical contractile changes of the isolated urinary bladders of STZ-treated, diabetic rats in response to bath-applied acetylcholine were compared with those obtained from isolated urinary bladders of normal, age-matched, control rats. Results obtained show that urinary bladders from diabetic rats consistently weighed more, and were always more spontaneously active after mounting, than those of the age-matched normal, control rats. ft A Acetylcholine (ACh, 10" -10" M) provoked concentration-related, atropine-sensitive contractions of the isolated urinary bladders of both diabetic and age-matched normal, control rats. However, acetylcholine always induced more powerful and greater contractions of the diabetic bladders compared with bladders from the age-matched normal, control rats. The enhanced contractile responses of the diabetic bladder strips to bath-applied ACh were detected soon after induction of diabetes, and the magnitude and/or intensity of the enhanced contractile responses to ACh continued to increase as the diabetic state of the animals progressed. Although this preliminary study could not establish the mechanism of the increased contractile responsiveness of the diabetic bladders to the muscarinic agonist (ACh) used, the results tend to suggest that alterations in diabetic urinary bladder synaptosomal, vesicle-bound neurotransmitter (ACh) concentrations and the compensatory increase in the density of muscarinic M3-receptor population in diabetic bladders are two of the most attractive plausible mechanisms of the increased diabetic bladder responsiveness to bath-applied acetylcholine.
Antimicrobial and chemical analyses of selected bulbine species.
(2000) Mocktar, Chunderika.; Essack, Sabiha Yusuf.; Rogers, B. C.; Dangor, Cassim Mahomed.
The use of plant materials for the treatment of various diseases is very common in African countries. As traditional medicine used by the rural people does not always have a proper scientific basis, research programmes have to be undertaken to evaluate their therapeutic efficacy and safety. In traditional African medicine various Bulbine species are used to treat a number of conditions including sexually transmitted diseases, wound infections, dysentery and urinary tract infections. The Bulbine species belong to the family Asphodelaceae. There are over fifty South African Bulbine species and they are mostly herbs. Their leaves are evergreen and succulent in appearance. Bulbine species have thick fleshy tuberous roots, are easy to grow, are able to withstand drought and heat and are able to grow in poor soil. There is very little documented information on the antimicrobial activity and chemical properties of the Bulbine species. Therefore research programmes of this nature have to be undertaken. Various Bulbine species, viz., B. natalensis Bak, B. frutescens Willd (yellow flowers), B. narcissifalia Salm Dyck, B. abyssinica A Rich and B. frutescens Willd (orange flowers) were collected. The plants were washed with tap water, air dried and separated into the different components. Each component was cut into small pieces and immersed in methanol: dichloromethane (1:1, v/v) for extraction. The organic solvent was decanted from the plant material and evaporated under reduced pressure. The resultant crude extracts were stored in glass vials in the freezer. In addition, the roots, stems and leaves of B. natalensis and B. frutescens (yellow flowers) were extracted aqueously. The crude organic and aqueous were subjected to various tests to evaluate their antimicrobial and cytotoxic potential. To evaluate their antibacterial activities, the Disk Diffusion and Bore Well Methods were employed. The crude extracts were tested against various pathogens implicated in wound and urinary tract infections and dysentery. In these experiments the Disk Diffusion Method produced better results than the Bore Well Method. The crude organic and aqueous extracts were found to be effective against many of the bacteria used in this study including K. pneumoniae, S. aureus, S. typhi and S. flexneri which are considered to be troublesome pathogens. The TLC bioassay was employed to evaluate the antifungal potential of the various crude extracts against Aspergillus and Penicillium and the Disk Diffusion and Bore Well methods were used to evaluate the antifungal potential of C. albicans. The Bulbine species displayed no antifungal activity against Penicillium and limited antifungal activity against Aspergillus. The two method used to evaluate the antifungal activity of. C albicans was chosen because C. albicans grows in a similar manner to bacteria on solid and liquid culture media. Only the root extracts of the two B. frutescens varieties were inhibitory to C. albicans. The Brine Shrimp Bioassay was used to ascertain the cytotoxic potential of the crude extracts. The majority of the extracts were cytotoxic at the most concentrated dilution (i.e., dilution 1) but not cytotoxic at the lower dilutions. The only extracts that were not cytotoxic at the most concentrated dilution were the organic extract of the root of B. frutescens (yellow flowers), the organic extract of the root of B. narcissifolia and the organic extract of the leaf of B. abyssinica. TLC and column chromatography was carried out to evaluate the chemical composition of the Bulbine species. The TLC indicate that this technique could be a valuable tool in identifying the different species in the genus Bulbine. Column chromatogram was carried out on the extract which displayed a significant amount of antibacterial activity against the bacteria used in this study. The stem extract of B. natalensis was chosen for further analysis. The stem extract was fractitioned into different fractions but unfortunately none of the chemical component could be identified. According to the results obtained in this study, there is considerable scope for further studies of this genus.
Formulation and evaluation of modified release eudragit® matrices containing diclofenac sodium.
(1998) Hurbans, Nivriti.; Dangor, Cassim Mahomed.; Chetty, D. J.
The aim of the present study was to formulate oral modified release matrices of diclofenac sodium, using the Eudragit® polymers. In addition to the formulation processes, numerous variables had to be investigated, which included dissolution variables, formulation variables, and processing variables. The application of the tabletting technique as well as the use of Eudragit® polymers to modify the release of diclofenac sodium is motivated at the outset. A comprehensive review of modified drug release, the use of the tabletting methodologies and the application of Eudragit® polymers are presented. In-process quality control tests as well as the mechanisms and interpretation of the dissolution process are outlined. Diclofenac sodium, a potent nonsteroidal anti-inflammatory drug, was used in the present study, hence a brief review of this drug is also presented. The direct compression as well as the wet granulation tabletting methods were investigated. The major limitation of the direct compression method was found to be the lack of suitable flow properties of the powder blend. The wet granulation technique however, was successfully employed to prepare various diclofenac sodium Eudragit® matrix tablets. All tablets were prepared to contain 100 mg diclofenac sodium. The optimisation process was shown to be an integral procedure in influencing the matrix characteristics. In addition, it was shown that drug release was significantly influenced by different types and concentrations of Eudragit® polymers. A specific formulation was selected to investigate the integrity of the matrices produced by the wet granulation technique. The drug release profile of a commercially available modified release preparation containing diclofenac sodium viz. Veltex® 100 CR (reference standard) was also obtained. A comparison of the drug release profiles of Veltex® 100 CR capsules and the selected formulation showed them to be markedly dissimilar. Hence, a strong motivation is provided for rationalising the selection of the particular formulation in the present study, that was shown to release diclofenac sodium optimally. The selected formulation was prepared using a combination of the Eudragit® RL and Eudragit® RS polymers. In vitro dissolution studies on the selected as well as various other formulations demonstrated the wet granulation method to be both predictable and reproducible. However, absolute drug release independency of dissolution methods, media and agitation rates was unattainable. Furthermore, drug release was shown to be pH dependent. The selected formula was subjected to certain formulation and processing variables. An increase in the concentrations of lactose and starch was shown to increase drug release. Different types of diluents were also shown to influence drug release from the tablets. The method of incorporation of the lubricant, magnesium stearate, was investigated. Compression studies demonstrated the susceptibility of the tablets to changes in drug release behaviour and morphological characteristics as the hardness was varied. X-ray diffraction studies demonstrated that the processes of granulation and compression did not promote any atomic rearrangement of the drug and Eudragit® polymers. Scanning electron microscopy was useful in investigating the integrity and surface morphology of newly formulated as well as stored samples, while energy dispersive x-ray microprobe analysis adequately revealed the elemental composition of the tablets. The selected formulation was shown to be stable at room temperature (21 ±1°C) and low temperature (5± 1°C), while storage at 37°C with 80% relative humidity and 40°C demonstrated significantly decreased drug release behaviour during short term (3 months) stability testing. Tablet hardness evaluated during the stability testing showed that there were virtually no differences in tablet hardness between the room temperature and low temperature samples, while tablets stored at 37°C with 80% relative humidity and 40°C hardened considerably. However, tablet potencies and the moisture content of the samples were not significantly influenced during the storage period. In addition to usual observations and mathematical manipulation, some of the data generated from this study were also evaluated statistically.
Formulation, evaluation and characterization of an oral modified realease naproxen sodium preparation.
(1997) Moopanar, Kevindren Ramachandran.; Dangor, Cassim Mahomed.
The motivation for the present study is systematically presented and the aims and objectives of the study are clearly defined. A comprehensive review on modified release drug delivery has been presented to provide the basis for the meltable aqueous dispersion technique as an approach to the formulation of a multiple-unit oral modified release drug delivery system. In addition, a brief discussion on the theory of dissolution testing and the mechanisms and interpretation of the dissolution process has been presented. Naproxen sodium, a potent non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic activity employed in the study, has been briefly discussed. In the present study, the coacervation phase separation technique utilizing ethylcellulose was initially investigated but proved unsuccessful in producing a formulation displaying suitable drug release characteristics. Subsequently, the meltable aqueous dispersion technique utilizing cetostearyl alcohol was successfully employed to formulate a multipleunit modified release naproxen sodium preparation containing 550 mg of naproxen sodium. The use of cetosteary!alcohol, as·a·retarding material, generated modified ·drug release characteristics as a function of its content. Magnesium stearate (anti-tackiness agent) and Span 20 and Tween 60· (surfactants) were incorporated in the formulation to optimize particle size and sphericity. The influence. of various formulation variables on drug release characteristics were investigated: An optimized formulation displaying a desirable modified release profile of naproxen sodium was achieved employing a 1:1 ratio of naproxen sodium:cetostearyl alcohol, 2% m/m .. .. magnesium stearate, and 1%m/m Span 20 dispersed in a liquid manufacturing vehicle of pH 0.6 containing 2% m/m Tween 60. In vitro dissolution studies on the selected formulation showed drug release to be predictable and reproducible, dependent on the dissolution method, agitation rate, and the pH of the dissolution media (i.e. pH-dependent drug release). The density of the microspheres was shown to decrease as the concentration of cetostearyl alcohol increased whilst the mean specific surface area increased with increasing concentrations of cetostearyl alcohol. Differential scanning calorimetric studies reveals a change in the thermograms which is suggestive of eutectic formation. Scanning electron microscopy proved useful in evaluating the integrity and surface morphology of the microspheres as well as in elucidating the drug release characteristics of the formulation. Energy dispersive x-ray microprobe analysis revealed the elemental composition of the microspheres to be a composite of the pure ingredients. X-ray mapping and the line scan depicted the homogenous distribution of drug within the microspheres and confirmed that the formulation is a matrix-type modified release I' preparation. Stability studies were performed on the selected formulation at room temperature (21 :t 1°C), 40°C, 37°C with 80% relative humidity, and at low temperature (5 :t 1°C). The shelf-life of the selected formulation was determined to be 1.29 years. Applying the data to five different kinetic models to investigate the drug release mechanisms showed that first order and cube-root release characteristics were exhibited by the microspheres.
The toxicological properties of Scilla nervosa (Burch.) Jessop (Hyacinthaceae) in cultured HepG2 liver cells.
(2011) Pillay, Prishania.; Bodenstein, Johannes.; Chuturgoon, Anil Amichund.; Du Toit, Karen.
Background and Aims of Study. Scilla nervosa is a member of the Hyacinthaceae plant family that has been naturalised in the grasslands of Southern Africa. The bulbs are traditionally used to treat a variety of ailments. For example, the Zulu people use aqueous decoctions of the bulbs as analgesics in the treatment of rheumatic fever, crushed bulbs are used by the Sotho people as laxatives and the Tswana people use cooked bulbs to treat infertility in women as well as cold aqueous extracts to treat infections. It was recently demonstrated in our laboratory that extracts prepared from the bulbs possess potent anti-inflammatory properties, and this may therefore provide a rationale for the traditional use of the plant as an analgesic. Several studies have demonstrated that the bulbs contain homoisoflavanones and stilbenoids that could be responsible for their therapeutic effects. Although the plant has diverse medicinal applications, and despite it being recognised as a poisonous species particularly in livestock, little is known about its toxicity in human liver cells. The objectives of this study were therefore to investigate the potential toxicity of the bulbs on the liver, a major detoxifying organ. A human liver cell line was treated with an aqueous extract of the bulbs to investigate (1) cell viability, (2) potential mechanisms of cytotoxicity, (3) DNA integrity, and (4) changes in the cytochrome P450 enzyme activity. Materials and Methods. This study was conducted on the cultured HepG2 human hepatocellular carcinoma cell line, a model system to investigate the cytotoxicity of xenobiotics. The viability of cultured HepG2 liver cells in the presence of varying concentrations of an aqueous extract of the bulbs was determined after 24 hours treatment, and the concentration that reduced viability to 50% (IC50) was derived. Potential mechanisms of cytotoxicity at the IC50 were investigated. These included changes in metabolic activity (intracellular adenosine triphosphate (ATP) quantification), apoptosis induction (phosphatidylserine (PS) externalisation, caspase-8 and -9 induction and changes in mitochondrial membrane potential), and oxidative damage via free radical formation (lipid peroxidation). Genotoxicity was investigated by determining changes in DNA integrity (DNA fragmentation). The ability of the extract to stimulate or {¹ Du Toit, K., Kweyama, A., Bodenstein, J. 2011. Anti-inflammatory and antimicrobial profiles of Scilla nervosa (Burch.) Jessop (Hyacinthaceae). South African Journal of Science, 107:96-100.} inhibit enzymes commonly involved with drug metabolism was investigated by determining cytochrome P450 3A4 (CYP3A4) activity. Results Cell-viability decreased in a concentration-dependent manner and the IC50 was determined as 0.03 mg/ml. Treating the cells at the IC50 resulted in (1) a 1.2-fold increase in intracellular ATP levels, (2) no significant change in PS externalisation, (3) a 1.3-fold increase in caspase-8 activity, (4) a 1.1-fold decrease in caspase-9 activity, (5) no significant change in mitochondrial membrane potential, (6) a 1.9-fold increase in lipid peroxidation, (7) evidence for genotoxicity as demonstrated by DNA fragmentation, and (8) no evidence of changes in CYP3A4 activity. Conclusion. Results suggest that HepG2 liver cells are sensitive to an aqueous extract of the bulbs of S. nervosa. The extract has the potential to (1) induce apoptosis, (2) increase oxidative stress and (3) cause genotoxicity in vitro. peroxidation, genotoxicity
Drug-related problems among geriatric outpatients at a public sector hospital : an intervention study.
(2000) Moodley, Pathma.; Dangor, Cassim Mahomed.; Perumal, D.
Introduction: Although drug-related problems (DRPs) are known to be prevalent in elderly patients, there are not many studies that have been performed in geriatric outpatients at public health facilities in South Africa. Thus, the prevalence of DRPs in elderly outpatients attending Addington Hospital was investigated and suitable preventive intervention strategies to overcome or minimise these DRPs were developed. Research Methodology: The study was conducted in two phases. Phase 1 was conducted in March and April 1998, during which 281 elderly patients on chronic medical treatment were chosen for the study by systematic random sampling, according to specific inclusion criteria. Data collection was via a retrospective review of the elderly patient's medical notes and by personally interviewing the patient. Two research instruments were used in this phase. The customised Patient Profile (PF) form helped to delineate DRPs in the elderly patients. A Prescription Intervention Form (PIF) was used to inform the prescriber of the DRP and to make recommendations to change the drug therapy in order to overcome the DRP. In phase 2 of the study, intervention strategies were devised to address some of the major DRPs identified in phase 1 of the study. A patient counselling leaflet, prescribing guidelines for geriatric patients and a protocol for counselling of in-patients were developed. In addition, two DRP reporting systems were developed for surveillance of adverse drug reactions and medication errors during dispensing. Results and Discussions: Most geriatric subjects suffered from multiple, chronic conditions, these being hypertension (64.8%) followed by ischaemic heart disease (43.8%), musculoskeletal disorders (arthritis or gout) (42.7%), diabetes (29.2%), chronic obstructive airways disease (13.2%), hypercholesteremia (11.7%) and arrythmias (atrial fibrillation) (11.0%). The 281 patients were taking 1730 prescribed drugs, with a mean of 6.2 (range 3 to 15) prescribed drugs per patient. An astounding 45.6% of the total geriatric patients were taking or using between 7 to 9 medicines and 10.3% were taking or using between 10 to 15 medicines. The antihypertensives (15.9%) were the most widely prescribed drugs followed by medicines acting on CNS (10.9%), coronary vasodilators (9.1%), diuretics (9.1%) and medicines acting on the musculoskeletal system (8.7%). A total of 856 actual DRPs experienced by 262 geriatric patients (93.2%) ranged from 1 to 11 DRPs. The greater the number of prescribed drugs the greater the actual DRPs experienced by geriatric patients (p = 0.000). The most common DRPs were those involved in drug safety (56.6%); effectiveness of the drug therapy (20.8%); compliance (7.8%) and indication of drug therapy (7.6%). 159 elderly patients (56.6%) experienced 223 adverse effects either with their current or past prescribed medicines. The most common ADRs were as follows: gastro-intestinal ulceration (11.0%), cough (9.3%), diuretic side effects (dehydration, fatigue, hypotension, etc) (7.1%), constipation (6.8%), equilibrium problems (6.4%) and headaches (6.4%). For those DRPs warranting interventions, the mean number of prescription interventions in the entire sample population of 281 elderly patients was 0.65 ± 1.16. 87 elderly patients (30.1 %) had from 1 to 4 interventions on their current prescription. The most common prescription interventions were on problems involving drug therapy monitoring (26.9%), safety of drug therapy (26.5%), indication of drug therapy (17.5%), prescribing errors (15.3%) and prescription information omission (11.1 %). The three intervention strategies and DRPs surveillance reporting systems were successfully devised and developed. Conclusions: A profile related to the elderly patient's medical history and pharmacotherapy was completed for each of the 281 patients. General trends of prescribing pattern prevalence of DRPs and the prescribed inappropriate medication was established. The interventions of problem prescriptions were based on a newly developed PIF. The development and implementation of suitable intervention strategies to minimise DRPs were as follows: a compliance information leaflet, prescribing guidelines and the protocol for counselling in-patients. A medication error form as well as an adverse drug reaction reporting forms was developed for surveillance of DRPs. The recommendations for clinical practice and directions for future research that are presented should help to make drug therapy in the elderly safer and more effective.
Pharmaceutical availability on newly formulated oral sustained release pellets containing the antihistamine, chlorpheniramine maleate.
(1991) Mathir, Zohra Mohamed.; Dangor, Cassim Mahomed.; Veltman, A. M.
The main objective of the present study was to determine the feasibility of obtaining aqueous polymer-coated pellet formulations using EudragitR NE 30 D dispersion and chlorpheniramine maleate as the model drug. Many factors influence the rate of drug release from coated beads including, the substrate, the coating formulation and the coating process. A drug release profile that was comparable to that of the reference standard, DykatussR Capsules was obtained with a formulation employing 8.3% EudragitR NE 30 D, 0.5% talc and 1% polyethylene glycol. In vitro dissolution tests on this formulation showed drug release to be predictable, reproducible and independent of the dissolution methods or media. Short term storage confirmed the stability at room temperature (20°C) and low temperature (5C). Scanning electron micrographs of pellets stored at elevated temperatures i.e. 37°C with 80% relative humidity and 40°C illustrated the phenomenon of 'further gradual coalescence' which corresponded to the decrease in release of drug from the pellets.
The pharmacokinetics of phenobarbitone in fasting and non-fasting dogs.
(1990) Thurman, Graham Duncan.; Miller, Raymond Martin.; McFadyen, Margaret Lynn.
Practicing clinical veterinarians in large companion animal practices are often faced with the phenomena of epileptic seizures which occur commonly in dogs. The high incidence of non-responsive cases is often frustrating, and the literature offers incomplete, conflicting and often inaccurate information. The concept of therapeutic anti-epileptic drug concentration monitoring, as applied in man as an aid to treatment, appears attractive in order to provide an improved service to the patient and client. An investigation into the pharmacokinetics of phenobarbitone, particularly at steady state, became necessary in order to interpret the application of drug serum concentration monitoring. The trend of veterinarians to extrapolate human kinetics to dogs is common and unsound. This study was an attempt to identify the similarities and dissimilarities between the pharmacokinetics of dogs and humans. No literature was available, both for man or animal, on the effect of food on the absorption of phenobarbitone. As dog owners frequently have to administer oral medication in food, this was an important factor to examine. The kinetics of the drug was determined in a group of epileptic dogs in order to provide a possible base-line therapeutic regime on commencement of treatment, and the practical application of therapeutic drug monitoring in order to individualize and improve response to treatment was explored.
The effect of alcohol, isoniazid, rifampicin, paracetamol and hexane on hepatic gluconeogenesis and bromosulphthalein clearance.
(1988) Khedun, Shaun Mahabeer.; Leary, W. P. P.
The first workers to use the isolated perfused rat liver for the study of gluconeogenesis were Corey and Britton (1941). Subsequently, other investigators found the modified method of Miller et al (1951) to be more suitable. This technique, with modifications introduced by Mortimore (1961) and Hems et al (1966) was used in the present study. The isolated liver is perfused through the portal vein with saline, supplemented by bovine serum albumin and washed human erythrocytes, under a pressure of about 20cm of water, maintained by a reservoir of adjustable height. The perfusate which passes through the liver enters the inferior vena cava and passes, via a cannula, to a collecting vessel from which it is pumped to the top of a multiple bulb oxygenator and then returned to the liver for re-perfusion. This technique has proved to be a satisfactory means of assessing changes in the metabolic status of hepatic cells in response to starvation and exposure to halothane. The study described here was performed to determine whether the isolated liver perfusion technique can be used to measure the effects on liver perfusion of therapeutic and supratherapeutic doses of various drugs, some of which have been reported to affect liver metabolism adversely in the intact animal. Liver function was assessed by studying gluconeogenesis and bromosulphthalein clearance. Alcohol and hexane were administered in toxic doses, rifampicin and isoniazid in high doses and paracetamol in therapeutic doses. Inbred male Wistar rats were used for these studies. Hexane was injected subcutaneously, while the other drugs were given per os on 7 consecutive days each week for a period of 90 days; with the exception of the control group in the hexane study, all the control groups were untreated. Pyruvate, a precursor for gluconeogenesis (synthesis of glucose from non-carbohydrate sources) is an excellent substrate for the formation of oxaloacetate, which is probably an obligatory intermediate in the pathway to glucose synthesis. It has been used over a number of years by different investigators who have .studied gluconeogenesis using the isolated liver perfusion technique. It was used for the same purpose in the present study. Methylene blue, a redox dye, capable of oxidising NADH to NAD+, was used to determine whether an altered NADH : NAD+ ratio would have any effect on the output of glucose in the ethanol, paracetamol and hexane studies. Fructose, a non-NAD+ dependent precursor of glucose. was also used for this purpose in the ethanol study. All the drugs studied were found to inhibit gluconeogenesis. This was shown by a decrease in glucose levels and an increase in lactate : pyruvate ratios in the perfusion medium of experimental livers. The decreased glucose production by the experimental livers, which occurred pari passu with an increased pyruvate utilization, indicates that in these animals pyruvate was used for the production of other compounds such as lactate. In contrast. glucose production and pyruvate utilization were increased in the control group indicating that pyruvate was used mainly for the production of glucose. In the ethanol group, impaired gluconeogenesis was probably due to a change in the NADH : NAD+ ratio; when methylene blue was introduced into the perfusion medium of this group the output of glucose was high. Impaired gluconeogenesis in the paracetamol and hexane-treated groups was probably related to the non-availability of oxaloacetate or impairment of the activity of key enzymes involved in gluconeogenesis; when methylene blue was added to the perfusion medium of these animals the glucose output remained low. Except for the rifampicin study. bromosulphthalein clearance was impaired in all the experimental groups. Histological examination of liver tissue obtained from the hexane-treated animals demonstrated severe fatty change. In conclusion, these studies have demonstrated that the isolated liver perfusion technique is a suitable method of evaluating the effect of therapeutic and supra-therapeutic doses of some drugs which affect hepatic function. Ethanol, isoniazid, rifampicin, paracetamol (in therapeutic doses) and hexane were found to alter liver function as evidenced by impaired gluconeogenesis and bromosulphthalein clearance. In addition, histological evidence of liver damage was noted in rats treated with hexane.
Studies on molluscicidal properties of some South African medicinal plants used in the control of schistosomiasis in KwaZulu-Natal.
(2002) Tsepe, Wendy C.; Ojewole, John Akanni Oluwole.
Schistosomiasis is an important public health issue for rural communities located near,or around slow moving water bodies in the tropical and subtropical areas. Successful control of the disease involves multifaceted approaches, which include snail control, environmental sanitation, health education and chemotherapy. Although snail control might be an effective method of controlling schistosomiasis, there has been a general lack of control initiatives, largely due to the cost of available molluscicides. Plants offer a wide array of compounds which, on extraction, may show molluscicidal activity. If molluscicidal compounds that occur in indigenous plants can be extracted using local labour and simple technology, then there should be culturally acceptable and inexpensive molluscicides. The aim of this study was, therefore, to screen some Zulu medicinal plants for molluscicidal activity. We have also attempted to isolate the active chemical compounds from such plants. Aqueous and methanolic crude extracts of ten (10) Zulu medicinal plants, used for different medicinal and domestic purposes, were screened for molluscicidal activity on Biomphalaria pfeifferi and Bulinus africanas snails reared in the laboratory during the time of bioassay. Bayluscide® (niclosamide) was used as a positive control for comparison, while de-chlorinated tap water was used as the negative control. Six of the plants were not active against the snails. Extracts from four of the plants demonstrated weak to moderate molluscicidal activities. These plants are: (i) Sclerocarya birrea stembark, (ii) Psidium guajava (hybrid) leaves, (iii) Leonotis leonurus aerial parts and (iv) Ekerbegia capensis stem-bark. The LC50 values of the plant extracts were 78 ppm, 100 ppm, 398 ppm and 600 ppm respectively. Of the 4 plants that showed molluscicidal activity, S. birrea aqueous and methanol extracts were the most active against the snails, with LC50 values of 82 ppm and 78 ppm respectively. For the other plant extracts, only the methanolic extracts showed activity. Brine shrimp toxicity assay was performed with all the active extracts. Psidium guajava showed 10% survival of the shrimps at 1000 ppm, whereas no survival was observed for the other plant extracts at this concentration (1000 ppm). The results obtained in this study indicate that further studies have to be conducted, especially with S. birrea extracts, whose both aqueous and methanolic extracts showed significant activity against the snails.
Measure of pharmacists role in the management and adherence of HIV infected patients in a public sector hospital of KwaZulu-Natal.
(2011) Govender, Saloshini.; Esterhuizen, Tonya.; Naidoo, P.
Background:- The HIV and AIDS epidemic is a major catastrophe that affects millions of people worldwide. Antiretroviral medication combinations have revolutionised HIV treatment since 1996, transforming the virus from a death sentence to a manageable condition. In order to obtain full therapeutic benefits it is vitally important that patients adhere to their prescribed medication. Being informed about the disease and medication contributes to patient adherence and management. Pharmacists are considered to be the most accessible health professional and can help HIV -infected patients deal with barriers to medication access, manage adverse effects and medication interactions, and adhere to medication regimens by appropriate counselling. The public sector is defined as that part of an economy that is controlled by the state. At the study site, which is a public sector facility, the roll out of antiretroviral medication started in 2006. At the time all patients were counselled by trained counsellors, before seeing a doctor. At the pharmacy the medication was collected with no intense counselling by a pharmacist as the patients would have visited the trained counsellors first. Subsequently it was found that there were many queries regarding HIV and AIDS. It was then decided in October 2007, that the pharmacist support the counselling done by the counsellors in that they should reinforce what was said by the counsellors, together with giving detailed information to patients on their health and medication. This study was therefore undertaken to measure pharmacists' role in the management and adherence of HIV infected patients at this institutional facility. Method: The study was undertaken at a public sector health facility using anonymous structured questionnaires and was divided into 3 phases: Pre-Intervention, Intervention and Post-Intervention phases. After obtaining patient consent the questionnaires were administered during the 1st phase. A month later all patients visiting the pharmacy were counselled intensely on various aspects of HIV and the antiretroviral medication. Thereafter patients who took part in phase 1 were asked to participate in the 2nd phase. After obtaining their consent again, the same questionnaire was administered to them. Quantitative variables were compared between pre and post intervention using paired t-tests or Wilcoxon signed ranks tests. Categorical variables were compared using McNemar's chi square test (Binary) or McNemar-Bowker test for ordinal variables. Results: A response rate of 87.5% was obtained with the majority of the patients being female. Almost 70% of the participants were in the age-range of 21-40 years old. The majority of the participants did not have post school education. Most of the participants (95.4%) did not know that HIV is a virus that causes AIDS in the pre intervention phase, but this decreased to 93.7% in the post intervention phase. The participants knowledge of people who have sexually transmitted diseases are least at risk of getting HIV, healthy food will cure HIV and smoking and drinking alcohol will weaken the HIV virus, increased significantly from the pre-intervention phase to the post intervention phase. Knowledge on the modes of transmission either increased or remained unchanged. Overall the mean knowledge score on the disease itself had increased significantly (SD 6.6%) [p<0.01] after the pharmacists' intervention (pre-intervention was 82.1 %, post-intervention was 86.3%). In both phases, over 40% of all patients stored their medication in the cupboard. The majority of the patients took their medication either with or without food at both phases of the study. After the intervention, the frequency of taking medication with a fatty meal or any time they remember was decreased to 0. A significant improvement was noted in the overall knowledge score with regards to medication taking and storage (p<0.05). Conclusion: Pharmacist intervention had a positive impact on HIV infected patients' HIV and AIDS knowledge on the disease and on the antiretroviral medication use and storage.
An investigation into the effects and possible mechanisms of action of cimetidine and ranitidine on the sexual behaviour of male rats.
(1985) Badri, Roopram.; Du Preez, A. L.; Du Preez, Marie J.
The development of a new class of antihistamines, the H2-receptor antagonists, introduced a new era in the treatment of peptic ulcer diseases. Cimetidine, the first clinically effective H2-blocker, was introduced in 1976. Recently ranitidine, a second member approved for clinical use, has been found to be as effective as cimetidine in the management of peptic ulcer diseases. Soon after the introduction of cimetidine several reports of loss of libido, impotence and gynaecomastia were described in male patients who were on normal or high therapeutic doses of cimetidine. A few unsubstantiated reports of loss of libido and gynaecomastia attributed to ranitidine therapy have also appeared in literature. This study was undertaken to examine in detail the effects of acute and subchronic treatment with cimetidine and ranitidine on mating behaviour in sexually active male rats. Motor activity counts were recorded immediately before sexual behaviour observations. The animals were tested on every third day and observations were terminated after the first intromission of the next series of copulations. In the single dose study, mating behaviour tests were commenced 2 hours after treatment; mating tests during the subchronic dose studies were done 4 to 7 hours after the 6hOO dose. The following measures were used in the analysis of data: mount latency, intromission latency, mount frequency, intromission frequency, ejaculation latency, and the postejaculatory intromission latency. At the termination of the subchronic dose studies blood samples were collected by cardiac puncture and the animals were subsequently autopsied. Cauda epididymal sperm counts and motility were determined, testes and accessory sex organs were weighed, and one testis was processed for histological examination. Cimetidine in the low dose, 128.6 mg/kg, significantly shortened the ejaculatory latency and to a lesser extent the postejaculatory intromission latency. At the higher dose, 257.1 mg/kg, cimetidine markedly prolonged the postejaculatory intromission latency and to a lesser extent increased the ejaculation latency. The inhibitory effect of cimetidine on copulatory behaviour at the higher dose level was accompanied by significant depression in motor activity. At the conclusion of the subchronic dose studies marked reductions in serum testosterone levels and decreased testes and accessory organ weights were observed in the cimetidine group. No significant changes in sperm counts were observed, although the sperm counts in the cimetidine group were lower than the control values. Histological examination of testes showed apparently normal spermatogenesis in all three treatment groups. However, in spite of the reduced testosterone levels and decreased testes and accessory sex organ weights in the cimetidine group, no impairment in mating behaviour was observed. In both the acute and the subchronic dose studies, similar to placebo, treatment with ranitidine showed no effect on mating behaviour. On final analysis of the results it is concluded that cimetidine, and not ranitidine, disrupts sexual behaviour in male rats. Furthermore, it is concluded that the effect of cimetidine on sexual behaviour is not related to H2-receptor blockade as equipotent doses of ranitidine did not produce similar effects. The mechanism of cimetidine-induced impairment of sexual performance in the male rat may possibly be attributed to some non-specific, direct or indirect action of cimetidine on some neurotransmitter system responsible for the control of sexual behaviour. It is further suggested that the effect may possibly be mediated by a blockade of central dopamine receptors. However, it must be stressed that further experimentation is necessary to elucidate the mechanism of action of cimetidine on sexual behaviour.
The influence of the application of pharmacokinetics on the effects of theophylline utilisation upon members of the Indian population.
(1989) Pillai, Goonaseelan.; Miller, Raymond Martin.
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.
Computational insight into the glycosidase enzyme using bioinformatics tools and molecular dynamic simulations.
(2013) Ebrahim, Mahaseen.; Soliman, Mahmoud Elsayed Soliman.
One of the subjects focused on by theoretical and computational studies is that of the molecular systems. Molecular dynamic simulations can provide useful insights into the dynamic, thermodynamic and structural properties of the system. It is also a convenient way to study enzyme reactions. The glycoside hydrolase enzyme xylanase, a family GH-11 enzyme, hydrolyses xylan with a net retention of anomeric configuration via a double displacement mechanism. Catalytic residues Glu78 acts as a nucleophille and Glu172 as the general acid/base. In its catalytic cycle, the enzyme passes through different phases, three in particular: the free enzyme phase, the covalent enzyme-substrate complex and the non-covalent substrate in the enzyme pocket. All-atom molecular mechanic MD simulations were performed on the enzyme at each of the above phases for a total of 10ns, to study the effect of the substrate binding on the configuration and movement of the thumb-finger region. Various metrics were implemented to estimate the dynamics of this movement. The study has shown that the covalently bound substrate shows a shortening of the thumb-finger distance, assumedly to hold the substrate in the cleft for the reaction to occur, compared to the non-covalent system in which the distance widens at the beginning of the pathway to allow the substrate into the active site cleft and at the end of the process to expel the substrate. The enzyme was also investigated using binding free energy calculations, MMGBSA and MMPBSA, on 2ns simulation at all-atom MM level as well as AM1 level of description of the QM/MM simulation. Calculations were performed on the wild-type, Glu78Asp, Glu172Asp, Tyr69Phe, Tyr80Phe and Arg112Asn mutants. Results show that the catalytic residues Glu78 and Glu172 do not play a role in substrate binding yet they are crucial for the catalytic mechanism. The Tyr69 residue however, plays an important role in binding, since it is the hydrogen bond that stabilizes the boat conformation that is essential to reach TS. Tyr80 and Arg112 similarly play a role in binding. Future calculations that are in progress are QM/MM simulations at PM3, DFTB and RM1 level of description to verify the accuracy of each method. The information from this study sheds further light on factors that affect the catalytic process of the glycoside hydrolase enzyme such as the thumb-finger dynamics as well as the role played by some key residues in substrate binding, and can be used to aid the design of potential inhibitors.

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