The reliability of data obtained from the existing United States Pharmacopeia (USP) method, USP <231> for elemental impurities (EI) have been questioned in the literature. New regulations regarding EI in pharmaceutical products were recently implemented on the 1st January 2018. The new regulations are USP <232>/<233> and the International Council for Harmonisation equivalent guidelines (ICH Q3D). The new regulations include the use of instrumentation such as inductively coupled plasma optical emission spectroscopy (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS). The aim of this work was to develop, optimise and validate analytical methods for the determination of Class 1 and Class 2A elements, arsenic (As), cadmium (Cd), mercury (Hg),lead (Pb), cobalt (Co), nickel (Ni) and vanadium (V) simultaneously in pharmaceutical products in compliance with the new guidelines. The developed ICP-OES and ICP-MS methods were validated using the only available solid standard reference material (SRM) NIST 3280 Multivitamin/Multielement tablets. It was found that relying solely on spiked addition technique as suggested by USP<233> is inefficient as it may not reflect clearly the method’s accuracy particularly when the sample preparation involves the use of microwave (MW)-assisted acid digestion step, which is very common for pharmaceutical samples. Sample preparation was performed using a developed MW-assisted acid digestion method with reverse aqua regia. It was found that reaching a temperature of 210°C for sample’s digestion is necessary to get EI recoveries of greater than 95% and pre-digestion grinding was found to be beneficial to minimise variation in data and get relative standard deviation (RSD)of less than 5%. The validation results showed good linearity (R2>0.995) over a wide range with low limits of detection (LoDs) and limits of quantification (LoQs). The calculated LoQs in ng/mL are As (5.86, 1.149), Cd (0.87, 0.037), Hg (2.23, 1.701) Pd (4.73, 0.041), Co (1.58, 0.299), Ni (1.74, 0.159) and V (7.64, 0.485) for ICP-OES and ICP-MS incorporated with collision reaction cell (CCT) respectively. Twenty-four commercially available pharmaceutical products including analgesic tablets, cough remedies, flu powders and antacids were analysed. Four products contained Cd in concentrations exceeding the permitted daily exposure limit (PDE) of 5μg/day when the maximum dose is taken, and nine products exceeded the 5μg/day PDE of Pb. This is especially concerning for the paediatric products because children are more susceptible to EI adverse effects as for example, they can absorb up to 40-70% of ingested Pb. The antacids were found to contain As and although the levels quantified were below the PDE (15μg/day), a speciation method using an ion-pair reversed phase high performance liquid chromatography (HPLC)-ICP-MS was optimised and validated according to ICH Q2B guidelines as no information regarding what species are present in such products is available in the literature. Four arsenic species were selected, arsenite (AsIII), arsenate (AsV), monomethyl arsonate (MMA) and dimethyl arsenate (DMA). Calibrations with R2>0.995 for all four species in the range of 1 to 50 ng/L and % recoveries>95% with RSD<5% were obtained. Arsenic was extracted from the samples using MW assissted extraction with 0.3M phosphoric acid at 55°C for 10 miutes, 75°C for 10 minutes and 95°C for 1 hour. The species were stable after being exposed to the extraction procedure (spiked recoveries >95%). This method was able to extract 95% or more of arsenic for all products. The ion-pair reversed phase chromatography was performed using a mobile phase: 10mmol/L tetrabutylammonium, 20mmol/L potassium dihydrogen orthophosphate and 2% methanol at pH 6 with a C18 column. The speciation analysis results for all the antacids showed that approximately 50% of the extracted As was present as the most toxic AsIII form. The work demonstrates some of the potential issues with the new regulations and the availability of suitable solid SRM and seeks to provide workable solutions for the analysis.

Epidermal Langerhans cells (LCs) and multiple subsets of dermal dendritic cells (dDCs) make skin a valuable route for vaccination, offering the potential for antigen-sparing immunisation. The interconnected immunological functions of dDC subsets and LCs are not fully understood however. This Thesis therefore aimed to explore the interactions of skin immune cells with viral pathogens and vaccines to inform the development of future therapeutics and intradermal vaccines. LCs and dDCs were isolated from ex vivo human skin tissue using a walkout protocol which allowed the enrichment of the migratory cells from the tissue. LCs and dDCs were infected with a lentiviral vector encoding GFP, allowing study of post-entry HIV viral restriction. The study uncovered the existence of a SAMHD-1-independent antiviral factor unique to LCs. LCs and dDCs from ex vivo skin were used to examine the cross-presentation of an inactivated influenza virus-derived matrix peptide to CD8+ T-cells. Two CD11c+ subsets of dDCs were found to potently cross present the antigen. Delivery of VLPs, which lack genetic material, markedly reduced cross-presentation, suggesting that viral genetic material is vital for dDCs to activate cross-presentation pathways. Future work is required to determine if this is true of other influenza peptides or pathogens. Vaccine delivery studies performed using murine and human models found that dDCs were responsible for the greatest uptake of ovalbumin peptide antigen and LCs did not migrate out of the epidermis in the first 4 hours after inactivated influenza virus vaccine delivery respectively. Collectively, this work highlighted the importance of dDCs in antigen uptake and cross-presentation to prime cytotoxic T-cell responses. Innovative delivery methods such as microneedles offer a means of accessing the dermal compartment in a pain-free manner, though further work is required to determine the optimal combination of vaccine formulation and delivery method to harness the immunostimulatory abilities of dDCs.

The aim of this research was to establish whether or not mouse interferon could reverse the phenotype of transformed cells so that they behaved in a more normal manner. For this study, clonal isolates of transformed cells from two continuous cell lines and fibroblasts extracted from mouse embryos were used. It was found that interferon could inhibit the growth of both normal and transformed cells. With several transformed clones interferon also reduced their saturation densities, which were normally several fold higher than those of the non-transformed parents. This suggested that interferon had induced a partial reversion to density-dependent growth control. Butyric acid also inhibited growth rate and acted additively with interferon when cells were treated with the two agents together. Interferon had a variable effect on the ability of dispersed cells to form colonies on plastic substrate in liquid media, but had a consistently greater effect on the ability of transformed cells to form foci on a monolayer of normal cells, and to grow suspended in agar, two growth conditions specific to the transformed state. It was concluded that interferon had inhibited focus formation and growth in agar by a combination of its growth inhibitory activity and an effect specific for the transformed phenotype. Interferon also affected the morphology of both normal and transformed cells. The cells became more spread-out, and in transformed cells there was a partial restoration of the microfilament bundle system. Despite these effects on the cytoskeleton, the extracellular matrix of fibronectin fibrils appeared to be little altered by interferon, except when added in conjunction with butyric acid. Under these circumstances, the fibronectin matrix became much more extensive. These data increase the likelihood that interferon's in vivo antitumour activity involved a direct effect on the tumour cells themselves, such that these cells behave more normally.

HIV associated lipodystrophy (HIVLD), an adverse effect of combination antiretroviral therapy (cART), further introduces complexity in the management of HIV infection. There is also increased of cardiovascular disease in HIV patients, even in the absence of HIVLD. cART impairs adipogenesis and dysregulates the secretion of adipokines, fat and glucose metabolism in the adipose tissue. This is seen with both protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors. The aim of this thesis was to examine the pathogenesis of cART-induced metabolic disturbances using in vitro models (adipocytes) and in vivo (gene association) studies. Plasma levels of IL18, an adipokine associated with insulin resistance, are elevated in HIVLD patients. The murine 3T3-F442A cell line was used as an in vitro model to assess the effects of PIs (lopinavir [LPV], ritonavir [RTV], atazanavir [ATV]) and NNRTIs (efavirenz [EFV]) in the presence or absence of telmisartan (TEL; 1-5μM). All antiretrovirals (ARV) resulted in a dose dependent increase in IL18 protein levels by ELISA (LPV, 330pg/ml+2.1 [p=0.008]; ATV, 267.3+5.1 [p=0.0001]; RTV, 265.7+2.2 [p=0.0005] and EFV, 98.6+2.4 [p=0.0004]) as compared to the vehicle control; this also correlated with IL18 gene expression determined by RT-PCR. Sequenom MALDI-TOF was used to genotype 14 single nucleotide polymorphisms (SNPs) in the IL18 gene in ARV-treated patients with (HIVLD+; n=115) and without LD (HIVLD-; n=51), but no association was identified. ARV treatment also resulted in the upregulation of NFATC4 gene expression (LPV, 1.9+0.05 [p=0.0015]; ATV, 2.1+0.1 [p=0.0007]; RTV, 1.4+0.05[ p=0.0002] and EFV, 1.8+0.85 [p=0.0001]) as compared to the vehicle. Co-incubation with TEL partially attenuated ARV-mediated upregulation of IL18 (1.6+0.2 [p=0.01) and NFATc4 (1.2+0.1 [p=0.0001]). siRNA knockdown of NFATc4 in adipocytes resulted in significant upregulation in the levels of adiponectin and PPARgamma and down-regulation in IL6 secretion levels following treatment with ARVs. The data suggest that ARV-induced upregulation of NFATc4 could be a mediator of ARV-induced adipocyte toxicity and potentially insulin sensitivity. This study also observed changes in the regulation of various miRNAs following ARV treatment. Validation experiments confirmed LPV to result insignificant downregulation of miR-103 (0.5+ 0.01[p=0.002]) and miR-107 (0.4+ 0.03[p=0.001]) along with their target gene, Cav-1 (0.6+ 0.01[p=0.01]) during adipogenesis; this was reversed by co-incubation with Tel. A systematic review of the genetic associations with HIVLD was also undertaken – this identified that polymorphisms in mitochondrial DNA and cytokines had been the primary ones studied using a candidate gene approach. The results showed that several SNP associations have been identified which are biologically plausible, but in almost all cases, replication of the findings in different cohorts has either been contradictory or limited. This may be due to several reasons including small sample sizes, different diagnostic criteria used for HIVLD, differences in genetic strategy, ethnic variation in genetic architecture and differences in drugs used across different cohorts. Although further studies in larger patient groups with HIVLD should be undertaken, this may not be possible given its rarity now in clinical practice, and perhaps the emphasis should switch to insulin resistance per se. In summary, PIs and NNRTIs upregulate proinflammatory cytokines with NFATc4 potentially playing a major role in their transcriptional upregulation. Differential regulation of specific miRNAs were also found to be important in ARV-mediated dysregulation ofadipogenesis; further validation work which evaluates their role in adipocyte toxicity in vitro and in vivo is now warranted. Whilst this study did not find any genetic association with HIVLD, future studies using larger sample sizes and better defined phenotypes are now required.

Introduction: A variety of evidence based pharmacological strategies are recommended to reduce the risk of stroke recurrence. The exact medications used will differ dependent on stroke aetiology and typically include antithrombotic, blood pressure lowering and lipid lowering strategies for ischaemic stroke and blood pressure lowering strategies for haemorrhagic stroke. Non-adherence to secondary preventative medications after stroke is common and is associated with poor outcomes. Failure to adhere to medication regimens can be intentional, whereby the patient deliberately decides not to take medication or can be unintentional. For example, patients with limited financial resource or cognitive problems may struggle to adhere to the complex secondary prevention regimens often required post stroke. In turn, several factors contribute to these types of non-adherence. For example, intentional non-adherence may arise following an adverse event or be due to motivational factors whereas unintentional non-adherence can be due to impaired memory function. Stopping medication after stroke may be entirely reasonable if the clinical condition and balance of risks and benefits has changed. Understanding factors associated with adherence could inform strategies to improve it and improve clinical outcomes. Numerous strategies exist to promote adherence but the feasibility and extent of resulted improvement in stroke patients is unclear. Strategies include educational, motivational or practical interventions; however, a combination of these is usually needed in order to reach sufficient improvement. This research aimed to establish the extent of non-adherence to secondary preventative medications after stroke, explore factors associated with poor adherence and describe interventions used to enhance adherence to preventative medication after stroke. Methods The first chapter covers a thorough literature review of the evidence-based recommendations for the secondary prevention after stroke and looked generally at reported rate of adherence and reasons for non-adherence. Systematic reviews and meta-analyses were used to identify predictive factors of non-adherence in chapter 2 and strategies used to enhance adherence to secondary preventative medication after stroke in chapter 5. Both followed PRISMA guidelines in designing the search criteria and reporting of the results. Also, chapter 3 contains a descriptive analysis of a retrospective data of stroke patients enrolled into clinical trials including patients’ characteristics and their medication intake behaviour in the first 90 days after stroke. Chapter 4 investigated the factors associated with non-adherence to secondary preventative medication within the population described in chapter 3 using survival analysis. Then, a pilot study of a promising intervention in post-stroke population was performed based on the findings of the systematic review of effective interventions that enhanced medication adherence in stroke population and the findings of this study are presented in chapter 6. Results Chapter 2: This systematic review identified several factors in different categories that were associated with adherence to secondary preventative medication after stroke. These involved patient related factors such as having concerns about treatment, socioeconomic factors such as presence of carer, health related such as co-morbidities and disability, medication regimen factors including polypharmacy and cost of medication, caregiver factors like adequate communication and continuity of care, or stroke related factors including severity of stroke and stroke subtype. However, none of the factors included in meta-analyses was of significant effect on medication adherence; which is possibly due to heterogeneity in included studies. Prevalence of medication non-adherence in included studies was 32.8% of overall medication regimen (95% CI: 32.2-33.3%). Chapter 3: 10304 Patients were included in the analysis; 54.5% were males and the mean age of participants was 69.4 ± 12.4 years. Of secondary preventative medication prescriptions, 21.3% of patients received anti-coagulants, 64.1% received anti-platelets, 18.2% received hypoglycaemic drugs, 17.9% received lipid-lowering drugs and 56% received Blood Pressure (BP) lowering drugs. Adherence rate was 88% to anticoagulants, 81.3% to anti-platelets, 68.9% to hypoglycaemic drugs, 86.7% to lipid-lowering agents and 78% to BP lowering drugs. Patients in this analysis received a mean of 7.1 (SD, 7) or a median of 5 (IQR, 3 – 9) medication per day. Chapter 4: In Cox-regression survival analysis using multivariable analysis, frequent factors associated with non-adherence to secondary preventative medication classes. To anti-platelets medication- female gender, atrial fibrillation, ischaemic heart disease, polypharmacy (treatment with > 5 drugs), cortical involvement, recurrent ischaemic or haemorrhagic stroke or bleeding while on treatment all associated with non-adherence. To anti-coagulant drugs- more severe stroke, smoking, polypharmacy, bleeding and recurrent ischaemic or haemorrhagic stroke associated with less adherence. To lipid-lowering drugs- non-white ethnicity, more severe stroke, smoking, congestive heart failure, previous stroke and recurrent ischaemic or haemorrhagic stroke all associated with decreased adherence. To BP lowering drugs- more severe stroke, smoking, previous stroke, thrombolysis treatment at baseline, cortical involvement in stroke, syncope, hypotensive episodes, and recurrent ischaemic or haemorrhagic stroke associated with non-adherence; whereas history of hypertension and polypharmacy associated with better adherence. Chapter 5: Interventions that involved patient education and counselling about medication at hospital discharge, provided a computerised educational program regarding risk factors management after stroke, encouraged self-care after stroke, motivated the patients to modify health behaviour or provided cues or reminders to take medication lead to significant improvement in adherence to secondary preventative medication after stroke. When combined in meta-analysis for each medication class, interventions significantly enhanced adherence to antithrombotic drugs (anti-coagulants and anti-platelets), lipid-lowering drugs and BP lowering drugs but not to the overall secondary preventative medication regimen. Chapter 6: Ten participants were recruited to this pilot study, half of which were randomised to the intervention group i.e. received daily reminders. Mean age of participants was 59.6 ± 14.7 years and eight were males. All patients completed the study visits (baseline, 1-month and 3-months visits) where they were given an education session at baseline and medication adherence was assessed in each visit using a validated medication adherence scale. At 3-months post intervention, adherence to secondary preventative medication improved for two participants in the intervention group but reduced in two participants in the control group. Conclusion Studies in this thesis quantified rate of adherence to secondary preventative medication after stroke in real-life and clinical trials stroke patients. These studies added to the previous knowledge that non-adherence was common after stroke with around 30% of all patients discontinued treatment. Many factors were identified and associated with reduced adherence in stroke population. This finding could inform stroke clinicians to give extra care to those at risk of stopping secondary prevention measures. In addition, various strategies found by this research to be useful in improving medication adherence in stroke population. Such interventions need to be included in after stroke care. There is a major need for larger studies to investigate what are the best strategies to enhance adherence to medication after stroke.

Diabetes is a lifelong condition caused by an inability of the body to break down glucose due to a defect in either insulin synthesis or the target cells becoming resistant to secreted insulin. There are two main types of diabetes, type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus. T2DM mainly occurs due to insulin resistant, inability of cells to respond to normal levels of insulin, the treatment of T2DM usually involves exercise, diet control, drugs and in some cases insulin is needed. In T1DM, the immune system starts to attack the β-cells, the cells responsible for insulin hormone synthesis and secretion from the endocrine pancreas. The aim of T1DM management is to restore carbohydrate metabolism as close to the normal condition as possible. To achieve this goal insulin hormone must be provided daily. Insulin is given in different ways such as injection (which is the most common method), pump and inhalation. Insulin sources can be either recombinant or animal-based. Treatment of T1DM is continuous and even with the best treatment options people with diabetes can develop serious complications such as acute diabetic coma or other long-term complications. These include diabetic cardiovascular disease, diabetic retinopathy, and diabetic nephropathy. Injection of insulin and daily monitoring of glucose levels presents a substantial burden to both the diabetic patient and also to associated dependents or carers i.e paediatric diabetes. So there is a strong need to develop an alternative treatment to reduce the burden, enhance control, and even ultimately cure diabetes mellitus. A recent medical invention is the use of stem cells in the treatment of many disease conditions. Stem cells have a remarkable ability to develop into many different cell types. Stem cells therapy offers a new method for treating disease such as diabetes. The results of many studies demonstrate the capability of mesenchymal stem cells (MSCs) in the treatment of bone disease, cardiac disorder, and multiple sclerosis. However, much work remains to be done in the clinic and laboratory to optimise the use of these cells. The main aim of this study was to explore the therapeutic effectiveness of MSCs conditioned media to restore the viability and function of β-cells. In order to establish an in vitro model of cytokine driven β-cells apoptosis, pancreatic β-cells were treated with rising concentrations of pro-inflammatory cytokines TNF-α, IFN-γ and IL-1β and endotoxin LPS for 24 h. The optimal concentration of each cytokine or endotoxin was assessed by MTT assay. Optimal concentrations were deemed to be those that induced an approximate reduction in cell viability of 50%. The cells were treated with the optimal concentration and cell viability was monitored over time in addition to assessment of anti-apoptotic gene induction via qPCR assay. Mesenchymal stem cells (MSCs) secretome was collected as conditioned media and the β-cells cultured in non-conditioned and conditioned media during cytokine-driven apoptotic induction. β-cell viability and anti-apoptotic gene expression was determined to evaluate the therapeutic effectiveness of mesenchymal stem cells conditioned media (MSC-CM) in protecting β-cells from pro-inflammatory cytokines. We observed a significant increase in the viability of pancreatic β-cell lines cultured in conditioned media when compared to those cultured in non-conditioned media. After that, we sought to identify a possible candidate that is present in the MSC-CM and help the cells to overcome the effect of pro-inflammatory cytokines. We found a high concentration of IL-10 in our conditioned media, in addition to the presence of IL-4, PIGF and VEGF in variable amount. Based on our present findings, cytokine-induced apoptosis is mediated through the TRAIL-dependent pathway. However, the addition of MSC-CM blocked cytokine-induced apoptosis and downregulated the genetic expression of A20 and TRAIL. Also, IL-10 was able to block IFN-γ and TNF-α-induced apoptosis.

Pulmonary arterial hypertension (PAH) is characterised by elevated pulmonary arterial pressures and obstructive lesions in the distal vasculature. As a result, the right ventricle is placed under excessive strain resulting in adaptive hypertrophy, progressing to maladaptive hypertrophy and failure. Women develop PAH more frequently than men. It is postulated that 17β-estradiol (E2) plays a role in disease pathogenesis and/or the E2 metabolic axis may be dysregulated in PAH. Growing evidence also implicates a role for ROS and oxidative stress in PAH, yet mechanisms linking these systems are elusive. We hypothesised that either E2 or the E2 metabolite, 16α-hydroxyestrone (16αOHE1), stimulates Nox-induced ROS generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMC) and that, in PAH, aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of E2-Nox-dependent processes was studied in female Nox1-/- and Nox4-/- mice exposed to chronic hypoxia. HPASMCs from female non-PAH individuals (control hPASMC) and female PAH patients (PAH-hPASMC) were exposed to E2 and 16αOHE1 in the presence/absence of inhibitors of Nox1, Nox2 and Nox4, cytochrome P450 1B1 (CYP1B1) and estrogen receptors (ER), ERα, ERβ and G-protein coupled estrogen receptor (GPER). E2, through ERβ, increased Nox1 and Nox4-derived O2- and redox-sensitive growth in control hPASMCs. 16αOHE1, through ERα activation, stimulated O2- production in control hPASMCs and PAH-hPASMCs. E2- -stimulated O2- production was inhibited by CYP1B1 blockade. Basal expression of Nox1 and Nox4 was potentiated in PAH-hPASMCs. In control hPASMCs, 16αOHE1 increased p47phox and poldip2 and Nox1 expression. In PAH-hPASMCs, 16αOHE1 decreased nuclear factor erythroid-2-related factor-2 (Nrf-2) activity and expression of Nrf-2-regulated antioxidant genes in PAH-hPASMCs. Female Nox1-/-, but not Nox4-/- mice were protected against chronic hypoxia-induced pulmonary hypertension and vascular remodeling. Expression of CYP1B1 was increased in pulmonary arteries of wild-type and Nox4-/- mice exposed to hypoxia, yet this induction in CYP1B1 expression was absent in those arteries from hypoxic Nox1-/- mice. Findings detailed in Chapter 3 show that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth through both Nox1 and Nox4. In vivo studies exhibited protection against pulmonary hypertension specifically in Nox1-/- mice. This study provides new insights through Nox1/ROS and Nrf-2 whereby 16αOHE1 influences hPASMC function, which when upregulated may contribute to vascular injury in PAH.

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No description available.

This thesis examines the use of hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) or ethylcellulose, alone or in combination with other adjuncts, to control the release of propranolol hydrochloride from matrices. Gels were characterized by U tube viscometry and their cloud points of gels. The properties of polymers and their mixture in matrices or in gels were investigated by differential scanning calorimetry (DSC). Compendial dissolution methodology was used to determine drug release from matrices and their release exponents. Propranolol hydrochloride increased the solubility of HPMC and altered the water distribution in their gels. The release of propranolol hydrochloride from HPMC matrices was dependent on the square root of time. Release exponents were - 0.6, indicating that diffusion and erosion contributed to drug release. The release rates of propranolol hydrochloride from NaCMC matrices decreased as the NaCMC content increased. Addition of propranolol hydrochloride to NaCMC gels produced an insoluble complex which, in matrices, controlled the drug release. The interaction between propranolol hydrochloride and NaCMC was confirmed by DSC and dialysis. The viscosity grade of NaCMC affected the drug release. NaCMC matrices showed fast erosion. The release of sodium ions from matrices containing NaCMC was enhanced propranolol hydrochloride, confirming the occurrence of the interaction in matrices. The release of propranolol hydrochloride from NaCMC matrices was not dependent on either the square root of time or time. Large increases in release rates from matrices containing NaCMC in acidic media implied the polymer was unable to gel provide or a sustained release of propranolol hydrochloride at low pH. A synergistic increase in viscosity in gels containing HPMC and NaCMC probably played a minor role in propranolol release from matrices containing both polymers. NaCMC decreased the cloud point of HPMC. Drug release from matrices containing HPMC and NaCMC was very complicated, but zero order release was achieved from matrices containing 285 mg of 1: 3 HPMC : NaCMC. Addition of HPMC to NaCMC matrices suppressed an initial burst release of propranolol. The release of propranolol hydrochloride from matrices containing HPMC and NaCMC was dependent on pH. Ethylcellulose was capable of binding = 14% w/w water. Matrices containing ethylcellulose 7 cP (<125 pm) showed lower release rates than matrices containing ethylcellulose 10 cP, or at greater particle sizes. Compaction pressure generally did not affect drug release. The release exponent from matrices containing ethylcellulose was 0.44 - 0.49 indicating diffusion predominated drug release. Admixture of ethylcellulose with HPMC did not change the release exponent (0.59 < n < 0.61) from that of HPMC alone, whereas the exponents of NaCMC:ethylcellulose matrices was altere. Addition of ethylcellulose to HPMC increased the initial uptake of water. The incorporation of a complex of propranolol and β-cyclodextrin failed to retard the release of drug or alter the release exponent.