Endocrinological effects of single daily ketoconazole administration in male beagle dogs

Abstract. Some endocrinological effects of single daily oral administration of 150 mg ketoconazole for 15 days were investigated in 4 male beagle dogs. Plasma testosterone fell markedly within 3–4 h and then progressively returned to control concentrations by 10 h after drug administration. On the other hand, plasma 17α-hydroxyprogesterone, progesterone and 17α,20α-dihydroxyprogesterone increased within 3–10 h before returning to basal values after 24 h. Plasma LH did not rise significantly though some high individual levels were noted. Plasma cortisol and oestradiol-17α levels were not significantly modified by the treatment. These results confirm that a high therapeutic dose of ketoconazole, given orally once a day, transiently inhibits in vivo the 17–20 lyase enzyme of the testis, without modifying basal cortisol and oestradiol-17β plasma concentrations and that enzymatic inhibition still occurs after daily treatment for up to 2 weeks but remains transient and parallels the resorption profile of the drug so that normal plasma testosterone levels are observed from 10 to 24 h after drug intake. However, permanent inhibition of androgen biosynthesis might be obtained by the administration of high doses of ketoconazole given several times a day.

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EFFECT OF ETHINYLOESTRADIOL ON PLASMA TESTOSTERONE LEVELS AND URINARY TESTOSTERONE EXCRETION IN MAN

Acta Endocrinologica ◽

10.1530/acta.0.0500051 ◽

1965 ◽

Vol 50 (1) ◽

pp. 51-54 ◽

Cited By ~ 14

Author(s):

Enrico Forchielli ◽

Govind S. Rao ◽

Inder R. Sarda ◽

Norman B. Gibree ◽

Peter E. Pochi ◽

...

Keyword(s):

Oral Administration ◽

Plasma Testosterone ◽

Testosterone Levels ◽

The Mean ◽

Normal Men ◽

Daily Oral Administration

ABSTRACT The daily oral administration of one mg of ethinyloestradiol to normal men decreased the mean plasma testosterone from 0.84 ± 0.07 μg per 100 ml to 0.20 ± 0.04 in 21 trials and decreased the urinary testosterone from 63 ± 1.1 μg per day to 8 ± 0.3 in 16 trials.

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Comparison of the feedback effect of magnesium and calcium on parathyroid hormone secretion in man

Journal of Endocrinology ◽

10.1677/joe.0.1130117 ◽

1987 ◽

Vol 113 (1) ◽

pp. 117-122 ◽

Cited By ~ 31

Author(s):

O. Ferment ◽

P. E. Garnier ◽

Y. Touitou

Keyword(s):

Parathyroid Hormone ◽

Urinary Excretion ◽

Hormone Secretion ◽

Plasma Concentrations ◽

Magnesium Salt ◽

Saline Injection ◽

Molar Basis ◽

Magnesium Salts ◽

High Doses

ABSTRACT Administration of high doses of magnesium is known to produce a decrease in parathyroid hormone (PTH) secretion in human patients but the effect of magnesium on the secretion of PTH in healthy man is not known. We have looked at the effect of a relatively moderate i.v. dose of magnesium (7·08 mmol) in seven healthy men. In addition and for comparison the effect of calcium (4·25 mmol) was studied. Two magnesium salts were considered, magnesium sulphate (MgSO4) and magnesium pyrrolidone carboxylate (MgPC). Four i.v. injections were given at 08.00 h (MgPC, NaCl (control), MgSO4 and Ca gluconate), with an interval of 1 week between each injection. Whatever the magnesium salt the variations in plasma concentrations of magnesium were the same whereas no change in erythrocyte magnesium was observed. Plasma concentration of C-terminal PTH did not show significant variations after MgPC or saline injection. Both MgSO4 and Ca gluconate produced a statistically significant 30% decrease in plasma PTH levels 45 min after the injection. The effect was more sustained with calcium (2 h) than with magnesium (45 min). The urinary excretion of magnesium was significantly higher after injection of MgSO4 than after MgPC. These results suggest (1) that magnesium was, on a molar basis, less potent than calcium in regulating PTH secretion in vivo, (2) that the nature of the magnesium salt used must be kept in mind for the interpretation of the effect of magnesium on PTH secretion in vivo and (3) that the decrease in plasma PTH can partly explain the larger urinary excretion of magnesium after MgSO4 than after MgPC. J. Endocr. (1987) 113, 117–122

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Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05710-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 70-74 ◽

Cited By ~ 32

Author(s):

Paul M. Beringer ◽

Heather Owens ◽

Albert Nguyen ◽

Debbie Benitez ◽

Adupa Rao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Oral Administration ◽

Maximum Concentration ◽

Airway Remodeling ◽

Plasma Concentrations ◽

Compartment Model ◽

Time Curve ◽

Elimination Half ◽

Dose Oral

ABSTRACTCystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg.Cmaxand time to maximum concentration of drug in serum (Tmax) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [Ka], 0.414 h−1; lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effectsin vivoand should be evaluated in clinical trials.

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Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

Natural Product Communications ◽

10.1177/1934578x1501000921 ◽

2015 ◽

Vol 10 (9) ◽

pp. 1934578X1501000 ◽

Cited By ~ 1

Author(s):

Rosario Russo ◽

Angelo Mancinelli ◽

Michele Ciccone ◽

Fabio Terruzzi ◽

Claudio Pisano ◽

...

Keyword(s):

Oral Administration ◽

Plasma Concentrations ◽

Compartmental Analysis ◽

Pharmacokinetic Profile ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Sprague Dawley ◽

Time Curve ◽

Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

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Orally Active Inhibitors of the Imatinib Resistant Bcr-Abl Mutant T315I.

Blood ◽

10.1182/blood.v108.11.2180.2180 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2180-2180 ◽

Cited By ~ 5

Author(s):

William C. Shakespeare ◽

Frank Wang ◽

Qihong Xu ◽

Xiaotian Zhu ◽

Narayana Narasimham ◽

...

Keyword(s):

Oral Administration ◽

Cellular Proliferation ◽

Kinase Inhibitor ◽

Tumor Regression ◽

Point Mutations ◽

Drug Binding ◽

Separate Model ◽

Daily Oral Administration

Abstract Resistance to the Bcr-Abl kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML) is associated with emergence of Bcr-Abl point mutations that preclude effective drug binding. Although most mutants are effectively inhibited with the second generation inhibitors dasatinib and nilotinib, neither compound inhibits the T315I mutant which represents ~ 25% of all clinically observed mutants. Through our program of structure-guided design, we have identified a series of compounds that inhibit the T315I mutant of Bcr-Abl both in vitro and in vivo. AP24534, a representative member of this new series, inhibited the kinase activity of both the wild-type enzyme and the T315I point mutant with IC50s of 3 and 31 nM respectively, and inhibited the proliferation of their respective BaF3-derived cell lines with IC50s of 2 and 14 nM. Additionally, AP24534 inhibited the proliferation of BaF3 cells expressing the clinically relevant mutants Y253F, E255K, H396P, or M351T with IC50s of 2, 7, 1, and 1 nM respectively. Inhibition of cellular proliferation directly correlated with decreased cellular phosphorylation of Bcr-Abl. Daily oral administration of AP24534 to mice bearing subcutaneous xenografts of Bcr-Abl-T315I-expressing BaF3 cells elicited dose-dependent tumor shrinkage, with complete tumor regression observed at the highest doses. In a separate model, daily oral administration of AP24534 significantly prolonged the survival of mice injected intravenously with these cells, at doses ranging from 5–30 mg/kg. These data indicate that this class of inhibitors has the potential to address CML refractory to current targeted agents.

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THE IN VIVO CONVERSION OF DEHYDROEPIANDROSTERONE AND ANDROSTENEDIONE TO TESTOSTERONE IN THE HUMAN

Acta Endocrinologica ◽

10.1530/acta.0.0410400 ◽

1962 ◽

Vol 41 (3) ◽

pp. 400-406 ◽

Cited By ~ 54

Author(s):

Virendra B. Mahesh ◽

Robert B. Greenblatt

Keyword(s):

Oral Administration ◽

Plasma Testosterone ◽

Testosterone Levels ◽

Before And After ◽

Normal Women

ABSTRACT Plasma testosterone levels were measured by the method of Finkelstein et al. (1961) before and after oral administration of dehydroepiandrosterone and Δ4-androstenedione in normal women. The results suggest in vivo conversion of dehydroepiandrosterone and Δ4-androstenedione to testosterone. The implications of these findings are discussed.

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Effect Of Aspirin On The Production Of PGI2 By Various Blood Vessels And Mda By Platelets

10.1055/s-0038-1652097 ◽

1981 ◽

Author(s):

M Takada ◽

H Tsukada ◽

H Tanaka ◽

H Gonmori ◽

N Kobayashi ◽

...

Keyword(s):

Coronary Artery ◽

Oral Administration ◽

Vessel Wall ◽

Initial Level ◽

Femoral Vein ◽

The Other ◽

Differential Inhibition ◽

Caval Vein ◽

Single Oral Administration ◽

Daily Oral Administration

This study was desinged to determine whether the differential inhibition of prostacyclin(PGI2) production by vessel wall and malondialdehyde(MDA) production by platelet might be possible by oral administration of aspirin(ASA). Rabbits weghing 2-3kg were used. MDA production by platelet was measured by the Stuart’s method with minor modification. The PGI2 production by vessel wall was assessed by the Moncada’s method with minor modification.The PGI2 production by caval vein, pulmonary artery, pulmonary vein,femoral artery, femoral vein and coronary artery was 148±55%, 136±56%, 153±55%, 134±56%, 123±64%, 103±55% to that of aorta, respectively. The PGI2 production by these vessels was inhibited to 20-40% to their initial level 6h after the single oral administration of 0.3g ASA, and restored to the initial level by 24h, while the MDA production was inhibited more conspicuously and remained at less than 50% of the initial level even 48h.The effect of daily oral administration of ASA on production of PGI2 by aorta and MDA by platelet was investigated. PGI2 production was suppressed to about 10% of the initial level 24h after the last dose of 3 to 7 daily administration of 0,3g of ASA. This indicates that the daily ASA administration results in the cummulative inhibition of PGI2 production. On the other hand, when administered every other day, the same amount of ASA exerted significantly less inhibition of PGI2 production, being at about 50% of initial level 24h after the last dose. MDA production was nearly completely inhibited over the observation periods.These results suggests that the differential inhibition of vascular PGI2 production and platelet aggregation may be possible by the administration of ASA at an appropriate amount and proper interval.

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Development of the ovine fetal cardiovascular defense to hypoxemia towards full term

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00504.2006 ◽

2006 ◽

Vol 291 (6) ◽

pp. H3023-H3034 ◽

Cited By ~ 69

Author(s):

Andrew J. W. Fletcher ◽

David S. Gardner ◽

C. Mark B. Edwards ◽

Abigail L. Fowden ◽

Dino A. Giussani

Keyword(s):

Gestational Age ◽

Plasma Concentrations ◽

Cardiovascular Responses ◽

Full Term ◽

Fetal Bradycardia ◽

Basal Cortisol ◽

Ovine Fetal ◽

Constrictor Response ◽

Transient Bradycardia

We tested the hypothesis that fetal cardiovascular responses to hypoxemia change close to full term in relation to the prepartum increase in fetal basal cortisol and investigated, in vivo, the neural and endocrine mechanisms underlying these changes. Fetal heart rate and peripheral hemodynamic responses to 1 h of hypoxemia were studied in 25 chronically instrumented sheep within three narrow gestational age ranges: 125–130 ( n = 13), 135–140 ( n = 6), and >140 ( n = 6) days (full term ∼145 days). Chemoreflex function and plasma concentrations of vasoconstrictor hormones were measured. Reductions in fetal arterial Po2 during hypoxemia were similar at all ages. At 125–130 days, hypoxemia elicited transient bradycardia, femoral vasoconstriction, and increases in plasma concentrations of catecholamines, neuropeptide Y (NPY), AVP, ACTH, and cortisol. Close to full term, in association with the prepartum increase in fetal basal cortisol, there was a developmental increase in the magnitude and persistence of fetal bradycardia and in the magnitude of the femoral constrictor response to hypoxemia. The mechanisms mediating these changes close to full term included increases in the gain of chemoreflex function and in the magnitudes of the fetal NPY and AVP responses to hypoxemia. Data combined irrespective of gestational age revealed significant correlations between fetal basal cortisol and fetal bradycardia, femoral resistance, chemoreflex function, and plasma AVP concentrations. The data show that the fetal cardiovascular defense to hypoxemia changes in pattern and magnitude just before full term because of alterations in the gain of the neural and endocrine mechanisms mediating them, in parallel with the prepartum increase in fetal basal cortisol.

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Cushing's disease: a comparison of pituitary corticotroph microadenomas and macroadenomas

Acta Endocrinologica ◽

10.1530/eje.0.1380153 ◽

1998 ◽

pp. 153-159 ◽

Cited By ~ 33

Author(s):

P Selvais ◽

J Donckier ◽

M Buysschaert ◽

D Maiter

Keyword(s):

Cushing’S Disease ◽

Plasma Cortisol ◽

Clinical Presentation ◽

Cushing's Disease ◽

Visual Field Defects ◽

Resonance Imaging ◽

Acth Secretion ◽

Basal Cortisol ◽

Igf I ◽

High Doses

Cushing's disease appears as a functionally heterogeneous disease, but criteria that are able to distinguish between different clinical forms remain elusive. We compared two subgroups of patients with proven Cushing's disease according to the size of the pituitary adenoma, evaluated by computed tomography or magnetic resonance imaging. Our series comprised 11 patients with a microadenoma and 10 with a macroadenoma (median volumes (range): 173 (13-270) and 3022 (500-10312) mm3 respectively; P < 0.0001). The clinical presentation was similar in the two groups, but the time elapsed before diagnosis was longer, and visual impairment was less frequent in the patients with a microadenoma (1.5+/-0.8 years and 0%) than in those with a macroadenoma (0.7+/-0.6 years and 40%; P < 0.05). Morning and evening peripheral concentrations of ACTH were greater in patients with macroadenoma (134+/-78 and 130+/-7 ng/l respectively) than in those with microadenoma (52+/-28 and 56+/-19 ng/l, P < 0.05). Hypokalaemia and lymphopenia were also more pronounced in patients with macroadenoma (3.4+/-0.3 mmol/l and 1273+/-401 lymphocytes/mm3) than in those with microadenoma (3.8+/-0.3 mmol/l and 1852+/-668 lymphocytes/mm3 P < 0.05), although morning and evening plasma cortisol concentrations were similar in both groups. In patients with macroadenoma, there was less relative nycthemeral variation of ACTH concentrations (28+/-24%, compared with 62+/-39% in those with microadenoma; P < 0.05), less suppression of plasma cortisol by high doses of dexamethasone (-30+/-14%, compared with -61+/-25%; P < 0.05), and a reduced concentration ratio of mean basal cortisol to ACTH (7+/-3, compared with 12+/-5; P < 0.05). Plasma IGF-I concentration and the TSH peak response to TRH were significantly lower in patients with macroadenoma than in those with microadenoma (0.4+/-0.2 x 10(3) IU/I and 2.3+/-1.8 mIU/I, compared with 1.8+/-0.6 x 10(3) IU/I and 5.2+/-1.6 mUI/l; P < 0.05). Thus, in comparison with microadenomas, corticotroph macroadenomas are characterized by a greater and more autonomous ACTH secretion, inducing more pronounced biological signs of hypercorticism, and are more often accompanied by visual field defects and impairment of other pituitary hormonal secretions.

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