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Biomedical subjects

L Ekman

Publications and source records attributed to L Ekman.

At least 19 recordsLinked to original sources
PubMed1992

Liver tumors in male rats following treatment with glucocorticosteroids.

Male rats treated with either budesonide, prednisolone, or triamcinolone acetonide in drinking water for up to 104 weeks developed slightly increased incidences of basophilic foci, and significantly increased incidences of combined hepatocellular adenomas/carcinomas as compared to controls. Based upon reduced body weight gains and survivals, the doses administered were considered to be toxic. It was concluded that the positive findings represented a class effect, and probably involved glucocorticoid receptors.

Adenoma↗
PubMed1991

Dose-proportionality of eltoprazine. Pharmacokinetics of single oral doses in healthy subjects.

Eltoprazine. HCl belongs to a new class of psychotropic drug, the serenics. The dose-proportionality and pharmacokinetics of eltoprazine HCl has been investigated after single oral doses of 5, 10, 20 mg (18 subjects) and 30 mg (12 subjects) in a partly randomized, cross-over design. Eltoprazine was well tolerated and there were no relevant changes in safety parameters. All subjects showed irregular plasma-concentration-time profiles, some subjects demonstrating secondary peaks. The mean half-life was calculated to be about 6.5 h. The renal excretion of eltoprazine was characterized by net tubular secretion. AUC, peak plasma concentrations and the amount excreted unchanged in the urine were linearly related to the dose. Renal clearance and t1/2 were independent of dose. Thus, eltoprazine HCl was well tolerated orally and exhibited a linear pharmacokinetic profile.

Administration, Oral↗
PubMed1990

Protein synthesis in skeletal muscle during starvation and refeeding: comparison of data from intact muscle and muscle biopsy material.

The intact extensor digitorum longus (EDL) preparation in rat is a well-documented model for assessing protein synthesis in skeletal muscle. Human muscle biopsy material has also been used, but the extent to which biopsy material is representative for evaluation of muscle protein synthesis has not been established. Therefore, the aim of this study was to compare protein synthesis in intact muscle and in muscle biopsy material simultaneously in rats. The animals (70 g) were divided into three groups: fed (n = 22), starved for 36 hours (n = 22), and refed for 24 hours (n = 19). Protein synthesis and RNA content were measured in each group. Protein synthesis was determined as the incorporation of 14-C-phenylalanine into muscle protein in the intact EDL muscle from one leg and in a muscle biopsy from the contralateral EDL muscle. The incorporation of 14-C-phenylalanine was linear over time in both preparations, but was consistently lower in the muscle biopsy compared with the intact muscle. The relative change in incorporation, in % of that obtained in the fed state, showed a decrease in incorporation after 36 hours of starvation, in both intact muscle and in muscle biopsy material, 33% +/- 10% and 42% +/- 6%, respectively. After 24 hours of refeeding, an overshoot in protein synthesis was seen, to 136% +/- 6% in the intact muscle and to 133% +/- 6% in the muscle biopsy, as compared with the fed state. The RNA content decreased during the starvation period from 21.6 +/- 0.7 to 14.5 +/- 0.4 mg RNA/g protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine.

Long-term administration of some long-acting inhibitors of gastric acid secretion has been associated with the development of gastric enterochromaffin-like (ECL)-cell carcinoids in the rat. It has been argued that short-acting, surmountable histamine H2-receptor blockers such as ranitidine do not cause carcinoids. In this study, female rats (n = 100) were treated for 2 years with the histamine H2-receptor blocker ranitidine, 2 g/kg/day in the diet. Specimens from the stomachs of all rats, including 50 controls, were stained for argyrophil cells. Plasma gastrin and ranitidine levels were measured in separate groups of rats at different times during the study. The mean plasma level of ranitidine was 37.5 mumol/l, measured at midnight when the maximal level after food intake was expected. The resulting acid inhibition was associated with an approximately 3-fold increase in plasma gastrin which persisted throughout the whole period of the study. The ranitidine treatment resulted in a pronounced hyperplasia of gastric ECL cells. In 19 rats carcinoids were found, 4 of which were micro-invasive. No carcinoids were found in the control animals. The results provide further support for the gastrin mechanism, i.e. that the development of ECL-cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia and is not a unique effect of any individual acid-inhibiting drug.

Animals↗
PubMed1990

Gastrin and gastric enterochromaffin-like cell carcinoids in the rat.

Life-long administration (greater than or equal to 2 years) of a number of long-acting gastric acid inhibitors (including H2-receptor antagonists, omeprazole and ciprofibrate) has been associated with the development of gastric enterochromaffin-like cell (ECL cell) carcinoids in rats. It has been postulated that they are a consequence of some unique property of the longer-acting acid inhibitors. There is, however, a great deal of evidence to support the hypothesis that these gastric ECL cell carcinoids develop as a result of life-long hypergastrinaemia in rats. Several lines of investigation reported here show that gastric ECL cell hyperplasia occurs when gastrin levels are increased without the use of acid-inhibiting drugs. In rats, hypergastrinaemia developed after 4 weeks' administration of exogenous gastrin (4 micrograms/kg/h). The number of gastric ECL cells per visual field had increased to 250 compared with 180 in the controls. Long-term hypergastrinaemia, induced by partial gastric corpectomy, increased plasma gastrin levels from 200 to 800 pg/ml and the density of gastric ECL cells increased from 190 to 310 cells/visual field 10 weeks after the operation. Importantly, gastric ECL cell hyperplasia, which was produced in rats by administration of omeprazole, 14 mg/kg/day for 1 year, was fully reversible following normalization of gastrin levels. Until now, gastric ECL cell carcinoids have not been reported in studies of shorter-acting, reversible H2-receptor antagonists such as ranitidine, perhaps because the correct staining techniques (i.e. Grimelius and Sevier-Munger silver stains) have not been used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids.

The N-demethylation of ethylmorphine was studied in liver microsomes from human fetuses and adult patients as well as from human fetal adrenals and kidneys. Unexpectedly the reaction was catalysed at the same rate in fetal (42.3-1277.4 pmol/mg/min in 11 individuals) and adult microsomes (414-1617.8 pmol/mg/min in two individuals), which also had similar values of the apparent Km (1.50, 1.72 mM respectively) and Vmax (1.33, 1.81 nmol/mg/min respectively) in studies of the enzyme kinetics. There was a close correlation (r = 0.96) between the semiquantitative immunoblotting assessment of cytochrome P-450 HL-p in fetal liver microsomes (with the use of a monoclonal antibody against pregnenolone-16-alpha-carbonitrile induced rat hepatic cytochrome P-450) and the catalytic activity. The fetal adrenal microsomal N-demethylation was only 11-30% of the hepatic activity when compared within three fetuses in which such a comparison was possible. No activity was measurable in the kidneys. Two drugs that are believed to be substrates of the cytochrome P-450 HLp were tested as inhibitors of the ethylmorphine N-demethylation in human fetal and adult liver microsomes and in rat liver microsomes. Midazolam was a potent inhibitor (100% at 0.4 mM) of the reaction in all specimens, whereas cyclosporin A inhibited the reaction clearly only in adult liver microsomes. Endogenous steroids of importance in the fetal circulation were also tested as inhibitors. Progesterone and dehydroepiandrosterone inhibited the reaction by 75-80% at a concentration of 0.4 mM, whereas pregnenolone and 17-alpha-hydroxyprogesterone were almost devoid of inhibitory potency. These results are of interest in the discussion about the physiological role of the human fetal cytochrome P-450 HLp which has an unprecedented relative abundance in the liver.

Adrenal Cortex Hormones↗
PubMed1989

Cellular basis of immunomodulation by cholera toxin in vitro with possible association to the adjuvant function in vivo.

Cholera toxin (CT) is a potent oral immunogen that also acts as a strong mucosal adjuvant for immune responses to related as well as unrelated Ag. To elucidate the immunomodulating effects of CT at the cellular level we have examined interactions of CT with APC and with B and T lymphocytes in vitro. CT markedly stimulated the production of IL-1 from APC (mouse peritoneal macrophages or macrophage cell line P388D1) but did not induce Ia-Ag and had marginal, if any, effect in potentiating Ia Ag expression stimulated by rIFN-gamma on these cells. CT had differential effect on T cell proliferation in vitro, usually strongly inhibitory but on Con A-stimulated spleen cells during prolonged (greater than or equal to 5 days) culture or when added on day 4 or later to these cultures up to a two- to three-fold enhancement of proliferation was seen. CT-induced inhibition of T cell proliferation was associated with decreased production of IL-2 and anergy to exogenously added IL-2 despite apparently normal expression of IL-2R. Similar to what was found with T cells LPS-stimulated spleen B cells demonstrated both inhibition and enhancement of proliferation in the presence of CT: in high concentrations (greater than or equal to 10(-8) M) and early in culture (day 3) CT had a strong inhibitory effect on the proliferation of B cells, whereas later (day 6) and/or at lower CT concentrations (10(-9) to 10(-11) M) the proliferation was increased up to 10-fold. The net effect of CT treatment on Ig-production by LPS-stimulated spleen B cells was seen as an enhanced level of IgA and IgG but not IgM in culture supernatants. The differential effects of CT on the cells of the immune system observed in vitro may, singly or in combination, explain the immunostimulatory function of CT.

Adjuvants, Immunologic↗
PubMed1989

N-acetyl-L-tyrosine and N-acetyl-L-cysteine as tyrosine and cysteine precursors during intravenous infusion in humans.

The usefulness of N-acetyl-L-tyrosine (NAT) and N-acetyl-L-cysteine (NAC) as tyrosine and cysteine precursors during intravenous infusion was investigated in humans. Plasma levels and urinary excretion of NAT, tyrosine, NAC, and total cysteine were determined, and the site of deacetylation was examined by measuring the splanchnic and renal balances. Eleven healthy volunteers were given 5 g of either NAT or NAC as a 4-hour intravenous infusion. Plasma levels of NAT and NAC increased rapidly, accompanied by a 25% increase in tyrosine levels and a 35% decrease in total cysteine. Urinary excretion of NAT and NAC in 4 hours accounted for 56% and 11% of the infused amount, respectively. No net production of tyrosine or cysteine was found from the splanchnic area, but from the kidneys there was a small release of both tyrosine (10 +/- 3 mumol/min) and cysteine (64 +/- 3 mumol/min). We conclude that under these conditions the usefulness of NAT and NAC as precursors for the corresponding amino acids in humans is not apparent.

Acetylcysteine↗
PubMed1989

Utilization of intravenously administered N-acetyl-L-glutamine in humans.

L-glutamine is too unstable for inclusion in solutions for parenteral nutrition, but its acetylated analogue, N-acetyl-L-glutamine is not. The purpose of this three-part study was to investigate the utilization of intravenously (IV) administered acetylglutamine in humans. In study 1, nine healthy postabsorptive subjects were given 9.4 g acetylglutamine IV during four hours. In study 2, five healthy subjects were studied on two occasions following an overnight fast. They were given 9.4 g of acetylglutamine or an equivalent amount of glutamine as part of a total parenteral nutrition (TPN) regimen during 7.2 hours. A control group of five subjects was given the same TPN regimen, but without acetylglutamine or glutamine. The nutrient solution included glucose, amino acids, and a fat emulsion, supplying 9.4 g nitrogen and 6,300 kJ in a total volume of 1.8 L. In study 3, four patients were studied the day after major surgery. They were given the same TPN regimen as in study 2, containing 9.4 g acetylglutamine, during 7.2 hours. Plasma concentrations and urinary excretion of acetylglutamine and glutamine were measured in all three studies, and so were splanchnic and renal exchange of acetylglutamine and glutamine in study 1. In study 1, the plasma concentration of glutamine rose from 594 +/- 28 mumol/L to 728 +/- 26 mumol/L (P less than .001), whereas plasma levels of acetylglutamine exceeded 1,000 mumol/L in all subjects at the end of infusion. The eight-hour urinary excretion of acetylglutamine and glutamine corresponded to 18% of the infused amount of acetylglutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Dose and sex-dependent disposition of ketoconazole in rats.

The disposition of the antifungal drug ketoconazole was studied in mature (60-day-old) male and female rats given single intravenous doses of 10, 20 or 40 mg/kg body weight. The plasma profiles of ketoconazole were characterized by an initial rapid decline, followed by an apparent zero-order decline and a subsequent first-order elimination phase. In male animals the zero-order phase was less pronounced, resulting in a 3-5 times higher overall rate of elimination. A consequence of the dose-dependent disposition was that a 4-fold increase in dose resulted in a 9- and 17-fold increase in the area under the plasma concentration-time curve (AUC) of females and males, respectively. Terminal half-lives were independent of dose in both sexes. The disproportionate increase in AUC with dose, together with the observation that no intact ketoconazole was excreted in urine and only very small amounts in bile (less than 1% of given dose), suggest that the dose-dependent disposition is caused by saturation of metabolizing enzymes. These enzymes are most likely under the influence of androgens, since the capacity of males to eliminate ketoconazole was reduced by castration and in females this capacity was increased by testosterone treatment.

Animals↗
PubMed1987

Protein synthesis in skeletal muscle of rats following starvation and refeeding.

Determination of protein synthesis in individual tissues is important to understand the changes in protein metabolism during catabolic states. Three methods based on different underlying assumptions were compared in assessing muscle protein synthesis during nutritional manipulation. Rats were nonstarved, starved for 1 or 3 days, or refed for 2 days after 3 days of starvation. The extensor digitorum longus (EDL) muscles from the two hindlegs were used for analysis. In one EDL muscle the concentration and size distribution of ribosomes as well as the incorporation of [14C]leucine into protein in a cell-free system were determined. The other EDL muscle was incubated as such and the incorporation of [14C]phenylalanine into protein was measured. The total ribosome concentration per milligram of DNA decreased to 65% on the third day of starvation and remained low after refeeding. The amount of polyribosomes in the percentage of total ribosomes fell to 90% on the first day of starvation, regained the initial level on the third day, and reached 110% upon refeeding. During refeeding amino acid incorporation into protein in a cell-free system decreased to 40% and that in intact muscle to 64% of the prestarvation level. Upon refeeding, the activity increased to or above the original values. The use of several different techniques in parallel to assess protein synthesis in skeletal muscle is recommended since it gives information about the factors involved in regulation of the translational process in intact mammalian tissues.

Animals↗
PubMed1987

The relationship of the pharmacokinetics of chloroquine to dose in the rabbit.

Four albino rabbits were treated with 4 different doses of chloroquine phosphate (30-50 mg kg-1) given intragastrically and 10 others were given the hydrochloride (2.5-12.5 mg kg-1 i.v.). The i.v. doses were given as bolus into the median ear vein over 5-8 min. Samples (3-5 mL) of whole blood were subsequently collected at intervals for up to 6 weeks and analysed by HPLC. From the results, log concentration-time curves were drawn and the i.v. data fitted by computer to 3-compartment (8 rabbits) or 2-compartment curves (2 rabbits). The area under the curve (AUC) and half-lives were calculated for the different doses. A plot of AUC versus dose yielded a straight line but the half-lives showed wide inter-individual variation from the same doses.

Animals↗
PubMed1987

The metabolic response to glycerol during parenteral nutrition.

The use of various nonprotein energy sources in parenteral nutrition regimens has been discussed for many years. Besides glucose, glycerol, xylitol, fructose and sorbitol are currently being used as water-soluble parenteral fuels. Despite the increasing frequency with which these glucose substitutes are being used, little information is available regarding the differences they evoke in host responses. All experimental evidence to date has shown glycerol to be equally effective in sparing body nitrogen as glucose when supplied in hypocaloric amounts. Results from studies in injured animals suggest that exogenously administered glycerol is a more potent inhibitor of fatty acid oxidation than glucose. Although results from human volunteers have been variable, glycerol administration after injury appears to markedly reduce fatty acid oxidation and ketogenesis, as well as increase hepatic glycogen. Glycerol toxicity appears to result only from its excessive administration, or when administered intraperitoneally or subcutaneously. Intravenous administration of hypocaloric quantities of glycerol alone or as a component of total parenteral nutrition is safe and effective.

Dose-Response Relationship, Drug↗
PubMed1987

New developments in lipid emulsions for parenteral nutrition.

More than one thousand publications have demonstrated the safety and efficacy of today's lipid emulsions including long chain fatty acids under experimental and clinical conditions. This has resulted in a general acceptance of a dual energy system comprising both carbohydrates and lipids as non-protein calories in total parenteral nutrition. Non-carnitine-dependent fatty acid has been suggested as a superior energy source in clinical situations where carnitine may be in the subnormal range. A medium chain triglyceride (MCT) emulsion would provide an energy source with a more readily oxidizable substrate. The tolerance of MCT is less than that of long chain triglyceride (LCT), whereby only physical mixtures of these emulsions will be used in humans. A structured lipid (SL) is a triglyceride which includes both medium and long chained fatty acids within the same triglyceride. Emulsions including SL have demonstrated a decreased protein energy expenditure and increased serum albumin in burned animal. The SL has also been superior to LCT emulsions in stimulating muscle protein synthesis and maintaining body weight in hepatectomized animals. These positive effects on protein kinetics have been concomitant with a lower RES involvement during septicemia in burned guinea pigs. Emulsions including fatty acids with odd-number carbons give a possibility to provide a fat emulsion which also could contribute positively to the glucose homeostasis. The omega-3 family of fatty acids has demonstrated a potential pharmacologic effect with regard to their ability to decrease blood viscosity and improve survival rate in endotoxin shock in an experimental model. These observations have been ascribed to changes in thromboxin A2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Fat Emulsions, Intravenous↗
PubMed1987

Toxicity study of the new glucocorticosteroid budesonide in rats.

16 alpha,17 alpha-Butylidenedioxy-11 beta,21-dihydroxypregna-1,4-diene-3,20- dione (budesonide) was administered subcutaneously to male and female Wistar rats at the doses 0.01, 0.1 and 5 micrograms/kg/d (10 animals/group), and 5, 20 and 80 micrograms/kg/d (15 animals/group) for 26 weeks in two separate studies. A dose-dependent decrease in body weight gain in the groups given 5, 20 and 80 micrograms/kg/d compared with the control group was noted as well as a dose-related reduction in food intake in males receiving 20 or 80 micrograms/kg/d. Increased values for packed cell volume, hemoglobin concentration and erythrocyte counts were found for both sexes at the dose levels 20 and 80 micrograms/kg/d. Also a marked decrease in the number of lymphocytes was seen for both sexes at 80 micrograms/kg/d, and for females also at 20 micrograms/kg/d. Pathological changes associated with treatment with budesonide were found in the liver--panacinar hepatocytic fine vacuolation in females receiving 80 micrograms/kg/d; cervical lymph nodes--low numbers of small lymphocytes in both males and females receiving 20 or 80 micrograms/kg/d; mesenteric lymph nodes--low numbers of small lymphocytes in females receiving 20 or 80 micrograms/kg/d; thymus--low numbers of small lymphocytes in females receiving 80 micrograms/kg/d; mammary glands--acinar hyperplasia and secretion in both sexes receiving 20 and 80 micrograms/kg/d; uterus--dilation of the lumen in females receiving 20 or 80 micrograms/kg/d. Treatment with budesonide at doses of 5 micrograms/kg/d and below was without effect upon the morphology.

Animals↗
PubMed1986

Effects of tumor-load and malnutrition on myocardial function in the isolated working rat heart.

Marked differences in cardiac associated morbidity and mortality have been reported between patients with and without malnutrition. Tumor-associated cachexia may impair heart function, which further aggravate host wasting and thereby create a vicious circle. The aim of this study was to evaluate to what extent a malignant tumor may influence heart function under well-defined experimental conditions. The perfused working rat heart was used as a model. Study groups of freely-fed sarcoma-bearing rats, starved and protein-calorie malnourished (PCM) non-tumor rats were compared to freely-fed control animals. All groups of malnourished animals (tumor-bearing, starved and PCM) lost significant amounts of body and heart mass compared to freely-fed controls. Loss of heart contractile mass in tumor-bearing rats and malnourished animals did not lead to impaired heart function in any respect. The rate of oxygen uptake was significantly higher under all experimental conditions in perfused hearts from tumor-bearing rats compared with hearts from starved, PCM and freely-fed control rats. Oxygen uptake per left ventricular work was significantly higher in tumor-bearing rats but significantly lower in starved and PCM rats compared with control animals. Norepinephrine at various concentrations (10(-9)-10(-5) mol/l) in the perfusate stimulated the contractility and the left ventricular peak pressure significantly more in hearts from malnourished animals compared with that of freely-fed controls. The results show that adaptive functional changes can be recorded in the isolated perfused rat heart from sarcoma-bearing rats and after a period of comparatively acute undernutrition in non-tumor rats. A malignant tumor or the associated malnutrition does not induce impaired pumping performance despite a reduction in contractile heart mass. Increased oxygen consumption in hearts from tumor-bearing animals may contribute to elevated energy expenditure in a cancer-bearing host.

Animals↗
PubMed1986

Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans.

The pharmacokinetics of chloroquine were studied after intramuscular and intravenous administration of the drug to healthy African adults. Chloroquine was analysed in plasma using an h.p.l.c. method and pharmacokinetic parameters were derived from the concentration-time data using a non-linear computer programme. A two-compartment open model was assumed. Chloroquine was rapidly absorbed from an intramuscular site, producing a plasma concentration-time profile similar to that obtained after a 15 min i.v. infusion of a comparable dose. The pharmacokinetics of chloroquine after i.m. and i.v. administration were characterised by a long half-life and a very large volume of distribution. There was no significant difference between the values of each parameter obtained from the different routes. It is suggested that the high Cmax obtained after i.m. and i.v. administration of chloroquine might contribute to its toxicity when these routes are used in treatment.

Adult↗