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MDMA (3,4-methylenedioxymethamphetamine) use can cause neurochemical, behavioral and endocrine alterations, similar to those produced by exposure to acute stress, suggesting its potential as a "chemical stressor." It is known that stressful stimuli can produce a depression of immune function and an alteration in immune cells distribution. In vitro exposure to MDMA resulted in a modulation of several immune functional parameters such as T-cell regulatory function, cytotoxic T-lymphocyte activity, natural killer cell activity and macrophage function. Administration of MDMA in rats produced a rapid and sustained suppression of induced lymphocytes proliferation and a significant decrease in circulating lymphocytes. These alterations in rat immune function were accompanied by a significant rapid increase in plasma corticosterone concentrations. It was postulated that the result of altered induced proliferation response of lymphocytes could have been due to a combined effect of direct action of MDMA on lymphocytes and to the activation of the hypothalamic pituitary adrenal axis (HPA axis) and/or the sympathetic nervous system (SNS) via central mechanisms. In humans, acute MDMA treatment produced a time-dependent immune dysfunction associated with MDMA plasma concentrations. Although total leukocyte count remained unchanged, there was a decrease in CD4+ T-cells and functional responsiveness of lymphocytes to mitogenic stimulation, while percentage of natural killer cells significantly increased. A rise of cortisol plasma concentrations similar to that observed in the rat model supported the hypothesis of MDMA-induced release of corticotrophin-releasing factor from the median eminence of the hypothalamus and subsequent HPA axis and SNS activation. The present findings indicate that MDMA ingestion may represent a potential health hazard for an increased risk of immune system-related diseases.

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MDMA given at recreational doses (range tested 50 to 150 mg) to healthy volunteers, produced mydriasis and marked increases in systolic and diastolic blood pressure, heart rate, and pupillary diameter. MDMA induced changes on oral temperature. The time course of this observation was biphasic, as a slight decrease at 1 h and a slight increase at 2 and 4 h were observed. MDMA induced a slight dose-dependent impairment on psychomotor performance. MDMA produced a marked rise in plasma cortisol and prolactin concentrations. The elimination half-life of MDMA was about 8-9 h. Drug concentrations increased, and a parallel increase in physiologic and hormonal measures was observed. Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to baseline values 4-6 h after drug administration.

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The purpose of the present work was to investigate the transport of cyclic AMP (cAMP) and analogs in the rat liver. The experimental system was the isolated once-through perfused liver. Transport was measured by employing the multiple-indicator dilution technique. The single-pass recovery of tracer [(32)P]cAMP was equal to 94.4 +/- 1. 4%; no significant extracellular transformation of cAMP occurred during a single passage. The unidirectional influx rates of dibutyryl-cAMP were a saturable function of its concentration, with K(m) = 72.75 +/- 9.24 microM and V(max) = 0.464 +/- 0.026 micromol min(-1) (mL cellular space)(-1). The unidirectional influx rates of cAMP were much lower than those of dibutyryl-cAMP and were a linear function of the concentration (up to 100 microM). The transfer coefficient for influx (k(in)) was equal to 0.860 +/- 0.058 mL min(-1) (mL extracellular space)(-1). cAMP inhibited the influx of dibutyryl-cAMP; the IC(50) was 0.83 mM. The following series of increasing unidirectional influx rates was found: cAMP < monobutyryl-cAMP approximately 2-aza-epsilon-cAMP < rp-cAMPS approximately sp-cAMPS < 8-Br-cAMP approximately dibutyryl-cGMP approximately 8-Cl-cAMP < O-dibutyryl-cAMP. There was no precise correlation between the rates of influx of the various cyclic nucleotides and their lipophilicity. It was concluded that the penetration of cAMP and its analogs into the liver cells was a facilitated process. Lipophilicity was not the only factor determining the rate of transport. The transformation of dibutyryl-cAMP was limited by both transport and activity of the intracellular enzymic systems. The intracellular transformation of exogenous cAMP, however, was limited by the transport process.

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A kinetic model describing the behavior of extracellularly supplied cAMP in the perfused rat liver was derived and compared with experimental data. The model was based on the following conditions and assumptions: a) labeled cAMP is being constantly infused (step input); b) permeation of the cell membrane is an essentially irreversible step (k(in) as transfer coefficient); c) the adenine moiety of cAMP incorporates into a nucleotide pool (km1 as transformation coefficient), which cannot permeate the cell membrane; d) the adenine moiety of cAMP can be transferred from the nucleotide pool to a nucleoside + free base pool (km2 as transformation coefficient), which is able to permeate the cell membrane (k(ef) as transfer coefficient). These events were described by a series of differential equations for which an analytical solution was obtained. Total cellular incorporation of label derived from [3H]cAMP was measured in the isolated perfused rat liver. The equations of the model were fitted to these experimental data by means of a least-squares procedure. In the fitting procedure the previously determined k(in) value (0.55 ml min(-1) ml cellular space(-1)) was used. The model is able to describe the experimental data (correlation coefficient = 0.993 +/- 0.008) with km1, km2 and k(ef) values of 17.11, 0.0948 and 1.385 min(-1), respectively. Simulations revealed the following sequence of decreasing intracellular pool sizes: nucleotide pool > nucleoside + free base pool > intracellular cAMP. The intracellular cAMP concentrations correspond to only 3.2% of the extracellular ones. This low proportion explains why it was generally difficult to detect cAMP in the cell space when this compound was added to an isolated cell system. The model and the parameters determined in the present work can be used to predict intracellular cAMP concentrations in the perfused liver for specific extracellular concentrations.

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OBJECTIVES: To summarize national survey results for key clinical preventive services provided by primary care physicians, characterize the results by demographic and practice attributes of the respondents, and compare the results to those obtained in other studies. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 3881 clinicians who provided primary care at least 50% of their time, randomly sampled from the professional associations representing family practitioners, pediatricians, internists, and OB-GYNs. MEASURES: The Primary Care Providers Survey instrument of 1992, administered through the Office of Disease Prevention and Health Promotion, designed to assess the provision of clinical preventive services by primary caregivers. MAIN RESULTS: Few of the physicians surveyed reported providing most indicated clinical preventive services more than 80% of the time. For the purposes of this paper, > 80% provision of preventive services is considered adequate. Female physicians reported providing more preventive services involving exercise, diet, alcohol/drugs, seatbelts, sexual activity, family planning, immunizations, and screening procedures. Physicians aged < 50 reported providing more preventive services involving smoking, alcohol/drugs, seatbelts, sexual activity, and family planning. Older physicians generally reported more delivery of vaccines and screening procedures. Practitioners from big metropolitan areas reported more preventive services involving alcohol/drugs and family planning while respondents in rural areas reported less immunizations and screening procedures. When analyzed by specialty, physicians reporting the most preventive care varied by type of preventive care. CONCLUSIONS: Small differences in the self-report of provision of clinical preventive services between specialties and demographic subgroups did exist. At the time of this survey, however, no group of primary care physicians reported providing clinical preventive services to their patients at adequate levels.

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The influence of flufenamic acid and other nonsteroidal anti-inflammatories on sulfate transport in the liver was investigated. The experimental system was the isolated perfused rat liver. Perfusion was accomplished in an open, nonrecirculating system. The perfusion fluid was Krebs/Henseleit-bicarbonate buffer (pH 7.4), saturated with a mixture of oxygen and carbon dioxide (95:5) by means of a membrane oxygenator and heated to 37 degrees C. Sulfate transport (equilibrium exchange) was measured by employing the multiple-indicator dilution technique with simultaneous injection (impulse input) of [35S]sulfate. [3H]sucrose (indicator for the distribution of the sinusoidal transit times), and [3H]water (indicator for the total aqueous space). Analysis was accomplished by means of a space-distributed variable transit time model. Flufenamic acid and other anti-inflammatories inhibited sulfate transport in the liver. For a concentration of 100 microM, the following decreasing series of potency could be established: flufenamic acid (53.4 +/- 2.9%) > niflumic acid (41.1 +/- 1.4%) > mefenamic acid (35.6 +/- 3.3%) > piroxicam (16.6 +/- 1.9%) > naproxen (13.5 +/- 8.4)%) nimesulide (11.6 +/- 5.8%). Inhibition of sulfate transport by flufenamic acid was clearly concentration dependent; 250 microM flufenamic acid produced more than 95% inhibition. Flufenamic acid in the range between 50 and 250 microM did not affect the mean transit times of tritiated water (t water) and [3H]sucrose (t suc), the same applying to all other anti-inflammatory agents (100 microM) tested in this work. This means that these agents do not affect vascular and cellular spaces, even when present at high concentrations. The ratio of the intra- to extracellular sulfate concentrations ([C]i/[C]e), generally between 0.4 and 0.5 under control conditions, was affected only by 250 microM flufenamic acid and 100 microM niflumic acid. In the first case, this phenomenon is possibly due to the high degree of transport inhibition (more than 95%), which does not allow a uniform tracer distribution over the whole cellular space during a single passage through the liver. The degree of inhibition of sulfate transport by 100 microM flufenamic acid was a function of the concentration of nontracer sulfate. With sulfate in the range between 1.2 and 25 mM, the inhibition degree increased linearly with the concentration. In the presence of flufenamic acid, the saturation curve of equilibrium exchange showed a substrate inhibition-like phenomenon, which was absent in the control curve. As inhibitors of sulfate transport in hepatocytes, flufenamic and niflumic acids are less active than in erythrocytes by a factor of 10(2). This observation is most probably indicative of structural differences between the hepatic sulfate carrier and the anion carrier of erythrocytes. It is unlikely that the action of flufenamic acid and its analogs on sulfate transport is a consequence of energy metabolism inhibition. Nimesulide is as active as flufenamic or niflumic acid in inhibiting energy metabolism but considerably less efficient as an inhibitor of sulfate transport. Our results as well as literature data reveal that the interactions of the nonsteroidal anti-inflammatories with the liver membranes and intracellular structures are ample and complex. Even at high concentrations, however, these interactions are not so intense as to change the vascular and cellular spaces.

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The following aspects were investigated in the present work: (a) the action of flufenamic acid on hepatic metabolism (oxygen uptake, glycolysis, gluconeogenesis, uricogenesis and glycogenolysis), (b) the action of flufenamic acid on the cellular adenine nucleotide levels, and (c) the transport and distribution space of flufenamic acid in the liver parenchyma. The experimental system was the isolated perfused rat liver. Perfusion was accomplished in an open, non-recirculating system. The perfusion fluid was Krebs/Henseleit-bicarbonate buffer (pH 7.4), saturated with a mixture of oxygen and carbon dioxide (95:5) by means of a membrane oxygenator and heated to 37 degrees C. The distribution space of flufenamic acid was measured by means of the multiple-indicator dilution technique with constant infusion (step input) of [3H]water plus flufenamic acid. The results of the present work indicate that the metabolic effects of flufenamic acid are the consequence of an uncoupling of oxidative phosphorylation, a conclusion based on the following observations: (a) flufenamic acid increased oxygen uptake, a common property of all uncouplers; (b) the drug also increased glycolysis and glycogenolysis in livers from fed rats (these are expected compensatory phenomena for the decreased mitochondrial ATP formation); (c) flufenamic acid inhibited glucose production from fructose, an energy-dependent process; (d) the cellular ATP levels were decreased by flufenamic acid whereas the AMP levels were increased; and (e) the total adenine nucleotide content was decreased by flufenamic acid and uric acid production was stimulated. Indicator-dilution experiments with flufenamic acid revealed that this substance undergoes flow-limited distribution in the liver and that its apparent distribution space greatly exceeds the aqueous space of the liver. Flufenamic acid changed its behaviour when the portal concentration was increased from 25 to 50 microM. At 25 microM the initial upslope of the outflow profile clearly preceded that of all other concentrations. From the trend of the curves obtained with 50, 100 and 250 microM, one would expect an initial upslope situated at the right of the 50-microM curve. Furthermore, the time of appearance of flufenamic acid in the outflowing perfusate was practically the same irrespective of the portal concentration. For theoretical reasons one would expect progressively longer appearance times when the portal concentration was decreased. It is possible that the amount of flufenamic acid bound to the cell membranes during the early stages of the infusion produced changes that enabled these structures to bind a larger quantity of the drug than originally possible.

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