The Federal Policy for the protection of human subjects in research is built on a positivist ideology which effects Institutional Review Boards (IRB) and the research it reviews. An ideological criticism of the regulations through a positivist and postmodernist perspective reveals its initial purpose for biomedical research and its negative effects on research not discussed during its development. Such effects are a shift in focus on regulation over ethics in IRBs, extended oversight of regulations, revisions in research design and objectives, and self-regulation through the punishment of noncompliance.

Background: In the bone marrow, hematopoietic and mesenchymal stem cells form a unique niche, in which oxygen tension is low. Hypoxia may have a role in maintaining stem cell capacity for self-renewal and multipotency. We have shown previously a positive influence of platelet-derived growth factors (PDF) on increase of multiplication rate of human mesenchymal stem cells cultured in normal atmosphere. Objective: The goal of this study is to examine effects of platelet-derived factors and thrombin on multiplication of adult human mesenchymal stem cells derived from bone marrow (hBMMSC) in a low or in a high oxygen environment in vitro. Hypothesis: It is hypothesized that PDF will have no effect on multiplication of BMMSC cultured in a low oxygen environment and that thrombin will have no effect on multiplication of BMMSC in either low or high oxygen atmosphere. Materials and methods: Adult human mesenchymal stem cells isolated from bone marrow aspirate (Lonza) were used. Cells were grown in plastic flasks or dishes. The human mesenchymal stem cell basal medium (Lonza) was supplemented with adult human serum with or without PDF or with or without thrombin. High and low oxygen environment (Biospherix) was applied during expansion of hBMMSC. Results: Cultivation medium containing PDF in 5% oxygen increased multiplication rate of hBMMSC. Thrombin addition to the cultivation medium had a positive influence on cell multiplication in 21% oxygen atmosphere, but not in presence of 5% oxygen. Conclusions: PDF enhanced proliferation of hBMMSC grown in 5% oxygen when compared to controls. Thrombin had a stimulatory effect in 21% oxygen environment. These findings will be utilized in an optimized protocol used for cultivation of hBMMSC preceding their clinical application. The hBMMSC need to be grown in physiological conditions and for the shortest cultivation period possible. 6

Intravenous administration of tetracycline has been known to result in fatty degeneration of the liver. This study was undertaken in order to elucidate some of the actions of tetracycline on mammalian cells in culture and to attempt to relate these findings to the clinical condition of fatty degeneration of the liver mentioned above. It is suggested that lipid accumulation occurring after tetracycline administration is possible the result of a decrease in B-lipoprotein synthesis and enzyme inhibition. These factors could result from the high blood levels of tetracycline seen after large and rapid intravenous injections of the drugs into normal patients or those suffering from kidney impairment.

This study was conducted in an attempt to define the anti inflammatory efficacy of cryogenine, the major alkaloid of Heimia salicifolia Link and Otto. The anti inflammatory effects produced by cryogenine, phenylbutazone, indomethacin, mefenamic acid, paramethasone, hydrocortisone and 6-mercaptopurine were compared considering the sequential changes in various motameters during the course of adjuvant-induced polyarthritis in rats. Polyarthritis was induced by the subplantar injection of a suspension of heat-killed Mycobacterium butyricus in mineral oil into the right hind paw of Sprague-Dawley rats. The manifestations of the diseases were monitored in terms of hind paw swelling, subjective appearance of secondary lesions, impairment of body growth, and various hematological/serological changes. Effects produced by cryogenine in ganglia and acute cardiovascular interactions with various mediators of inflammation and vasoactive agents were also investigated in the rat. Although cryogenine is structurally unrelated to any known class of anti inflammatory, antipyretic or analgesic compounds, it has been shown to be effective in several experimental inflammatory conditions which respond to the anti inflammatory drugs presently in clinical use. Its nonspecificity of action against neuro- and tissue hormones suggest that its anti inflammatory activity is not related primarily to inhibition of acute phase reactants or to peripheral neurotrophic effects. Involvement of the pituitary-adrenal axis in the therapeutic efficacy of cryogenine seems improbable.

It would seem appropriate that studies be conducted on the development of an oral inhalation dosage form antinauseant. The present project will consist of developing and testing a series of aerosol formulations to determine their feasibility in antinauseant therapy. In vitro pressure, valve release, spray pattern, particle size, and aging studies will be performed. The present work will also include an in vivo evaluation of promising formulations.

One intent of this study was to detect and to define any antibradykinin capacity that cryogenine may have using both in vivo and in vitro pharmacological models. The activity of cryogenine in these tests was compared to a variety of clinically-proven anti-inflammatory compounds as well as to other agents known to possess anti-inflammatory activity in certain experimentally-induced inflammations. Cryogenine is an unusual anti-inflammatory agent since it is an alkaloid - all of the commonly used anti-inflammatories (aspirin, phenylbutazone, indomethacin, etc.) are organic acids.

An in vitro method was tested whereby the processes of dissolution and distribution of active ingredient into a lipoid solvent were combined in one model and evaluated. The objectives of this research project were: (1) to evaluate the efficacy of the in vitro model known as the Desaga Resomat, in the testing of gastrointestinal absorption; (2) to apply the procedure and instrument to a group of therapeutically important products in determining their absorption characteristics; (3) to graphically illustrate the absorption profile of a specific drug as per cent absorbed vs. time, simulating in vivo absorption; (4) to compare the profile data with experimentally determined dissolution studies; (5) to relate, biopharmaceutically the application of the profile data to absorption characteristics. A literature survey was performed including the history of dissolution rate methodology and its influence on the bioavailability of medication from the dosage form. A discussion of tile experimental procedure was presented including the graphical illustration of tile resorption profiles for the three commonly known drugs used in the verification of the apparatus. The method was applied to a group of therapeutically important products, specifically, thiazide diuretics as well as non-thiazide diuretics such as Spironolactone, Acetazolamide, Ethacrynic Acid, Chlorthalidone, and Furosemide. Dissolution properties for each drug were determined using the Desaga Resomat as well as the '"Beaker Method" of Levy and Hayes. The method used in this work involved the use of a glass model apparatus which showed the basic physical and chemical principles of the absorption process, namely, the solubility of a drug in the aqueous phase and its distribution into a lipoid phase. The dosage form was placed into an aqueous buffered solution. The pH of the buffered solution was adjusted so as to correspond to the pH of the gastro-enteral system. As a result of pressure changes corresponding to peristalsis the dissolved drug passed through a sinter and was then subjected to distribution, with a suitable lipoid solvent. The absorption profiles were determined by measuring, spectrophotometrically, the concentration of the drug in the lipoid phase. Graphical displays were constructed representing the solubility and distribution of the drug at specific pH-time-intervals.

Local burn therapy usually includes the application of medicated ointments and dressings in order to minimize and eradicate infection. As this approach to local therapy may present problems regarding application and removal techniques, it was the purpose of this study to formulate a topical dosage form that may be applied to denuded areas of the skin without inunction. Using the concept of topical films, a dosage form was formulated that is highly water soluble, flexible , and adherent to both denuded and intact areas of the skin.

The purpose of this research was to investigate home intravenous antibiotic therapy (HIVAT) in a multicenter, retrospective study in 1986 and 1987. The stability of reconstituted ceftizoxime and cefonicid in normal saline were evaluated by HPLC to investigate their usability for HIVAT. Using the three HHCPs' records, 457 patients were screened, and 30 patients were randomly selected/HHCP/year using the study's inclusion criteria (n = 180). Outcomes of HIVAT for osteomyelitis patients (n = 90) were compared with that for osteomyelitis inpatients (n = 13) discharged to HHCP1 from the referral hospital. Outcomes were classified as "success", "complication", and "failure". Types and frequency of problems were categorized as problems with antibiotics, and problems with administration procedures. Demographic data were analyzed to test the homogeneity of each group of patients. Data were analyzed using ANOVA, chi-square test, Kruskal-Wallis test, and multiple comparisons among proportions. (Abstract shortened with permission of author.)

Tumor necrosis factor is a cytokine which has specific, rapid cytolytic activity against susceptible animal tumors and human tumors in nude mice suggesting antitumor activity in humans. It has also been implicated as an important mediator of the lethal effects of endotoxic shock and cachexia of chronic infection. This phase I study aimed to investigate toxicity, tolerance and some metabolic effects of recombinant tumor necrosis reactor (rTNF) administered as a continuous infusion to cancer patients. Fourteen patients received treatment at two consecutive dose levels and dosages were administered on a microgram/m$\sp2$ basis. Patients were monitored closely for signs and symptoms of toxicity. Besides, several studies were conducted to investigate physiological and metabolic effects plus pharacokinetic behavior and therapeutic potential of rTNF administered to cancer patients. Systemic symptoms of mild fever, chills, and rigors were the most frequently seen evidence of rTNF toxicity at all dose levels. Reductions in WBC and platelet counts were observed regularly at the highest dose level, but none were clinically significant. No significant alteration in the biochemical parameters was found that could reflect some organ damage or reduced function even at highest dose levels. Elevations in C-reactive protein were observed in all patients at all dose levels, demonstrating an acute phase response of the body towards rTNF administration. Besides an elevation of serum ferritin and drop in serum iron at highest doses suggesting some type of protective mechanism against that rTNF insult. There was no change in heparin-releasable serum lipoprotein lipase levels despite increase in serum triglycerides, measured during a meal profile test, at highest doses of rTNF. This might suggest that the effects of rTNF on lipid metabolism may be directed more toward lipogenesis rather than increased lipolysis in peripheral adipocytes. No potential therapeutic effect of rTNF was observed in this advanced cancer opulation suggesting the need for altering dose regimens (with minimal toxicity possible), or use of combination or local therapy, or use of this agent in less advanced disease.