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Biomedical subjects

R A Freeman

Publications and source records attributed to R A Freeman.

At least 19 recordsLinked to original sources
PubMed2001

Synthesis and structure-activity relationships of naphthamides as dopamine D3 receptor ligands.

A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D2 and D3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19-25), (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo[3.3.1]nonan-3beta-yl)-4-bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D2 and D3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D3 dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D2 and D3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity at D3 receptors, or (c) decrease the affinity at D2 receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K(i)) values of 1.8 and 0.2 nM for D2 and D3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K(i) values of 62.8 and 2.4 nM for D2 and D3 receptors, respectively. Radioligand binding results for sigma receptors indicated that the structure of the amine moiety and the N-(1-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the sigma1 and sigma2 sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3beta-yl central ring were found to be selective for sigma2 receptors.

Animals↗
PubMed2001

Synthesis of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole analogues and their binding affinities for dopamine D(2) and D(3) receptors.

A series of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole derivatives was prepared and their affinity for dopamine D(2) and D(3) receptors was measured using in vitro binding assays. Several oxadiazole analogues were also prepared and tested for their affinity for dopamine D(2) and D(3) receptors. The results of receptor binding studies indicated that the incorporation of an imidazole moiety between the phenyl ring and the basic nitrogen did not significantly increase the selectivity for dopamine D(3) receptors, whereas the incorporation of an oxadiazole at the same region resulted in a total loss of affinity for both dopamine receptor subtype binding sites. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinomethyl)imidazole (5i), which has a D(3) receptor affinity of 21nM and a 7-fold selectivity for D(3) versus D(2) receptors. The binding affinity for sigma(1) and sigma(2) receptors was also measured, and the results showed that several analogues were selective sigma(1) receptor ligands.

Animals↗
PubMed2000

Characterization of (125)I-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors.

The properties of an (125)I-labeled structural analog of 2, 3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3. 1]nonan-3beta-yl]benzamide (MABN), (125)I-IABN, are described. (125)I-IABN was developed as a high-affinity radioligand selective for the D2-like (D2, D3, and D4) dopamine receptor subtypes. (125)I-IABN binds with picomolar affinity and nonselectively to rat D2 and D3 dopamine receptors expressed in Sf9 and HEK 293 cells. (125)I-IABN binds with 7- to 25-fold lower affinity to human D4.4 dopamine receptors expressed in HEK 293 cells. Dissociation constants (Kd) calculated from kinetic experiments were in agreement with equilibrium Kd values obtained from saturation binding studies. Saturation plots of the binding of (125)I-IABN with rat caudate membrane preparations were monophasic and exhibited low nonspecific binding. The pharmacologic profile of the binding of (125)I-IABN to rat caudate was consistent with a D2-like receptor, suggesting that the ligand binds primarily to D2 dopamine receptors. In addition, IABN was found to bind with low affinity to D1 dopamine receptors, as well as to the sigma1 and sigma2 receptor subtypes. Quantitative autoradiographic studies using rat brain slices indicate that (125)I-IABN selectively labels the striatum and the olfactory tubercle area, which is consistent with the labeling of D2-like receptors. IABN blocks dopamine-dependent inhibition of adenylyl cyclase activity at D2 or D4.4 receptors expressed in HEK cells. Therefore, (125)I-IABN appears to be a high-affinity, selective antagonist at D2-like dopamine receptors. Finally, a unique property of the azabicyclononane benzamide (125)I-IABN compared to previously studied substituted benzamides is that the binding of this radioligand is not effected by variations in Na(+) concentration.

Animals↗
PubMed1994

The use of pharmacoeconomic data in formulary selection.

Pharmacists are encouraged to improve their knowledge and use of pharmacoeconomic data in formulary selection. The formulary selection process has changed significantly in recent years. Among its most significant uses is its potential for cost containment strategies. An overview is presented of the origin as well as the potential impact of pharmacoeconomic data. The need to balance the economic benefit with the clinical advantages for any proposed new drug for formulary inclusion remains the most critical decision to be made by pharmacists.

Cost Control↗
PubMed1994

Minimizing bias in industry-sponsored outcomes research.

Industry-sponsored research is receiving a considerable amount of attention from public policy makers and private sector decision makers on issues such as bias, objectivity, ethical conduct, and methodological standards. In the case of outcomes research, industry sponsorship often carries the burden of perceived bias and lack of creditability simply because the research has direct, transparent linkages with drug marketing activities. There are, however, widely accepted principles for conducting and assessing good outcomes research, and these should be followed regardless of the funding source and regulatory initiatives.

Bias↗
PubMed1993

A physiologically based model for gastrointestinal absorption and excretion of chemicals carried by lipids.

Pharmacokinetic models which incorporate independently measured anatomical characteristics and physiological flows have been widely used to predict the pharmacokinetic behavior of drugs, anesthetics, and other chemicals. Models appearing in the literature have included as many as 18, or as few as 5 tissue compartments. With the exception of the multiple-compartment delay trains used by Bischoff to model the delays inherent to the appearance of drug metabolites in bile and segments of the intestinal lumen, very little effort has been made to incorporate the available information on gastrointestinal anatomy and physiology into more accurate gastrointestinal absorption/enterohepatic recirculation submodels. Since several authors have shown that the lymphatic system is the most significant route of absorption for highly lipophilic chemicals, we have constructed a model of gastrointestinal absorption that emphasizes chylomicron production and transport as the most significant route of absorption for nonvolatile, lipophilic chemicals. The absorption and distribution of hexachlorobenzene after intravenous vs. oral dosing are used to demonstrate features of this model.

Animals↗
PubMed1990

A two-channel hypothesis for regulation of cell division and differentiation.

We propose the hypothesis that extracellular regulation of cell division and differentiation acts through just two communications channels. These channels consist of a series of redundant components: extracellular messenger hormones; these hormones' receptors; cytoplasmic proteins activated by the hormone-receptor complex; and trans-activating nuclear regulatory proteins. One channel, here labeled "D" ("differentiate"), includes transforming growth factor-beta as one of its hormones; the other, labeled "G" ("growth") includes epidermal growth factor. We postulate that signal reception occurs as a result of competition between different actuating proteins for equilibrium-controlled binding to critical DNA sites. Stem cells commit to mitosis when some high proportion of critical sites is occupied by actuating proteins of the G class, and to terminal differentiation when a high proportion is occupied by "D" actuators. Intermediate occupancy can either lead to division into one differentiated and one stem cell, or to maintenance of cells in the reference state, quiescence. Equilibrium control of binding implies that critical site occupancy will be proportional to the relative concentrations of "D" and "G" actuating proteins in the nuclear fluid. These concentrations depend on the external hormone concentrations, the numbers of receptors on the cell membrane, and the coefficients of the rate-determining steps between internalization of the hormone-receptor complexes and activation of the actuating proteins. All of these quantities can be affected by various factors, including endocrine hormones. This model is consistent with most reported behavior of various growth factors, interferons, etc, toward a variety of cells in culture. It predicts that under otherwise constant conditions, high relative concentrations of a D-hormone (e.g. transforming growth factor-beta) will induce commitment to terminal differentiation, while high relative concentrations of a "G" hormone (e.g. epidermal growth factor) will induce mitosis. We have seen no report of an experiment which adequately tests this prediction. The model implies that cancer causing mutations are those which increase the relative intensity of the "G" signal; this can occur via changes in components of either channel. Such mutant cells should be both more likely to divide and less likely to differentiate than normal stem cells. Conversely, mutations which increase relative sensitivity to the "D" signal during embryonal development can lead to premature differentiation, cessation of growth, and structural abnormalities (terata).

Animals↗
PubMed1989

Physiological pharmacokinetic model of hexachlorobenzene in the rat.

A physiologically based pharmacokinetic model was developed to describe the distribution of hexachlorobenzene (HCB) in the rat after oral administration or injection. The model was based on flow-limited blood perfusion of HCB to tissues and organs of the body. A set of simultaneous differential equations were solved for the different tissue concentrations as a functions of time. The model allowed for elimination of HCB by excretion. The model also allowed for differential growth of various tissues over the course of an experiment. Computer simulations using the model indicated that growth of animals during the course of dosing experiments can greatly increase the apparent half-life of HCB.

Animals↗
PubMed1986

Designing new substance abuse treatment services for a competitive environment.

A multivariate analysis of the relationships between service attributes and physician perceptions was conducted as an approach to marketing substance abuse treatment services. The results of this attribute-perceptive-preference study indicate: the physician(s) on staff attribute makes the greatest contribution to perceived quality and efficiency; easy referral admission makes the largest contribution to accessibility perceptions; and providing feedback produces the greatest contribution to perceived continuity. The JCAH attributes neither adds to nor subtracts from the perceptions of any of the four perceptual attributes. Other findings indicate that perceived efficiency produces the greatest contribution to overall consumer preference. Quality perceptions make the second largest contribution to overall preference, followed by continuity and accessibility perceptions.

Community Mental Health Centers↗
PubMed1986

Attitudes of Nigerian physicians toward a National Health Service.

Despite efforts to improve health services in Nigeria, considerable problems in distribution and access persist. At present, the health care system in Nigeria is organized and financed at the states' level rather than at the national level. A severe maldistribution of resources exists, as does a lack of coordination among states. An alternative system, albeit expensive, is a National Health Service (NHS). The purpose of this research is to quantify physicians' attitudes towards the concept of NHS. Although physicians in Nigeria are mandated to provide government-funded support, a substantial private practice thrives. Accordingly, physicians' attitudes that may be transferred into behavior are a major determinate of a potential NHS' long term success. In summary, Hausa physicians from the north tended to be more favorable to NHS than did others. Also, younger physicians and those who believed Nigeria's present system to be inadequate favored NHS. There was no association between a physician's gender, locus of medical education, and source of support for medication education and attitude. Finally, physicians in private practice and those in urban areas held more negative attitudes. In spite of Nigeria's present difficulties, a NHS may become a viable alternative. At this point, the overall concept is not opposed by physicians.

Adult↗
PubMed1986

Comparative fire risk study of PCB transformers.

A risk assessment comparing the acute effects of mineral oil and PCB-askarel dielectric fluids in two transformer sites was performed. The first site has the installation characteristics for a PCB-askarel-filled transformer with sprinkler fire protection. A risk comparison is made between two types of transformers (PCB-askarel-filled and mineral oil-filled) for this site. The second site (a vault) has the installation characteristics for a mineral oil-filled transformer, and a risk comparison is made in a fashion similar to the first site. Risk is expressed in terms of frequencies of one or more acute injuries or fatalities per transformer year.

Accidents↗
PubMed1986

Students' attitudes toward university health services.

This study measured students' attitudes toward a university's student health services (SHS) and identified factors that were related to their attitudes. A questionnaire surveying students' attitudes was administered to a sample of 150 students at the Oxford Campus of the University of Mississippi. Analysis of the data revealed that students' attitudes had a statistically significant correlation with the following variables: perceived medical care cost, amount of health information/education received during medical encounters, time spent in the waiting room of the SHS, sex of the student, and income of the student. There was no significant relationship between attitude and age.

Adult↗