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Biomedical subjects

S Lindgren

Publications and source records attributed to S Lindgren.

At least 19 recordsLinked to original sources

Purification and properties of the cGMP-inhibited cAMP phosphodiesterase from bovine aortic smooth muscle.

Pure cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) in micrograms quantities was isolated from bovine aortic smooth muscle after more than 5000-fold purification using DEAE ion-exchange and affinity chromatography with a derivative of the specific cGI-PDE inhibitor cilostamide conjugated as a ligand to aminoethyl agarose (CIT-agarose). The cGI-PDE, which constituted about half of the high affinity cAMP-PDE activity of a tissue homogenate, was identified with a 105-kDa protein on SDS-PAGE through use of antibodies towards the human platelet, bovine cardiac and bovine adipose tissue cGI-PDE in Western blot and immunoprecipitation/immunoinactivation analysis. As observed during purification of the enzyme from other tissues the enzyme protein was exquisitely sensitive to proteolytic nicking during purification, resulting in several 30-77-kDa polypeptide fragments. Rapid immunoprecipitation from fresh tissue extracts was the only was found to partially prevent the proteolysis. The native enzyme had apparent molecular sizes of approx. 100,000 or, mainly approx. 220,000 by gel chromatography, presumably indicating the presence of monomeric and dimeric forms. The enzyme hydrolyzed cAMP and cGMP with normal Michaelis-Menten kinetics with Km of 0.16 and 0.09 microM, respectively, with Vmax for hydrolysis of cAMP of 0.3 compared to 3.1 mumol/min per mg protein for cAMP. The enzyme was potently and selectively inhibited by cGMP (IC50 approximately 0.25 microM) and the cardiotonic/vasodilatory drugs OPC-3911 (a cilostamide derivative), milrinone and CI-930 (IC50 approximately 0.05, 0.40 and 0.25 microM, respectively). The cGI-PDE was phosphorylated by cAMP-dependent protein kinase as has been reported for the analogous enzymes in heart, adipose tissue and platelets. The identification of a cGI-PDE in the aortic smooth muscle and its inhibitor specificity is consistent with the hypothesis that inhibition of this enzyme is important in the mechanism through which these drugs produce vasorelaxation.

3',5'-Cyclic-AMP Phosphodiesterases

Hepatitis C in chronic liver disease: an epidemiological study based on 566 consecutive patients undergoing liver biopsy during a 10-year period.

We analysed the presence of hepatitis C virus (HCV) antibodies in 566 patients undergoing liver biopsy. While over 20% of the patients were anti-HCV positive according to ELISA, only 13.8% had HCV antibodies when tested with a four-antigen recombinant immunoblot assay (RIBA 2). At the time of inclusion in the study, most patients were asymptomatic, irrespective of whether they were HCV-positive. Histological findings in anti-HCV-positive patients were chronic persistent hepatitis, chronic active hepatitis or cirrhosis in greater than 75% of cases. Only four of the patients who were anti-HCV-positive according to the RIBA 2 had autoimmune chronic active hepatitis. Risk behaviour could be identified in the majority of cases. Community-acquired sporadic cases were rare (12%). Of the 153 patients who died during follow-up, 23 subjects were anti-HCV positive. Although age- and sex-adjusted survival was not shorter in anti-HCV-positive patients than in anti-HCV-negatives, the risk of hepatocellular cancer was higher (P = 0.01). We conclude that HCV infection is associated with chronic liver disease, even when critical evidence of viral aetiology is slight. Truly sporadic cases are rare. Patients infected with HCV are at increased risk of developing hepatocellular cancer.

Adolescent

Influence of bed rest on the pharmacokinetics of phenazone.

The pharmacokinetics of a single dose of phenazone was studied in six objects while ambulant and during bed rest for 3 days. Elimination of the drug was followed for 12 h after oral and intravenous administration. The elimination rate constant and total body clearance were significantly increased during bed rest as compared to the ambulant period, but the differences were small. The apparent volume of distribution decreased significantly. No consistent change due to bed rest was found in the rate of absorption or bioavailability of the oral dose.

Administration, Oral

Metabolism of phenazone in man after hydrocortisone administration.

The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250--400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone of placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.

Adult

Glial cell characteristics in bulk-prepared cell fractions from human brain tumours.

The heterogeneity of brain tumours, especially in the glioblastoma group, makes biochemical characterization of pieces of the tumours hazardous even with extensive histological controls. This study employs a technique by which separate cell populations are subsequently isolated from the tumours by means of density gradient centrifugation. Cells isolated from glial brain tumours with low density sedimentation rates show the highest levels of glial cell characteristics, i.e. S-100 content and active uptake of the neurotransmitter GABA.

Astrocytoma

Pharmacokinetics of N-desmethyldiazepam in healthy volunteers after single daily doses of dipotassium chlorazepate.

Dipotassium chlorazepate was administered to 12 healthy volunteers (8 males and 4 females), aged 22-38 years, as a single daily dose of 20 mg for 14 days. Plasma concentrations of N-desmethyldiazepam were monitored with a gas-chromatographic method during the medication period and for 5 days after withdrawal of the drug. The plasma half-life (t1/2), the elimination coefficient (Kbeta), the concentration (Css), and the apparent volume of distribution (Vbeta) were calculated at steady state, and the mean values +/- SEM were 53 +/- 6 h, 0.0147 +/- 0.0013 h-1, 884 +/- 73 ng/ml, and 1.13 +/- 0.08 1/kg, respectively. A moderate interindividual variability was observed regarding these parameters. There was no tendency toward a biexponential elimination. A significant difference in the apparent volume of distribution was found when males and females were compared.

Adult

Bioavailability of D-propoxyphene, acetyl salicylic acid, and phenazone in a combination tablet (Doleron): interindividual variation and influence of food intake.

The influence of food intake on the bioavailability of three analgesic compounds--propoxyphene chloride, acetyl salicylic acid and phenazone--in a combination tablet, Doleron, has been examined in eight healthy volunteers. A single oral dose was given both on an empty stomach and together with a standardized breakfast meal. The plasma concentrations of propoxyphene, its major metabolite norpropoxyphene, salicylic acid and phenazone were determined by mass fragmentography, spectrofluorimetry and gas chromatography. Concomitant food intake had no consistent influence on the bioavailability of any of the components. Hence, doleron may be taken together with meals as well as between meals. Large interindividual variations in propoxyphene and phenazone concentrations were found, indicating that an optimal effect will not always be obtained by standard doses.

Adult

Sarcoid-like disorder of the intracranial optic nerve.

Two cases with a sarcoid-like disorder apparently restricted to the intracranial optic nerve and the adjacent dura mater are described, doublilng the number of reported cases. In both instances there were unilateral visual loss and unusual radiographic changes in the optic canal area. Biopsy samples showed localised infiltration of tissues with non-caseating tubercles containing epithelioid and multinucleated giant cells.

Aged