Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas.

High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first principles, we designed and synthesized a novel class of cyclic ureas that incorporates this structural water and preorganizes the side chain residues into optimum binding conformations. Conformational analysis suggested a preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl substituents and an enantiomeric preference for the RSSR stereochemistry. The X-ray and solution NMR structure of the complex of HIV-1PR and one such cyclic urea, DMP323, confirmed the displacement of the structural water. Additionally, the bound and "unbound" (small-molecule X-ray) ligands have similar conformations. The high degree of preorganization, the complementarity, and the entropic gain of water displacement are proposed to explain the high affinity of these small molecules for the enzyme. The small size probably contributes to the observed good oral bioavailability in animals. Extensive structure-based optimization of the side chains that fill the S2 and S2' pockets of the enzyme resulted in DMP323, which was studied in phase I clinical trials but found to suffer from variable pharmacokinetics in man. This report details the synthesis, conformational analysis, structure-activity relationships, and molecular recognition of this series of C2-symmetry HIV-1PR inhibitors. An initial series of cyclic ureas containing nonsymmetric P2/P2' is also discussed.

Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450.

BACKGROUND: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. RESULTS: We have synthesized DMP 450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of 10 mg kg-1 DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC90 suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. CONCLUSIONS: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.

Marketing backgrounds and activities of community mental health center CEOs.

More than 300 directors of community mental health centers responded to a survey concerning their marketing training and the marketing activities in which their centers had been engaged. Formal marketing training was found to be in the backgrounds of few of the respondents. The majority had not been engaged in a listing of marketing activities.

Noncompliance with medication regimens.

Noncompliance is a complex problem involving the physician, the patient, and the health care system as contributors and victims. Since identifying noncompliers is not an easy task, the authors review the determinants of compliance and provide several strategies for dealing effectively with noncompliant patients.

Preparation and antiarthritic and analgesic activity of 4,5-diaryl-2-(substituted thio)-1H-imidazoles and their sulfoxides and sulfones.

A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles was synthesized and evaluated as antiinflammatory and analgesic agents in the rat adjuvant induced arthritis assay and the mouse phenyl-p-benzoquinone writhing (PQW) assay. Several analogues were found to be more potent than phenylbutazone and indomethacin. Structure-activity relationships are discussed. One of the compounds, 4,5-bis(4-fluorophenyl)-2-[(1,1,2,2-tetrafluoroethyl)-sulfonyl]-1H- imidazole (8d, tiflamizole), was found to be 8 times as potent as indomethacin in the rat adjuvant induced arthritis assay and is presently undergoing clinical trial as an antiarthritic drug.

Use of vitamin-mineral supplements by AFDC children.

Slightly more than 11 percent of the 1,616 children in Northern Mississippi households receiving Aid to Families with Dependent Children regularly used vitamins, according to the 540 personal interviews conducted in this study. Of the vitamins used, about 20 percent were obtained by prescription. Participation in Early and Periodic Screening, Diagnosis and Treatment (EPSDT) was found not to be related to vitamin use. The pharmacy was the main source of vitamins, which most frequently were those widely advertised on television. It is suggested that pharmacists, physicians, and EPSDT personnel might take a more active role in nutrition counseling. The population is poor by definition and rural by study design. In the face of these facts, it was interesting to find that the most often used vitamin was Flintstones, one of the more expensive brands of children's vitamins. Some other vitamin products used, in descending order of frequency were One-A-Day vitamins, generic prenatal vitamins, and Neo-Vadrin with Iron. Data on shopping behavior and sources of products indicate that the population may not be making the best use of products or funds. Informal counseling by pharmacists at the point of sale has the potential to reduce these problems.

Solutions to the problems of chronic disease management in rural settings.

Recent changes in disease patterns in the United States from acute to chronic disorders and the maldistribution of medical manpower have disproportionately affected rural residents. Programmatic attempts to alter the medical care system in rural areas have traditionally centered on increasing the number of primary providers. In central Mississippi, two innovative alternative models of chronic disease management have been evaluated. The disease focus was high blood pressure and the two management models emphasized: the use of local residents as health facilitators or health counselors, and the use of self-help groups in family and church settings. Eighteen months of outcome data indicated that the health facilitator model was controlling 80 percent of the hypertensives participating; the family-based self-help groups were controlling 90 percent; and, the church-based self-help groups were controlling 79.9 percent. These community-based models of chronic disease management have broad implications for other geographic areas and other chronic disorders.

A study of pharmacists' involvement in drug use by the elderly.

Three hundred elderly persons in a single Mississippi county were interviewed to determine drug use patterns and relationships with pharmacists. Although three-fourths had used the same pharmacy for longer than five years, only one in six used that pharmacy as their usual source for over-the-counter (OTC) drugs. More than eight percent incorrectly identified the use of their prescription drugs and 140 instances of potential drug interaction were identified. Communications with pharmacists were limited, as only one-fifth had talked with the pharmacist at the time their last prescription was filled and only one in six mentioned the pharmacist as someone they would ask about prescription drugs.

Patterns of medication use among children in households enrolled in the Aid to Families with Dependent Children program.

This study examined patterns of medication use among children in 791 families, in two counties in Mississippi, which had children enrolled in the Aid to Families with Dependent Children (AFDC) program. One-twelfth of the interviews were conducted each month via household interviews. Interviews were completed in 540 households containing 1616 children (48.8% male, 80.9% black). Thirteen percent had taken at least one prescription drug and 21.5% had taken at least one over-the-counter (OTC) drug in the previous 2 wk. Analgesics (29.4%), cough/cold remedies (19.2%), vitamins (15.7%), and anti-infective agents (12.4%) accounted for three-fourths of the instances of drug use. Over three-fourths (76.4%) of the prescriptions were new and 61.2% were paid for by Medicaid. Approximately three-fifths (62.7%) of OTC medicine uses were with medications already on hand. For prescription medications the physician was the source of information on use in 87.7% of uses. For OTC use, the comparable percentage was 24.6.

Evaluation of the use of rural health clinics: attitudes and behaviors of primary care physicians in service areas of nurse practitioner clinics.

In response to concerns of the directors of Rural Health Initiative projects in Mississippi, a study was conducted to examine factors related to use of rural health clinics. This report focuses on attitudes and behaviors of primary care physicians in the service areas of four clinics staffed by nurse practitioners. Data for this evaluation were obtained via mail questionnaires sent to 41 primary care physicians in the service areas of the clinics. Usable responses were received from 25 (61.0 percent) of the physicians. The data indicate that a majority of these physicians approve of the nurse practitioner concept. Although there is evidence to support a positive correlation between previous experience and knowledge concerning nurse practitioners and physician acceptance of the nurse practitioner concept, only about half of the physicians reported that anyone had ever contacted them to talk about the clinic. Only about a quarter of the physicians had ever visited the rural health clinic, but 60 percent indicated that they would like to do so. These findings indicate a need to develop closer working relationships with all primary care physicians in the service area of a rural health clinic. The data indicate that when such a closer relationship existed, physicians were satisfied with the outcome of interactions. Twelve (48 percent) physicians stated that they had patient(s) referred to them by the clinic. Among these physicians 77.8 percent were satisfied with the information that they had received on the patient's condition. Fewer physicians (8 or 32.0 percent) reported that they had received a call from the nurse practitioner clinic to consult about one of the physician's patients. The physicians were satisfied with the outcome of the consultation in each instance that was reported.

An investigation of prescribed and nonprescribed medicine use behavior within the household context.

The goal of this study was to study empirically individual and household characteristics and their relation to individual medicine use behavior. The study accounted for 40% of the variance in prescribed medicine use and 20% of the variance in nonprescribed medicine use behavior for 545 AFDC households in Northern Mississippi. Perceived morbidity was the primary mediator of medicine use and 57% of the explained variance in nonprescribed medicine use. Age was a significant contributor to the variance explained in prescribed medicine use behavior. The use of nonprescribed medicines by other members of the household also significantly enhanced individual nonprescribed medicine use. Although many of the other individual and household variables were significant predictors of medicine use behavior they contributed little to the total explained variance. Research concerning medicine use in the context of the household is in the initial stage of theory development.

Attitudes of pharmacy students towards psychosocial factors in health care.

An attitude scale was administered on a cross-sectional basis to pharmacy students in 3 professional years and alumni 1 year post-graduation. The instrument, previously used in a study of social awareness among Canadian health professional students, revealed, on application, that social attitudes tended to decline as students progressed through school. Students with prior degrees had generally higher scores. Male students generally held stronger views than did female students, whether favorable or unfavorable.

Consumer expectations compared to the reported use of pharmacy services in rural areas.

Selected households in three northern Mississippi counties were surveyed to assess their primary medical care needs. Consumers' expectations concerning pharmaceutical services were analyzed. The results indicate that the surveyed population expects comprehensive pharmaceutical services. Patient profiles were the most desired service. Consumers were least interested in pharmacist counseling on health matters unrelated to drugs. Most services, however, are sought and/or delivered less frequently than expected. Pharmacists need to make consumers aware of available services.