The goal of this research was to determine if the Pharmaceutical Care Services Program (PCSP) significantly changes the utilization and cost of medical services for Medicaid recipients. The University of Maryland Center on Drug and Public Policy (CDPP) has contracted with the Maryland Department of Health and Mental Hygiene (DHMH) to provide pharmaceutical care services for Maryland Medicaid recipients. The main goal of PCSP is to improve the appropriateness and cost-effectiveness of physician prescribing decisions and patient drug use. The program accomplishes this by placing clinical pharmacists in hospital clinics to review drug therapy and provide advice to physicians and counseling to patients. A quasi-experimental pretest and post-test design with three control groups was performed in this study. The subjects who received PCSP and met the study criteria were the study group. The subjects who were Medicaid enrollees and relatively similar to the study subjects in terms of age, sex, hospital, and ACG (ambulatory care group) classification were randomly selected into the control groups by using a multiple computerized matching process. Differences in utilization and cost of medical services between study and control groups were tested for statistical significance. Cost-benefit analyses were then performed from budgetary and societal perspectives by applying a net present value method. The mortality and morbidity productivity loss estimations were specifically addressed as the indirect benefits in this study. Lastly, a sensitivity analysis was performed to test the assumptions (discount rate and wage rate) underlying the analysis. In this study, the utilization and costs comparisons between the PCSP patients and control patients revealed that: (1) PCSP "capped" the total cost of services by holding them constant while the control groups' costs rose sufficiently to create a significant difference between the PCSP and control groups; (2) specialty care physician visits remained stable for PCSP while increasing in the control groups; (3) primary care physician visits remained stable for PCSP recipients while they declined in the control groups; (4) less prescription medication was used in PCSP group than in the control group; (5) while the total cost of prescriptions increased for both groups, the cost of PCSP prescriptions was less than the control group cost; (6) PCSP showed no significant impact on the use of the emergency room and hospitalizations. The cost-benefit analysis illustrates that PCSP saved the Medicaid program $204.32 per patient for the first year intervention and $2,043.20 for the future 10 years from a budgetary perspective. From a societal perspective, PCSP saved society $4,116.01 per patient for the future 10 years period. Theoretically, if PCSP were expanded to serve all Medicaid, adult, non-institutionalized patients receiving drug therapy, the state of Maryland should be able to save as much as $27 million in the next fiscal year from a budgetary perspective. The society should be able to save as much as $259 million in the next fiscal year from both direct and indirect savings.

A novel solid oral dosage form, a tablet which can disintegrate rapidly in water to form homogenous suspension of high viscosity to deliver sustained release medication was developed. Such a system avoids the administration of large doses of drugs at one time and circumvents the stability problems encountered when sustained release coated pellets are incorporated in a suspending vehicle. The key to the dosage form is a rapidly disintegrating tablet followed quickly by the development of a viscous suspension system. By design, the viscous gel does not form until disintegration of the tablet is complete. The system contains a processed swellable material, composed of carbomer produced by extrusion-spheronisation which is able to generate viscosity on contact with water, an active drug substance exhibiting sustained release properties from polymethacrylate copolymer coated beads, and freeze-dried cushioning beads composed of microcrystalline cellulose (MCC) and croscarmellose sodium. The cushioning beads, produced by extrusion-spheronisation, possess certain properties among which are compactibility and the capability of disintegrating rapidly. The incorporation of carbomer as a fine powder impedes the disintegration process due to the networking of the carbomer in the tablet matrix and at the surface which upon hydration results in a voluminous mass. However, processing of the viscosity enhancer into beads produced by either extrusion-spheronisation with microcrystalline cellulose (MCC) using a hydroalcoholic system or powder layering onto sugar spheres using alcoholic PVP as a binder provided a solution to the problem. Freeze-drying the cushioning beads containing MCC and croscarmellose sodium produced beads which possessed high compactibility and the ability to maintain good content uniformity and weight variation (less than 5%) when mixed with the drug-loaded membrane-coated beads. The cushioning beads exhibited initial fragmentation into primary powder particles followed by plastic deformation during compaction with the drug-loaded membrane-coated millispheres. They were able to not only to fill the voids between the drug-loaded millispheres but also to surround them so that the tablet was held together by excipient-excipient contact. Moreover, the compacts formed from those cushioning beads were able to disintegrate rapidly and release intact drug-loaded beads with minimal effect on drug release kinetics. Compression force, percentage of drug-loaded membrane-coated beads and the type of membrane coating were important factors affecting the release profile of the tablet compacts. Unlike ethylcellulose, polymethacrylate copolymer coatings were able to resist the mechanical stresses of compaction with relatively small changes in drug release profiles. The increase in the percentage of drug released from the tablets containing 12.5% sustained release theophylline beads in freeze-dried cushioning beads compacted at a pressure of 332 Kg/cm2 relative to the uncompacted beads was 20, 21, 19, 16, 10, 7, 4 and 2% at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours, respectively. This increase in the drug release was attributed to the fracturing of the membrane-coated beads present at the tablet surface. The formulation of tablets for instantaneous preparation of sustained release suspension was achieved by compressing a blend composed of 8.3% drug-loaded beads coated with polymethacrylates, 16.7% carbomer beads produced by extrusion-spheronisation and the freeze-dried cushioning beads. These tablets disintegrated quickly in water forming a homeogenous suspension after stirring for 1-1.5 minutes.

The intent of this study is to understand the extent to which consumers' are willing to pay to have access to community-based pharmacist services. These services are distinct from the physical skills of dispensing a pharmaceutical product. The contingent valuation method was used to determine consumers' willingness-to-pay (WTP) for these services. Contingent valuation is a survey method that asks individuals to express their WTP for a good or service currently not available and/or not priced in well-functioning markets. A convenience sample of 348 adult, working individuals from four locations around Baltimore city were asked their WTP for five individual pharmacist services and then for a package of all services in hypothetical market scenarios. Consumers were asked their WTP via three payment mechanisms: an out-of-pocket payment, a monthly insurance premium and an annual membership fee payable to a pharmacy of their choice. The survey was administered using a self-administered, computerized interview to obtain WTP bids in dollar terms for community-based pharmacist services. All WTP values for pharmacist services are significantly greater than zero. A two-part estimation model that corrects for the biased estimates of zero dollar bidders, was used to separate WTP bidding behavior into two stages. The first stage separates individuals by their decision to bid for pharmacist services and then a decision about how much to bid conditional on bidding in the first place. The probability of bidding ranged from 0.595 for advice on nonprescription medication to 0.837 for the pharmacists attention to safety when dispensing a prescription medication. Respondents were WTP most to have the pharmacist review the appropriateness of all their medication ($4.76, SD 5.90) and to have all pharmacist services available based on an annual fee ($89.14, SD 161.37). Individuals are more likely to bid if they are non-white and have a positive attitude towards paying and are less likely to bid if they have an income exceeding $50,000/year. Non-whites are WTP significantly more than whites. Tests of starting point bias and the effect of information on WTP bids were not significant. The WTP bids obtained for community-based pharmacist services are subject to rational interpretation.

Metoprolol (I) is a widely used beta-blocking agent used in the treatment of cardiovascular disorders. It is administered as a racemic mixture (R and S isomers) of metoprolol tartrate. Its pharmacokinetics in extensive metabolizing (EM) subjects is variable because of the extent of stereoselective oxidative first-pass metabolism to alpha-hydroxymetoprolol (II) diastereomers and an optically active acid (ACMB). Literature reports on the disposition of similar drugs suggested that differences in the disposition of S- and R-enantiomers may depend on input rate of drug delivered to the liver. Therefore, two clinical studies were conducted with EM subjects, aged 18--55 years, to determine if differences in the disposition of metoprolol enantiomers occur in humans when the input rate of metoprolol is altered. The first clinical study was a four-way crossover study (seven subjects) with slow (S), moderate (M) and fast (F) extended release matrix-based metoprolol tartrate racemic 100 mg tablets with different release rates and a racemic 50 mg oral solution (Sol). The second study was (11 subjects) a two way parallel study using a racemic 100 mg metoprolol tartrate extended release tablet (A) and an encapsulated bead formulation (C). Plasma samples were assayed for total metoprolol and metabolites and their enantiomers by stereospecific and nonstereospecific high performance liquid chromatographic methods, specifically developed and validated for this purpose. The diastereomers of II, 1R2R and 1R2S, and 1S2S and 1S2R, were not chromatographically resolved and were seen as two peaks IIA and IIB, respectively. For all extended release formulations the amount of II, IIA and IIB formed were lower relative to the solution but all were equal for ACMB, R-ACMB and S-ACMB. The mean AUCinf ratio of the enantiomers (S/R) in all formulations ranged from 1.4-1.6 for I, from 1.3-1.4 for II and 0.9 for ACMB. Significant differences in S/R ratios were observed between absorption and the elimination phases for I, II and ACMB for the faster inputs (Sol and F) but no difference was observed for the slower inputs (S and C). The differences in rates of metabolism of drug enantiomers with varying input rates may have important clinical implications, because of an altered pharmacodynamic response.

Disintegrants are substances included in tablet formulations to cause the compressed tablet to break apart and promote drug dissolution when placed in an aqueous environment. In the past two decades, three categories of newer disintegrants have come into widespread use. These substances are chemically modified starch (sodium starch glycolate), chemically modified cellulose (croscarmellose sodium) and a synthetic polymer (crospovidone). Because of their high efficiency at low levels of addition compared to traditional starch, these substances are often called "super disintegrants." One objective of this dissertation was to identify among different sources of disintegrants of each type meeting NF standards, differences in physical properties thought to be related to functionality. A second objective was to develop standard performance tests and use those tests to determine the hypothesized relationship between these physical differences and disintegrant functionality. Dissolution was performed on a model tablet formulation of hydrochlorothiazide using either an insoluble filler (dicalcium phosphate dihydrate) or a soluble filler (spray-dried lactose) and test disintegrants at a 1% level. Disintegrants tested exhibited significant differences in the rate and extent of liquid uptake and in the ability to develop axial and radial disintegrating forces. Lowering the pH altered the rate and extent of liquid uptake of sodium-starch glycolate and croscarmellose sodium. Since there are no ionizable groups in crospovidones, lowering the pH did not affect their liquid uptake performance. Sources of crospovidone containing larger particle size fractions showed greater rate of liquid uptake, however crospovidones with greater porosity showed greater extent of liquid uptake. Liquid uptake study on sieve fractions of crospovidones showed greater rate and extent of uptake for larger sieve cuts, whereas smaller sieve cuts of starch glycolates showed greater rate and extent of liquid uptake. For tablets containing water-insoluble filler dicalcium phosphate, disintegration times for sources of crospovidone containing larger particle size were lower and showed correspondingly faster dissolution rates. The rate of disintegration and dissolution followed the same rank order as the extent of liquid uptake. However, when the filler was changed to spray-dried lactose, although the disintegration of all tablets containing different sources of crospovidone was faster than in the insoluble filler, no significant differences were detected in either the disintegration times or dissolution amongst the disintegrants from different sources. Tablets containing croscarmellose sodium or sodium starch glycolate from different sources, in either filler showed no significant differences in disintegration times and their corresponding rates of dissolution were also not different, indicating that dissolution of hydrochlorothiazide is the rate limiting step. This study indicates that liquid uptake study, particle size and porosity should be included in crospovidone monographs, whereas liquid uptake studies and/or settling volume studies in a low pH medium should be included in compendial monographs for sodium starch glycolate and croscarmellose sodium. (Abstract shortened by UMI.)

Patient drug consumption behavior has an impact on the outcomes, effectiveness, and costs associated with therapy. Patients' beliefs influence their health behaviors and little is known about how patients form beliefs. Therefore, an understanding of belief formation will assist professionals in developing interventions that effectively influence health behaviors. This study used the model of belief processing proposed by Smith, Benson, and Curley (1991) to examine the belief formation used by arthritis patients regarding their medication. Study subjects included arthritis patients from a health maintenance organization population. Forty-six subjects were randomly assigned to four groups. Three groups received different levels of information about a drug and were asked about their beliefs regarding its helpfulness. Subjects in the final group were asked about their beliefs regarding the helpfulness of nabumetone, a drug they were currently taking. Verbal protocols were independently coded by three coders using operational definitions from the literature and constructs in the model. The codes were tallied and the hypotheses were tested using ANOVA and MANOVA. Subjects used more practical reasoning than judgments or calculation to form their beliefs. Most subjects used responses that corresponded with two or more modules of the model. Contrary to expectations, providing more information did not influence the use of practical reasoning or judgments. Amount of information also did not influence subjects' use of most argument types. These findings suggest that (1) patients use practical reasoning rather than formal logical reasoning to form beliefs about the helpfulness of medications; (2) the "expectancy x value" approach is not appropriate in modeling the reasoning patients use to form beliefs about their medications; (3) the Smith, Benson, and Curley model contains constructs used by patients to form beliefs; (4) experience decreases the use of authoritative arguments in forming beliefs; and (5) increased information may influence beliefs, but it does not seem to influence the processing used to form beliefs.

This study was designed to add to knowledge in the field of epidemiology and the social behavioral sciences. It is based on the theoretical precepts that there are sociocultural and demographic differences in obesity in African American women, apart from genetic predisposition, that account for excess prevalence. The literature shows that African American women have multiple problems that may contribute to this, including: limited income, mixed beliefs about weight control, multiple health problems, and high preferences for high fat, high sodium, low fiber diets. Forty-one African American Women, 22 volunteer Community Health Workers and 19 volunteers from the University of Maryland at Baltimore secretarial staff were stratified and randomized to an intervention and control group for a twelve week clinical trial of a behavioral intervention designed to decrease consumption of dietary fat as a percentage of total calories, and to increase physical activity levels. The twelve weekly sessions were structured to include both individualized and group interactive teacher-trainer meetings consisting of health education, skills development, demonstrations, recommendations for healthy outcomes, tracking clinical measurements, and facilitated discussions on the concepts of depression, stress, and general well being. Validated instruments were used to collect the outcome measures. The intervention group showed significant improvements over the control group in the reduction of saturated fat, total fat and cholesterol, total body fat, percent of body fat, an increase in lean body mass, a decrease in BMI, and a reduction in the risk factors of diastolic and systolic blood pressures and fasting total cholesterol. There were no significant changes in fasting blood glucose, compared to the control group. Physical activity levels increased in the categories of moderate, hard and very hard activities significantly different for the experimental group as compared to control group. Inference from this study confirm that lack of adherence to diet and weight control and adequate levels of physical activity are rooted in cultural and societal patterns that determine the group's perceptions and beliefs about health and illness as they relate to proper diet and nutrition and adequate physical activity. The study concludes that given a lack of normative values for maintaining a healthy weight, a culturally consistent behavioral change strategy can provide positive social and professional support to initiate, enable, and reinforce changes in behavior in a high risk population.

The objectives of this study were to establish a rational basis for choosing parameters for conducting the tensile strength and indentation hardness test on pharmaceutical compacts, to describe the changes in tableting indices based on the different parameters, to develop a method to spherically crystallize ibuprofen, and to compare the mechanical and micromeritic properties of spherically crystallized ibuprofen and naproxen to the starting materials. This work described the importance of establishing the appropriate test parameters for tensile strength and indentation hardness tests so that reliable and predictive tableting indices could be determined. The fracture strength for diametral compression of ibuprofen compacts was determined for two modes of stress application, constant stress rate and constant strain rate. The tensile strength for diametral compression of ibuprofen and naproxen compacts was determined using a constant strain rate (0.05 to 16 mm/min). The static indentation hardness (Meyer hardness) of ibuprofen and naproxen compacts was determined at varying solid fractions and indentor depth of penetration. Results from these studies were used to establish an appropriate rate of stress application during diametral compression and an appropriate depth of penetration for indentation hardness testing in order to calculate tableting indices. The tableting indices calculated from the aforementioned properties were: the brittle fracture index (BFI), the best case bonding index (BIb), the worst case bonding index (BIw), the brittle/viscoelastic bonding index (bBIv), and the viscoelastic index (VI). In addition, changes in compactibility between the starting materials and their spherically crystallized products were assessed through the analysis of Athy-Heckel profiles. A comparison of micromeritic properties included particle size, porosity, surface area, bulk density, tap density, true density, and flowability as measured by the Carr Index. The spherically crystallized products of ibuprofen and naproxen were shown to be free flowing, less compressible, and more compactible than the starting materials. The spherically crystallized ibuprofen product was optimized for improved tensile strength, bonding index, and minimal particle size using response surface experimental design methodology. Key process factors in the quasi-emulsion solvent diffusion method employed to spherically crystallize ibuprofen were: the amount of additive, hydroxypropylmethyl cellulose, added to the nonsolvent, the agitation rate during the crystallization process, and the amount of agglomerating solvent. Naproxen was spherically crystallized using a solvent change method adopted from the open literature. Thermal analysis and x-ray powder diffraction analysis showed that both ibuprofen and naproxen spherically crystallized products were the same highly crystalline form as the starting materials. The relative contribution of the different micromeritic properties to the changes in the mechanical properties was exemplified by the change in BFI. (Abstract shortened by UMI.)

The issue of stereoisomers in drug development and therapy is becoming increasingly important as a more complete understanding of differences between drug isomers is developed with respect to pharmacokinetics and pharmacodynamics. Mivacurium chloride is a short-acting, non-depolarizing neuromuscular blocking agent. Mivacurium is a mixture of three stereoisomers: the trans-trans, the cis-trans, and the cis-cis diester. The pharmacokinetics and pharmacodynamics of these isomers were investigated in humans and dogs to develop a mathematical model. This model may be used in a closed-loop system to optimize drug administration and patient monitoring and, henceforth, to improve clinical outcomes. A bolus dose (0.01-0.02 mg/kg) and two infusion rates (1.0-1.5 {dollar}\mu{dollar}g/kg/min) of mivacurium were administered to four beagle dogs. Dogs were anesthetized with 5% isofluorane. NMB was assessed by train-of four (TOF) and single twitch stimulation. Each dog received two treatments with a washout period of ten days. Blood samples were collected up to 6 min after the bolus dose, for 4 min after the administration of each infusion and during recovery. Eleven subjects agreed to participate in a pharmacodynamics study. Patients received a bolus dose (0.10-0.20 mg/kg) and sequential infusions of mivacurium as needed to maintain twitch height (TH) 10% baseline. NMB was assessed by TH depression after TOF stimulation. Another group of five subjects, agreed to participate in a pharmacokinetics-pharmacodynamics study. The dosing schedule and monitoring ofthe paralysis was as previously discussed. Blood samples were collected up to 10 min after the bolus dose, and up to 10 min after the administration of the last infusion. Samples were analyzed using a stereospecific KPLC-fluorescence method. Modeling of the data was accomplished using ADAPT II. The pharmacokinetics of the two major isomers of mivacurium in dogs were best described by a two-compartment model. TOF was a more sensitive measure of onset and offset of NMB than TH. Onset of action showed dose-dependence. The pharmacokinetics of isomers of mivacurium were best described by a two-compartment model in three of the five patients. The model developed with the first eleven patients was predictive of the concentration-effect (CE) relationship. The CE relationship was best described by a sigmoid E{dollar}\rm\sb{lcub}max{rcub}{dollar} model in humans and dogs. The value of pharmacokinetics-pharmacodynamics models should be to allow better insight into the principles governing the time course of drug action and to get a better predictive estimate of the patients response to dosing and to improve drug therapy outcomes.

The intermolecular relationship governing the conformational change of the polyanhydride poly(carboxyphenoxypropane-sebacic acid){dollar}\sb{lcub}20:80{rcub}{dollar}, (poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar}) in both solution and solid state was investigated and related to the drug delivery of specifically chosen drugs from a poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} matrix. The occurrence of conformational change, the underlying factors which induce change, and the ultimate impact of conformational change on poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} degradation and drug release were investigated in order to develop a fundamental basis by which formulations and processes could be developed to produce reliable and effective polyanhydride dosage forms. Solution studies carried out in methylene chloride, chloroform, tetrahydrofuran, and dioxane revealed that both the conformation and degradation of poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} were solvent-dependent. Infrared studies in the carbonyl stretching region (1830-1730 cm{dollar}\sp{lcub}-1{rcub}{dollar}) indicated that a stronger polymer-solvent interaction occurred in the chlorinated solvent solutions due to hydrogen-bonding with the carbonyl oxygens. The solutions exhibiting stronger polymer-solvent interactions produced a more expanded conformation determined by intrinsic viscosity studies. Degradation of the polyanhydride linkage was conducted using methanol (2.5%w/v) as the degradative reactant and quantified by an absorbance decrease in the anhydride asymmetric stretch (1815 cm{dollar}\sp{lcub}-1{rcub}{dollar}). The rate of poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} degradation was faster in chloroform and methylene chloride than that in tetrahydrofuran and dioxane. The effect of solvent on degradation was due either to electron-withdrawing or conformational differences between the solvent types. The conformational behavior of poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} in the solid state was evaluated by differential scanning calorimetry (DSC) and infrared analysis of the carbonyl stretching region. At temperatures above 30{dollar}\sp\circ{dollar}C and below the melting point, the polymer was shown to undergo time-dependent conformational changes resulting in increased heats of fusion and melting points. The change in thermal behavior was attributed to hydrogen-bonding detected by an increased infrared shift in the carbonyl stretch associated with the carboxylic acid end group of a poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} film treated at 40, 50, and 60{dollar}\sp\circ{dollar}C.;The effect of drug type and temperature on drug release from a poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} matrix was evaluated by flow cell analysis. Salicylic acid and salicylamide were chosen as model drugs due to their similarity in chemical structure with the exception that salicylic acid had a greater potential for hydrogen bonding due to a carboxylic acid side group. Both drugs exhibited a decrease in drug release with increased dwell temperatures of 40, 50 and 60{dollar}\sp\circ{dollar}C. The release profiles of salicylamide were less affected than salicylic acid, possibly due to hydrogen-bonding differences within the matrix. The salicylic acid release profile was profoundly decreased after storage at 37{dollar}\sp\circ{dollar}C for 12 and 24 hours indicating that drug release may be retarded or prevented due to conformational changes at physiological temperatures. The understanding of the role of temperature and hydrogen-bonding in polyanhydride conformation is recommended as a critical component to the development of a stable poly(CPP-SA){dollar}\sb{lcub}20:80{rcub}{dollar} dosage form.