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PubMed2002

Experimental manipulation of steroid concentrations in circulation and in egg yolks of turtles.

Steroid hormones in egg yolks are increasingly recognized as an important component of maternal and offspring fitness in oviparous vertebrates. Yet, except for in birds, the mechanism by which females allocate these resources is poorly understood. We manipulated systemic levels of hormones in reproductively mature female red-eared slider turtles (Trachemys scripta elegans) with silastic implants to test the hypothesis that hormones are allocated to developing follicles as a quantitative function of circulating levels in the females. Turtles exhibited similar amounts (<1 ng/ml) of circulating steroids (dihydrotestosterone, estradiol-17 beta, or testosterone) in early September immediately prior to experimental manipulation. After treatment with silastic implants, circulating levels of steroids increased markedly. By the following April after hibernation, circulating levels of dihydrotestosterone had returned to preimplantation levels, but circulating levels of estradiol-17 beta and testosterone in estradiol-17 beta- and testosterone-treated turtles, respectively, remained substantially elevated through April. Focusing on testosterone, we detected nearly six-fold higher concentrations in yolk from mature follicles from testosterone-treated turtles than in yolk from mature follicles from control turtles. Our results provide support for the hypothesis that concentrations of steroids in egg yolks of turtles reflect circulating concentrations of steroids during follicular development rather than the hypothesis that females selectively allocate specific amounts of steroid hormones to each egg separately. Our findings also highlight an unambiguous physiological mechanism by which nongenetic maternal effects in oviparous species can directly influence the nutritional milieu experienced by developing embryos.

Animals↗
PubMed2004

Steric stabilization of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes mediates prolonged circulation and tumor targeting in mice.

BACKGROUND: Efficient tumor targeting of polymeric gene transfer systems (polyplexes) represents a major challenge. To establish tumor targeting after intravenous (IV) administration, the circulation lifetime of these systems should be sufficiently long. Since naked polyplexes are rapidly eliminated from the circulation after IV adminstration, strategies have to be developed to improve their pharmacokinetics. METHODS: Complexes of plasmid DNA and poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-graft-PEG or AB di-block copolymers of pDMAEMA and PEG, as well as PEGylated complexes prepared via PEGylation of preformed complexes (postPEGylation), were evaluated for their physicochemical properties (size and charge) their interactions with blood constituents and transfection activity in vitro. The pharmacokinetics and biodistribution of PEG-polyplexes were studied in mice after IV administration. The degree of accumulation in two subcutaneous (SC) mouse tumors after IV administration was evaluated for the system with the longest circulation time. RESULTS: It is shown that the surface charge of the pDMAEMA-polyplexes was effectively shielded by two PEGylation methods (i.e. the use of pDMAEMA-graft-PEG polymers and postPEGylation). The shielding effect was the highest for the postPEGylation method with PEG(20000), yielding polyplexes that hardly show interactions with blood components (i.e. albumin and erythrocytes) and show substantially prolonged circulation time in mice after IV administration. The superior colloidal stability and circulation kinetics of the postPEGylated polyplexes translated into tumor accumulation which amounted to about 3.5% of the injected dose per gram tumor tissue in a SC Neuro2A tumor model and to about 4.2% of the injected dose per gram tumor tissue in a SC C26 tumor model. CONCLUSIONS: This study shows that postPEGylation of pDMAEMA-based polyplexes is the most attractive method to prepare polyplexes with long circulating properties. Tumor targeting capacity after intravenous administration was demonstrated in two subcutaneous tumor models.

Adenocarcinoma↗
PubMed1981

Effects of calcium and calcitonin on circulating levels of glucagon and glucose in diabetes mellitus.

The effects of Ca2+ and calcitonin infusions on circulating glucagon, glucose, C-peptide, Ca2+, and calcitonin were investigated in hyper-glucagonaemic insulin-dependent diabetics. In 14 insulin-deprived diabetics and 12 healthy volunteers 2h infusions of saline (0.154 mol/1), Ca2+ (0.375 mmol/kg body weight), and calcitonin (4.5 IU/kg body weight) were performed. There were no significant changes during saline infusion. In the diabetics, Ca2+ infusions induced a rise of plasma Ca2+ up to 3.2 +/- 0.1 mmol/1 and a fall of circulating glucagon (-26.4 +/- 5.7%; p less than 0.001) and glucose (-23.3 +/- 3.6%; p less than 0.05). Plasma calcitonin rose to twice basal values (p less than 0.025). During calcitonin infusions plasma Ca2+ decreased slightly to 2.1 +/- 0.2 mmol/1; a fall was found in both glucose (-24.4 +/- 4.0%; p less than 0.05) and circulating glucagon (-22.5 +/- 4.3%; p less than 0.001). Two groups of 6 healthy volunteers were subjected to saline and Ca2+, or to Ca2+ and calcitonin infusions. Both Ca2+ and calcitonin infusions induced a fall of serum insulin (-30.1 +/- 6.6%; p less than 0.05). Calcitonin depressed circulating glucagon by -18.6 +/- 4.4% (p less than 0.025), whereas during Ca2+ infusions glucagon decreased only by -6.5 +/- 1.9% (p greater than 0.1). We conclude from our results that an increase of circulating calcitonin induced by Ca2+ infusions or by exogenous calcitonin administration appears to depress elevated circulating glucagon and glucose in insulin-dependent diabetics.

Adult↗
PubMed1994

Circulating forms of immunoreactive parathyroid hormone-related protein for identifying patients with humoral hypercalcemia of malignancy: a comparative study with C-terminal(109-141)- and N-terminal(1-86)-region-specific PTHrP radioassay.

We evaluated the circulating forms of immunoreactive PTHrP in 115 healthy subjects and 122 patients with malignant diseases by using radioassay systems (RAS) specific for the C-terminal (109-141) fragment of PTHrP (C-RAS) and for the N-terminal(1-86) (N-RAS). PTHrP levels in healthy controls ranged from 1.5 to 38.2 (mean: 24.5) pmol/L with the C-RAS and from 0.9 to 2.5 (mean: 1.7) pmol/L with the N-RAS. The ratio of circulating N-terminal fragment (N) to C-terminal fragment (C) of PTHrP was calculated to be about 1: 14.4 in the healthy subjects. Of the 122 patients with malignant diseases, 40 (32.8%) had circulating PTHrP levels undetectable with the N-RAS, but only 11 (9.0%) patients had levels undetectable with the C-RAS. Of the former 122 patients, 41 (33.6%) had high PTHrP as determined with the C-RAS, and 10 (8.2%) had high PTHrP as determined with the N-RAS. The former of these included only 8 (19.5%) HHM patients, while the latter included 8 (80.0%) HHM patients. The circulating N to C ratio was about 1: 70.7 in the HHM patients. The N and C obtained with the different RASs showed a close correlation (r = 0.86). The values also showed a close correlation with serum Ca; r = 0.75 for C-RAS and r = 0.81 for N-RAS. In addition, the correlations between the PTHrP reading obtained with the different RASs and serum Cr were: r = 0.42 with C-RAS and r = 0.26 with N-RAS. The circulating form of immunoreactive PTHrP fragments is therefore comprised mainly of PTHrP(109-141). In contrast, circulating concentrations of the PTHrP(1-86) fragment are very low, but detection of the PTHrP(1-86) fragment with the N-RAS is a more useful indicator of HHM with fewer false positive results and is less likely to be influenced by renal function than the detection of the PTHrP(109-141) fragment with C-RAS.

Adolescent↗
PubMed2002

Circulating CD34+ cells to predict the adequate harvest of peripheral blood progenitor cells in platinum-based chemotherapy.

OBJECTIVE: The aim of this study was to clarify the appropriate timing for peripheral blood progenitor cells (PBPC) harvesting after platinum-based mobilization chemotherapy by measurement of the circulating CD34+ cell concentrations. PATIENTS AND METHODS: PBPC were collected for autotransplantation via a total of 68 leukaphereses in 16 patients with gynecological cancer. Circulating CD34+ cell concentrations were measured by CD34-side scatter parameter analysis. RESULTS: Data could be fitted into a linear regression line described by the equation y = 0.33 + 4.14 x (x) (R2 = 0.256), where y = the number of harvested colony-forming unit granulocyte macrophage (CFU-GM (x10(5)/kg) and x = the percentage of circulating CD34+ cells and y = 1.747 + 44.53 x (x) (R2= 0.475), where y = the number of harvested CD34+ cells (x10(6)/kg) and x = the percentage of circulating CD34+ cells. Failure to mobilize sufficient CFU-GM numbers (>1 x 10(5)/kg) occurred in 29 of 31 leukaphereses when the percentage of circulating CD34+ cells was less than 0.10%. CONCLUSIONS: Harvesting procedure may be avoided when circulating CD34+ cells showed less than 0.10% after platinum-based mobilization chemotherapy.

Adult↗
PubMed1999

Circulating prostate-specific antigen mRNA during radical prostatectomy in patients with localized prostate cancer: with special reference to neoadjuvant hormonal therapy.

To determine the potential risk of hematogenous dissemination of prostate cancer cells during radical prostatectomy (RP), we investigated the pre- and intraoperative circulating prostate-specific antigen (PSA) mRNA in patients with clinically localized prostate cancer, with special reference to neoadjuvant hormonal therapy (NHT). Using a nested reverse transcriptase (RT) polymerase reaction (PCR) assay, PSA mRNA in the peripheral blood was evaluated pre- and postoperatively in a total of 23 patients, 10 of whom received NHT with antiandrogens. The RT-PCR assay employed detected one LNCaP cell in 10(7) mononuclear blood cells, and showed no positive signal in the blood samples from all 15 healthy controls. Pre- and intraoperative circulating PSA mRNA was positive in 11 (48%) and 18 patients (78%), respectively. All 11 patients with positive preoperative PSA mRNA continued to be positive during RP, and seven (58%) of 12 patients with negative preoperative PSA mRNA had a positive conversion. Although the patients' ages, preoperative serum PSA values and clinical or pathological stages were not associated with the pre- and intraoperative PSA mRNA results, the NHT group showed a significantly lower incidence of preoperative PSA mRNA positivity (2/10) than the group receiving RP alone (9/13) (20% vs 69%, P = 0.036). NHT, however, showed no suppressive effect on either intraoperative positivity or positive conversion of circulating PSA mRNA. The present study suggests that a substantial number of patients receiving RP are at risk of hematogenous dissemination, and NHT with antiandrogens has a minimal or no suppressive effect on the circulating PSA mRNA during surgical manipulation of the prostate. Because the clinical significance of circulating cancer cells remains to be determined, long-term follow-up in association with the circulating cancer cells assessed by the RT-PCR is essential in order to establish the role of molecular staging as well as NHT.

Aged↗
PubMed2005

Changing circulation rate of human metapneumovirus strains and types among hospitalized pediatric patients during three consecutive winter-spring seasons. Brief report.

From 2001 through 2004, 808 pediatric patients admitted to hospital because of acute respiratory infections were examined for presence of respiratory viruses by either direct fluorescent staining using monoclonal antibodies or RT-PCR during three consecutive winter-spring seasons. On the whole, 336 (42%) patients were detected as positive for one or more respiratory viruses. The most widely circulating virus was human respiratory syncytial virus (hRSV) infecting 50% of positive patients, followed by human metapneumovirus (hMPV) found in 13% of patients, and then by influenza virus type A, human parainfluenzaviruses and coinfections. Significant variations in the circulation rate of hRSV, hMPV and influenzavirus type A were observed during the individual seasons. In addition, the circulation rates of the different types of hMPV changed yearly. In 2001-2002 and 2002-2003 hMPV circulated at a significant lower proportion than hRSV, while in 2003-2004 the circulation rates of the two viruses were closer. In conclusion, the 4 hMPV subtypes circulated yearly in Northern Italy flanking hRSV as major respiratory pathogens in the infantile patient population.

Child↗
PubMed2006

Relation between plasma oxLDL antibodies and oxLDL in the circulation.

OBJECTIVES: To investigate the possible relationship between circulating oxLDL and oxLDL Ab concentrations in order to better understand the role of oxLDL Ab in atherosclerosis. DESIGN: In a cross-sectional study of 86 patients undergoing ultrasonographic scanning of the carotid artery, concentration of circulating oxLDL and oxLDL Ab were determined by ELISA. For multivariate analysis, we also measured many conventional cardiovascular risk factors. Spearman's rank correlation test and chi-square test were used to evaluate the correlation between circulating oxLDL and oxLDL Ab. A stepwise multiple regression analysis and Logistic regression analysis were used to study the influencing factors. RESULTS: There was no linear correlation between circulating oxLDL and oxLDL Ab. Circulating oxLDL was influenced by HDL, systolic blood pressure and body mass index, while only TC was independent factor associating with oxLDL Ab. CONCLUSIONS: The present study showed that oxLDL was present at a low concentration in the circulation, and that plasma oxLDL had no linear correlation with oxLDL antibodies. However, the issue still needs further study.

Adult↗
PubMed1977

Appearance of circulating DNA during hemodialysis.

The appearance of circulating DNA during hemodialysis was investigated by use of a modified counterimmunoelectrophoresis assay capable of detecting as little as 0.02 to 0.05 microng of native DNA per milliliter of plasma. It was found that free DNA was regularly released during procedure in widely varying amounts which ranged as high as 5 microng/ml. Both the amount of plasma DNA and its rate of appearance increased progressively throughout the procedure and had no temporal correlation with the transitory early leukopenia that was previously described. Circulation in vitro of fresh blood through a dialysis coil also resulted in the appearance of plasma DNA suggesting that passage of blood through the coil itself can account, at least in part, for circulating DNA, presumably by release from leukocytes. Neither the presence (nor reversal) of the uremic state per se nor removal of inhibitors of the assay during hemodialysis are able to account for the findings. Whether free circulating DNA is of clinical importance is, as yet, unknown. A hypothesis is proposed linking chronic exposure to circulating intracellular materials, including DNA, to the accelerated atherosclerosis recently described as a late complication of hemodialysis. Currently, hemodialysis is the only clinical state known to be characterized by the presence of circulating DNA over long periods of time. Since this phenomenon is iatrogenically induced, further exploration of possible pathogenetic implications seems particularly important.

Adult↗
PubMed1978

Vasoconstrictive effects of prostaglandins in sheep placental circulations.

Changes in the uterine and umbilical circulations after intra-aortic injection of prostaglandin E2 (PGE2) or protaglandin F2alpha (PGF2alpha) to either the fetus or the mother have been examined in 13 ewes at late gestation. PGF2alpha vien to either the fetus or the mother is vasoconstrictive in both uterine and umbilical circulations. PGE2 given to the fetus results in a dissociated response with vasodilation of the uterine circulation and vasoconstriction of the umbilical circulation. PGE2 given to the mother causes a uterine contraction that precludes specific hemodynamic analysis. Therefore, exposure of either maternal or fetal ovine circulation to exogenous prostaglandins in associated with acute changes in both placental circulations. Similar responses to pertubations in endogenous prostaglandin levels may exist in pregnant sheep.

Animals↗
PubMed1982

Species differences in circulating prostaglandin metabolites. Relevance for the assay of prostaglandin release.

The profiles of circulating metabolites of prostaglandin F2 alpha were investigated in a number of species, viz. rat, rabbit, guinea pig, cattle and sheep. The aim of the study was to identify in each animal major plasma metabolites that outlast the initially formed, short-lived 15-keto-13, 14-dihydroprostaglandin F2 alpha and might thus serve as better parameters for monitoring prostaglandin production in vivo. Tritium-labeled prostaglandin F2 alpha was injected intravenously and frequent blood samples were collected. The metabolic profiles at different stages were visualized using two-dimensional thin-layer chromatography and autoradiography. Identification of circulating products was achieved by comparison with reference compounds using several chromatographic methods, and by gas chromatography-mass spectrometry in cases where larger amounts of the prostaglandin had been administered. In the rabbit a similar study was also done with tritium-labeled prostaglandin E2. Certain species differences were seen in the removal of labeled compounds from the circulation, the elimination being most efficient in the guinea pig. Further differences were seen in the profiles of circulating prostaglandin metabolites. The first appearing major prostaglandin F2 alpha metabolite was always 15-ketodihydroprostaglandin F2 alpha. However, this compound was later replaced in the circulation by a number of more degraded products, the profiles of which were relatively typical for each species. Thus, in cattle, rat and guinea pig, the earliest-formed metabolites, 15-ketodihydroprostaglandin F2 alpha and its tetranor counterpart, 5 alpha, 7 alpha-dihydroxy-11-ketotetranorprostanoic acid, remained comparatively prominent plasma products, whereas highly polar dicarboxylic acids rapidly dominated the metabolite spectrum in the ovine and lapine circulation. These differences were further supported by separate kinetic experiments, using unlabeled prostaglandin F2 alpha and radioimmunological determination of formed products. These latter experiments also demonstrated further pronounced species differences in the rat of elimination of the different prostaglandin metabolites. A considerable interconversion between prostaglandin E and F compounds was also demonstrated in some species. In conclusion, the traditional prostaglandin parameters in plasma, the 15-ketodihydrometabolites, were found not to be the best parameters in all species. It is suggested that species differences in prostaglandin metabolism are taken ito consideration when the optimal analytical protocol is sought for future biological studies. Some alternatives are suggested in the present paper.

Animals↗
PubMed1983

The relationship between immunization and circulating antigen-specific plaque-forming cells.

The relationship between the appearance of cells producing antibody to tetanus toxoid (TT) in the circulation and the serum titers of anti-TT IgG following booster immunization has been studied. It was found that cells producing anti-TT antibody can be detected in the circulation in a hemolytic plaque assay using sheep red blood cells (SRBC) coated with TT by the chromic chloride method. In symmetric inhibition studies using cells from TT or keyhole limpet hemocyanin (KLH)-immune donors, the homologous antigen inhibited 100% of the PFC with no cross-inhibition. Thus, the plaque-forming cells (PFC) detected in this assay are specific for the immunizing antigen. No evidence of polyclonal B-cell activation in response to TT was found, as shown by a failure to detect any PFC against unmodified or KLH or human serum albumin-treated SRBC. In addition, the increase in total Ig-secreting cells observed in a staphylococcal protein A reverse hemolytic plaque assay was always accounted for by the number of anti-TT antibody-producing cells observed. The peak number of anti-TT antibody-producing cells varied between donors, but the kinetics of their appearance was highly reproducible--none before Day 5, peak numbers between Days 6 and 8, and a sharp decline with only rare anti-TT Ig-secreting cells in the circulation by Day 15 postimmunization. Anti-TT antibody-producing cells appeared in the circulation prior to any detectable increase in serum anti-TT antibody titers, and following the disappearance of PFC from the circulation, there was no further increase in serum IgG anti-TT levels. These observations demonstrate a marked specificity of B-cell activation on boosting with a recall antigen, and a parallelism between the appearance of activated B cells in the circulation and of IgG anti-TT synthesis by the subject as a whole.

Adult↗
PubMed1985

Thyrotropin increases the iodine content of rat circulating thyroglobulin as measured by equilibrium density gradient centrifugation.

In previous work we demonstrated that circulating thyroglobulin contains very little or no iodine. We have now characterized circulating thyroglobulin following administration of thyrotropin (TSH) to determine whether its iodine content remains low or increases after stimulation. The iodine content of circulating thyroglobulin was estimated from its density determined by equilibrium density gradient (isopycnic) centrifugation. TSH stimulated thyroglobulin from 182 +/- 28 ng/ml to 571 +/- 83 ng/ml at 8-14 h. Circulating thyroglobulin in the basal state had a density consistent with very little or no iodine. Its density increased following TSH to a maximum at 8-14 h which was nearly the same as the density of thyroglobulin extracted directly from the thyroid. To determine whether selective peripheral metabolism, based on the degree of iodination, could account for the density shift, purified rat thyroid thyroglobulin was injected into thyroidectomized rats. The density of thyroglobulin remained unchanged for 25 h during which time it was metabolized by more than 97%. Therefore, selective metabolism of thyroglobulin based on iodine content did not occur. We conclude that TSH causes a marked increase in the iodine content of circulating thyroglobulin. It is most likely that in the basal state circulating thyroglobulin comes from selective release of poorly iodinated molecules, while after TSH, it comes from release of previously synthesized, iodinated and stored molecules.

Animals↗
PubMed1995

Circulating antigen: bad or good for immunoscintigraphy?

There is ample evidence to show that circulating antigen can restrict effective localization of radiolabelled murine monoclonal antibodies in human tumours growing as xenografts in Nude mice. This is the result of the formation of immune complexes in the circulation. Surprisingly this effect is not seen in patients with circulating antigen, although immune complexes are formed in the circulation, and immunoscintigraphy is not compromised. Moreover, at least in some situations, the presence and level of circulating antigen correlates positively with the sensitivity of tumour imaging, and circulating antigen can be used as a criterion of patient selection for immunoscintigraphy. The reason for the dichotomy between mouse and man is unclear, and seems to be the subject of little or no current research. The introduction of chimeric or fully human monoclonal antibodies in place of murine monoclonal antibodies means that clinical situations will now mimic more precisely the animal models. The species of antibody complexing with antigen will be homologous to the patients, and this could result in handling of those complexes in a manner different from the handling of complexes with foreign (i.e. murine) antibodies. Clearly this subject warrants further investigation.

Animals↗
PubMed2005

Circulating levels of MCP-1 and eotaxin are not associated with presence of atherosclerosis or previous myocardial infarction.

The chemokines are a family of signalling proteins that participate in regulation of the immune system and have been implicated in the pathogenesis of vascular diseases. Deleting the gene encoding the chemokine MCP-1 in mouse models of atherosclerosis reduces lipid lesion formation and circulating chemokines are upregulated in man immediately following myocardial infarction (MI) or coronary angioplasty. We have therefore investigated whether circulating levels of two chemokines (MCP-1 and eotaxin) differ between subjects with and without atherosclerosis. We have used three different methods of measuring the presence and extent of atherosclerosis in human subjects: duplex ultrasonography of the carotid arteries and clinical diagnosis of coronary heart disease on individuals from the general population and coronary angiography on patients with suspected heart disease. There was no difference in the levels of circulating MCP-1 or eotaxin, measured by ELISA, between subjects with and without atherosclerosis. Furthermore, any increase in circulating MCP-1 following acute MI must be short-lived, since chemokine levels were not different in subjects who had had an MI previously compared to those who had not. We conclude that although there may be a transient increase in circulating chemokine levels following coronary angioplasty, there is no difference in the levels of circulating MCP-1 or eotaxin in subjects with and without atherosclerosis.

Aged↗
PubMed2004

Relationships between bone mass and circulating leptin concentrations in Hutterites.

A limited number of previous studies have shown inverse associations between bone mass or density and circulating leptin in humans. Relationships between bone mass and circulating leptin in Hutterites, who have elevated bone density, are unknown. Knowledge gained from studies in mice suggests that Hutterites exhibit traits consistent with a deficiency in circulating leptin or in leptin signaling. We examined relationships between whole body (WB) and regional (lumbar, total hip, femoral neck, trochanter) bone mineral content (BMC) by dual energy X-ray absorptiometry and circulating leptin in 249 Hutterites (137 female) ages 20-55 years and 72 similarly aged non-Hutterites (37 female). We tested the hypothesis that (1) Hutterites will have low circulating leptin concentrations for a given amount of body fat compared to non-Hutterites, and (2) controlling for body fat, there will be an inverse relationship between BMC and circulating leptin among Hutterites. Hutterites had higher BMC than non-Hutterites at all skeletal sites after adjusting for site-specific bone area, age, and sex (P </= 0.02). Hutterite females had higher leptin concentrations than non-Hutterite females [geometric mean and 95% confidence interval (CI): 18.38 (17.18, 19.67) vs. 14.30 (12.55, 16.28), P </= 0.001) after adjusting for WB fat mass. Hutterite males also had higher leptin concentrations than non-Hutterite males [geometric mean and 95% CI: 6.53 (6.11, 6.98) vs. 5.62 (4.98, 6.35), P = 0.03) after adjusting for WB fat mass. We used backward stepwise regression to determine significant (P </= 0.10) covariates to include in models predicting WB and regional BMC among Hutterites (separately by sex). Subsequently, we entered leptin (log-transformed) to models to test for significance (P </= 0.05). After adjusting for covariates, leptin concentration was not a significant predictor of BMC at any site, in either sex, among Hutterites. It is possible that genetic influences that interfere with hypothalamic leptin signaling, in a manner unrelated to adipocyte leptin production, contribute to elevated Hutterite bone density.

Adult↗
PubMed2006

Effects of aquaculture related stressors and nutritional restriction on circulating growth factors (GH, IGF-I and IGF-II) in Atlantic salmon and rainbow trout.

The effects of aquaculture related stressors on circulating levels of GH, IGF-I and for the first time, IGF-II in Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) were investigated. Specifically, circulating growth factor levels were measured in four different experiments. Two 24 h confinement stressor procedures, (one with Atlantic salmon, the other with rainbow trout); following a hypo-osmotic stressor (freshwater bath) in salt water acclimated, adult, Atlantic salmon; and during a 22 day starvation and re-feeding protocol with juvenile Atlantic salmon. Handling and confinement resulted in significant decreases in circulating levels of all three growth factors in Atlantic salmon, and IGF-I and IGF-II (but not GH) in rainbow trout. A 2-3 h freshwater bath to remove gill parasites on a commercial Atlantic salmon aquaculture operation caused a significant decrease in circulating GH and IGF-I concentrations, but no significant change in IGF-II concentration, 2 days post bathing. Starvation for a period of 15 days in Atlantic salmon resulted in a significant increase in circulating GH levels and a significant decrease in circulating IGF-I and IGF-II. Re-feeding of starved fish for 7 days resulted in a significant decrease in GH to the concentration measured in continually fed fish, however re-feeding did not change plasma levels of IGF-I and IGF-II relative to continually starved fish. The results presented here confirm previously observed handling and confinement stressor induced effects on GH and IGF-I and, for the first time, on IGF-II in salmonids. Furthermore this study confirms the nutritional regulation of GH, IGF-I and IGF-II in juvenile Atlantic salmon.

Animals↗
PubMed2006

Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites.

BACKGROUND: In vitro experiments suggest that circulating metabolites of oxycodone are opioid receptor agonists. Clinical and animal studies to date have failed to demonstrate a significant contribution of the O-demethylated metabolite oxymorphone toward the clinical effects of the parent drug, but the role of other putative circulating active metabolites in oxycodone pharmacodynamics remains to be examined. METHODS: Pharmacokinetics and pharmacodynamics of oxycodone were investigated in healthy human volunteers; measurements included the time course of plasma concentrations and urinary excretion of metabolites derived from N-demethylation, O-demethylation, and 6-keto-reduction, along with the time course of miosis and subjective opioid side effects. The contribution of circulating metabolites to oxycodone pharmacodynamics was analyzed by pharmacokinetic-pharmacodynamic modeling. The human study was complemented by in vitro measurements of opioid receptor binding and activation studies, as well as in vivo studies of the brain distribution of oxycodone and its metabolites in rats. RESULTS: Urinary metabolites derived from cytochrome P450 (CYP) 3A-mediated N-demethylation of oxycodone (noroxycodone, noroxymorphone, and alpha- and beta-noroxycodol) accounted for 45% +/- 21% of the dose, whereas CYP2D6-mediated O-demethylation (oxymorphone and alpha- and beta-oxymorphol) and 6-keto-reduction (alpha- and beta-oxycodol) accounted for 11% +/- 6% and 8% +/- 6% of the dose, respectively. Noroxycodone and noroxymorphone were the major metabolites in circulation with elimination half-lives longer than that of oxycodone, but their uptake into the rat brain was significantly lower compared with that of the parent drug. Pharmacokinetic-pharmacodynamic modeling indicated that the time course of pupil constriction is fully explained by the plasma concentration of the parent drug, oxycodone, alone. The metabolites do not contribute to the central effects, either because of their low potency or low abundance in circulation or as a result of their poor uptake into the brain. CONCLUSIONS: CYP3A-mediated N-demethylation is the principal metabolic pathway of oxycodone in humans. The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.

Administration, Oral↗