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.
Beta-lactamase mediated resistance in Escherichia Coli isolated from state hospitals in KwaZulu-Natal.
(2008) Mocktar, Chunderika.; Essack, Sabiha Yusuf.; Sturm, Adriaan Willem.
Escherichia coli, one of the most common pathogens causing urinary tract infections, has shown increased resistance to commonly used antibiotics. In this study we analyzed the β-lactamase profiles of 38 inhibitor-resistant E. coli isolates obtained from public hospitals at three different levels of healthcare in KwaZulu-Natal, selected on the basis of their resistance profiles to the three antibiotic/inhibitor combinations, viz., amoxicillin/clavulanate, ampicillin/ sulbactam and piperacillin/ tazobactam. The isolates were subjected to MIC determinations, IEF analysis, plasmid profile analysis, PCR of the different β-lactamase genes and sequencing thereof to detect the possible mechanism/s of resistance. A range of β-lactamases including two novel inhibitor-resistant TEM β-lactamases, TEM-145 and TEM-146 were detected in two isolates whilst a novel plasmid-mediated AmpC-type β-lactamase, CMY-20 was detected in three isolates. Other β-lactamases included OXA-1, TEM-55, SHV-2, CTX-M-l and TEM-1. Changes were detected in the chromosomal AmpC promoter/attenuator regions in one isolate. Diverse β-lactamase genes and plasmid profiles inferred extensive mobilization of β-lactamase genes causing the concern of limited therapeutic options in the face of increasing resistance.
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.
Design, synthesis and screening of novel PCU-peptide/peptoid derived HIV protease inhibitors.
(2011) Makatini, Maya Mellisa.; Govender, Patrick.; Kruger, Hendrik Gerhardus.; Maguire, Glenn Eamonn Mitchel.; Govender, Thavendran.
The AIDS epidemic in Africa has reached dramatic proportions. Of the 42 million people infected with HIV worldwide, 30 million are in Africa. Current available therapies have begun to transform this fatal disease into a chronic condition but there are still major obstacles that have resulted in a great demand for new and better drugs. The aim of this study was to synthesize novel and effective HIV protease inhibitors. This work describes the first account of pentacycloundecane (PCU)-peptide and peptoid based protease inhibitors. These inhibitors are proposed to bind the wild type C-South African HIV protease (C-SA) catalytic site via the norstatine or dihydroxylethelene type functional group of the PCU. The desired compounds were synthesized by the coupling of the peptides and peptoids to the PCU cage which resulted in a series of promising and structurally diverse HIV-1 protease inhibitors. The inhibitors were characterized by Nuclear Magnetic Resonance (NMR) and evaluated against the wild type C-SA enzyme for its ability to inhibit 50 % of the enzyme’s activity (IC50). Two of the compounds reported herein, inhibited the enzyme activity at concentrations less than 80 nM. NMR investigations indicated that the activity was related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. Employing the new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy (EASY-ROESY) technique enabled us to obtain vital information about the 3D structure of these small linear peptides and peptoids in solution. This technique is the first example describing the successful through space correlations of such small peptides. Furthermore, docking and a combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics MD simulation at the AM1 semi empirical level mirrored the observed NMR results and the experimental IC50 activity profile of the considered inhibitors. The combination of these experimental and theoretical methods provided a powerful insight into the interaction mode of these cage peptide and peptoid inhibitors with the enzyme.
Synthesis and evaluation of novel tetrahydroisoquinoline organocatalysts in asymmetric catalysis.
(2012) Naicker, Tricia.; Govender, Thavendran.; Kruger, Hendrik Gerhardus.; Maguire, Glenn Eamonn Mitchel.; Arvidsson, Per Ingemar.
Organocatalysis has rapidly expanded in the last decade to encompass a wide variety of small organic molecules that are capable of either activating substrates or transforming them into more reactive forms. The aim of this study was to develop novel chiral organocatalysts based on the tetrahydroisoquinoline backbone and evaluate them on asymmetric reactions. Three organocatalytic modes of activation have been investigated for C-C bond forming asymmetric reactions. In chapter 2, for the first time organocatalysts bearing a secondary nitrogen within a cyclohexane ring were evaluated in the asymmetric Diels–Alder reaction. These catalysts were tested over a range of dienes and dienophiles and displayed promising chemical conversions of up to 100 % with up to 64 % ee when triflic acid was employed as the cocatalyst. Density functional theory computational studies and 2D NMR spectroscopy were used to determine the structure of the intermediate iminium ion formed between the most efficient catalyst and cinnamaldehyde. Chapter 3 includes a series of novel tetrahydroisoquinoline chiral N-oxide organocatalysts and their evaluation in the asymmetric allylation reaction of aromatic and α-β-unsaturated aldehydes with allyltrichlorosilane. The chiral homoallyl products were obtained with good chemical efficiency (up to 93 % yield) and high enantioselectivity (up to 91 % ee) under mild reaction conditions (23 °C). Chapter 4 is the simple and practical microwave-assisted synthesis of new tetrahydroisquinoline guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and β-ketoesters with nitro-olefins. In addition, a novel microwave assisted procedure of introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and excellent enantioselectivity (up to 97 % ee). Chapter 5 is a collection of all X-ray crystal structures that were published from novel compounds synthesized pertaining to Chapters 2-4, it contains 15 published crystal structures while Chapters 3-4 contain 3 other X-ray crystal structures. It should be noted that with the exception of the introduction and Chapter 4 (submitted for publication), the remaining chapters of this thesis have been published in international peer reviewed journals. In the next section (DECLARATION 2 – PUBLICATIONS) a precise description of my contribution to each of the publications/chapters is provided.
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
Synthesis and biological activities of natural homoisoflavanones.
(2011) Shaikh, Mahidansha Mahiboob.; Du Toit, Karen.; Kruger, Hendrik Gerhardus.
Plants have formed the foundation of traditional medicine systems throughout the world for thousands of years and continue to provide mankind with new remedies for various ailments. A large portion of the black South African population still depends on medicinal plants as primary health care due to its affordability, accessibility and cultural importance. These medicinal plants need to be investigated since new lead compounds are often found in nature. Homoisoflavanones isolated from South African and Indian plants were found to exhibit anti inflammatory activities although the mechanism of action has not yet been determined. A few reports on the anti fungal activities of these compounds were also found. Four new and three known homoisoflavanones of the 3-benzylidene-4-chromanone type were synthesized and tested for anti-inflammatory and antifungal activities. Two novel intermediates were also synthesised. Enantiomers of a homoisoflavanone of the 3-benzyl-4- chromanone types were also synthesized from the corresponding 3,5-dimethoxy phenol via 4- chromanone in six steps. This is the first report of the synthesis of an enantiomerically pure homoisoflavanone compound together with its opposite isomer. The enantiomers and racemate were tested for anti-inflammatory activity. All the synthesized homoisoflavanones were screened for cytotoxicity. The structures of these homoisoflavanones were elucidated by NMR spectroscopy along with HRMS data. The crystal structure of a homoisoflavanone with anti-inflammatory and antifungal activity is reported. The anti-inflammatory activity of the homoisoflavanones was determined in an acute croton oil-induced auricular dermatitis mouse model. The antifungal activity was performed in vitro against a Candida albicans strain. Compounds were tested for cytotoxicity against a Chinese Hamster Ovarian (CHO) cell line using the 3-(4,5-dimethylthiazol-2-yl)-3,5- diphenyltetrazoliumbromide (MTT) assay. In conclusion, the synthetic homoisoflavanones showed anti-inflammatory as well as antifungal activity. Some of the compounds showed anti-inflammatory activity comparable to that of the commercially available diclofenac.
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.
The injectable contraceptive : user, social and pharmacological perspectives.
(2003) Smit, Jennifer Ann Bodley.; McFadyen, Margaret Lynn.; Botha, Julia Hilary.; Preston-Whyte, Eleanor.
Despite its widespread use, little research has been undertaken on the use of progestogen-only injectable contraceptives by South African women. This thesis is comprised of two sections. Section 1 provides the first comprehensive description of injectable contraceptive use among rural South African women. It includes an analysis of the contraceptive method mix, prevalence of injectable contraceptive use, discontinuation patterns and reported side effects. A comparison of depot medroxyprogesterone acetate (DMPA) versus norethisterone oenanthate (NET-EN) focuses on utilization patterns and costs. The second section gives an account of the pharmacokinetics of DMPA including the first ever population analysis. A cross-sectional, community-based household survey was undertaken in the Hlabisa sub-district of KwaZulu-Natal, South Africa. Interviews were held during 1998 and 1999, with 848 randomly selected women (aged 15-49 years) and with 14 focus groups. There was a heavy reliance on injectable contraceptives which were used by 74% of women practising contraception. By contrast, the condom was the current method of only 4%. The injectable method was the most commonly used method among teenagers. However, in most cases, contraceptive use appeared to commence only after the first pregnancy. Slightly more NET-EN (54%) than DMPA (46%) was used, with younger women more likely to use NET-EN than DMPA (p=0.001). No significant differences in self-reported side effects were found between current users of the two injectables. Health workers played an important role in women's decisions to use the injectable, and in product selection, with NET-EN being recommended for younger women on the basis of concerns about method reversibility. While some women used injectables for long periods of time, discontinuation rates at two years were high, most commonly due to menstrual disturbances. Many side effects were reported by users of both DMPA and NET-EN, with amenorrhoea the most common, experienced by 63% of current injectable users. Heavy bleeding was most commonly reported by previous users (38%). Vaginal wetness was also common, mentioned by 18% and 29% of current and previous users respectively. Utilisation patterns of the two injectable products (DMPA and NET-EN) were analysed by means of a Pareto analysis of injectables issued from four South African provincial pharmaceutical depots over three financial years (1997/8, 1998/9 and 1999/2000). Injectables accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from two depots increased over the period of analysis, even though DMPA was the cheaper option. The pharmacokinetic analysis was undertaken amongst DMPA users routinely attending family planning services in three Durban clinics in 1996. Medroxyprogesterone acetate levels at the end of the dosing interval were analysed for 94 women. In addition a population pharmacokinetic analysis of 291 serum levels from 111 DMPA users was undertaken. This involved the use of Non Linear Mixed Effect Modelling (NONMEM) to fit the data and determine the pharmacokinetic parameters, apparent clearance (CLIP) and apparent volume of distribution (VIP), and to estimate the influence of covariates on CLIP and VIP (where P is the bioavailability). The final model estimates for CLIP and VIP were 1080 (95% confidence interval: 994, 1166) litres/day and 86200 litres (95% confidence interval: 68246, 104154) respectively. No significant relationships were found between the covariates tested and CLIP and VIP. Concerns raised in the literature about the influence of weight or ethnicity on the pharmacokinetics of DMPA were shown to be unfounded. In the context of South Africa's HIV epidemic, the heavy reliance on injectable contraceptives, which offer no protection against HIV, should be addressed by expanding the contraceptive method mix to include barrier methods such as the female condom. Health providers are influential in contraceptive decision-making and should be encouraged and supported to redress the dependence on the injectable method alone, taking into account the need of many for dual protection against HIV and unwanted pregnancy. Provider counseling should also focus on adherence to dosing regimens, improving continuation rates, and should provide appropriate advice for women complaining about vaginal wetness with injectable use. Promotion of one injectable product over another to younger women is not appropriate. Since DMPA is the cheaper product, provider training about the rational use of injectable contraceptives should include cost considerations.
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.
Studies on some pharmacological properties of Capsicum frutescens-driven capsaicin in experimental animal models.
(2012) Jolayemi, Adebayo Taiwo Ezekiel.; Ojewole, John Akanni Oluwole.
The present study investigated pharmacological properties of Capsicum frutescens-derived capsaicin, including its analgesic, anti-inflammatory and coagulatory properties. The effects of capsaicin on gastrointestinal and myocardial muscles, as well as on myocardial ischaemic-reperfusion, were also investigated. Capsaicin pre-treatment in neonatal rats has been found to abolish the development of thermal hyperalgesia produced in a model of neuropathic pain in rats (Toth-Kasa et al., 1986). In addition, capsaicin sensitivity has been found to be dependent on continued presence of nerve growth factor (NGF), whose concentration increases in inflamed tissues (Bevan and Winter, 1995). By stimulating the release of excitatory amino acids (EAA); such as glutamate and neuropeptides [(CGRP, neurokinin A (NKA) and Substance P (SP)] from both the peripheral and central terminals of sensory neurones by two mechanisms (Kroll et al., 1990; Del Bianco et al., 1991; Lou et al., 1992; 1994; Woolf et al., 1994); capsaicin has been shown to produce a longer-term inhibitory effect. This is one likely mechanism for capsaicin analgesic and anti-inflammatory actions (Bleakman et al., 1990). Within the gastro-intestinal tract, SP and NKA are involved in the physiological control of several digestive functions, such as motility, fluid and electrolyte secretion, blood flow, and tissue homeostasis (Otsuka, 1993; Holzer et al., 1997). Consistent with this finding, upsurge of SP in irritable bowel syndrome (IBD) was confirmed by Mantyh et al, (1988). Pre-treatment of rats with either capsaicin or NK-1R antagonists dramatically reduced fluid secretion, mucosal permeability, and intestinal inflammation in animal models of acute and chronic inflammation (McCafferty et al, 1994; Pothoulakis et al., 1994). Capsaicin can modulate endocrine and paracrine activities, immune responses, as well as gastro-intestinal and cardiovascular functions. Moreover, up-regulation of Substance P receptors was found to be associated with chronic inflammatory conditions (De et al., 1990). Stimulation of transient receptor potential vanilloid 1 also results in the activation of nociceptive and neurogenic inflammatory responses (Rigoni et al., 2003). vi The pharmacodynamic effects of capsaicin on the cardiovascular system remain elusive. Some actions of capsaicin on the heart were attributed to an interaction at K+ channels (Castle, 1992), or liberation of neuropeptides, most notably calcitonin-gene-related-peptide (CGRP) from the vanilloid-sensitive innervation of the heart (Franco-Cereceda et al., 1988; 1991). The possibility of a direct effect of capsaicin on the heart via a cardiac vanilloid receptor (VR), or through interaction of vanilloid receptors with purinergic receptors, and subsequent release of nitric oxide (NO), leading to vasodilatation were considered. Evidence abound in the literature that Ca2+ ions are released through 1, 4, 5 inositol phosphatase by the release of phospholipase C, or through interaction of the vanilloid receptors with cannabinoids. In an earlier study, Jaiarj et al. (1998) found that capsaicin acting on the heat-sensitive vanilloid receptors, had thrombolytic effects. Though weak evidence, Jaiarj et al. (1998) observed that individuals who consume large amounts of Capsicum have lower incidence of thromboembolism. Following ethical approval, the study reported in this thesis was conducted in phases. Identification of Capsicum frutescens (facilitated by a botanist in the Department of Botany, Westville campus of the University of KwaZulu Natal). Chromatographic extraction of capsaicin from Capsicum frutescens was followed by Nuclear Magnetic Resonance (NMR) analysis of the extract. Animal studies were conducted using capsaicin extract (CFE) and/or a reference capsaicin (CPF), using „hot plate. and „acetic acid. test methods to investigate the role of capsaicin on analgesia. Fresh egg albumin-induced inflammation was used to investigate the role of capsaicin in inflammation, following pre-treatment with CFE and CPF. Concentraton-response curves of increasing concentrations of capsaicin, acetylcholine and other agonist drugs with specific antagonists on strips of chick oesophagus, guinea-pig ileum, and rabbit duodenum were constructed following investigations on gastrointestinal (GIT) smooth muscles. The effect of capsaicin on coagulation was assessed by measuring international normalized ratio (INR) of animals that were exposed to different concentrations of capsaicin (CFE and CPF). Furthermore, parallel control studies were conducted in each of these investigations using distilled water or saline as placebo-control or specific-prototype agonists. negative-control. Cardiovascular investigations included studies on the effects of capsaicin on the heart rate, inotropy, vii coronary perfusion pressure, and ischaemic-reperfusion injury, using Langendorf.s rat heart models. Collated data were triangulated by manual hand-written and PowerLab data acquisition, or computerised capture. Statistical analysis were performed by either one or two of the following: Student.s t-test, ANOVA (repeated or single–use modes), facilitated and confirmed by Graph Pad Prism, Microsoft Excel or CPSS software(s). Reproducibility and relevance to the stated objectives of the various studies were confirmed by assessing which of the Null or Alternative hypothesis is validated by the results from the test. Treatment with CFE or CPF at all doses significantly (p<0.01) increased MRT. By comparison with control, writhing responses to acetic acid were significantly reduced following pre-treatment with various doses of CFE or CPF. The results in both parallel groups of CFE and CPF in the hot plate and acetic acid tests had Pearson correlation of one (1). Compared to the diclofenac (DIC) group, the degree of inhibition of paw oedema by CFE and CPF was statistically significant (P<0.05-0.001), best in the first 4 hours of treatment. The results of the in vitro laboratory animal study indicate that relatively low concentration of CPF (20 or 40 .g) produced significant (p.0.05), concentration-related inhibitions of acetylcholine (0.1-5 .g)-induced contractions of the chick isolated oesophagus, guinea-pig isolated ileum and rabbit isolated duodenum. Biphasic effects, which were noticed at low concentrations, consisted of initial brief contractions, followed by longer-lasting relaxations and reductions of the contractile amplitudes of the muscle preparations. Percentage inhibitions of the smooth muscle contractions by CFE or CPF were concentration-dependent, ranging from 20-70% (p<0.02).
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.

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