Pharmaceutical Sciences

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Bioavailability studies on various dosage forms of the anorectic, diethylpropion hydrochloride.
(1984) Dangor, Cassim Mahomed.; Veltman, A. M.
The stereo-chemistry, structure activity relationships and the metabolism of the anorectic drug, diethylpropion hydrochloride, have been reviewed briefly, together with the analytical methods for the determination of this drug and its metabolites in biological fluids. In addition, the physico-chemical properties, mode of action, pharmacology and uses of the metabolites have been presented. A comprehensive review on general principles of salivary excretion of drugs and their therapeutic drug monitoring in saliva with relevant published data on saliva/plasma drug concentration relationships has been outlined. Sensitive and specific assay procedures, based on gas-liquid chromatography for the identification, separation and determination of diethylpropion and its two major metabolites i.e. ethylaminopropiophenone (11) and diethylnorpseudoephedrine (IV) in aqueous and biological fluids, have been developed. These methods were used to study the urinary excreUon as well as saliva and plasma levels of the two major metabolites and, where possible, the unchanged drug, in man. Sustained release pellets with diffusion rate-controlled membranes were employed to control the rate of input into the body by oral or rectal route of administration. Urinary excretion data and plasma levels of metabolites 11 and IV in volunteers, where the urine was controlled at an acidic pH, were used for the evaluation of the bioavailabilities of different dosage forms of diethylpropion hydrochloride. The concentrations of metabolites 11 and IV were also measured in saliva and in plasma after administration of the drug in different doses and dosage forms: relationships between saliva and plasma concentrations (S/P) and between urinary excretion rates and plasma concentrations (U/P) were developed for each of the two metabolites during plateau levels after oral administration of the sustained release pellets (Lot R 7773). The potential use of salivary excretion of the metabolites as an index to monitor their plasma levels and bioavailabilities, was examined. The distinct advantage of using a subdivided controlled release system (i. .e. sustained release pellets) to a single unit sustained release tablet (erosion-core type) in relation to influence of the physical presence of food on the rate and extent of absorption has been demons t rated . It was found that the route of administration (oral or rectal) did not significantly affect the bioavailability of the sustained release pellets. The study also involved the investigation of the release of the drug from the pellets. Because the release control step was diffusion, no significant influences on dissolution rates were observed with the use of different dissolution test models and agitation intensities. The influence of the concentration and composition (presence of cations viz. Na+ and K+ i~r anions viz . phosphate and borate) of the dissolution medium on the release of the drug from sustained release pellets, was also studied. Any potential changes in the dissolution pattern on storage of the pellets under different conditions (4°C, room temperature and 37°C) ovrr, a period of at least one year, were investigated. The in vitro and in vivo correlations of two lots of sustained release pellets, each exhibiting different dissolution profiles, and administered rectally and orally, were developed: the in vitro data on the free drug were related to the sum of the urinary excretion data of metabolites II and IV. An attempt to use an empirical approach to predict urinary excretion rate profiles of metabolite II after oral administration of the sustained release pellets, was promising; the calculated profiles were reasonably comparable with those of in vivo studies. However, the complete validity of such equations needs further investigations.
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 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.
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.
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.
A study of the relationship between the pharmacokinetics and the pharmacodynamics of atenolol in black and white subjects using an effect modelling technique.
(1991) McFadyen, Margaret Lynn.; Miller, Roger.; Miller, Roger.
Abstract is available in PDF file.
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.
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.
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.
An investigation of the antidiabetic herbal remedies used by traditional healers in Northern KwaZulu-Natal and their effect on blood glucose levels.
(1998) Ziqubu-Page, Thembelihle Thandekile.; Chetty, Manoranjenni.; Makubalo, L. E.; Dangor, Cassim Mahomed.
This research study undertook to investigate and evaluate for efficacy and safety, the herbal remedies used for treating Diabetes mellitus in northern KwaZulu-Natal. In addition, it sought to gain knowledge and better understanding of traditional healing systems and the medicinal use of the natural flora. During the process of assimilating the desired information, the epidemiological and socio-economic factors which determine the form of medicine chosen by rural people in the region, were quantified. Both aspects of explanatory studies i.e. experimental and observational were used. Firstly, to evaluate the safety of the two herbal remedies, laboratory animals were given an oral dose of the herbal medicine and observed for a period of 14 days. Efficacy was assessed by treating Streptozotocin-induced diabetic rats with the herbal remedies and comparing their effect on blood glucose with that of a conventional sulphonylurea. The second part of the study was observational and it involved monitoring human subjects (patients) for twelve months, who were already taking the herbal preparations (n=56) and comparing their prognoses with that of a group taking conventional medicine (n=97). A third group using both types of medicine (n=42) was included as control measure for a possible confounding factor. Main outcome measures; Both subjective and objective measures of the perceived health of the diabetic patients were measured, as well as the determinants of using traditional medicine versus conventional medicine. The battery of toxicity tests which utilises behavioural and functional observations of the laboratory animals, yielded no signs of toxicity or abnormal behaviour. The histopathological examination results of the sample organs from the treated rats also revealed no signs of abnormality that could be attributed to the herbal remedies tested. There was no sex variation recorded in the response. The first HP tested (HP-1) demonstrated minimal hypoglycaemic effect whereas HP-2 significantly lowered the blood glucose of the streptozotocin-induced diabetic rats by an average of 59%. This was comparable to the conventional medicine (Glibenclamide) used in the experiment. After 12 months of follow-up, 93 % of traditional medicine users (n=56) were convinced that their blood sugar was controlled because of the traditional remedy they were using. The proportion of diabetic cases who used conventional medicine were no better off than those who used traditional medicine or vice versa. Health status and the financial situation (income) of the respondents greatly influenced their choice for diabetic treatment. The herbal remedies that were investigated were non-toxic and safe for use and internal consumption. One preparation demonstrated a significant hypoglycaemic effect, which was comparable to the conventional allopathic medicine used in treating Diabetes mellitus. This study should serve as a springboard to encourage more pharmacological evaluation of herbal medicines.
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 pharmacokinetics/pharmacodynamics of theophylline in premature neonates during the first few days after birth.
(2000) Du Preez, Marie J.; Botha, Julia Hilary.; McFadyen, Margaret Lynn.
Theophylline is one of the few preparations available for the treatment of apnoea of prematurity. Currently little data is available on the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationships of theophylline for premature neonates during the first few days of life, a time when neonates undergo profound physiological changes and when the drug is most often used. Furthermore, the influence of theophylline on hypoxaemic episodes has not yet been quantified. The study aimed to investigate optimal theophylline dosing in this group by establishing pharmacokinetic parameters, assessing the effectiveness of the drug in abolishing apnoea and hypoxaemic episodes and investigating the concentration/effect relationship. The project was conducted in the neonatal wards of King Edward VIII Hospital, Durban, South Africa. The study group comprised a total of 105 Black, apnoeic, premature neonates, with respiratory distress syndrome, who were receiving intravenous theophylline. Serum samples (263), collected from patients during routine care, were analysed for theophylline. Forty-six patients were monitored before and after theophylline therapy with a neonatal capnograph linked to a data acquisition. Apnoea incidents were classified into total (all apnoea <_5 seconds) and pathologic (all apnoea >_20 seconds) and a hypoxaemic episode was defined as a >_10% fall for >10 seconds in peripheral oxygen saturation. Within each of these groups patients were assessed as responders (>_50% reduction in the clinical effect from baseline to the last recording) and non-responders. Patient characteristics were identified as possible markers of non-response to theophylline therapy. The Nonlinear Mixed Effects Model (NONMEM) was used to derive population pharmacokinetic models and parameters for theophylline as well as to assess the concentration-effect relationship. The pharmacokinetic analysis estimated a low clearance and volume of distribution, with oxygen support enhancing clearance. Relatively high inter-individual and residual variability values were obtained prompting testing for inter-occasion variability. This resulted in a decrease of inter-individual variability for clearance and volume of distribution as well as in residual variability. In the theophylline doses used, a significant reduction in total and pathologic apnoea but not in hypoxaemic episodes occurred over the first three days after birth. The most positive improvement was seen on the first day of treatment after the loading dose. A statistically significant increase in the average pulse rate and a decrease in episodes of bradycardia from baseline to all three days of monitoring were recorded. Most patients responded at serum theophylline concentrations of 3 to 9 mg/L. Most serum theophylline concentration measurements were also in this range and it was not possible to clearly define a concentration-effect relationship. The cumulative percentage of non-responders was relatively high for total apnoea (48%) and hypoxaemic episodes (45%), but low for pathological apnoea (13%). Being one of a set of twins was identified as a marker of poor response for both total apnoea and hypoxaemic episodes. Other possible markers for poor response, in terms of total hypoxaemic episodes, were being born by caesarean section and having more than the 75th percentile pathologic apnoea per hour at baseline. It was interesting to note that, with regard to total apnoea, there were some features that seemed to predict a favourable response to theophylline. These were birth weight and 5 minute Apgar score below the 25th percentile, and patients with baseline total apnoea counts above the 75th percentile. The cumulative graphs of the responders and non-responders resembled the fixed effect model, which is the simplest model to explain drug-effect relationships. More sophisticated analysis of the concentration-effect relationship, using NONMEM and the count model proved difficult. None of the models tested were found to be satisfactory, but that which included the influence of a hypothetical respiratory depressant factor gave the most realistic value of EC50. It is suggested that further even more complex modelling may be required to accurately define the concentration-effect relationship (and hence the therapeutic range) for theophylline in neonatal apnoea.
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.
The role of kinins and cytokines in rheumatoid arthritis.
(2001) Cassim, Bilkish.; Bhoola, Keshavlal Daya Narotam.
Introduction: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by inflammatory synovitis. The histopathological features include synovial hyperplasia, an inflammatory cell infiltration, angiogenesis and an inflammatory exudate into the synovial joint with progression to bone and joint destruction. While the exact aetiology of RA is unknown, a number of inflammatory cells and mediators have been implicated in the pathogenesis. Kinins are vasoactive peptides that have the capacity to induce the cardinal features of inflammation and considerable evidence exists for a role for the kallikrein-kinin cascade in inflammatory arthritis. The proinflarnmatory cytokines are also important mediators in rheumatoid arthritis and there is evidence for a functional relationship between the kallikrein-kinin and cytokine cascades in rheumatoid arthritis. Methods: Following approval from the Ethics Committee of the University of Natal, synovial tissue samples were obtained at arthroscopy from patients with RA and at autopsy (for controls). The tissue samples were processed for light microscopy and immunostained by the immunoperoxidase method to detect tissue kallikrein and the kinin B 1 and B2 receptors. The intensity of the immunostaining was quantified by image analysis. Blood and synovial fluid samples were obtained from patients with RA and blood from age and sex matched healthy volunteers. The RA patients were assessed clinically to determine the degree of disease activity and the presence or concomitant diseases. Disease activity was determined by the duration of morning stiffness, the twenty eight tender and swollen joint counts, pain on a visual analogue scale, patient's and physician's global assessment of disease activity (Likert scale), a local activity index, the modified Health Assessment Questionnaire (HAQ), disease activity score (DAS) and the erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). In the synovial fluid (SF) samples, the functional activity of tissue kallikrein (TK) was demonstrated using an amidolytic assay and the total amount of TK was measured in a sandwich enzyme linked immunosorbent assay (ELISA). The Pearson's correlation coefficient was used to correlate the TK levels with measures of disease activity. Further, basal and generated kinins were measured in the SF by competitive ELISA, and the levels correlated with measures of disease activity. In the cytokine study, interleukin lP (IL IP) and tumour necrosis factor p (TNFP) were measured in the synovial fluid samples by ELISA, and the relationship between the cytokine levels and disease activity as well as TK, basal and generated kinins determined. Neutrophils were isolated from the blood and synovial fluid samples from the rheumatoid arthritis patients and from the blood samples from healthy volunteers. The circulating and synovial fluid neutrophils were immunostained to detect tissue kallkrein, the kinin moiety in the kininogen molecule and kinin BI and B2 receptors, and the immunofluorescence visualized by confocal microscopy. The images were digitally analysed using the Analysis 2.1 Pro system. The Kruskal Wallis and one-way ANOVA tests were used to compare the mean intensity of imrnunostaining in the control neutrophils with that present on the circulating and SF neutrophils harvested from RA patients. The intensity of labeling for these antigens was correlated with measures of disease activity. Results: 1. Synovial tissue samples: Labeling for tissue kallikrein was observed in the synovial lining and endothelial cells in control and rheumatoid tissue. There was a significant increase in the intensity of TK labeling in the endothelial cells of the rheumatoid tissue (p < 0.05). The kinin Bl and B2 receptor were visualized in the synovial lining cells, endothelial cells and the subintimal fibroblasts and macrophages in the control and rheumatoid synovial samples, with a significant increase in B 1 receptor labeling in the synovial lining cells in rhewnatoid synovial tissue (p < 0.01). 2. Tissue kallikrein activity and the total TK concentration was measured in the synovial fluid obtained from 20 patients with RA. There was no direct correlation between the between the enzymic and antigenic tissue kallikrein. There w as a significant negative correlation between the enzymic TK and the twenty eight swollen joint count (r = -0.464; p <0.05). 3. There was a significant negative correlation between the basal kinin and generated kinin levels (r= -0.454; p < 0.05). In addition, there was a negative correlation between the basal kinin levels and the C RP (r = -0.537; p < 0.05) and the disease activity score (r = -0.458; p < 0.05). In contrast, there was a positive correlation between the generated kinin levels and the twenty-eight tender and swollen joint counts (r = 0.536; p < 0.05 and r = 0.509; p < 0.05 respectively), the ESR (r = 0.598; p < 0.01), CRP (r = 0.725; p < 0.01) and the disease activity score (r = 0.676; p < 0.01). There was a significant correlation between the SF levels of IL IP and pain (r = 0.462; p < 0.05), physician's global assessment of disease activity (r = 0.549; p < 0.05), 28 tender joint count (r = 0.4 72; p < 0.05) and CRP (r = 0.530; p < 0.05). Although there appeared to be a correlation between the IL 1 p and disease activity score, this was not significant (r = 0.412; p = 0.07). In addition, the levels of synovial fluid lNF a correlated with the 28 tender joint (r = 0.458; p < 0.05) count and CRP (r = 0.653; p < 0.01). 4. There appeared to be a trend towards a negative correlation between the SF amidase TK levels and IL 1 p, however this was not significant. While there was no direct relationship between the SF levels of IL 1 P and the generated kinins, there was a positive correlation between low to moderate levels of IL 1 p and the generated kinins (r = 0.51, p < 0.05). In contrast, there was a negative correlation with higher levels of IL Ip (r = -0.5, p < 0.05). 5. Immunoreactive TK, kinin moiety and the Bl and B2 receptors were visualized on the circulating neutrophils from the healthy volunteers and the circulating and SF neutrophils from the RA patients. There was no statistically significant difference in the mean intensity of TK labeling in the circulating neutrophils from healthy volunteers (n=8) and the circulating and synovial fluid neutrophils of the RA patients n=8). However, when the intensity of labeling of the SF neutrophils (n=80) from the RA patients was compared to the circulating neutrophils (n=80) of healthy volunteers, there was a significant loss of TK labeling in the SF neutrophils of the RA patients (1-Way ANOVA, p < 0.01). In the RA patients, there was a loss of the kinin moiety from both the SF and circulating neutrophils compared to controls (Kruskal-Wallis: p < 0.05 and < 0.01 respectively). Although there was a clear increase in the intensity of labeling of the kinin BI receptor on the SF neutrophils from RA patients (n=8), when compared to the circulating neutrophils from healthy volunteers (n=8), the mean values did not reach significance (Kruskal Wallis; p > 0.05). However, a significant increase in Bl receptor labeling was observed on both the circulating and SF neutrophils of the RA patients (n=80) when compared to circulating neutrophils of the healthy volunteers (n=80) (1 Way ANOVA, p < 0.01 and < 0.05 respectively). In addition, there was a positive correlation between the immunoreactivity for the BI kinin receptor on the circulating neutrophils from the RA patients and the local activity index (r = 0.783; p < 0.05). Although there was a clear increase of the kinin B2 receptor on the circulating and SF neutrophils from the RA patients compared to circulating neutrophils from healthy volunteers, this was only significant for the circulating neutrophils from the RA patients (Kruskal-Wallis, p = 0.05). There was no correlation between the intensity of labeling of TK, the kinin moiety and the B2 receptor and measures of disease activity. Discussion and conclusions 1. This study provides the first evidence for the localization of TK and the kinin receptors in control and rheumatoid synovial tissue using antibodies specific for each protein and standard immunolabelling techniques. Synovial fibroblasts, macrophages and endothelial cells through the release of enzymes and cytokines have the ability to mediate the inflammatory changes and cartilage and bone destruction in RA. The presence of TK and the kinin receptors in these cells therefore provides evidence for a pathogenetic role for the kallikrein-kinin cascade in RA. 2. In addition, in RA there is an exudation of fluid into the joint space. Tissue kallikrein has been previously reported in the synovial fluid obtained from RA patients, however the correlation of TK levels and disease activity has not been previously studied. The negative correlation between enzymic TK and the twenty-eight swollen joint count, an indicator of disease activity suggests that there is a consumption of TK in inflammation, presumably due to increased kininogenase activity. Similarly, the kinin generating capacity of synovial fluid obtained from RA patients has been previously reported, however, this is the first study demonstrating a link between kinin generating capacity and validated markers of disease activity. The kinin generating capacity is a complex and dynamic cascade involving the bioregulation of all the components of the kallikrein-kinin system and is therefore more likely to accurately define the role of kinins in inflammatory arthritis than are individual components of the kallikrein-kinin cascade. Measurement of tissue kallikrein and basal kinins is affected by the presence of natural inhibitors and their short half-life in biological fluids. In addition to the synovial fluid study a decrease in the urinary TK activity and an increase in urine kinin generated kinins was demonstrated, suggesting that there is a systemic activation of the kallikrein kinin cascade in RA. 3. Although there is evidence for an interaction between the kallikrein-kinin and cytokine cascades in inflammation, in this study a direct correlation between the levels of interleukin 1 J3 and tumour necrosis factor J3 in the synovial fluid and TK and generated kinin levels was not found. This may be due to the wide variations in the levels of cytokines, the presence of inhibitors and anti-inflammatory cytokines, or a complex and dynamic relationship between the two cascades. However, the correlation of both generated kinins and interleukin l J3 and tumour necrosis factor J3 with disease activity provides circumstantial evidence for a synergistic role for these mediators in inflammatory arthritis. 4. In the neutrophil study, loss of immunoreactive tissue kallkrein and kinin moiety from the neutrophils obtained from RA patients was demonstrated. This finding supports the hypothesis that kinins are released from the neutrophils by the enzymatic action of tissue kallkrein and suggests that the kallkrein-kinin system is activated both locally and systemically in patients with RA. Further, there was upregulation of the both the kinin B 1 and B2 receptors on the neutrophils from the RA patients. While the B2 receptor is thought mediate most of the actions of kinins, the correlation of the intensity of B 1 receptors and the local activity index implies that the B 1 receptor may be important in inflammation. 5. These findings provide convincing evidence for the role of the kallikrein-kinin cascade in the pathogenesis of inflammation in RA. Further development of kinin receptor antagonists may provide a novel therapeutic modality.
Vasoactive peptides in acute renal allograft rejection and renal diseases: the role of endothelins, atrial natriuretic peptide and kinins.
(2001) Naicker, Saraladevi.; Bhoola, Keshavlal Daya Narotam.
Abstract available in PDF.
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.
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.
Some pharmacological properties of Harpagophytum procumbens DC [Pedaliaceae] secondary root extract
(2004) Mahomed, Ismail Mall.; Ojewole, John Akanni Oluwole.
Abstract available on PDF file.
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.
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.

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