Two parallel trials were carried out with levothyroxine sodium salt in 50 and 100 microg strengths, respectively, giving 100 microg day-1(50x2 microg day-1 or 100x1 microg day-1) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 microg day-1 of thyroxine sodium salt were enrolled in each trial. They were clinically and chemically euthyroid. Each trial lasted 114 days, with 57 days being devoted to the first treatment (test or reference) and 57 days to the other (reference or test), according to a two-period, two-sequence, two-formulation design in a steady state without wash-out. The test formulation was prepared with a technological improvement and is being produced to replace that at present on the market. Serum concentrations of free and total levothyroxine, and free and total levotriiodothyronine were assayed repeatedly during the treatment and in timed samples after the last dose of each formulation, using radioimmunoassays. Cmax and AUCss,tau were considered to be target parameters for bioequivalence which was assessed through 90% confidence intervals in the 0.80-1.25 range, as required by EU and US FDA operating guidelines. The results have shown that of these hormones, the free and total parent compound thyroxine is that which most clearly showed a peak after dosing, whereas its metabolite, free and total triiodothyronine, fluctuated around pre-dose concentrations. Bioequivalence was fully assessed with Cmax and AUCss,tau, with all four hormones tested and at both strengths administered. The two test formulations in 50 and 100 microg are thus bioequivalent with the two reference preparations. Tolerability was very good in all cases.

Adult↗

PubMed1999

High prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in northern Italy for initial screening.

To establish the prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in Northern Italy, we evaluated 25-hydroxyvitamin D (25(OH)D) levels in 570 postmenopausal women who had been consecutively referred to our clinic in the 12 months beginning October 1995. Parathyroid hormone (PTH), serum calcium (Ca), creatinine (Cr) and osteocalcin (OC), urinary calcium (Ca24h) and creatinine (Cr24h), and the bone mineral density of the lumbar spine (LBMD) and femur (FBMD) were also measured. 1,25-Dihydroxyvitamin D (1,25(OH)2D) concentrations were measured in 23 women. All women had normal electrolyte serum concentrations and kidney function. Mean +/- SD 25(OH)D concentration was 18.3 +/- 8.3 ng/ml. A significant (p < 0.001) seasonal variation was seen for both 25(OH)D and PTH. Women were divided into two groups based on their vitamin D status: low vitamin D status (25(OH)D < 12 ng/ml, n = 161, 28%) and normal vitamin D status (25(OH)D > or = 12 ng/ml, n = 409, 72%). Hypovitaminosis D was found in 38.5% of all the women in the time period December-May and in 12.5% in the other half-year; among women > 70 years old 51% had hypovitaminosis D in the time period December-May and 17% in the other half-year. PTH was significantly (p < 0.05) increased, and Ca24h, OC and FBMD significantly (p < 0.05) decreased in women with hypovitaminosis D. 1,25(OH)2D positively correlated with 25(OH)D (p < 0.0001), but did not correlate with PTH, age or creatinine clearance. In conclusion, hypovitaminosis D is an important, underestimated problem in Italian free-living postmenopausal women referred to an outpatient osteoporosis clinic.

25-Hydroxyvitamin D 2↗

PubMed1999

[The temples of Asclepius].

Explore the source record for details and available documents.

Greece, Ancient↗

PubMed1998

Glucocorticoid resistance and the immune function in the immunodeficiency syndrome.

Glucocorticoids, the final product of HPA axis, and their receptors (GRs) on mononuclear cells are crucial mediators in the endocrine-immune interaction. An alteration in GRs involving a lower receptor affinity (Kd) for glucocorticoids has been found in a group of advanced AIDS patients, who developed Addisonian symptoms (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis) in spite of hypercortisolism and normal or slightly elevated values of ACTH (AIDS-GR). In these patients, data for the suppression test showed decreased cortisol and ACTH suppression in response to exogenous dexamethasone. The inhibitory effect of dexamethasone on radiolabeled-thymidine incorporation in mononuclear cells from these patients was also reduced. Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/l that was higher than that of other AIDS patients (AIDS-C) (2.9 +/- 0.8 nmol/l) and normal subjects (2.0 +/- 0.8 nmol/l: p < 0.01). Correlations were found between plasmatic IFN-alpha and receptor Kd on monocytes of AIDS-GR (r = 0.77). Poly (i)-poly (c)-induced IFN-alpha production by monocytes was inhibited by glucocorticoids in the AIDS-C group and controls (approx. 80% in both groups): The effect was reversed by the receptor antagonist RU-486. By contrast, glucocorticoid did not inhibit IFN-alpha production in AIDS-GR group. In conclusion, levels of plasmatic IFN-alpha, a cytokine with antiviral properties, may be increased several times, and dexamethasone fails to inhibit monocytes' IFN-alpha production only in AIDS with cortisol resistance, a disturbance that confirms an important immunoregulatory role of glucocorticoids in HIV disease.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Within-patient variability of hormone and cytokine concentrations in heart failure.

Several studies on disease and treatment effects on neurohormones have been conducted with small numbers of patients, using one blood sample as representative of their states. The aim of this study was to assess the within-patient variability of plasma concentrations of several hormones and cytokines of recent interest, in patients with moderate heart failure and controlled stable background therapy over 3 weeks. Blood for neurohormone and cytokine assays was sampled in duplicate from 18 patients with moderate heart failure. After an initial visit, the patients were kept on stable therapy until the second blood sampling 21 +/- 3 days later. The plasma concentrations of several neurohormones (endothelin, renin, angiotensin II, aldosterone, norepinephrine) and cytokines (interleukin-6 (IL-6), interleukin-13 (IL-13), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF) and soluble receptor type I of tumour necrosis factor-alpha, (sTNF-RI) were measured with immunochemical methods. Some cytokines (IL-13, CNTF and LIF) were not detected. Despite clinically satisfactory ACE inhibition, circulating angiotensin II and aldosterone levels were still elevated in some patients, suggesting aldosterone escape. The between-visit agreement of plasma concentrations measured in duplicate was less than 35% for all circulating factors, except renin which showed a higher variability throughout the 3-week study period.

Aldosterone↗

PubMed1998

Microbial and fungal contamination contributes to physical stress in space flight: studies in the Euromir-95 mission.

Astronauts are subjected to flight-induced physical and psychic reactions which may be health threatening in the long term. Stress is a basic component of space missions, where astronauts are confined in a reduced volume, live in a hostile environment, have limited contact with the rest of the world and undergo a severe work load. Chronic stress in microgravity stimulates the HPA (hypothalamo-pituitary-adrenal) axis in astronauts with consequent hypercortisolim. Stress also stimulates the autonomic nervous system. Both increased cortisol and adrenergic stimulation suppress the immune function. For these reasons we developed experiments to contemporaneously measure the autonomic, HPA-axis and immune function in space missions. All measures are made with non-invasive methods. Autonomic adaptation is measured by spectral analysis of ECG derived interval, arterial pressure and respiration. HPA-axis function is assessed by measuring cortisol, F-Testosterone and DHEA in saliva. Immune function is monitored by measuring cytokine production and Th1/Th2 balance in saliva. Till now these experiments were performed on the ground. On 1998-99 space experiments will be performed and space technologies will be set up in collaboration with DMR company (Varese), to allow astronauts to measure stress factors directly in space. I.R.C.E.A. research, sponsored by the Italian Space Agency and selected by ESA and NASA, is focused on conditions which influence health in space flight: in particular, stress and microbial contamination. These two conditions are strictly correlated as infections causes stress and stress, by inhibiting the immune system, makes infection easier.

Adaptation, Physiological↗

PubMed1997

Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.

This randomized, double-blind, placebo-controlled study shows that 20-week fluvastatin treatment induces beneficial changes in the lipid panel and a shift in the fibrinolytic pathway toward activation through a decrease in tissue plasminogen activator antigen. Fluvastatin treatment causes no variation in lipoprotein(a) circulating levels.

Aged↗

PubMed1997

Glucocorticoids and the immune system in AIDS.

An interesting aspect of HIV disease is the immunoendocrine dialogue, via the hypothalamo-pituitary-adrenal axis, between glucocorticoids and cytokines and its potential role in HIV disease progression. This study reports recent data on the interaction between glucocorticoids and the immune system in AIDS patients with an acquired form of glucocorticoid resistance. Clinically, glucocorticoid-resistant AIDS patients (AIDS-GR; about 12% in our series of patients) present Addisonian symptoms (weakness, weight loss, hypotension, hyponatremia and intense mucocutaneous melanosis) in spite of elevated values of plasma cortisol and urinary free cortisol. Monocytes from these patients have a significantly lower receptor affinity (higher Kd) for glucocorticoids and a higher receptor density than other patients and controls. Such receptor alteration is associated with higher values of plasma interferon alpha (IFN alpha). In AIDS-GR there is a significant correlation between the values of receptor Kd and of plasma IFN alpha (r = 0.77). After poly(I):poly(C) stimulation, monocytes from AIDS-GR produce much more IFN alpha than other AIDS patients. While in patients with no resistance and in control patients, monocyte production of IFN alpha is inhibited by dexamethasone (the effect being reversed by RU-486), a very slight inhibition of dexamethasone on IFN alpha production is observed in monocytes from AIDS-GR. In conclusion, these data demonstrate that the immunosuppressive mechanisms acting in AIDS may be reversed, as shown by the increased stimulus on IFN alpha production found in cortisol-resistant patients. These data also suggest that antiglucocorticoid drugs may be helpful in HIV disease as they antagonize the excessive immunosuppression induced by the increased production of glucocorticoids found at every stage of HIV disease.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Glucocorticoids and the immune function in the human immunodeficiency virus infection: a study in hypercortisolemic and cortisol-resistant patients.

Immunological studies in human immunodeficiency virus (HIV)-positive patients suggest that the disease progression is accompanied by a defective production of type 1 cytokines (interleukin-2 (IL-2) and IL-12], an increased production of type 2 cytokines (IL-4, IL-6, and IL-10), and an increased production of IgE. HIV infection is also associated with activation of the hypothalamo-pituitary-adrenal axis function and increased plasma and urinary cortisol concentrations. As cortisol is involved in the physiological regulation of cytokines, a study was conducted to examine cytokine patterns in two groups of hypercortisolemic patients, one with normal sensitivity to glucocorticoids and the other with glucocorticoid resistance. Ten HIV-infected patients with normal receptor affinity to glucocorticoids (AIDS-C), 10 HIV-infected patients with low receptor affinity to glucocorticoids (AIDS-GR), and 20 healthy subjects were studied. Receptor characteristics of peripheral blood mononuclear cells were evaluated by [3H]dexamethasone binding. Serum cortisol and urinary free cortisol were measured by RIA. Serum ACTH and IgE were measured by immunoradiometric assay, and IL-2, IL-4, and IL-10 cytokines and interferon-gamma were measured by enzyme-linked immunosorbent assay. AIDS-C patients showed low IL-2 and high IL-4, IL-10, and IgE concentratios; conversely, AIDS-GR patients showed high IL-2 and low IL-4 and IgE concentrations. Thus, in HIV infection, elevated cortisol levels suppress cell-mediated immunity and stimulate humoral immunity, whereas this response is not detected in cortisol-resistant patients. These findings indicate that cortisol and its receptors are critically involved in the regulation of immune function in HIV infection.

Adrenocorticotropic Hormone↗

PubMed1997

Short-term variations in bone remodeling biochemical markers: cyclical etidronate and alendronate effects compared.

Bone-remodeling markers have been proposed to monitor antiosteoporotic therapy, as substantial changes in these markers usually occur in a relatively short time interval. In this study we have evaluated the short term effects of two bisphosphonates on bone-remodeling markers with the aim of 1) defining the shortest reliable time interval after which markers should be measured, and 2) comparing the effects of different bisphophonates. To do so, 74 postmenopausal women with a lumbar spine t score of at least -1 were randomly allocated to 4 different treatments: calcium carbonate (500 mg/day; n = 18), 5 mg/day alendronate (A5; n = 18), 10 mg/day alendronate (A10; n = 20), and cyclical etidronate (CE; n = 18). Serum and 24-h urine samples were collected at baseline and 14, 28, 56, and 84 days after the beginning of therapy. Type I collagen N-terminal (NTx) and C-terminal (CTx) telopeptides and total deoxypyridinoline (tDPD) were measured in urine and normalized for urinary creatinine excretion. Osteocalcin and bone alkaline phosphatase in serum were measured. Alendronate (at both doses) and CE significantly decreased bone-remodeling markers, whereas calcium carbonate did not. Bone resorption markers reduction reached a plateau 14 (A10) or 28 (A5 and CE) days after the beginning of treatment, whereas osteocalcin and bone alkaline phosphatase were significantly reduced at 56 (A10) and 84 (CE) days. The global effects of alendronate and CE on NTx and CTx (calculated as the area under the curve) were significantly different from those of calcium (P < 0.05), but were not significantly different from each other. The percent change from baseline obtained with tDPD, NTx, or CTx during bisphosphonate treatment were significantly different (P < 0.05), but this difference disappeared when the variability in the calcium carbonate group was taken into account. In conclusion, this study shows that 1) etidronate and alendronate induce a significant and rapid reduction in bone-remodeling markers; 2) the changes in NTx, CTx, and tDPD urinary excretions reach a plateau after 2-4 wk of treatment; and 3) short term treatments with CE or alendronate induce similar changes in the urinary excretion of NTx and CTx.

Adult↗

PubMed1997

Comparison of the clinical performance of the immunoenzymometric assays for N-terminal and C-terminal type I collagen telopeptides and the HPLC assay for pyridinium cross-links.

We evaluated the clinical performances of the immunoenzymometric assays for type I collagen N-terminal and C-terminal telopeptides and the HPLC assay for total deoxypyridinoline, in distinguishing between subjects with a moderately increased bone resorption rate (women in postmenopause) and subjects with normal bone resorption rate (women in premenopause). The postmenopausal group consisted of 61 women who had been in menopause for no more than 10 years, while the premenopausal group consisted of 52 healthy women with normal menstrual cycles. The biochemical markers were measured in a 24 hour urine sample and the results expressed as the molar ratio with urinary creatinine. The clinical performances were estimated by calculating the accuracy (as the area under a Receiver Operated Characteristic (ROC) curve: mean +/- SEM) and the discriminating power (as score) of each assay in distinguishing postmenopausal subjects from premenopausal subjects. Type I collagen C-terminal telopeptide, type I collagen N-terminal telopeptide and total deoxypyridinoline were significantly higher in the postmenopausal than in the premenopausal group (p < 0.01). Accuracies of these three markers ranged from 66.8 +/- 5.1% to 76.8 +/- 4.3%, while Z scores ranged from 3.54 to 5.67. Type I collagen C-terminal telopeptide, type I collagen N-terminal telopeptide and total deoxypyridinoline were not significantly different in their accuracy or discriminating power. All markers were highly correlated with coefficients of correlation ranging from 0.61 to 0.77. In summary, this study shows that 1) the immunoenzymometric assays for type I collagen N-terminal telopeptide and type I collagen C-terminal telopeptide show a high accuracy and discriminating power in distinguishing subjects with different bone resorption rate; 2) the results obtained with these immunoenzymometric assays are comparable to those obtained with the HPLC assay for total deoxypyridinoline. In conclusion our data support the use of the immunoenzymometric assays for type I collagen N-terminal telopeptide and type I collagen C-terminal telopeptide for estimating bone resorption.

Adult↗

PubMed1997

Analytical agreement and clinical correlates of plasma brain natriuretic peptide measured by three immunoassays in patients with heart failure.

Explore the source record for details and available documents.

Aged↗

PubMed1996

Affinity of angiotensin I-converting enzyme (ACE) inhibitors for N- and C-binding sites of human ACE is different in heart, lung, arteries, and veins.

Angiotensin-converting enzyme (ACE) has two enzymatically active domains: a C-domain in the carboxy terminal region and an N-domain in the amino terminal region. We based the pharmacologic characterization of these sites on the rat testis-lung model. In testis, only a truncate form of ACE is present (C-site), whereas both N- and C-sites are present in lung. In this model, captopril was shown to be N-selective and delaprilat to be C-selective. Ro 31-8472, a cilazapril derivative, and enalaprilat proved to be not site selective. We used these drugs to evaluate the affinity of C and N sites in various human tissues involved in the cardiovascular actions of ACE and used [125I]Ro31-8472 as ligand. The number and affinity of ACE binding sites were 17,680 +/- 2,345 fmol/mg protein (Kd = 0.32 +/- 0.04 nM) in lung, 560 +/- 65 (Kd = 0.36 +/- 0.05 nM) in heart, 237 +/- 51 (Kd = 0.37 +/- 0.06 nM) in coronary artery, 236 +/- 63 (Kd = 0.14 +/- 0.05 nM) in saphenous vein, and 603 +/- 121 (Kd = 0.50 +/- 0.06 nM) in mammary artery. The affinity (pKi) of captopril for the N sites ranged from 9.40 +/- 0.14 (lung) to 8.41 +/- 0.10 (coronary artery). The affinity for the C-site by delaprilat ranged from 9.97 +/- 0.15 (coronary artery) to 9.10 +/- 0.14 (mammary artery). Therefore, the affinity of C- and N-sites of ACE for ACE inhibitor (ACEI) drugs is different according to the organ involved. Because ACE is a glycosylated enzyme and glycosylation is organ dependent, we suggest that organ-specific glycosylation affects the binding characteristics of ACE inhibitors to N- or C-site of human tissular ACE.

Adult↗