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Effect of Ultraviolet Irradiation on Hyaluronic Acid in Vitro.
Hvidberg E., Kvorning S.A., Schmidt A., Schou J.
Effect of Prolonged Cortisone Treatment on Subcutaneous Connective Tissue in Mice
Hvidberg E., Schmidt A.
Caffeine Poisoning
Jokela S., Vartiainen A.
Determination of the Cholinesterase Activity in Blood and Organs by Automatic Titration. With some Observations on Serious Errors of the Method and Remarks of the Photometric Determination.
Jensen-Holm J., Lausen H.H., Milthers K., Møller K.O.
Effect of Ultraviolet Irradiation on Connective Tissue.
Hvidberg E., Kvorning S.A., Schmidt A., Schou J.
Plasma HDL Cholesterol and Growth Hormone in Epileptics Treated with Anticonvulsants
Luoma P.V., Myllyla V.V., Sotaniemi E.A., Hokkanen T.E.
Plasma high density lipoprotein (HDL) cholesterol and serum growth hormone (GH) levels were determined in 166 epileptic patients undergoing anticonvulsant treatment in 54 healthy controls. HDL cholesterol and GH levels were high in epileptics when compared to the levels in controls. Nineteen out of 31 patients (61%) with elevated GH had elevated plasma HDL cholesterol concentration. This relationship in patients with normal GH was 34/135(25%). In female epileptics with elevated GH plasma HDL cholesterol was in positive relationship to serum GH level (r = 0.47, P less than 0.05). The increase in GH secretion in epileptics might be associated with an increase in hepatic production of HDL.
The Effect of Lithium on the Incorporation of 3H-Glucosamine into Glycopeptides and the Transformation of 3H-Glucosamine into Sialic Acid in Rat Brain
Edelfors S.
Rats were fed a lithium-containing diet (40 mmol LiCl/kg of diet) for five weeks. The plasma-lithium concentration was 0.48 mmol Li+/l of plasma. 3H-glucosamine (400 nCi/kg body weight was injected intraperitoneally, and 24 hrs later the brain was divided anatomically into hemisphere, cerebellum, pons and thalamus. The brain parts were defatted and the sialic acid-containing glycopeptides were separated by column chromatography before determination of 3H-glucosamine, 3H-sialic acid and total sialic acid. Neither the total amount nor the specific activity of sialic acid were influenced by the lithium treatment. Also the 3H-content of the sialic acid-free glycopeptides remained unchanged.
HPLC-Determination of some Antiinflammatory, Weak Analgesic and Uricosuric Drugs in Human Blood Plasma and its Application to Pharmacokinetics
Nielsen-Kudsk F.
HPLC-determination of naproxen, indomethacin, ketoprofen, fenoprofen ibuprofen, diclofenac sodium, tolfenamic acid, phenylbutazone, mofebutazone, salicylic acid, acetylsalicylic acid, phenacetin, paracetamol, sulfinpyrazone and probenecid by means of an adjustable, rapid accurate and specific method is described. Plasma samples of 0.2 ml were deproteinised and the drugs extracted simultaneously with pure acetonitrile. Aliquots of 25 mul of this primary extract were directly injected on the column. As elution solvent for drug screening was basically used 55% methanol in 50 mM phosphate buffer at pH 4.0. Optimal separation of some drugs or reasonable elution times for others were obtained by varying the methanol concentration of the elution solvent or possibly its pH. The method used for individual drug determinations is very applicable for therapeutic monitoring purposes as well as for use in pharmacokinetic investigations. As an example, the practical detection limit for naproxen in plasma was about 0.2 microgram ml-1. By concentrating the extract this could be lowered to about 0.04 microgram ml-1. The method was applied in a study of the pharmacokinetics of naproxen in a person, who ingested a single oral dose of 2.5 mg kg-1. Pronounced two-compartment kinetics were found. Vc was 0.038 1 kg-1, Vdss 0.138 1 kg-1, t 1/2 (beta) 21.3 hrs, t 1/2 (alpha) 0.99 hr and t 1/2 (ka) 0.67 hr.
The Distribution of Chlorpromazine between Plasma and Erythrocytes
Lund A.
Chlorpromazine is found to be taken up by the erythrocytes in a dissociable binding similar to that of the plasma protein binding so that an equilibrium is attained between these binding sites. The plasma/cell ratio is on an average 2 but is subject to large interindividual variations. This ratio is only moderately influenced by the presence of other drugs and anticoagulants in the blood. The consequences of the cell binding of drugs for the analytical result when using plasma or whole blood and the evaluation of blood concentrations of their relation to the therapeutic effect are discussed.
Radioimmunoassay for Doxepin and Desmethyldoxepin
Virtanen K., Salonen J.S., Scheinin M., Iisalo E., Mattila V.
A simple and sensitive radioimmunoassay (RIA) for the determination of doxepin and desmethyldoxepin in plasma or serum has been developed using a previously reported antiserum to the tricyclic anti-depressants. Before assay, doxepin is separated from desmethyldoxepin with selective extraction at different pH values enabling each to be measured specifically. 3H-imipramine is used as tracer. By using the extraction procedure doxepin and desmethyldoxepin concentrations can be measured down to 9 nmol/1 from a 0.1 ml sample. If necessary, sensitivity can be doubled by taking a 0.2 ml sample to extraction. Recoveries of doxepin and desmethyldoxepin were quantitative when the drugs were added at different concentrations to normal, pooled human plasma and the inter- and intra-assay coefficients of variation did not exceed 9%. The concentrations obtained from patient samples by the present RIA correlated well with those by high-pressure liquid chromatography. The RIA was also shown to be useful in pharmacokinetic single dose studies with doxepin.
The Effect of Antineoplastic Drugs on the Pharmacokinetics of Antipyrine in the Rat
Høyem-Johansen T., Slerdal L., Høylandskjaer A., Aarbakke J.
The pharmacokinetics of antipyrine was investigated in individual rats pretreated with cyclophosphamide, 5-fluorouracil and methotrexate. Before oral dosing a complete emptying of the rat stomach was obtained by 24 hours of fasting and prevention of coprophagy. Antipyrine was given intravenously via a cannula in an inguinal vein and repeated samples of blood were drawn from a cannula in an inguinal artery. Systemic availability of oral antipyrine was studied in rats given the 14C-labelled drug intravenously and the 3H-labelled drug orally after pretreatment with cyclophosphamide. The log plasma concentration versus time curve of antipyrine given orally showed a short absorption and distribution phase followed by a linear elimination phase. Peak antipyrine concentrations were reached 3-6 minutes after oral dosing in control rats. The rate of absorption of antipyrine was moderately decreased by methotrexate. All drugs increased the area under the curve (AUC) of antipyrine. The systemic availability of oral antipyrine after cyclophosphamide pretreatment (0.88) was not changed, but the metabolic clearance of the drug was reduced. The apparent elimination rate constant was decreased by methotrexate and the apparent volume of distribution was decreased by cyclophosphamide and 5-fluorouracil. The results indicate that antineoplastic agents may change drug kinetics in different ways in rats.
Digitalis Induced Haemodynamic Changes in Patients with Vascular Disease during a Preoperative Exercise Test
Bille-Brahe N.E., Engell H.C., Sørensen M.B.
Haemodynamic studies at rest and during exercise before and after digitalization were carried out in 11 patients with vascular disease. Haemodynamic parameters at rest were within normal limits except for one patient, who had a cardiac index (CI) below 2.51/min/m2. During exercise 7 of the patients showed impaired left ventricular function. In the resting patients digitalization produced a significant decrease in pulmonary capillary wedge pressure (PCWP) and an increase of approximately 15% in left ventricular stroke work index (LVSWI) and total oxygen consumption. Myocardial oxygen consumption seemed unchanged as no significant changes were found in the product of mean arterial blood pressure and heart rate. After digitalization 6 of 7 patients with impaired left ventricular function showed improved haemodynamic response to exercise while the 4 patients with normal left ventricular function had an unchanged haemodynamic response.
Effects of Different Monoamine Oxidase Inhibitors on Respiratory Activity in Rats with Chronically Impaired Central Serotonergic Function
Mueller R.A., Lundberg D., Breese G.
Resting and CO2 stimulated respiration were measured by means of a whole-body plethysmograph in rats lightly anaesthetized with halothane. Rats pretreated neonatally with intracisternal 5,7-dihydroxytryptamine (5,7-DHT) to destruct permanently central serotonergic neurones had significantly lower resting and CO2 stimulated respiratory frequency (RF) and minute volume (VM) than naive rats. In the 5,7-DHT pretreated rats, but not in naive rats, the monoamine oxidase inhibitors clorgyline and pargyline further reduced both resting and CO2 stimulated RF and VM, whereas 1-deprenyl stimulated respiration. The results provide additional evidence that monoaminergic mechanisms are involved in central modulation of respiration in which activation of a serotonergic neuronal system depresses, and dopaminergic activation stimulates respiration.
Effect of Nickel on the Levels of Dopamine, Noradrenaline and Serotonin in Different Regions of the Rat Brain
Ali S.F., Hasan M., Hasan M.Z., Anwar J.
Modification of GABAergic Activity and Thyrotropin Secretion in Male Rats
Mattila J., Männistö P.T.
The effect of GABA on basal and stimulated TSH secretion was studied in male rats. The effects of drugs on basal TSH levels were not consistent. Muscimol(0.5 mg/kg subcutaneously, but not 2 mg/kg) increased whereas baclofen (10 mg/kg intraperitoneally), amino-oxyacetic acid (AOAA, 20 mg/kg intraperitoneally) and bicuculline (2 mg/kg intraperitoneally, but not 1 or 4 mg/kg) decreased basal TSH concentrations. Muscimol, AOAA and baclofen dose-dependently reversed the TSH cold-response, as did a large dose of di-n-propylacetate (DPA, 400 mg/kg intraperitoneally) and 500 mg/kg (but not 50, 100 or 1500 mg/kg intraperitoneally) of GABA itself. Bicuculline was not effective alone. Neither did it modify the effects of muscimol, AOAA and GABA on the cold-stimulated TSH response. None of the drugs studied (AOAA, GABA, bicuculline) modified TRH-induced (100 ng intraperitoneally) TSH-response. GABA injected into the third ventricle (5-50 microgram/rat) or into the medial basal hypothalamus (MBH, 5 microgram/rat) had no effect on the basal TSH levels. However, the TSH cold-response was inhibited when GABA (5 microgram/rat) was infused into the MBH but not when it was infused into the third ventricle (5-50 microgram/rat). The results suggest that GABAergic pathways may have an inhibitory effect on the stimulated TSH secretion in male rats. The locus of this inhibition is not situated in the anterior pituitary, but possibly in the MBH.
Concentration of Serotonin Metabolites in the Cerebrospinal Fluid from Alcoholics before and during Disulfiram Therapy
Beck O., Borg S., Holmstedt B., Kvande H., Skröder R.
The levels of 5-hydroxytryptophol and 5-hydroxyindoleacetic acid were measured in the cerebrospinal fluid before and after one week of disulfiram treatment (400 mg/day) from ten male hospitalized alcoholic patients. The disulfiram treatment induced elevated (P less than 0.001) levels of 5-hydroxytryptophol. The levels were higher than in a control group, both before (P less than 0.01) and after (P less than 0.001) the treatment. No effects on the levels of 5-hydroxyindoleacetic acid were noted. The results indicate an altered serotonin metabolism in alcoholics, which is further potentiated by disulfiram treatment.
Enhancement of Urinary Prostaglandin Excretion by Chlorazanil in Rats. Effects of Indomethacin
Olsen U.B., Eilertsen E., Arrigoni-Martelli E.
In conscious unloaded Sprague-Dawley female rats chlorazanil (10 mg/kg orally) markedly increased urinary prostaglandin E2-excretion from 51 +/- 9 to 813 +/- 112 ng/kg/6 hrs. Urinary flow rate increased from 12.8 +/- 0.6 to 42.0 +/- 1.4 ml/kg/6 hrs and urinary sodium excretion from 0.96 +/- 0.12 to 3.86 +/- 0.33 mmol/kg/6 hrs Urinary potassium excretion was unchanged. Indomethacin pretreatment (5 mg/kg orally) greatly induced the effect of chlorazanil on urinary prostaglandin E2-excretion. In addition indomethacin modified the excretory effects of chlorazanil, thus the enhancement of urinary flow rate was attenuated, the potassium excretion decreased, while sodium excretion tended to be potentiated. In non-pretreated condition chlorazanil variably affected urinary kallikrein excretion (TAMe-esterase activity) from 108 +/- 6 to 92 +/- 33 mEU/kg/6 hrs. After indomethacin pretreatment chlorazanil invariably reduced urine enzyme excretion from 111 +/- 6 to 32 +/- 4 mEU/kg/6 hrs.
Plasma and Brain Levels of Δ6-THC and Seven Monooxygenated Metabolites Correlated to the Cataleptic Effect in the Mouse
Ohlsson A., Widrnan M., Carlsson S., Ryman T., Strid C.
Abstract: The brain and plasma levels of unchanged Δ6-tetrahydrocannabinol (Δ6-THC), 7-hydroxy-Δ6-THC, the five side-chain hydroxylated Δ6-THC derivatives and 1α, 2α-epoxyhexahydrocannabinol (EHHC) were correlated to the cataleptic effect in the mouse up to 60 min. after intravenous administration of radiolabelled compounds in the range 1.3 to 12.4mg/kg. All cannabinoids except Δ6-THC and l″-hydroxy-Δ6-THC showed a very good correlation between brain/plasma concentrations and cataleptic effect. 4″-Hydroxy- and l″-hydroxy-Δ6-THC reached the highest concentration in the brain but the most potent cannabinoids were: Δ6-THC, 7-hydroxy-, 3″-hydroxy-Δ6-THC, and EHHC followed by 5″-hydroxy-, 4″-hydroxy-, 2″-hydroxy-, and 1″-hydroxy-Δ6-THC in decreasing order. It was concluded that structural rather than pharmacokinetic features are most important in determining the psychoactivity of the various cannabinoid metabolites of THC.
Differences in Metabolic Behaviour and Liver Toxicity Between the Optical Isomers of Bufenadrine Hydrochloride, a Substituted Diphenhydramine, in the Rat
Hespe W., Mulder D., Eeken C.J.
Abstract: Among the alkyl-substituted amino ethers derived from diphenhydramine, bufenadrine, 2-[(o-tert-butyl-α-phenylbenzyl)oxy]-N,N-dimethylethylamine, is a remarkable example of the role of structural factors in liver toxicity. Non-published toxicological investigations with both optical isomers of this compound revealed that (–)bufenadrine is exclusively or mainly responsible for the toxic activities of the racemic compound. Metabolic studies in rats with both optical isomers labelled N-14CH3 showed that after a single dose profound differences already occur with regard to their metabolic fate. Over the period studied the elimination of radioactivity after a dose of both 2 mg/kg, intravenously, and of 10 mg/kg, orally, of the (–)isomer was lower in the urine, faeces and bile and higher in the respiratory air than with the (+)isomer. When an oral dose of 50 mg/kg was given, the elimination in the respiratory air, too, was lowest in the case of the (–)isomer. Since no significant difference in binding to serum constituents or to homogenated liver tissue was observed, it seems likely that the metabolic differences originate in the liver. The data obtained suggest the inability of the liver to metabolize (–)bufen-adrine at a rate sufficient to prevent the accumulation of the substance which triggers off the toxic mechanism.
Postnatal Development of the Effects of Alcohol and of the Induced Tolerance to Alcohol in Mice
Lagerspetz K.Y.
: The effects of single and repeated intraperitoneally injected doses of ethyl alcohol on selected reflex responses and open field behaviour of mice aged from 2 to 46 days were studied. The effect of alcohol came on very rapidly in the youngest age groups, the maximum effect occurring already 3 minutes after the alcohol injection. The effect was smaller in 20 days old animals than in 8, 14, or 46 days old mice. Significant growth reductions were found in 14 days old mice which had received alcohol daily for 6 days, and in 46 days old mice which had received alcohol daily for 8 or 18 days. Increased tolerance to alcohol was found in 28 days old and in 46 days old animals after 8 daily injections, but not in 20 days old animals after 6 injections or in the younger age groups. The earliest age at which the induced tolerance to alcohol was found to develop corresponds to the age of maturation of the noradrenergic brain mechanisms, as reflected in the attainment of the adult noradrenaline level in the brain.
