The participation of pregnant women in clinical research| Implications for practice within the U.S. pharmaceutical industry

The purpose of this study was to develop and validate a risk-adjustment index for one year healthcare resource use specific to diabetic patients, based on severity of illness measures; and to profile quality of diabetes care between outpatient clinics. The data for this study was collected from four outpatient clinics within the Southern Arizona Veterans Affairs Healthcare System, Tucson, AZ. The DRCI was developed using a sample size of 367 diabetic subjects that had complete information on diabetes-specific variables. Individual DRCI weights, based on the magnitude of one year healthcare resource use and socio-demographic characteristics, ranged from -471.5 to 3,081.2 for total healthcare costs, from -304.3 to 1,582.1 for outpatient costs, and -0.19 to 0.93 for risk of hospitalization. The DRCI was better than or equivalent to the Chronic Disease Score in predicting health care costs. Diabetics in the second cohort were predominantly elderly (mean = 66yrs ± 11.1), married (61%), white (73%), males (96%), had a high BMI (31 ± 6.3 kg/m²), and mean comorbidity score of 4.2 ± 1.8 conditions. Screening for HbA1c and microalbuminuria was frequently performed in all clinics. Overall, 61% and 36% of study patients did not have evidence of foot or eye examinations during the entire study period, respectively. Approximately, 27% (n = 408), 41% (n = 643), and 26% (n = 515) of the study patients had poor glycemic, renal function, and lipid control, respectively. Significant differences (p < .05) in HbA1c and creatinine clearance rates between the clinics were observed after adjusting for patient case-mix. However, differences between the clinics in cardiovascular outcome were not observed after adjusting for patient case-mix. This study demonstrated an association between diabetes severity with healthcare resource and costs. The DRCI, using laboratory data, is a diabetes-specific severity measure for prediction of one year healthcare resource use. Future studies are needed to validate this index in other settings. Finally, the results from this study emphasize the need to adjust for case-mix variable when comparing quality of diabetic care outcomes between outpatient clinics.

Formulary decision-makers must make choices based upon the safety, efficacy, and projected budgetary impact of medications. Models used to predict cost impacts are rarely assessed to determine how accurately they predict treatment cost changes. The purpose of this research was to assess the ability of a decision analytic based deterministic model and a regression analytic based stochastic model to predict the average diabetes-specific costs incurred by a managed care organization during the 12 month period following the addition of metformin to an HMO formulary. The ability of the stochastic model to predict the average diabetes-related costs and total health care costs was also assessed. The deterministic model, a decision tree, was constructed within an equilibrium framework using literature-based probabilities and internal costs to predict the expected diabetes-specific costs. The estimate of the total diabetes-specific cost impact came within 5% of the actual costs. The model underestimated the diabetes-specific medical costs (predicted was 73% of actual) and overestimated the diabetes-specific pharmacy costs (predicted was 258% of actual). A regression model was constructed using medical and pharmacy claims data to predict the expected diabetes-specific, diabetes-related and total health care costs. The average total cost estimates produced by the total health care cost model were within 7% of the actual average costs incurred. The diabetes-related and diabetes-specific cost models produced estimates that were within 12% and 18% of the actual costs incurred, respectively. The total, diabetes-related, and diabetes-specific average medical costs produced by the regression models were within 6%, 50%, and 46% of the actual costs respectively. The total, diabetes-related, and diabetes-specific average pharmacy costs were within 20%, 45%, and 49% of the actual costs respectively. Further research is needed to determine the best way to construct a model to estimate the economic impact of adding a medication to the formulary. A decision tree constructed with internal data should be used to predict the disease-specific economic impact of adding a medication to the formulary when only medical and pharmacy claims data from the previous year are available. A regression model should be used to predict the total health care cost impact.

For most persons with schizophrenia (PWS), adherence with taking neuroleptic medication defines their course of illness. PWS who consistently take medication spend less time in the hospital, preserve recovery gains, and place less burden on families and society. Most extant research focuses on the correlation of discrete, provider-defined variables with the outcome of adherence. In contrast, this research used the person's perspective on the meaning of medication-taking to describe the complex phenomena of neuroleptic medication adherence by PWS. A phenomenological framework was used to examine the lived experience of neuroleptic medication-taking among PWS. Ten males and one female with a DSM-IV diagnosis of schizophrenia were interviewed regarding their experience of taking neuroleptic medication. Interviews were transcribed verbatim by the investigator and meanings were extracted that rendered a description of the essential structure of medication-taking by PWS. An audit trail was established that verified the research process and findings. Interview analysis showed their experience had three interconnected, overlapping theme categories Being-Out-of-Being, On a Rocky Road, and Making a New Way. In summary, the essential structure revealed that: Acquiring an unasked for and frightening being-out-of being was the genesis of the medication-taking experience, and although it brought some relief, medication never fully remitted the illness. Consistent medication-taking developed over time and in concert with finding the right medication. The right medication was one with tolerable side effects and that suppressed the illness enough so that PWS could recover a sense of self. With consistent medication-taking, PWS learned about their illness response, developed personal treatment plans, and decided medication-taking was essential for keeping their illness controlled. In the end, even when they took the medication, PWS had to endure the uncertainty of living with an ever-present but submerged illness that skewed their sense of the world. These findings provide a description of the little-researched experience of living with schizophrenia and its troublesome primary treatment, that may identify points of nursing intervention for aiding persons with schizophrenia in the difficult task of neuroleptic medication-taking.

Asthma has become one of the most commonly talked about and politically charged health topics in India. Yet, less than a decade ago, international studies reported that rates of the disease in the country were among the lowest in the world. This dissertation examines how asthma rapidly became a preeminent health concern in Tamil Nadu. I document and critically examine factors that have led to the phenomenon of asthma, from the multiple perspectives of its sufferers, the practitioners who diagnose and treat the disease, and the pharmaceutical companies that develop and market products for its management. I examine how popular representations of asthma and allergy--which view the disease as the result of an increasingly toxic environment, a more susceptible population, and new, modern ways of life--have influenced the social meaning and medical management of asthma. Using a variety of data, I describe patterns of health care seeking, the therapeutic regimens prescribed for asthma, and the important role played by factors such as the affordability of medications, and the perceptions of the activity and potential harm of medications, such as steroids. I look at increasing coverage of asthma in the Indian print media, and the efforts of the private health care industry and Indian environmental organizations, to draw further attention to the disease. Through detailed clinical observations and interviews with a wide range of allopathic and traditional Indian medical practitioners, I outline the variety of professional understandings and therapeutic approaches toward asthma, describe important differences in the interpretations of its symptoms, and examine the medical and social factors contributing to misdiagnoses, underdiagnosis, and undertreatment. In addition to medical knowledge about asthma, practice patterns are determined by a variety of practical logics, including economic competition in the pluralistic marketplace, the social relations of disease labels, and the pressures to forge a stable relationship between practitioner and patient. Finally, I describe the variety of techniques through which some of the leading drug companies in India have actively promoted asthma and allergy, and provide an ethnographic account of the introduction of new asthma drugs--the leukotriene receptor antagonists--to the Indian market.

The aims of this research were to determine the level of satisfaction with pharmacy services among enrollees of a managed care organization, compare the level of satisfaction between mail pharmacy and traditional pharmacy patrons, and evaluate the relationship between satisfaction with pharmacy services and health status. Data was collected via telephone interviews with 1,362 enrollees of the managed care organization. The overall response rate was 65%. Satisfaction was measured using previously developed items for traditional pharmacy services, and newly developed, parallel items for mail pharmacy services. Scores were calculated for hypothesized multi-item dimensions of satisfaction. Health status was measured using the physical and mental health composite scores of the SF-12 Health Survey. Satisfaction with pharmacy services was compared between patron groups using ANOVA and ANCOVA models. Confirmatory factor analysis and structural equation modeling (SEM) were used to evaluate the dimensional structure of satisfaction with pharmacy services and the relationship between satisfaction with pharmacy services and health status. The results indicated that mail pharmacy patrons were more satisfied than traditional pharmacy patrons with their pharmacy services in general, and specifically with the financial aspects and technical quality of those services. When the comparisons were adjusted for general satisfaction with medical care and mental health status, mail pharmacy patrons still had greater levels of general satisfaction with pharmacy services. However, when these covariates were included in the comparison of satisfaction with financial aspects and technical quality of pharmacy services, dimension scores between the two patron groups were not significantly different. Internal consistency reliability coefficients for the multi-item dimensions of satisfaction were in the range of 0.53 to 0.77, with the exception of the Written Information dimension for mail pharmacy service, where the alpha coefficient was 0.37. A positive correlation between the dimension scores for general satisfaction with pharmacy services and general satisfaction with medical care lends support to the construct validity of the measurements. Additionally, it was concluded that, as expected, general satisfaction with pharmacy services was positively correlated with mental health status, but there was no significant relationship between physical health and satisfaction with pharmacy services.

<p> The purpose of this quantitative meta-analytic study was to investigate the prescribing medication practices of primary care providers among elderly patients 65 years of age and older. Two statistical analyses were conducted on approximately 3 million geriatric patients in a variety of health care settings throughout the United States. The first meta-analysis involved 26 peer-reviewed studies that compared the prescribing medication practices of primary care providers among geriatric patients in the United States with the prescribing practice recommendations of the Beers Criteria. The second meta-analysis involved 8 peer-reviewed studies that compared the prescribing medication practices in America of physicians who received training in geriatric medicine with physicians who received training in general medicine. The predictor variable (i.e., independent or observed variable) was the prescribing medication practices of primary care providers. The outcome variable (i.e., dependent or expected variable) was the prescribing practice recommended by the Beers Criteria. The third variable was the moderating variable of physician training in geriatric medicine. The first findings revealed that primary care providers in the United States prescribed potentially inappropriate medications to geriatric patients. The second findings indicated that physicians without training in geriatric medicine prescribed more potentially inappropriate medications than those with training in geriatric medicine. Serious health care dilemmas among the geriatric population are high incidences of inappropriate dispensation of prescriptions by primary care providers. Inappropriate prescriptions are common in geriatric clinical settings among primary care providers who function in a fragmented medication prescription system and who lack training in geriatric medicine.</p>

La technique du laser femtoseconde (fs) a été précédemment utilisée pour la production de nanoparticules d'or dans un environnement aqueux biologiquement compatible. Au cours de ce travail de maîtrise, cette méthode a été investiguée en vue d'une application pour la fabrication de nanocristaux de médicament en utilisant le paclitaxel comme modèle. Deux procédés distincts de cette technologie à savoir l'ablation et la fragmentation ont été étudiés. L'influence de la puissance du laser, de point de focalisation, et de la durée du traitement sur la distribution de taille des particules obtenues ainsi que leur intégrité chimique a été évaluée. Les paramètres ont ainsi été optimisés pour la fabrication des nanoparticules. L’évaluation morphologique et chimique a été réalisée par microscopie électronique et spectroscopie infrarouge respectivement. L'état cristallin des nanoparticules de paclitaxel a été caractérisé par calorimétrie differentielle et diffraction des rayons X. L'optimisation du procédé de production de nanoparticules par laser fs a permis d'obtenir des nanocristaux de taille moyenne (400 nm, polydispersité ≤ 0,3). Cependant une dégradation non négligeable a été observée. La cristallinité du médicament a été maintenue durant la procédure de réduction de taille, mais le paclitaxel anhydre a été transformé en une forme hydratée. Les résultats de cette étude suggèrent que le laser fs peut générer des nanocristaux de principe actif. Cependant cette technique peut se révéler problématique pour des médicaments sensibles à la dégradation. Grâce à sa facilité d'utilisation et la possibilité de travailler avec des quantités restreintes de produit, le laser fs pourrait représenter une alternative valable pour la production de nanoparticules de médicaments peu solubles lors des phases initiales de développement préclinique. Mots-clés: paclitaxel, nanocristaux, laser femtoseconde, ablation, fragmentation / Femtosecond (fs) laser ablation and fragmentation, a novel technique based upon the breakdown of material using laser energy was previously used for the production of fine gold nanoparticles in suspension. This technique has been newly investigated for the fabrication of paclitaxel nanocrystals in aqueous solution. In this work, we report the fabrication and characterization of paclitaxel nanocrystals generated by fs laser technology. Two distinct methods of this technology have been explored: ablation and fragmentation. The influence of the laser power, focusing position and treatment time on the particle size, size distribution and chemical integrity of the drug has been studied. Morphology and chemical composition of the finest paclitaxel nanocrystal formulation was studied by scanning electron microscopy and Fourier-transform infrared spectroscopy respectively. Differential scanning calorimetry and X-ray diffraction analyses were employed to evaluate the polymorphic state of the paclitaxel nanocrystals. Optimal laser fabrication parameters have been established for the fabrication of uniformly small sized paclitaxel nanocrystals. Those optimal conditions generated finely-sized paclitaxel nanoparticles (400 nm, PDI ≤ 0.3) with a considerable degradation. The drug remained crystalline upon nanonization at high power, though the anhydrous crystals were converted to a partially hydrated form. These findings suggest that drug nanocrystals could be produced using the fs laser technology; however, this technique may be inappropriate for drugs sensitive to degradation. Moreover, the simple fabrication of drug nanocrystals using the fs laser fragmentation presents a great asset for the intial phases of preclinical development of many poorly soluble drug candidates, which are not as sensitive as paclitaxel. Keywords: paclitaxel, nanocrystals, femtosecond, ablation, fragmentation

One strategy to overcome intrinsic or acquired resistance of cancer cells to ionizing radiation (IR) and genotoxic chemotherapeutic agents is to modulate DNA repair. IR and some of these agents induce DNA double strand breaks (DSBs) that are primarily repaired in mammalian cell via the nonhomologous end joining (NHEJ) pathway. NHEJ is a crucial process that has been conserved highly throughout eukaryotic evolution. A DNA-dependent protein kinase (DNA-PK) multi-protein complex plays an important role in NHEJ, and its increased level or activity is associated with acquired drug resistance of several human tumors. The core protein of the DNA-PK multi-protein complex is represented by a Mr ~ 460,000 catalytic subunit (DNA-PKcs) which, in itself, is a serine-threonine kinase. Ku86 and Ku70 at an equimolar ratio form the Ku heterodimeric protein, a binding subunit of the DNA-PK complex. The Ku protein binds to DNA ends and other types of discontinuity in double-stranded DNA. Ku86 is well preserved in organisms as evolutionarily disparate as bacteria and humans and its role has also been implicated in a variety of cellular responses such as the regulation of telomere length and the control of transcription. / The aim of this thesis was to investigate whether down-regulation of the Ku86 gene, by 2'-O-methoxyethyl/uniform phosphorothioate chimeric antisense oligonucleotides (ASOs), would increase the sensitivity of cancer cells to IR and anticancer drugs. To our expectations, transfection of several cancer cell lines with Ku86 antisense ASOs was associated with a specific decrease in Ku86 mRNA levels (IC50 <25 nM; n = 3) and a concomitant rapid decrease (<10% of control) in Ku86 protein expression. Moreover, a decrease in Ku86 protein levels was associated with a 2-fold increase in cell death after treatment with IR and several chemotherapeutic agents. In our effort to improve the efficacy of antisense in vivo delivery we also evaluated polyethyleneimine (PEI, 2kDa) alone or grafted with non-ionic amphiphilic block copolymer PluronicRTM (P85) as a carrier for Ku86 ASO delivery. In athymic nude mice bearing subcutaneous human HT29 colon adenocarcinoma xenografts, Ku86 ASO - P85-g-PEI (2kDa) administration (15 mg/kg, s.c.) with a Q1D x 7 treatment schedule, when combined with a single dose of ionizing radiation (6Gy), caused a significant inhibition of HT29 tumor growth compared with mismatch- and naked antisense-pretreated control groups (time from 200 to 1,000 mm3, 126.9 vs. 84.18 and 87.76 days, P<0.005). (Abstract shortened by UMI.)

Contexte: Bien que plusieurs algorithmes pharmacogénétiques de prédiction de doses de warfarine aient été publiés, peu d’études ont comparé la validité de ces algorithmes en pratique clinique réelle. Objectif: Évaluer trois algorithmes pharmacogénomiques dans une population de patients qui initient un traitement à la warfarine et qui souffrent de fibrillation auriculaire ou de problèmes de valves cardiaques. Analyser la performance des algorithmes de Gage et al., de Michaud et al. ainsi que de l’IWPC quant à la prédiction de la dose de warfarine permettant d’atteindre l’INR thérapeutique. Méthodes: Un devis de cohorte rétrospectif fut utilisé afin d’évaluer la validité des algorithmes chez 605 patients ayant débuté une thérapie de warfarine à l’Institut de Cardiologie de Montréal. Le coefficient de corrélation de Pearson ainsi que l’erreur absolue moyenne ont été utilisés pour évaluer la précision des algorithmes. L’exactitude clinique des prédictions de doses fut évaluée en calculant le nombre de patients pour qui la dose prédite était sous-estimée, idéalement estimée ou surestimée. Enfin, la régression linéaire multiple a été utilisée pour évaluer la validité d’un modèle de prédiction de doses de warfarine obtenu en ajoutant de nouvelles covariables. Résultats : L’algorithme de Gage a obtenu la proportion de variation expliquée la plus élevée (R2 ajusté = 44 %) ainsi que la plus faible erreur absolue moyenne (MAE = 1.41 ± 0.06). De plus, la comparaison des proportions de patients ayant une dose prédite à moins de 20 % de la dose observée a confirmé que l’algorithme de Gage était également le plus performant. Conclusion : Le modèle publié par Gage en 2008 est l’algorithme pharmacogénétique le plus exact dans notre population pour prédire des doses thérapeutiques de warfarine. / Background: Although numerous genotype-based warfarin dosing algorithms have been published, there is little data comparing the predictive ability of these algorithms in real clinical practice. Objectives: Our goal was to evaluate the performance of pharmacogenetic algorithms in an unselected patient population initiating warfarin treatment for atrial fibrillation or valve disease in a real-world clinical setting. The principal objective of the analysis was to determine if Gage’s, Michaud’s, and IWPC algorithms could predict the dose achieving the therapeutic International normalized ratio (INR). Methods: Data from a retrospective cohort study of 605 patients initiating warfarin therapy at the Montreal Heart Institute was used. We compared the dose predicted by the algorithms to the dose achieving the therapeutic INR. Pearson’s correlation coefficient and mean absolute error (MAE) were used to evaluate the predictive accuracy of the algorithms. Clinical accuracy of the predictions was assessed by computing the proportion of patients in which the predicted dose was under-estimated, ideally estimated, or overestimated. Finally, we used multiple linear regression analysis to evaluate the accuracy of a predictive model obtained by adding additional covariables in predicting therapeutic warfarin doses. Results: The proportion of variation explained (adjusted R2) was the highest for Gage’s algorithm (R2 = 44 %) and the mean absolute error was the smallest for the predictions made by Gage’s algorithm (MAE = 1.41 ± 0.06). Moreover, when we compared the proportion of patients whose predicted doses are within ± 20 % of the observed stable dose, Gage’s algorithm also performed the best overall. Conclusion: The algorithm published by Gage et al. in 2008 is the most accurate pharmacogenetically based equation in predicting therapeutic warfarin dose in our study population.