<p>Artemisia Afra, a popular South African traditional herbal medicine is commonly administered as a tea infusion of the leaves. However, clinical trials proving it safety and efficacy are lacking mainly due to the absence of good quality dosage forms and credible placebos for the plant. The objectives of this study were to prepare a standardized preparation of the plant leaves and freeze-dried aqueous extract powder of the leaves, in a tea bag dosage form and to design and prepare credible placebos for these plant materials.</p>

Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.

The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.

In severely ill hospitalised patients with diabetes mellitus (type 1 and type 2) there is an increase in metabolic rate. Insulin requirements are increased and glycaemic control becomes more difficult to achieve. The insulin sliding-scale is a form of „top up‟ therapy used to supplement the patients existing hypoglycaemic medication. In 2002, research at Livingstone Hospital found that 14 different sliding scales were used in 38 patients (Du Plessis, 2002: 79). In 2006 the nurses and doctors working in the general medical wards at Livingstone Hospital indicated that they were willing to use a standardised insulin sliding scale protocol (Smith, 2006: 56). Thus the aim of this study was to assess whether a standardised insulin protocol can be effectively implemented. The objectives of the study were to: 1) assess insulin usage via insulin sliding scales prior to the implementation of the standardised insulin protocol; 2) implement the standardised insulin protocol; and 3) reassess insulin usage after the implementation of the standardised insulin protocol. As the study involved evaluating the use of insulin via the insulin sliding scale and the implemented insulin protocol, it occurred in four phases. The preliminary phase entailed obtaining ethical approval. The pre-intervention phase included data collection in the form of a nursing questionnaire and the auditing of patient medical records using a data collection tool. The intervention phase involved education sessions on the new insulin protocol for the nursing staff, and the implementation of a standardised insulin protocol, while the post-intervention phase comprised of post-intervention data collection, which included a nursing questionnaire, a prescribers questionnaire and the auditing of patient medical records using a data collection tool. The overall impression obtained from the comparison between the pre- and post-intervention nursing questionnaire was conflicting; in some aspects the educational intervention was successful in others not. Regardless the indication obtained was that the nursing staff require more in-service training on a more regular basis as a lack of knowledge regarding diabetes mellitus as a disease state may negatively affect patient outcomes. The overall response from the nursing staff towards the insulin protocol was positive. The prescribers‟ response to the insulin protocol was conflicted. The number of correct insulin sliding scale doses administered in the pre-intervention and post intervention phase improved by 5.25 percent. The number of incorrect insulin sliding scale doses administered during the pre- and post -intervention phase decreased by 5.25 percent. These results are positive and may be due to fewer sliding scales being prescribed in the post-intervention phase and the implemented insulin protocol. Only three (5.55%; n=54) inpatients with Type 1 diabetes mellitus were placed on the implemented protocol that is, the basal bolus regime, and rarely were dose adjustments to their insulin made rendering the effectives of the protocol undesirable. Only four (7.40%; n=54) inpatients with Type 2 diabetes mellitus were placed on the implemented protocol that is, an intermediate- to long-acting insulin (Protophane®). However all four patients experienced immediate improvements in their fasting blood glucose levels. These results indicated that by adding an intermediate- to long-acting insulin (Protophane®) to the therapy of a patient with Type 2 diabetes mellitus fasting blood glucose levels decrease. This would improve patient outcomes and decrease the risk of related diabetic complications. These limited results may indicate a clinical inertia on the part of the prescribers. Unfortunately overall the educational intervention was not successful and the implementation of the protocol was not successful and did not yield the desired results.

Made available in DSpace on 2014-06-11T19:23:45Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-11-29Bitstream added on 2014-06-13T20:11:34Z : No. of bitstreams: 1 araujo_ra_me_jabo.pdf: 208132 bytes, checksum: 25e53edf94ff2edd161c660b654017a1 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O estudo objetivou avaliar a segurança da administração oral da dose terapêutica do firocoxib por 14 dias em equinos saudáveis. Foram utilizados 9 equinos, 4 machos e 5 fêmeas, com peso médio de 405±31 Kg e idade média 11±3 anos que receberam uma vez ao dia, 0,1mg/kg de firocoxib. Hemograma, avaliação dos parâmetros de coagulação e bioquímicos séricos e urinálise foram realizados antes do início do tratamento (D1), após 7 e 14 dias de tratamento (D7 e D14) e 7 dias após o final do tratamento (D21). Foi realizado exame gastroscópico 1 dia antes do início do tratamento (D0) e dois dias após a última coleta de dados. O número de leucócitos diminuiu na avaliação do D14 em relação ao D1, voltando aos valores basais no D21- 7 dias após o final do tratamento. A concentração de hemoglobina aumentou nos momentos D14 e D21 em relação ao do D1. A concentração plasmática de fibrinogênio aumentou no momento D21 em relação a D7 e D14. O tempo de tromboplastina parcial ativada e o tempo de protrombina aumentaram em D7 e D14 e D21 quando comparadas as médias em relação à média do D1. A contagem de plaquetas diminuiu nas avaliações em D7, D14 e D21 em relação ao momento D1. A atividade sérica da aspartato aminotranferase aumentou no D14 em relação ao D1. A atividade sérica da fosfatase alcalina aumentou nos momentos D7 e D14 em relação ao D1. A concentração de ureia diminuiu no D14 em relação ao D1. A creatinina se manteve estável no período de tratamento porém, no D21 apresentou diminuição em relação a D1, D7 e D14. A atividade sérica da gama glutamiltranferase diminuiu no D21 quando comparada ao D14, mas não houve diminuição em relação ao D1 e ao D7. Não foram observadas alterações na urinálise e no exame gastroscópico. Conclui-se que a administração do firocoxib em equinos é segura uma vez... / The study aimed to evaluate the safety of oral administration of the therapeutic dose of firocoxib for 14 days in healthy horses. Were used 9 horses, 4 males and 5 females, with a mean weight of 405 ± 31 kg and an average age 11 ± 3 years who received once a day orally 0.1 mg/kg firocoxib. CBC, evaluation of coagulation parameters and serum biochemical and urinalysis were performed before the initiation of treatment (D1) after 7 and 14 days of treatment (D7 and D14) and 7 days after end of treatment (D21). Gastroscopic examination was conducted 1 day prior to initiation of treatment (D0) and two days after the last data collection. The number of leukocytes decreased in evaluating the relative D14 to D1, returning to baseline at D21-7 days after end of treatment. The hemoglobin concentration increased during times D14 and D21 in relation to the D1. The plasma concentration of fibrinogen increased when compared to D7 D21 and D14. The activated partial thromboplastin time and prothrombin time increased at D7 and D14 and D21 compared the averages from the average of D1. Platelet count decreased in assessments in D7, D14 and D21 compared to D0 moment. Serum activity of aspartate aminotranferase increased in D14 compared to D1. The serum alkaline phosphatase activity increased in times D7 and D14 compared to D1. The concentration of urea has decreased compared to the D14 D1. Creatinine remained stable during treatment but showed a decrease in D21 compared to D1, D7 and D14. Serum activity of gamma glutamyltranferase decreased when compared to the D21 D14, but no decrease from D1 and D7. No changes were observed in the gastroscopic examination and urinalysis. It is concluded that administration of firocoxib is safe in horses since it was not able to promote the appearance of adverse effects, allowing... (Complete abstract click electronic access below)

Carbamazepine (CBZ) is a first-line drug used for the treatment of partial and tonic-clonic seizures. It is also the drug of choice for use during pregnancy and recommended for the treatment of seizure disorders in children. CBZ possesses the ability to induce metabolism of drugs that are transformed in the liver and has the unique ability to induce its own metabolism by a phenomenon known as ‘auto- induction’, where its biological half-life is significantly reduced during chronic administration. Large doses of CBZ are often prescribed as daily divided doses and this often adversely affects patient compliance, with the result that therapy is ineffective. A sustained-release dosage form containing CBZ is currently marketed as Tegretol® CR and the development of a generic product would provide patients with an equivalent product with a similar dosing frequency, at a reduced cost. Therefore, the development of a polymer-based matrix tablet was undertaken to produce a sustained-release dosage form of CBZ, since these dosage forms are relatively simple and cheap to produce when compared to other, more sophisticated forms of sustained-release technology. Preformulation studies were conducted to assess moisture content of excipients and dosage forms and to identify possible incompatibilities between CBZ and potential formulation excipients. Furthermore, studies were conducted to assess the potential for polymorphic transitions to occur during manufacture. Stability testing was conducted to assess the behaviour of the dosage forms under storage conditions that the product may be exposed to. Dissolution testing was undertaken using USP Apparatus 3, which allowed for a more realistic assessment and prediction of in vivo drug release rates. Samples were analysed using a high performance liquid chromatographic method that was developed and validated for the determination of CBZ. Tablets were manufactured by wet granulation and direct compression techniques, and the resultant drug release profiles were evaluated statistically by means of the f1 and f2 difference and similarity factors. The f2 factor was incorporated as an assessment criterion in the design of an artificial neural network that was used to predict drug release profiles and formulation composition. A direct compression tablet formulation was successfully adapted from a prototype wet granulation matrix formulation and a number of formulation variables were assessed to establish their effect(s) on the dissolution rate profile of CBZ that resulted from testing of the dosage forms. The particle size grade of CBZ was also investigated and it was ascertained that fine particle size grade CBZ showed improved drug release profiles when compared to the coarse grade CBZ which was desirable, since CBZ is a highly water insoluble compound. Furthermore, the impact of the viscosity grade and proportion of rate-controlling polymer, viz., hydroxypropyl methylcellulose was also investigated for its effect on drug release rates. The lower viscosity grade was found to be more appropriate for use with CBZ. The type of anti-frictional agent used in the formulations did not appear to affect drug release from the polymeric matrix tablets, however specific compounds may have an effect on the physical characteristics of the polymeric tablets. The resultant formulations did not display zero-order drug release kinetics and a first-order mathematical model was developed to provide an additional resource for athematical analysis of dissolution profiles. An artificial neural network was designed, developed and applied to predict dissolution rate profiles for formulation. Furthermore, the network was used to predict formulation compositions that would produce drug release profiles comparable to the reference product, Tegretol® CR. The formulation composition predicted by the network to match the dissolution profile of the innovator product was manufactured and tested in vitro. The formulation was further manipulated, empirically, so as to match the in vitro dissolution rate profile of Tegretol® CR, more completely. The test tablets that were produced were tested in two health male volunteers using Tegretol® CR 400mg as the reference product. The batch used for this “proof of concept” biostudy was produced in accordance with cGMP guidelines and the protocol in accordance with ICH guidelines. The test matrix tablets revealed in vivo bioavailability profiles for CBZ, however, bioequivalence between the test and reference product could not be established. It can be concluded that the polymeric matrix CBZ tablets have the potential to be used as a twice-daily dosage form for the treatment of relevant seizure disorders.

Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.

Lack of quantitative adsorption data makes it difficult for a physician to determine the actual amount of insulin received by a patient against the amount added to the intravenous infusion system. This project was therefore initiated to determine quantitatively the extent of adsorption that would occur in a clinical setting. In order to achieve the above aim, varying amounts of carrier insulin containing I-labeled insulin were added to the intravenous infusion delivery system. Using the most commonly utilized mode of delivery and flow rate the tagged insulin solution was allowed to flow through the intravenous delivery system. Both the amount of activity delivered and the amount of activity remaining in the system were measured.

In the present study lanolin alcohol films were investigated as potential drug delivery systems for the controlled release of salicylic acid. A series of experiments were conducted in vitro to study the release of salicylic acid from these films. The effect of changes in film composition and stirrer speed on drug release were examined. Seven film compositions with varying proportions of lanolin alcohol and ethyl cellulose were prepared over the ethyl cellulose concentrations of 0-30% w/w, while keeping the drug concentration at 2.5% w/w. The release data obtained in this study were examined by the Q vs 1/2 relationship and the first-order relationship. This was done to probe deeper into the underlying mechanism of drug release. Upon examination of the release data by the Q vs 1/2 treatment, it was observed that the correlation coefficients were quite high and lag times were only slightly negative in agreement with the observed initial release data. In contrast, the first-order treatment of data showed somewhat lower correlation coefficients and very high negative lag times. These data strongly suggest that the unidirectional release of salicylic acid from the lanolin alcoholethyl cellulose films follows Higuchi's diffusion-controlled granular matrix model. The release rate constant showed an initial increase with inclusion of ethyl cellulose followed by a sharp decline as the ethyl cellulose concentration was further increased reaching a minimum value at about 15-20 percent of ethyl cellulose. Further increases in the concentration of ethyl cellulose increased the rate of drug release with a tendency to level off at about 30 percent ethyl cellulose concentration. The effect of stirring rate on the release rate constant showed that the rates of release of salicylic acid increased with increases in the stirring rate.

PART I: MARKERS OF INFLAMMATION IN DELAYED MUSCLE SORENESS Fifty-five untrained males were assigned to an experimental (E) or a control group (C), to re-examine the concept that DMS represents an acute inflammatory response. Subjects were assigned to receive either Indocin (Id; 100 mg per day) for 2 days prior to the treatment and a placebo (P) for 2 days after (Id-P); or the reverse combination (P-Id); or Id for- 4 days (Id-Id); or placebo (P-P). On the treatment day, to induce DMS, E subjects performed 30 min of bench-stepping with one leg leading throughout; C subjects rested for 30 min. Immediately before and after stepping/resting, all subjects used their right and left leg to perform 19 maximal and 15 submaximal repetitions on the Cybex II. Blood samples were collected -5 min before, immediately after bench stepping (0 h), 2 h after and 24, 48 and 72 h, to evaluate WBC. DMS was also monitored 0, 24, 48 and 72 h. All E subjects experienced a significant amount of DMS (p<.01) which peaked at 48 h after exercise (E=7.58 ± .79 vs 0 for C, X±SEM); however, no significant differences in soreness perception were observed between drug and placebo groups. Total WBC count ( cells/mm³ ) was significantly greater at 0 h (8,340±380) than at -5 min (6,699±365) for both E and C; this increase was most likely a response to Cybex exercise. At 2 h there was a significant increase in total WBC count for E ( 9,603±389) and no change for C ( 8,336±273}. Neutrophils increased significantly at 2 h for E only (6,428±375 vs 4,988±261 for C}. Bench-stepping leads to increases in DMS and increases in WBC count, particularly in neutrophils, 2 h after stepping; this data suggests that inflammation is involved in DMS. PART II: EFFECT OF AN ASPIRIN-LIKE DRUG ON PERCEIVED EXERTION DURING BENCH STEPPING The object of this study was to determine whether perceived exertion (RPE) for the limb performing predominantly positive work was significantly greater than for the limb performing predominantly negative work, during 30 min of bench stepping. A second objective was to determine the effects of indomethacin (Id) on RPE. Thirty-nine males were randomly assigned to a drug (Id) or placebo (P) group and administered 150 mg indomechacin or placebo, beginning 36 h prior to stepping. Results indicated no significant differences between RPE for "concentric" and "eccentric" limbs of the P group inspite of the fact that the metabolic demand of the "concentric" limb was much greater. Indomethacin did not significantly alter RPE during stepping however, when RPE scores were totaled over the entire bench stepping period, the Id condition was associated with a greater (p < .01) psychological cost for the "concentric" leg effort as compared to P; this indicated that indomethacin might alter effort sense related to concentric contractions. / Ph. D.