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Biomedical subjects

G Segre

Publications and source records attributed to G Segre.

At least 37 records · Page 2Linked to original sources
PubMed1989

Antagonism of aminoglutethimide and adrenocorticotropic hormone (ACTH) studied on slices of adrenal glands of the guinea-pig.

Aminoglutethimide at concentrations from 0.1 to 5 nM is able to inhibit the cortisol release elicited by adrenocorticotropic hormone (ACTH) (from 2.5 to 50 ng/ml) in guinea-pig adrenal cortex slices. The antagonism is a non-competitive one (in a Lineweaver-Burk plot), whereas other drugs (morphine, endorphin, indomethacin, etc.) inhibit ACTH competitively. This is in agreement with the known mechanism of action of aminoglutethimide, which inhibits the synthesis of cortisol by blocking reactions of enzymes such as aromatase and desmolase. From the data one can calculate the dissociation constant (Km) of ACTH with its receptor(s) to be 0.27 pg/ml and the inhibiting constant (Kl) of aminoglutethimide to be 49.78 x 10(-10) M. The maximal response of ACTH was 52.9 ng/ml.

Adrenal Glands↗
PubMed1989

Glutathione (GSH) in human stomach mucosa.

The role of glutathione and its function in patients affected by carcinoma and ulcer was studied. The dramatical decrease of this tripeptide evidenced by the authors, demonstrates its fundamental role in the above mentioned pathologies and permits to formulate a hypothesis of therapeutic presidium for some substances (e.g. cysteine), that showed to be able in recovering normal glutathione levels.

Adult↗
PubMed1988

Pharmacokinetics of flunoxaprofen in rats, dogs, and monkeys.

The kinetics of flunoxaprofen, an anti-inflammatory nonsteroidal drug, was studied in rats (Charles River), dogs (beagles), and monkeys (Macaca fascicularis). Plasma levels, after oral and iv administration of 20-40 mg/kg, and urinary excretion were followed for 24-72 h; the determinations were performed by gas chromatography. Levels in various organs and in rat bile were also determined. The pharmacokinetic parameters show noteworthy similarities in the three species studied: high bioavailability, extensive biotransformations with small urinary excretion of unmodified drug, total clearance between 40 and 50 mL/h/kg, and peak plasma levels of approximately 200 micrograms/mL. Rats show a high value in volume of distribution (2 L/kg), whereas dogs and monkeys show a volume of distribution between 0.13 and 0.18 L/kg. In the rat, the half-life of the drug is approximately 70 h, whereas in the dog and monkey, a half-life of approximately 2 h was found.

Administration, Oral↗
PubMed1988

The sojourn time and its prospective use in pharmacology.

Sojourn time in a given compartment i when the material has been injected in compartment i (Sji) corresponds to the average time spent by the particles of the material in i before their definitive exit from that compartment. Sojourn time is different from the mean residence time (tji), which is the average age of the particles leaving the system. If K denotes the transfer matrix of the compartmental system, then -K-1 provides the sojourn times in each compartment given initial arrival in each of the other compartments. It can be shown that Sji = xi(s)/xj. 0/s = 0, corresponds to the value of AUC in compartment i. Since AUCi/xj,0 = Fji.AUC/xi,0 (Fji = fraction of the dose in j reaching i), one has Sji = FjiSii.AUCi corresponds to a rectangle of height equal to xj,0 and base equal to Sii. Therefore in a compartment i a drug acts on the average for a time equal to Sii and the number of molecules in it depends on the dose and on Fji. In compartments which are not sampled the value of AUC can be calculated by a simulated curve or by -K-1. From the height of the rectangle whose area is equal to AUC one should subtract the threshold theta for a given effect; the resulting rectangle should indicate the intrinsic efficacy of the drug. These considerations could be applied in pharmacology, toxicology, and chemotherapy.

Mathematics↗
PubMed1988

Fractures and vertebral bone mineral density in patients with renal osteodystrophy.

We investigated the relationship of CT determined vertebral bone mineral density (BMD), type of renal osteodystrophy, N terminal PTH levels and fracture history in 31 dialysis patients. BMD for patients with bone biopsy documented osteitis fibrosa was 1.6 standard deviation (SD) above the normal value for age and sex matched controls, while those patients with low turnover osteodystrophy had a mean BMD 1.2 SD below normal (p less than 0.0001). Three patients with osteitis fibrosa who had previously been treated with prednisone had a low BMD (1.8 SD below normal, different than O, p = 0.0015). There was no correlation between BMD and time on dialysis (r = 0.1). An N terminal PTH level greater than 150 pg/ml was a sensitive (94%) and specific (100%) method of separating those patients with osteitis fibrosa from those with low turnover osteodystrophy, while BMD was much less useful in this differentiation. A low BMD was not predictive of fracture history but the type of renal osteodystrophy was. Patients with low turnover osteodystrophy had a fracture rate of 0.2 fractures/dialysis year in comparison to those with osteitis fibrosis who had 0.1 fractures/dialysis year. Patients with the former bone disease fractured mainly axial rather than appendicular bones in contrast to those patients with osteitis fibrosa. In conclusion we found that patients with osteitis fibrosa had increased BMD compared to normal while those with low turnover osteodystrophy had decreased BMD, but that the N terminal PTH level was a better predictor of the type of bone disease present than was BMD.

Adult↗
PubMed1988

Plasma and urine pharmacokinetics of free and of short-chain carnitine after administration of carnitine in man.

To 6 healthy volunteers 30 mg/kg of L-carnitine (1,3-hydroxy-4-N-trimethylamino-butyrate) were injected intravenously and plasma levels (mumol/l) of free and short-chain carnitine were determined at different times between 0.033 and 24 h. The urinary excretion of L-carnitine and short-chain carnitine in 24 h was also measured. After a period of wash-out the subjects received 100 mg/kg of L-carnitine orally and plasma levels were determined between 0.5 and 24 h. The urinary excretion of L-carnitine was measured for a period of 18.5-33 h after treatment. 3 of the volunteers also received 30 mg/kg of L-carnitine orally. Carnitine plasma levels were determined at different times between 0.5 and 18 h, while the urinary excretion of L-carnitine was measured for 48 h following the treatment. The results could indicate the presence of saturation phenomena in the absorption process for the oral doses used; specific research is required to ascertain this phenomena. The transfer of carnitine from central to extravascular volume is relatively rapid, as is its urinary excretion. The short half-life of carnitine and acetyl-carnitine can suggest the use of new forms of administration (slow-release).

Administration, Oral↗
PubMed1988

Serum and urine kinetics of rosaprostol in volunteers.

The kinetics of rosaprostol (9-hydroxy-19,20-bis-norprostanoic acid, Rosal) and of its metabolite (3-(2-n-hexyl-5-hydroxy-cyclopentyl)propionic acid) has been determined in plasma and in urine of 10 healthy volunteers after oral administration of 500 mg of rosaprostol. The peak of rosaprostol (of 524 ng/ml) appears at 4 h, whereas that of the metabolite (of 503 ng/ml) appears earlier (2 h); therefore the relationship between the two substances does not follow the precursor-successor relationship in plasma and a compartmental model has been used to fit the data. In this model the biotransformation process occurs before entering the central compartment (first-pass effect). The mean half-life of rosaprostol is equal to about 5 h and that of the metabolite is equal to 3 h. All of rosaprostol is biotransformed and only the metabolite is partially eliminated by the urine. The urinary excretion of the metabolite represents only a small fraction of the administered dose. The urinary clearance of the metabolite is equal to 5.3 l/h. The volume of distribution of both substances is equal to 21.2 l.

Anti-Ulcer Agents↗
PubMed1988

A new tricyclic fluoroquinolone, rufloxacin (MF-934), with interesting antibacterial and pharmacokinetic characteristics.

The kinetics of a new fluoroquinolone, rufloxacin (MF-934), have been studied in rats, dogs and monkeys. The drug is characterized by a long half-life, which is equal to 24, 12 and 15 h in the three species, respectively. A high tissue plasma ratio is observed in rats. In these animals the bioavailability is equal to 60%. The drug does not appear to enter the brain in rats and in monkeys, even after repeated administration (90 days). No accumulation is seen in rats and in monkeys after repeated daily administration for 90 days. The urinary excretion of unmodified drug is equal to about 27 and 40% of the dose in the rat and in the monkey, respectively.

4-Quinolones↗
PubMed1987

Quinolonecarboxylic acids. 2. Synthesis and antibacterial evaluation of 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acids.

A series of pyridobenzothiazine acid derivatives was synthesized and their in vitro antibacterial activity was evaluated. The 1,4-benzothiazine intermediates, which by Gould-Jacobs quinoline synthesis produced pyridobenzothiazine acids, were prepared by hydrolytic basic cleavage of substituted 2-aminobenzothiazoles and successive cyclocondensation with 1-bromo-2-chloroethane or alternatively with monochloroacetic acid, hence reduction by LiAlH4. The pyridobenzothiazine acids 10c, 30, and 31 show potent antibacterial activities against Gram-positive and Gram-negative pathogens. Structure-activity relationships are discussed. The compound 9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d e] [1,4]benzothiazine-6-carboxylic acid (31) (MF-934) has been found to possess, together with the antibacterial activity, a weak acute toxicity and interesting pharmacokinetic characteristics in several animal species (rat, dog, monkey, man).

Anti-Bacterial Agents↗
PubMed1987

Pharmacokinetic profile of fosfomycin trometamol (Monuril).

The kinetics of fosfomycin in serum and in urine was studied in 5 healthy volunteers after intravenous administration of disodium fosfomycin and after oral administration of trometamol fosfomycin at 50 mg/kg. The presence of secondary peaks in serum kinetics, more evident after oral administration, requires the use of a compartmental model with enterohepatic recirculation to which all the data of each subject were simultaneously fitted. The following values of the various pharmacokinetic parameters were calculated: central volume 10.6 +/- 0.92 liters; bioavailability 0.58 +/- 0.04; delay time in the recirculation 2.00 +/- 0.92 h; half-life 2.43 +/- 0.31 h; total clearance 8.3 +/- 1.6 l/h; urinary clearance 7.0 +/- 0.9 l/h; peak level 32.1 +/- 3.0 micrograms/ml; time of the peak 2.2 +/- 0.44 h. The fosfomycin concentration in urine remains above 1,000 micrograms/ml for 12 h and above 100 micrograms/ml for 48 h. The oral kinetics of fosfomycin is dose-dependent, as shown by serum and urine kinetics in other 4 volunteers after oral administration of 2, 3, 4 and 5 g; the fraction of the dose excreted by urine goes from 50% for 2 g to 22% for 5 g.

Administration, Oral↗
PubMed1987

Flunoxaprofen pharmacokinetics in elderly subjects.

Plasma kinetics and 24 h urinary elimination of flunoxaprofen, a nonsteroidal antiinflammatory drug, were studied in 23 elderly patients (mean age 69.9 years) and compared with the data obtained in four young volunteers. The drug was administered as a single oral 100 mg tablet and its plasma and urine concentrations were assayed by a high performance liquid chromatography method. Plasma kinetics fitted a 3-exponential equation with a mean half-life of 7.9 +/- 2.17 hours and a mean peak plasma of 8.5 +/- 2.97 micrograms/ml, which was observed at about the second hour. The values of the areas under the curves (AUC) and the values of total clearance (multiplied by the bioavailability) showed great variability, due to the large differences in the patients body weights; in fact the value of AUC was linearly correlated to the dose divided by the body weight. The mean residence time (MRT) of the drug in plasma was equal to 12.81 h. Low amounts of unmodified drug (about 10%) were found in 24 h urine sample, indicating a high degree of biotransformation. Small differences only were found in plasma kinetics of flunoxaprofen among the present group of elderly patients and the group of four young volunteers; the main difference corresponded to a slower rate of gastrointestinal absorption and to a longer mean residence time.

Aged↗
PubMed1987

Thiazolidine-4-carboxylic acid toxicity and glutathione levels in various organs of the rat.

Thiazolidine-4-carboxylic acid (TC) (a precursor of intracellular cysteine) was administered to rats at 50 mg/kg and at 400 mg/kg by an i.p. route and at 800 mg/kg per os, and the levels of glutathione (GSH) in gastric mucosa, gastric wall and liver were determined. GSH levels in the eyes were measured after oral administration of TC. No changes in GSH levels were observed at 50 mg/kg from 1 to 48 h. An initial increase of liver GSH levels was followed by a decrease (up to 12 h) at 400 mg/kg i.p. After oral administration of 800 mg/kg an initial increase of GSH levels in the liver and gastric mucosa was followed by a decrease (up to 24 h); the GSH levels in the gastric wall showed a persistent decrease. No significant changes were seen in the GSH levels of the eyes.

Animals↗
PubMed1986

The lymphatic route--II. Pharmacokinetics of human recombinant interferon-alpha 2 injected with albumin as a retarder in rabbits.

The aim of the present investigation was to define whether multisite subcutaneous (s.c.) administration in unanesthetized, unrestrained rabbits of human recombinant interferon-alpha 2 (rec. IFN-alpha 2) either in saline, human albumin (ALB) solution (4, 7 and 10% final concentrations), or in a solution containing 75 U of hyaluronidase, modified the pharmacokinetic parameters calculated from the IFN plasma levels. Plasma disappearance rates of rec. IFN-alpha 2 were measured in rabbits after intravenous (i.v.) administration and the kinetic was adequately represented by a three-pools mammillary model. This model was the basis for evaluating the absorption and distribution of rec. IFN-alpha 2 after s.c. administration. The increase of ALB concentration (from 4 to 10%) caused a significant reduction of the plasma IFN Cmax while both the mean residence time and the release time of IFN increased linearly with the ALB concentration. The data support the postulation that s.c. administration of albumin acts as an interstitial fluid expander and may favour absorption of IFN via lymphatics rather than blood capillaries. Improvement of therapeutic index of IFN by using this route remains to be shown in clinical trials.

Animals↗