A triple blind randomized controlled trial was undertaken in a Brazilian Amazon region (Cuiaba-MT), to compare the effectiveness and side effects of oral artesunate (7 days, total dose = 0.75 g) plus tetracycline (7 days, total dose = 10.5 g) (AT) and oral quinine (3 days, total dose = 6 g) plus tetracycline (7 days, total dose = 10.5 g) (QT). Eligible patients had uncomplicated P. falciparum malaria; age $ geq$ 14 years; no previous malaria treatment related to the present attack; and, if women, indication of absence of pregnancy. Clinical exam and blood tests were performed at baseline (day 0) and thereafter at days 2, 4, 7, 14 and 28. Effectiveness was assessed by cure rates (WHO criteria) and parasite clearance at day 2. / 176 patients were randomized, 88 to each group. 96.6% of the AT group and 93.2% of the QT group completed the 7-day treatment. 81.8% of the AT group and 78.4% of the QT group completed follow-up visits to day 28. Groups had similar clinical characteristics at baseline. The incidence of side effects was much higher in the QT group (82%) than in the AT group (50%) (p $<$ 0.0001). Cure rates were similar: 80% in the AT and 77% in the QT group (p = 0.68). Parasitemia (by day 2) cleared faster in the AT group than in the QT group (98.5% versus 47.6%, respectively) (p $<$ 0.0001). / These results indicate that AT is effective in the treatment of uncomplicated falciparum malaria and may provide a useful alternative to other treatment regimens.

<p> Diabetes is one of the most common chronic comorbid condition seen in elderly CRC patients. Outcomes of CRC patients with diabetes specifically stage at diagnosis, emergency condition for CRC surgery, survival, and mortality have been insufficiently explored. The aims of the study were to investigate the association between diabetes and stage at diagnosis of CRC in elderly Medicare beneficiaries; to check the association of diabetes with presenting as an emergency condition for CRC surgery in the elderly and; to explore the effect of diabetes on survival of elderly Medicare beneficiaries with CRC. Using the SEER-Medicare data from 2003-2005, patients newly diagnosed with CRC were selected and divided into diabetic and nondiabetic cohorts. The two cohorts were compared in terms of stage at CRC diagnosis, emergency presentation for CRC surgery, and five year survival. Logistic regressions were used to check the association between diabetes and stage at diagnosis and emergency condition for CRC surgery. Survival analysis was employed compare time to death between diabetic and non-diabetic CRC patients. Covariates used in the study included the three most common comorbid conditions besides diabetes: coronary atherosclerosis, congestive heart failure, and chronic obstructive pulmonary disease, age, sex, race, tumor location, region in the country, patient location, and frequency of physician office visits. For survival analysis additional treatment variables &ndash; chemotherapy, radiation, and surgery were included. For stage at diagnosis of CRC, diabetes showed a significant inverse association (OR 0.92; 95% CI 0.85-1.00). On adding quintile of physician office visits this association was not significant. Odds of being diagnosed at a later stage was significantly associated with the least number of office visits (OR 2.13; 95% CI 1.86-2.44) as was having a proximal tumor (OR 1.40, 95% C 1.30-1.51) Although the odds of a diabetic patient being an emergency patient were lower than a non-diabetic, this was not statistically significant (OR 0.89; 95% CI 0.79-1.01) Mortality risk was significantly greater for diabetic CRC patients than nondiabetics (HR 1.15, 95% CI 1.09-1.20). Presenting emergently increased the risk of mortality (HR 1.61, 95% CI 1.54-1.68). Surgery for CRC reduced the risk of mortality (HR 0.41, 95% CI 0.39-0.43) and although in bivariate analyses patients who received chemotherapy were more likely to die, the hazard model showed a significant benefit associated with chemotherapy or radiation (HR 0.70, 95% CI 0.67-0.74). The worse terminal outcomes seen in diabetic CRC patients indicates the need for early and timely screening to prevent the disease or diagnosis at earlier stages.</p>

Restenosis, currently estimated to occur in 30-50% of dilated lesions, continues to be a major limitation to the success of current interventional cardiovascular procedures. Presently, no established therapy prevents or ameliorates this complication. We propose an alternate method for reducing the rate of restenosis that utilizes localized delivery of inhibitors of smooth muscle cell (SMC) growth to injured arteries. SMCs were targeted because they are recognized as the major proliferative component of the stenotic lesion. The work in this thesis was specifically aimed at creating a biodegradable implantable microparticle delivery system, which when loaded with inhibitors of SMC growth, could be used to reduce the lesion. The effect of controlled delivery of two novel therapeutic compounds from this microparticle system on SMC growth was included in this investigation. A method was developed to fabricate poly(DL-lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) blend microparticles that involves a double-emulsion-solvent-extraction technique to investigate the effect of polymer blend ratio on release kinetics. Two model drugs (FITC-IgG and FITC-dextran) were entrapped using this technique with high efficiency. In vitro release studies showed that the initial burst effect was dependent on the PLGA/PEG blend ratio. Moreover, the release rate increased in direct relation to PEG content. A linear release profile was obtained for microparticles loaded with FITC-IgG for initial PEG weight fractions up to 5 wt%, and a biphasic release profile was obtained for FITC-dextran loaded microparticles with rates dependent on the PEG content. These results demonstrate the feasibility of modulating the release profile of entrapped drug compounds from biodegradable microparticles by adjusting the PLGA/PEG blend ratio. Tenascin, a large extracellular matrix glycoprotein, is thought to play an important role in SMC growth. Hence, we proceeded to investigate the inhibition of SMC proliferation and migration in vitro by an antisense (AS) oligodeoxynucleotide (ODN) targeted to the tenascin mRNA and released from PLGA/PEG blend microparticles. Release of AS-ODN was characterized by a small initial burst effect followed by a period of controlled release. SMC proliferation studies exhibited dose dependent growth inhibition with AS-ODN loaded microparticles. Microparticles loaded with scrambled (SC) ODN showed less growth inhibition than AS-ODN. Moreover, only the AS-ODN loaded microparticles inhibited migration. These results demonstrate the feasibility of entrapping an AS-ODN to rat tenascin into PLGA/PEG microparticles for controlled delivery to inhibit SMC proliferation and migration. Basic fibroblast growth factor (bFGF) is a potent mitogen for SMCs and is believed to play a key role in neointimal formation. Consequently, we fabricated PLGA/PEG blend microparticles loaded with an antibody (Ab) against bFGF, and determined the effect of the Ab-bFGF released on smooth muscle cell proliferation in vitro. This work demonstrated the feasibility of entrapping an Ab-bFGF into PLGA/PEG microparticles for controlled delivery to inhibit bFGF stimulated SMC proliferation. Lastly, preliminary in vivo studies demonstrated that PLGA/PEG microparticles can be implanted and immobilized adventitially in the rat carotid artery. (Abstract shortened by UMI.)

The erectile mechanism is a sequential cascade of events, involving many chemical messengers, perhaps the most important one being nitric oxide (NO). NO is a putative neurotransmitter involved in the non-adrenergic non-cholinergic (NANC) system and is synthesized by the enzyme nitric oxide synthase (NOS). NOS has been localized in peripheral autonomic nerves innervating vascular and non-vascular smooth muscles in many organ systems. / The introduction of intracavernous injection (ICI) of vasoactive agents in 1981 was an effective means to restore erectile function for men with erectile dysfunction (ED). Recent evidence supports the theory that increased blood flow can induce the release of NO from vascular endothelium, suggesting that ICI may have positive benefits for the host. / Our study looked at (1) a new delivery system for intracavernous injection and (2) the effect of modulation of penile flow on the regulation of NOS content and activity. A canine model assessed the effectiveness of a subcutaneous drug delivery as an alternate means to ICI. Additionally, a paraplegic rat model was developed to assess the effects of chronic ICI of papaverine on the expression of NOS in the penile tissue. / Our first objective, testing a new subcutaneous drug delivery system, yielded no data due to technical difficulties. The experiment involving the rat model, our results demonstrated that ICI of papaverine significantly increased the number of NOS fibers within the penile shaft, indicating that an increase in the flow of blood within the penis can alter levels of NOS within penile tissue. This result may in part explain the observation seen in patients, whereby after 1 year of ICI, spontaneous erections return and ICI therapy may be discontinued.

Use of benzodiazepines outside of recommended guidelines for older adults is associated with adverse outcomes. Such "less than optimal use" includes use of long-acting benzodiazepines, use of high daily doses and long-term continuous use. Most previous research on factors associated with these types of use has been carried out using administrative databases containing limited patient information. The objectives of this study were to assess the extent of these less than optimal uses among Quebec seniors and to evaluate the effects of patient and prescriber factors through examination of a research data base containing patient characteristics linked to an administrative data base containing prescription drug records. / Study subjects were 1423 community-dwelling Quebec adults age 66 and older who participated in the first phase of the Canadian Study of Health and Aging (CSHA1). Demographic and health data from CSHA1 were linked to prescriptions billed to the Regie de l'assurance maladie du Quebec (RAMQ). / One hundred and eighty-two (12.8%) subjects filled at least one prescription for a long-acting benzodiazepine within 365 days following CSHA1 screening (standardized one-year period prevalence 12.4%). Use of long-acting benzodiazepines was associated with male patient gender, earlier physician graduation and physician specialty status. In addition, relationships between use of long-acting benzodiazepines and physician factors were modified by patient anxiety. / One hundred and eight subjects (7.6%) filled at least one high dose prescription (standardized one-year prevalence 7.9%). High dose use was associated with patient age and anxiety. Physician specialist status was a risk factor for use of high daily doses among subjects with cognitive impairment but a protective factor among subjects without cognitive impairment. / The standardized one-year prevalence of long-term continuous use was 19.8% The one-year cumulative incidence of initiation of such use was 1.9%. Long-term continuous use was associated with increasing age. / This study confirmed that these three less than optimal uses of benzodiazepines occur relatively frequently among community-dwelling Quebec seniors. Both patient and prescriber determinants appear to play a role in such use, and patient factors may alter the relationship between less than optimal use and prescriber characteristics.

A delivery method for the oral administration of thalidomide for lowering tumor necrosis factor alpha (TNT-alpha), and thus Crohn's disease-related inflammation in the proximal small intestine, using two separate engineered polymer microcapsules is explored in this thesis. Membrane formation of both alginate-polylysine-alginate (APA) and alginate-chitosan (AC) capsules are discussed and thalidomide encapsulation procedures have been described. In-vitro tests have been used to monitor capsule degradation and drug release in a simulated gastrointestinal environment. Also, culture and use of RAW 264.7 mouse macrophage cells for the simulation of the human intestine is described. Results show two separate methods of drug delivery by the APA and AC capsules. APA capsules release thalidomide in a timed-release fashion whereas AC capsules release the drug in a burst manner. These results implicate the benefits of the use of both capsules to target separate sites along the small intestine. Also the cultured macrophage studies conclude that the proposed encapsulation therapy does indeed lower TNF-alpha levels and could therefore be of benefit for the lowering of inflammation associated with Crohn's disease. However, further animal study is needed before full potential of this approach can be realized.

Benzodiazepines, one of the most frequently prescribed class of medications in the elderly population, are known to impair motor function and cognitive skills. The evidence based on laboratory and experimental driving studies reporting the performance impairing effects of benzodiazepines is very convincing. However epidemiologic studies of the association between benzodiazepine use and the risk of motor vehicle crashes are inconclusive. The primary objective of this thesis was to determine the risk of injurious motor vehicle crashes among elderly drivers following the initiation of treatment with long and short half-life benzodiazepines. We also sought to determine when, after initiating treatment, the risk of experiencing this adverse event became elevated, and whether there was a continued risk with prolonged use. / The study was a nested case-control design within a cohort of 224,734 drivers from the province of Quebec, age 67 to 84, and followed from 1990 to 1993. The study outcome was involvement of a cohort member as a driver in a motor vehicle crash in which at least one victim (not necessarily the driver) sustained bodily injury. All 5,579 drivers involved in an injurious motor vehicle crash (cases) were identified from this cohort. A random sample of 10 subjects per case was selected as controls from a sub-cohort of 13,265 subjects. Study subjects were linked to the Quebec health insurance databases and a complete history of drugs dispensed was obtained. The rate ratio of crash involvement was estimated from logistic regression models controlling for demographic characteristics, a measure of health status, exposure to other central nervous system drugs and previous injurious crashes. / For long half-life benzodiazepines, the adjusted rate ratio of crash involvement within the first week of treatment initiation was 1.45 (95% CI 1.04-2.03). The rate ratio for continuous use of longer duration up to one year was slightly lower, but remained significantly elevated (rate ratio 1.26; 95% CI 1.09-1.45). In contrast, there was no increased risk following the initiation of treatment with short half-life benzodiazepines (rate ratio 1.04; 95% CI 0.81-1.34), or with their continued use (rate ratio 0.91; 95% CI 0.82-1.01). / In conclusion, brief or extended periods of exposure to long half-life benzodiazepines are associated with an increased risk of motor vehicle crash involvement in the elderly population. There appears to be no such raised risk for short half-life benzodiazepines.

In the past decade, the increasing costs incurred as a result of caring for Alzheimer's disease (AD) patients have led to the recognition of AD economic research as an important area of study in most industrialized countries. This thesis contains an overview of the AD economic literature published in recent years, focusing in particular on four cost-effectiveness analyses (CEA's), which employ Markov models to simulate disease progression through different health states. Methodological issues and key study assumptions related to modelling disease progression are identified and critically evaluated. Two of these issues, namely the assumption that transition probabilities are independent of a patient's age and the implications of MMSE (Mini-Mental State Examination) score misclassification, are investigated through re-analysis of MMSE data from two longitudinal cohorts of probable AD patients (N = 106). Simulations are carried out to assess the impact of score misclassification on transition probabilities. / Our findings suggest that younger age may be associated with a higher likelihood of progressing into more advanced stages of AD. Additionally, we conclude that, in the presence of score misclassification, the use of the MMSE in the context of CEA's would lead to underestimating disease progression and the time spent in the more severe stages of AD. Recommendations are made for future research.

<p> Objective: This study was designed to evaluate the use of low dose vaginal estriol and low dose vaginal estradiol creams for the treatment of vulvovaginal atrophy. Methods: We designed a 12-week randomized double blinded pilot study. Participants applied the study cream daily (estriol 10mcg, estradiol 10mcg, or placebo) for 2 weeks and then twice weekly for a further 10 weeks. Results: Sixty three women were accrued, of whom 56 completed the study. There was no statistical difference between the three groups in improvement in the symptoms of vulvovaginal atrophy. There was a within group improvement for vaginal dryness and itch in all 3 arms. The within group improvement for vaginal dryness was greatest in the estriol group. Estriol levels remained &lt;25ng/ml at baseline, week 2 and week 12 for all participants except 1 (in the placebo group at week 2 when it rose to 29.8ng/ml). Estradiol levels at week 2 in the estradiol group were significantly higher than week 2 levels in the estriol or placebo group. Conclusions: Low dose vaginal estriol cream is a feasible alternative to low dose vaginal estradiol cream for the treatment of vulvovaginal atrophy. Further research should include a larger volume of base cream and an adequately powered clinical trial.</p>

Background. Anticholinergic (ACH) medications are among biologically plausible and potentially modifiable risk factors of delirium. But the epidemiological findings on its role in hospitalized elderly patients are conflicting. Objectives. To evaluate the association between use of ACH medications and delirium severity and the potential effect-modification on this association by dementia. Methods. A cohort of 278 medical inpatients aged 65 years and over with diagnosed delirium was prospectively followed up with the Delirium Index (DI) every 2--7 days up to 3 weeks in a primary acute care hospital. Their DI scores were associated with measures of ACH medication exposure in the previous day using the mixed linear regression model adjusting for potential confounders or effect modifiers. Results . A total of 47 potential ACH medications were used in the cohort (mean: 1.4 per patient per day). An increase in daily ACH medication exposure of one such medication was on average associated with a subsequent increase in delirium severity of 0.52 DI points (95% CI: 0.3--0.8) after adjusting for dementia, baseline DI score, length of follow-up and concurrent use of non-ACH medications. Dementia did not modify the association. Sensitivity analyses using alternative definitions of ACH medications or excluding antipsychotics did not change the results. Conclusions. Exposure to ACH medications is independently and specifically associated with a subsequent increase in symptom severity of delirium among elderly medical inpatients.