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Biomedical subjects

L Renberg

Publications and source records attributed to L Renberg.

At least 19 recordsLinked to original sources
PubMed1999

Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin.

The functional inhibitory characteristics of the angiotensin II type 1 receptor blockers (ARB) candesartan; irbesartan; and losartan and its active metabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determined, and the binding was high (>98. 5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein bound concentrations in clinical use. In both vascular preparations, candesartan caused a marked decrease in the maximal contractile response of the angiotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbesartan caused a rightward parallel shift without any major effects on the maximal response to Ang II. The inhibitory effect of candesartan developed slowly (maximal effect after >30 minutes) and lasted >2 hours despite repeated washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing. The duration of the inhibitory effects of the ARBs were not related to lipophilicity of the compounds. Cooling of the rat portal vein preparations to 4 degrees C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37 degrees C. For the other ARBs studied, the magnitude of inhibition and the speed of recovery of the Ang II response were independent of the incubation temperature before washing. In addition, when candesartan was given to conscious rats, the inhibitory effect on Ang II-induced blood pressure responses persisted during the 24-hour period despite nondetectable plasma concentrations of candesartan at 24 hours. It is concluded that functional inhibitory characteristics of candesartan differ from those of the other ARBs tested. At clinically relevant concentrations, candesartan is an insurmountable and long-lasting antagonist of the vascular contractile responses to Ang II.

Angiotensin II↗
PubMed1998

Animal pharmacokinetics of inogatran, a low-molecular-weight thrombin inhibitor with potential use as an antithrombotic drug.

Pharmacokinetics, excretion, and metabolism of inogatran, a low-molecular-weight thrombin inhibitor, were studied in the rat, dog, and cynomolgus monkey. After intravenous administration the half-life was short in all three animal species, due to a small volume of distribution and a relatively high clearance. At doses of 0.1-5 mumol kg-1, the mean residence time was about 10 min in the rat, 35 min in the dog, and 20 min in the cynomolgus monkey. The oral bioavailability of inogatran was incomplete, presumably due to a low membrane permeability, and dose dependent. The bioavailability was 4.8% at 20 mumol kg-1 and 32-51% at 500 mumol kg-1 in rats, 14% at 10 mumol kg-1 and 34-44% at 150 mumol kg-1 in dogs, and 2.1% at 1 mumol kg-1 in cynomolgus monkeys. The radioactivity excreted in urine and faeces was predominantly unchanged inogatran. After intravenous administration the percentage of the radioactivity recovered in faeces was about equal to or higher than the urinary recovery, which indicates biliary excretion of inogatran. After oral dosing, most of the dose was excreted in faeces, as expected from the estimates of oral bioavailability. The plasma protein binding of inogatran in rat, dog, and human plasma, was 20-28%. The blood-plasma concentration ratio was 0.39-0.56, indicating limited distribution into red blood cells.

Animals↗
PubMed1988

Sublethal effects of tetrachloro-1,2-benzoquinone--a component in bleachery effluents from pulp mills--on vertebral quality and physiological parameters in fourhorn sculpin.

The effects of tetrachloro-1,2-benzoquinone (TCQ), a component in bleached kraft mill effluents (BKME), on vertebral and physiological parameters were investigated in juvenile fourhorn sculpin, Myoxocephalus quadricornis L. After about 4.5 months of exposure to 0.1 and 0.5 mg TCQ/liter in 7% salinity brackish water, the fish demonstrated vertebral deformities, aberrant mechanical properties of the vertebrae, effects on white and red blood cell counts, enhanced activity of delta-aminolevulinic acid dehydratase in erythrocytes, and increased levels of ascorbic acid in the liver. The effects are discussed in relation to those previously observed in fish exposed to complex BKME in the field and the laboratory.

Animals↗
PubMed1986

The use of the bivalve Mytilus edulis as a test organism for bioconcentration studies. II. The bioconcentration of two 14C-labeled chlorinated paraffins.

The bioconcentration of two 14C-labeled chlorinated paraffins (CP) has been studied in a flow-through test system using the common mussel Mytilus edulis. Both CPs showed a rapid uptake rate and the CP with C16 carbon chain and 34% chlorination had a bioconcentration factor (BCF) of about 7000 (fresh weight). The CP with a C12 carbon chain and 69% chlorination had a very high BCF of almost 140,000 which on a lipid weight basis corresponds to a BCF of around 8,000,000. The C12-CP showed a slow depuration rate in analogy with what has been observed earlier in fish. Radioactivity was recovered from both the fat and protein fractions after exposure to the C12-CP with a level in the protein of about two orders of magnitude lower than in the fat. It is concluded that studies with CPs so far reported indicate that short carbon chain/high chlorinated chlorinated paraffins are strongly bioaccumulating and persistent chemicals.

Animals↗
PubMed1986

The use of chemical and biological parameters to characterize complex industrial effluents.

Hitherto, the concern for possible environmental effects due to aqueous industrial discharges has been directed toward clearly observable effects such as eutrophication and fish kills. However, the development of environmental toxicology and chemistry has made it clear that more subtle and potential long-term effects also have to be taken into account in the regulatory work. The Swedish Environment Protection Board has recently completed a research project: "Characterization of Industrial Effluents." Initially, analytical methods and laboratory tests, originally developed for single substances, were identified. Laboratories were then invited to participate, with their own methods, in ring tests with a variety of industrial effluent waters. The studies indicated that a number of chemical and biological methods can be used to characterize complex industrial wastewaters with regard to their content of toxic, persistent, and bioaccumulative substances. A frame program was established for the construction of test batteries adapted to various administrative regulatory purposes. To date, this strategy has been applied to several industries by the authorities, resulting in valuable experience of cost-effectiveness and the usefulness in the administrative decision-making process. Besides the studies on single industries, two other approaches have been applied, namely for the assessment of the impact of several industries on a common receiving water body, and for the evaluation of a whole industrial branch, that is, kraft pulp mill bleachery effluents. In the latter case, the studies have resulted in a ranking of processes and treatment methods to protect the environment.

Environmental Pollution↗
PubMed1985

The use of the bivalve Mytilus edulis as a test organism for bioconcentration studies. I. Designing a continuous-flow system and its application to some organochlorine compounds.

Most bioconcentration studies have previously been carried out using fish as a test organism. Equally important is the use of bivalves for this purpose, from both an ecological and an economic point of view. A continuous-flow system has thus been designed for use also with extremely hydrophobic substances and evaluated using 2,4',5-trichlorobiphenyl, methoxychlor, pentachlorobenzene, and lindane. The variation of the uptake in the individuals after 3 weeks' exposure was quite small (relative standard errors varied from 10.1 to 15.3% depending on the test substance), indicating a high degree of reproducibility. The bivalves, however, are known to close their valves under unfavorable conditions, which occasionally may bias the results. To overcome this disadvantage, it is suggested that an internal standard--i.e., a chemically defined compound--be added to the water simultaneously with the test substances. Although there is a principal risk for interactive effects, unexpected variations in the uptake can thus be compensated for by relating the concentration of the test substance to the concentration of the internal standard in the organisms. Comparisons between continuous-flow systems and static systems have also been made. It is concluded that continuous-flow systems are more suitable for studying hydrophobic compounds than static systems.

Animals↗
PubMed1981

Chlorinated phenoxyacetic acids and chlorophenols in the modified Allium test.

The chlorinated phenoxyacetic acids 2-methyl-4-chlorophenoxyacetic acid (MCPA), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4,5-T butoxyethyl ester and the chlorophenols 2,4-dichlorophenol and 2,4,5-trichlorophenol were tested for genotoxicity in the modified Allium test, which is based on exposure to the test chemicals of growing onions. The mean length of growing roots were measured and chromosome damage was recorded. Of the substances tested, MCPA was the most toxic and the chlorophenoxyacetic acids were more toxic than the chlorophenols. The lower threshold values for growth retardation were below 0.1 ppm for the acids, approx. at 0.1 ppm for the ester and less than 5 ppm for the phenols. Though a monocotyledon, Allium cepa was sensitive enough to respond to even low concentrations of these dicotyledon-selecting pesticides.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1980

Detoxication disturbances and uncoupling effects in vitro of some chlorinated guaiacols, catechols and benzoquinones.

The effects of chlorinated guaiacols, catechols and benzoquinones - earlier identified in discharges from pulp and paper mills -- on oxidative phosphorylation in mitochondria and on detoxication mechanisms in microsomes have been investigated. The same biological systems have been used in testing outgoing water from a sulphite plant. Trichlorocatechol and tetrachlorocatechol and the corresponding guaiacols increase N oxygenation of N,N-dimethylaniline, while C-oxygenation decreases, indicating disturbances in microsomal detoxication. The substances tested have in general an uncoupling effect on mitochondrial oxidative phosphorylation. However, tetrachloroguaiacol seems to differ in having a specific effect on the succinate dehydrogenase part of the respiratory chain. Extracts from waste water from a sulphite plant have a considerable effect on the mitochondrial system such as to produce an increase in basal respiration and a loss of respiratory control. N- and C-oxygenation and phosphorylation have been extensively used in this and other laboratories for evaluating the toxicity of chemicals. The application on water extract described here is rapid and easily handled and thus provides a valuable complement to other water quality tests.

Animals↗
PubMed1977

Subcellular distribution, a factor in risk evaluation of pentachlorophenol.

Pentachlorophenol (PCP) is a potent uncoupler of mitochondrial phosphorylation in vitro and also interferes with microsomal detoxication functions in vitro. This favours flavin mediated oxygenation compared with flavin cytochrome P-450 dependent reactions. Gas chromatographic analysis of subcellular fractions, obtained by zonal centrifugation showed markedly lower PCP concentration in mitochondria and a high accumulation in microsomes compared with cytosol. This increases the likelihood that PCP in vivo causes a malfunction in microsomal detoxication.

Acetylation↗
PubMed1977

Disturbance of microsomal detoxication mechanisms in liver by chlorophenol pesticides.

The pesticide pentachlorophenol known as an uncoupler of mitochondrial oxidative phosphorylation was shown to disturb liver microsomal detoxication functions by a selective inhibition of the terminal oxygenation enzyme P-450. At lower concentrations the flavin moiety of this enzyme chain is not inhibited but rather is stimulated, whereby a qualitative shift in detoxication of aromatic amines from C-oxygenation to N-oxygenation is obtained. The effects were due to the pentachlorophenol itself and not to a metabolite. Similar effects of varying strength were also obtained with other chlorophenol pesticides; 2,4,di-, 2,4,6,-tri and 2,3,4,6-tetrachlorophenol, di- and hexachlorophen, tri- and nonachloro-2-hydroxydiphenyl ethers. The relevance of these findings to the possible synergistic influence of chlorophenols on the carcinogenic effects of polyaromatic amines and hydrocarbons is discussed.

Aniline Compounds↗
PubMed1976

Distribution and cytogenetic test of 2,4-D and 2,4,5-T phenoxyacetic acids in mouse blood tissues.

The phenoxyacetic acids 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), extensively used as herbicides, were tested for cytogenetic effects by means of induced micronuclei in erythrocytes of mouse bone marrow. Because of the hig experimental resolution power this is a particularly suitable test system for the detection of weak chromosome breaking activity in mammals. The cytogenetic tests were supplemented with chemical analyses of the concentration the the test substances reaching the target cells...

2,4,5-Trichlorophenoxyacetic Acid↗
PubMedDate not supplied

Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers.

The potential of stereoselective metabolism of tocainide was studied in six healthy volunteers after separate oral administration of the pure enantiomers in solution. A method was developed to convert the N-carbamoylglucuronide of tocainide in plasma and urine by base treatment to a hydantoin derivative which after extraction and silation was analysed by selected ion monitoring using a deuterated internal standard. Analytical problems concerning side-reactions during derivatization of the conjugate are discussed. The peak plasma levels of the enantiomers, observed at less than or equal to 2 h after dosing, were similar but plasma clearances and terminal half-lives were different after oral administration of (R)-tocainide (195.5 +/- 20.1 ml min-1 and 9.7 +/- 0.8 h) and (S)-tocainide (110.2 +/- 10.5 ml min-1 and 14.5 +/- 1.7 h). Over 0-96 h the averaged urinary recovery of (R)-tocainide was 36 per cent and of (S)-tocainide 50 per cent. Stereoselective metabolism was a likely mechanism for the observed differences as the urinary recovery of the conjugate formed from (R)-tocainide differed substantially from that of (S)-tocainide (45 vs 1.2 per cent of given dose). Plasma t1/2 of the (R)- and (S)-conjugate were 9.9 and 18.7 h, respectively, indicating formation rate limited kinetics of the metabolite. The renal clearances of the conjugates were not significantly different (131 vs 97 ml min-1).

Adult↗