Biomedical subjects

N Ferry

Publications and source records attributed to N Ferry.

30 records · Page 2Linked to original sources

PubMed1987

Isolation and characterization of 9-hydroxy-10-trans,12-cis-octadecadienoic acid, a novel regulator of platelet adenylate cyclase from Glechoma hederacea L. Labiatae.

We have identified and characterized a fatty acid, (9S,10E,12Z)-9-hydroxy-10,12-octadecadienoic acid (9-HODE) as a regulator of adenylate cyclase activity of human platelet membranes. This fatty acid was isolated from a methanolic extract of the plant Glechoma hederacea L. Labiatae (commonly known as 'lierre terrestre', 'ground ivy' or 'creeping Charlie'; it was identified by nuclear magnetic resonance and mass spectroscopy. This compound increased basal adenylate cyclase activity in platelet membranes about threefold and had an EC50 of 10-20 microM. This increase in adenylate cyclase activity occurred without a temporal lag, was reversible, and represented an increase in Vmax without a substantial change in Km for ATP, Mg2+ or Mn2+. In addition, 9-HODE additively or synergistically increased platelet adenylate cyclase activity in response to guanosine 5'-[beta,gamma-imido]triphosphate and forskolin, but the fatty acid failed to alter inhibition of adenylate cyclase activity mediated by epinephrine (alpha 2-adrenergic receptor). Studies of the interaction of 9-HODE with activation of platelet adenylate cyclase activity mediated by prostaglandin E1 (PGE1) and prostaglandin D2 (PGD2) indicated that this fatty acid produced a parallel shift in the concentration/response curve of PGE1 and PGD2 without altering maximal response, which was substantially greater than that observed with 9-HODE alone. From these results, we conclude that 9-HODE appears to be a partial agonist at PGE1 and PGD2 receptors on human platelets. We believe that this is a novel example of a plant-derived fatty acid which acts on cells to regulate adenylate cyclase via prostaglandin receptors.

Adenylyl Cyclases↗

PubMed1987

Determination of teicoplanin in human plasma and urine by affinity and reversed-phase high-performance liquid chromatography.

A sensitive, highly selective and simple high-performance liquid chromatographic method for the determination of teicoplanin, a novel glycopeptide antibiotic, composed of six components, in human plasma and urine is described. After an isolation step by affinity chromatography, the antibiotic substances were chromatographed on a Nucleosil C18 column with phosphate buffer-acetonitrile according to a gradient profile. All the components were detected by their UV absorption at 240 nm. The concentration of teicoplanin was determined by using the external standard procedure. This method was applied to the sum of the six major components as well as to each of them separately. The linearity of the method was checked between 0.5 and 50 micrograms/ml for plasma and between 2 and 50 micrograms/ml for urine. The limit of detection was 0.1 microgram/ml for both biological fluids. The coefficients of variation of the between-day assays did not exceed 8.6 and 8.9% in plasma and urine, respectively. The application of the method to a pharmacokinetic study of teicoplanin after a single intravenous therapeutic dose in a patient is reported. This rapid technique also appears to be suitable for drug monitoring.

Anti-Bacterial Agents↗

PubMed1987

Plasmin: a possible physiological modulator of the human platelet adenylate cyclase system.

Plasmin was recently reported to inhibit platelet aggregation. We report here on the interaction of plasmin with the adenylate cyclase system of human platelets. Human plasmin caused a dose- and time-dependent increase in adenylate cyclase activity when added to a crude platelet membrane preparation. Both basal and prostaglandin E1-stimulated adenylate cyclase activity doubled in presence of plasmin. This stimulatory activity was shared by papain and alpha-chymotrypsin, but not by thrombin which displayed a slightly inhibitory effect. Plasmin not only stimulated platelet adenylate cyclase activity, but also suppressed the GTP-dependent alpha 2-adrenergic inhibition, thereby producing a five- to six-fold increased activity measured in the presence of adrenaline and GTP. These effects of plasmin on the adenylate cyclase system were suppressed by the addition of the protease inhibitor leupeptin, and of soybean trypsin inhibitor, indicating that proteolysis mediated these effects. We also examined the adenylate cyclase activity in membranes prepared from intact platelets incubated with increasing doses of plasmin. Incubation of platelets with plasmin concentrations as low as 0.25 mg/ml resulted in an irreversible increase in membrane adenylate cyclase activity and suppression of the adrenaline-mediated inhibition of enzyme activity. These results suggest that the proteolytic stimulating effect of plasmin on the platelet adenylate cyclase system may account for the inhibition of platelet aggregation.

Adenylyl Cyclases↗

PubMed1987

Allospecific rat-mouse T hybridoma clones generated from kidney graft-infiltrating cells.

In order to dissect the cellular mechanisms that lead to allograft rejection, infiltrating cells can be isolated and expanded in vitro for functional assays. Since the maintenance of these lines and clones is time-consuming, and large numbers of specific cells cannot be easily obtained, we fused the graft infiltrating cells, after in vitro specific expansion, with the murine T lymphoma BW5147. The rat-mouse TT hybridomas thus generated were screened for antigen-dependent interleukin 2 production, for antigen-dependent polyclonal helper activity, and for surface phenotype. The high frequency of specific clones obtained indicates that this is a convenient approach to generate alloreactive hybridoma clones with specific functions from the inflammatory infiltrates of rejected grafts.

Animals↗

PubMed1987

Pharmacokinetics of teicoplanin in renal failure.

By using a highly specific chromatographic technique, the effect of renal failure on the pharmacokinetics of the six main components of teicoplanin, taken individually or as a whole, was assessed for over 120 h after administration of a 3-mg/kg intravenous dose to healthy volunteers (group 1, n = 6) and to noninfected patients with moderate (group 2, n = 6) or severe (group 3, n = 7) renal failure. In subjects with normal renal function, total teicoplanin was mainly excreted in urine and its concentrations in plasma could be adequately fitted to a three-compartment model. Renal failure did not affect the model or the distribution of teicoplanin but strongly decreased its renal clearance (9.3, 3.2, and 0.6 ml/h per kg, respectively, for the three groups of subjects), in close relationship with the creatinine clearance (r = 0.973, n = 18, P less than 0.001). The cumulative urinary excretion of unchanged total teicoplanin was decreased (50, 21, and 5% of the given dose for groups 1 to 3) and the terminal half-life was enhanced (62, 96, and 111 h for groups 1 to 3) by renal impairment. The relative behavior of the six major components was only slightly affected by renal failure. Consequently, the dosage regimen adjustment could be based on the total teicoplanin concentration, and simulations with the mean estimated pharmacokinetic parameters suggest that the 6-mg/kg daily dose, known to be effective in patients with normal renal function, could be given every 2 and 3 days in patients with moderate and severe renal insufficiency, respectively.

Adult↗

PubMed1987

[Tubulopapillary tumors of the kidney. Apropos of 20 new cases and a review of the literature].

Tubulo-papillary tumors constitute a particular group of renal tumor. A study of 20 cases treated personally and review of 130 cases reported in the literature showed: hypo or heterogenic ultrasound images, hypovascularization on angiography, particular density on CT scan image. Histologically they can be distinguished from clear cell epithelioma not only by their appearance (papillary and tubular structures, cystic and hemorrhagic changes) but also by the frequency of stage I on histology. The latter feature is not the only explanation for a more favorable prognosis: other significant factors are necrotic lesions and degree of anisocaryocytosis of epithelial proliferation.

Carcinoma, Papillary↗

PubMed1986

Inhibition of the catalytic subunit of ram sperm adenylate cyclase by adenosine.

Adenosine inhibits ram sperm adenylate cyclase activity which is membrane-bound and comprises only the catalytic subunit. The inhibition parameters of adenylate cyclase by adenosine were not modified when the enzyme was purified 3 to 5,000 fold. Optimal inhibition by adenosine was found to require a high concentration of manganese, and exhibited a noncompetitive pattern up to a concentration of 1 mM adenosine. Adenosine was the most potent inhibitor among various analogs tested with the following rank order of potencies: adenosine greater than 2'O-methyladenosine greater than 2'deoxyadenosine much greater than 2 chloroadenosine. Studies with agonists and antagonists of the "R"-type adenosine receptor led us to conclude that adenosine inhibits ram sperm adenylate cyclase via a "P"-site carried by the catalytic subunit itself.

Adenosine↗

PubMed1986

Critical assessment of the platelet adenylate cyclase system as a potential model for testing alpha 2 adrenergic activity.

We have studied the effects of KUM 32 and CBS 1276, two clonidine-related drugs, upon the adenylate cyclase system of human platelets. Both drugs behaved as potent antagonists of epinephrine-induced platelet aggregation. [3H]Yohimbine binding studies revealed that the drugs bind to the alpha 2 adrenergic receptor of human platelets. KUM 32 and CBS 1276 also behaved as strong inhibitors of adenylate cyclase activity. This inhibition, which was not competitive with respect to ATP, is not an alpha 2 adrenergic phenomenon since it was not antagonized by yohimbine and was still observed in the absence of GTP. Moreover, pretreatment of platelet membranes with islet activating protein from Bordetella pertussis (IAP) had no effect on the inhibition by KUM 32, CBS 1276 and adenosine, although it completely reversed the effect of epinephrine and partially reversed the effect of clonidine. These results show that clonidine-like drugs may have different impacts on the adenylate cyclase system of human platelets. This system cannot be used as a pharmacological predictive test for alpha 2 adrenergic agonist activity, as various compounds, known to have central alpha 2 adrenergic agonist properties, do not behave as full agonists for the alpha 2 adrenergic receptor of human platelets.

Adenylate Cyclase Toxin↗

PubMed1986

Pharmacokinetics of isoxicam in hepatic disease.

1 The pharmacokinetics of single and repeated oral doses of isoxicam, an extensively metabolized drug, were studied in patients with compensated and decompensated hepatic disease. 2 After a single oral dose, isoxicam was slowly absorbed and eliminated (half-life ranging from 10.5 to 53.9 h). Its pharmacokinetics did not differ from those observed in healthy volunteers and were not significantly influenced by the severity of hepatic disease. However, the t1/2 of isoxicam was found to be inversely (r = -0.700, P less than 0.05 n = 14) related to the log gamma-glutamyl transpeptidase plasma activity. 3 During chronic oral treatment in patients with compensated hepatic insufficiency, steady-state was achieved after 7-9 days of therapy. The mean elimination half-life of isoxicam in five patients was 42.6 +/- 4.5 h, a value which was not statistically different from that obtained in the single dose study. 4 It was concluded that patients with hepatic insufficiency do not require a systematic modification of drug dosage but that long-term treatment should be employed with caution in these patients.

Adult↗

PubMed1986

Desensitization of epinephrine-initiated platelet aggregation does not alter binding to the alpha 2-adrenergic receptor or receptor coupling to adenylate cyclase.

Several investigators have shown that incubating unstirred platelets with epinephrine blunts subsequent aggregation when the platelets are stirred. Using aspirin-treated platelets, we further characterized this desensitization of alpha 2-adrenergic receptor-initiated aggregation. Desensitization occurred with a t1/2 of 3-6 min and was maximal at 20-30 min, at which time the initial rate of aggregation and its maximal extent were about half that of control platelets. When we preincubated platelets with epinephrine, and then added phentolamine to block the alpha 2-receptors, ADP-initiated aggregation occurred normally. Thus, the desensitization of epinephrine-initiated aggregation was not associated with a generalized impairment of aggregation. At concentrations too low to initiate aggregation, epinephrine is known to potentiate aggregation initiated by other agents. Clonidine also acts at alpha 2-receptors to potentiate aggregation initiated by other agents, but it does not initiate aggregation by itself. Preincubating clonidine with platelets for 30 min abolished its potentiating effect on ADP-initiated aggregation. Thus, the ability of alpha 2-receptors to both potentiate and initiate aggregation desensitizes after a brief preincubation with agonist. We performed several types of experiments to investigate the mechanism of this desensitization. Platelet alpha 2-receptors are coupled to an inhibition of adenylate cyclase. We found, however, that alpha 2-mediated inhibition of prostaglandin E1-stimulated cAMP accumulation occurred normally in desensitized platelets. Similarly, epinephrine inhibited basal adenylate cyclase activity normally in membranes prepared from desensitized platelets. In membranes prepared from desensitized platelets, epinephrine competed normally for [3H]rauwolscine binding, and this competition was modulated normally by guanine nucleotides. Thus, the properties of the alpha 2-receptors, as measured in radioligand binding experiments, were unchanged by densensitization. In conclusion, desensitization of alpha 2-adrenergic receptor-mediated aggregation occurs without change in the alpha 2-adrenergic receptors or in their coupling to an inhibition of adenylate cyclase.

1-Methyl-3-isobutylxanthine↗

PubMed1985

High-performance liquid chromatographic determination of cicletanide, a new diuretic, in plasma, red blood cells, urine and saliva.

A sensitive, selective and easy to use high-performance liquid chromatographic method for the determination of cicletanide, a new diuretic, in plasma, red blood cells, urine and saliva is described. After extraction of cicletanide together with an internal standard with diethyl ether, or diethyl ether-n-hexane (20:80) for urine, the sample extracts are chromatographed with water-methanol-acetic acid (50:50:0.3) as eluent on to a Nucleosil C18 column. Both compounds are detected by their ultraviolet absorption at 280 nm. The calibration graph was linear between 0.2 and 20 micrograms/ml for plasma and between 0.2 and 5 micrograms/ml for the other biological fluids. The sensitivity limit was 20 ng/ml for plasma, red blood cells and saliva and 30 ng/ml for urine. The coefficients of variation of the between-day assays did not exceed 4.6% in plasma, 8.3% in red blood cells, 7.8% in urine and 4.2% in saliva for the lowest concentrations studied. The application of the method to a pharmacokinetic study of cicletanide after a single oral therapeutic dose in humans is reported.

Chromatography, High Pressure Liquid↗

PubMed1985

Influence of renal failure on the kinetics of zimeldine and norzimelidine.

The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0-144 = 17.3 and 6.8 mumol X l-1 X h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.

Adult↗