PubMed Health⌕ Search

Biomedical subjects

R Blomstrand

Publications and source records attributed to R Blomstrand.

At least 19 recordsLinked to original sources
PubMed1989

Non-linear kinetics of 4-methylpyrazole in healthy human subjects.

In order to evaluate the pharmacokinetic profile of the alcohol dehydrogenase inhibitor 4-methylpyrazole 4-MP, a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase-I study" was performed in healthy male volunteers at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4) and 100 mg.kg-1 (n = 3). In the 10 and 20 mg.kg-1 group, the elimination of 4-MP from the plasma followed non-linear kinetics with mean rates of concentration decline of 3.66 and 5.05 mumol.l-1.h-1, respectively. In the two highest dose groups, the elimination also appeared to be non-linear although the patterns were not followed long enough to confirm this. The mean rates of concentration decline at the higher doses were significantly increased, up to 14.9 mumol.l-1.h-1 at 100 mg.kg-1. The average renal clearance of 4-MP was low, 0.016 ml.min-1.kg-1, and only 3% of the administered dose was excreted unchanged in the urine, indicating metabolism as the major route of elimination. Because of the apparently unusual kinetics following single dose treatment, thorough multiple dose studies need to be carried out to determine a safe dosage regimen for 4-MP.

Adult↗
PubMed1988

4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses.

4-Methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, is a possible future drug for the treatment of methanol and ethylene glycol intoxications and the severe ethanol-disulfiram reaction. Therefore a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase I study" was performed in healthy volunteers in order to determine the tolerance of 4-MP at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4), and 100 mg/kg (n = 3). Along with each dose group, there were two placebos except with the 100 mg/kg group where there was only one placebo. In the 10 and 20 mg/kg group there were no side-effects in any subject. At the 50 mg/kg level, three out of four subjects experienced slight to moderate nausea and dizziness from 0 to 2.5 h after dosing. In the 100 mg/kg group all three subjects reported side-effects like nausea, dizziness, and vertigo, that were short-lived in two subjects, but lasted up to 30 h in one subject. The study was stopped after evaluation of the latter subject, so fewer subjects were completed in this last group. Despite these subjective side-effects, there were no significant changes in objective clinical parameters like pulse, blood pressure, body temperature, or blood and urine chemistries. We conclude that at a single dose of 4-MP (10-20 mg/kg) producing plasma levels within a probable therapeutic range, no side-effects were attributed to 4-MP.

Adult↗
PubMed1986

Occurrence of short chain aliphatic diols in human blood: identification by gas chromatography-mass spectrometry.

Patients attending a general hospital for various reasons were screened for raised serum gamma glutamyltransferase (gamma-GT) and positive blood alcohol concentration (BAC). The results served as objective biochemical tests of heavy drinking. Among 419 individuals, 50 (11.9%) met these requirements and blood samples were used to determine the presence of low molecular mass aliphatic diols. 1,2-Propanediol, 2,3-butanediol and 2,2-dimethyl-1,3-propanediol were determined by gas liquid chromatography-mass spectrometry (GC-MS). In patients with blood ethanol concentration less than 2 mmol/l, 1,2-propanediol and 2,2-dimethyl-1, 3-propanediol mainly occurred together at median concentrations of about 200 mumol/l. When blood ethanol was 2-42 mmol/1,2,3-butanediol was also present covering a wide concentration range: three patients had concentrations between 6 and 10 mmol/l. There was no apparent correlation between the concentration of 2,3-butanediol and the concentration of blood ethanol. The diols were below the limits of detection in blood from nonintoxicated control individuals and hospital in-patients.

Adolescent↗
PubMed1986

Dietary modulation of retina phospholipids and photoreceptor function with particular reference to phosphatidylinositol.

The effect of dietary partially hydrogenated herring oil (HHO) on the fatty acid composition of the phospholipids of rat retina and on the amplitude of the a-wave of the electroretinogram (ERG) was studied in rats raised for several generations on an essential fatty acid poor diet. The most significant effect of the dietary treatment was a decreased content of arachidonic acid (C20:4 omega 6) and an increased concentration of docosahexaenoic acid (C22:6 omega 2) and 18:1 isomers associated with the phosphatidylinositol (PI). The a-wave of the ERG showed a decreasing amplitude during the experiment and was reduced with about 30% (P less than 0.004) of the initial value in all rats at the end of the experiment. The pronounced change in the arachidonic content in PI and the decreased amplitude of the a-wave of the ERG suggest that arachidonic acid of the PI has an important function in the visual phototransduction process.

Animals↗
PubMed1986

Peripheral hormone levels in healthy subjects during controlled fasting.

The effect of one week of controlled fasting (31 of fluid containing 50 g of carbohydrate/day) upon the serum levels of hormones, sex hormone binding globulin, and albumin was studied in healthy subjects. Fasting caused decreased levels of prolactin and T3, no changes in the levels of TSH, FSH, LH, dehydroepiandrosterone, 4-androstene-3, 17-dione, total oestrone, and total testosterone, and increased levels of cortisol, dehydroepiandrosterone sulphate and albumin. A significant positive correlation was found between albumin and dehydroepiandrosterone sulphate. Fasting rapidly increased the levels of sex hormone binding globulin and decreased the percentage of free testosterone and the calculated free testosterone level in both sexes. A decreased metabolic clearance of certain steroids (cortisol, dehydroepiandrosterone sulphate) owing to an increased protein binding may be one of the endocrine consequences of fasting. An increased protein binding of testosterone may be outweighed by a decreased gonadal production, thus resulting in an unchanged total testosterone level. The increased sex hormone binding globulin level could not be explained by changes in gonadal and thyroid hormones.

Adult↗
PubMed1986

Simple diagnosis of the Zellweger syndrome by gas-liquid chromatography of dimethylacetals.

The absence of peroxisomes in patients with the cerebrohepatorenal syndrome of Zellweger leads to several biochemical abnormalities, including deficient synthesis of plasmalogens as well as accumulation of very long-chain fatty acids and intermediates in bile acid biosynthesis. Accumulation of very long-chain fatty acids in serum and fibroblasts has hitherto been used most extensively for diagnosis. Due to the relatively small amounts of the very long-chain fatty acids also in the Zellweger patients, and the risk for interfering impurities, such analyses are difficult. Direct assay of plasmalogens is also relatively difficult and time-consuming. In this report, we describe a relatively simple method for diagnosis, based on gas-liquid chromatography of a lipid extract of erythrocytes after methyl transesterification. The alpha, beta-unsaturated ether in the plasmalogen is converted to the dimethylacetal of the corresponding aldehyde, and the relative amount of plasmalogen is thus reflected by the ratio between 18:0 dimethylacetal and methyl stearate as well as by the ratio between 16:0 dimethylacetal and methyl palmitate. The ratio 18:0 dimethylacetal/methyl stearate was found to be 0.28 +/- 0.03 (mean +/- SD) after analyses of erythrocytes from healthy or non-Zellweger infants, but less than 0.02 in erythrocytes from three infants with the Zellweger syndrome. Preliminary work with amniotic fluid suggests that this analysis may be suitable also for prenatal diagnosis of the Zellweger syndrome.

Acetals↗
PubMed1985

Influence of dietary partially hydrogenated vegetable and marine oils on membrane composition and function of liver microsomes and platelets in the rat.

The aim of the present study was to investigate the influence of partially hydrogenated vegetable and marine oils on membrane composition and function of liver microsomes and platelets with particular reference to the metabolism of linoleic acid and the production of arachidonic acid metabolites. Four groups of male weanling rats were fed linoleic acid supplemented diets containing 20% (w/w) of partially hydrogenated low erucic acid rapeseed oil (HLRSO), partially hydrogenated herring oil (HHO), olive oil (OO) and trierucin + triolein (TE) for 10 weeks. An additional two groups were fed partially hydrogenated low erucic acid rapeseed oil and partially hydrogenated herring oil without linoleic acid supplementation (HLRSO- and HHO-, respectively). Substantial amounts of trans fatty acids were incorporated into liver microsomes (12.6% in group HLRSO) and platelets (7.0% in group HLRSO-). This incorporation was not dependent on the dietary linoleic acid level. Hepatic microsomal delta5 -desaturase activity was significantly increased after HLRSO feeding compared to 00 feeding. Delta6 -Desaturase activity did not vary in the linoleic acid supplemented groups. Both delta5 -and delta6 -desaturase activities were significantly increased in groups without linoleic acid supplementation. Docosenoic acid was incorporated into platelet phospholipids in contrast to liver microsomes. In the platelet, docosenoic acid seemed to have a special preference for phosphatidylserine. Very small amounts were incorporated into platelet phosphatidylinositol. Feeding diets HLRSO, HHO and 00 did not influence rat platelet cyclooxygenase or 12-lipoxygenase activity. Platelets from rats fed TE, however, produced significantly less 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) than platelets from rats fed OO. Feeding of HLRSO- and HHO- resulted in a significantly diminished production of the arachidonic acid metabolites 12-HETE, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 6-keto-prostaglandin F1alpha in stimulated platelets and aorta. Thus, high dietary levels of trans isomers of monoenoic acids do not interfere with platelet cyclooxygenase or lipoxygenase activity provided sufficient amounts of linoleic acid are available.

Animals↗
PubMed1985

Hydrogen concentration in expired air analyzed with a new hydrogen sensor, plasma glucose rise, and symptoms of lactose intolerance after oral administration of 100 gram lactose.

A rapid breath hydrogen analyzer to detect lactose malabsorption is described. After ingestion of a lactose solution the patient expires into a mouthpiece attached to a hydrogen sensor at 30-min intervals for 3 1/2 h. The hydrogen of the expired air causes a voltage change that can be transformed into ppm from a calibration curve. A tolerance test with a load of 100 g lactose was performed in 43 consecutive patients with various gastrointestinal disturbances, referred to the laboratory for the commonly used lactose tolerance test based on plasma glucose measurements. Eleven patients developed symptoms of lactose intolerance during the test. Biopsy specimens from the distal duodenum or proximal jejunum showed partial villous atrophy in one, in whom celiac disease with lactose intolerance was diagnosed; the other 10 had normal specimens. In nine of them lactose intolerance was diagnosed and confirmed by observation for months on a lactose-poor diet. The 10th patient (H.P.L.) did not improve on such a diet. He also showed pronounced symptoms of intolerance during a test with monosaccharides (glucose + galactose). His intestinal disease remained undiagnosed. The 11 patients with symptoms of intolerance and 3 patients without symptoms during the lactose load showed a flat plasma glucose curve after drinking the lactose solution--that is, a maximum rise of the glucose concentration of 1.5 mmol/l. One of the symptom-free patients dropped out and could not be observed, another did not improve on a lactose-poor diet, and the third noticed a favorable effect of the diet on stool consistency but not on other abdominal symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Studies on the effect of 4-methylpyrazole on methanol poisoning using the monkey as an animal model: with particular reference to the ocular toxicity.

Young cynomolgus monkeys (Macaca fascicularis) were chosen as a model to investigate the ocular toxicity in animals poisoned with methanol and treated with 4-methylpyrazole (4-MP). The metabolism of methanol in the monkey was investigated after administration of 4-MP. Plasma levels of methanol, formic acid, 4-MP and 4-hydroxy-MP (4-OH-MP) were determined. After intramuscular injection, 4-MP was rapidly absorbed and depressed the elimination rate of methanol as well as the accumulation of formate in the blood. The results show the same great individual variations in monkeys as in humans regarding the susceptibility to methanol poisoning. Administration of a single dose of 5 g/kg induces a serious intoxication in most monkeys, causing death to some of them. Two monkeys receiving a single dose of 6 g/kg of methanol developed a serious initial inebriation and were treated with 4-MP. These monkeys survived and showed no signs of toxicity on ocular examinations which included ophtalmoscopy and electroretinogram (ERG) recordings.

Alcohol Oxidoreductases↗
PubMed1984

Normal electroretinogram and no toxicity signs after chronic and acute administration of the alcohol dehydrogenase inhibitor 4-methylpyrazole to the cynomolgus monkey (Macaca fascicularis)--a possible new treatment of methanol poisoning.

High doses of 4-methylpyrazole (4-MP) could be administered to monkeys in long- and short-term experiments without yielding any general toxicity or any toxic influence on the retinal photoreceptors, the conduction of impulses through the retina or on the activity in the inner nuclear layer detectable by recording the electroretinogram (ERG). Both series included a low dose (20 mg/kg) and a high dose level (100 mg/kg), the former being a tentative therapeutic dose. In the first series the substance was administered for 6 weeks and the toxicity regarding clinical signs, hematology and blood chemistry, and gross and microscopic pathology evaluated. Furthermore ophthalmoscopy with assessment of the fundus structures and recordings of the ERG were performed. The second series was mainly concerned with revealing of any direct effect of 4-MP on the ERG. Because of the low toxicity of 4-MP and its powerful inhibitory capacity on alcohol dehydrogenase, the substance should prove a potential tool in clinical alcohol research and an effective antidote in clinical situations where inhibition of alcohol dehydrogenase (ADH) is the key to a successful outcome of, for example, methanol and ethylene glycol poisoning.

Alcohol Oxidoreductases↗
PubMed1979

Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: an approach to therapy against methanol poisoning.

4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD(+) oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 muM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.

Alcoholism↗
PubMed1978

Mass fragmentographic determination of docosenoic acid in rapeseed oils.

A highly sensitive and accurate reference method for determination of docosenoic acid (mainly erucic acid, 22:1n-9) in different rapeseed oils is described. A fixed amount of [1-14C] erucic acid methyl ester (about 1 microgram) is added to a fixed amount of oil. After treatment with sodium methoxide/methanol reagent and extraction with hexane, the amount of unlabeled erucic acid is determined from the ratio between the recordings at m/e 320 and m/e 322 obtained after analysis with a combined gas chromatograph-mass spectrometer equipped with an MID (multiple ion detector). The two ions used correspond to the M-32 peak in the mass spectrum of unlabeled and [1-14C] labeled erucic acid methyl ester. The relative standard deviation of the method is about 1.8%. The method was compared with a gas chromatographic method for determination of erucic acid.

Brassica↗
PubMed1978

Effect of different dietary triglycerides on 7alpha-hydroxylation of cholesterol and other mixed-function oxidations.

The effect of a diet containing triglycerides of different fatty acid composition on hepatic 7alpha-hydroxylation of cholesterol was studied. 7alpha-Hydroxylation of exogenous as well as endogenous cholesterol was significantly lower in the liver of rats fed trilinolein and triolein than in those fed tripalmitin and trierucin. The concentration of cytochrome P-450 in liver microsomes was significantly lower in the rats fed tripalmitin and trierucin than in those fed triolein and trilinolein. The inhibitory effect of triolein and trilinolein on 7alpha-hydroxylation of cholesterol and the stimulatory effect of these triglycerides on the concentration of cytochrome P-450 was not due to the small amounts of peroxides present in the unsaturated triglycerides. Thus addition of the antioxidant butylated hydroxyanisol did not change the general pattern with respect to 7alpha-hydroxylation and concentration of cytochrome P-450. However, a diet consisting of peroxidized linoleic acid further decreased 7alpha-hydroxylation of cholesterol. The difference between the effect obtained with triolein and trilinolein on the one hand and trierucin and tripalmitin on the other was observed also in experiments with lower concentrations of fat in the diet and in experiments with different lighting conditions and feeding patterns. The inverse relation between cytochrome P-450 and 7alpha-hydroxylation of cholesterol, as well as results obtained with substrates for mixed-function oxidation other than cholesterol suggest that most of the changes observed due to the different diets are specific for 7alpha-hydroxylation of cholesterol. The level of cholesterol 7alpha-hydroxylase activity was found to be better related to the degree of absorption of fat than to total amount of absorbed fat or degree of unsaturation of the fat. The results are discussed in relation to previous knowledge concerning mechanisms regulating biosynthesis of bile acid.

Animals↗