bluuebunny/crossref_metadata_2025 huggingface dataset:
Chlorprothixene and its Metabolites in Blood, Liver and Urine from Fatal Poisoning
Authors: Christensen Hanne
Published: July 2010

Abstract: A spectrophotometric method for the quantitative determination of chlorprothixene (CPT) and its metabolites in autopsy material has been developed. The method involves repeated extractions with non‐polar solvents at pH 11–12 and thin‐layer chromatographic separation, followed by u.v. spectrophotometry of hydrochloric acid‐methanol extracts of the chromatographic fractions. The method which has a lower detection limit of 0.1 μ/g material, was used for blood, urine and liver from 12 cases, in which CPT was considered as the only or contributory cause of death. In the cases in which death occurred due to CPT only (2.5–4 g of CPT orally), the total concentration of thioxanthenes (i.e. CPT and its metabolites) were 0–1 μg/mg in the blood, 0.1–15 μg/ml in the urine and 22–86 μg/g in the liver. This indicates an extremely uneven distribution of thioxanthenes in the body. In addition to unchanged CPT, 5 thioxanthene metabolites were detected in the material. Three metabolites were identified as chlorprothixen‐sulphoxide, N‐monodemethylchlorprothixene and N‐monodemethylchlorprothix‐cnsulphoxide, respectively. The two unidentified thioxanthenes on the basis of their u. v. absorption spectra were assumed to be a sulphoxide and a non‐sulphoxide metabolite of CPT. It is concluded that CPT is a more toxic drug than previously believed, and that the total concentration of thioxanthenes in the liver is the most suitable parameter for the toxicological evaluation of fatal CPT poisonings.
Enhancement of Microsomal Drug Hydroxylation and Glucuronidation in Rat Liver by Phenobarbital and 3‐Methylcholanthrene in Combination
Authors: Vainio Harri , Aitio Antero
Published: July 2010

Abstract:Both 3‐methylcholanthrene and phenobarbital increased the 0‐demethylation ofp‐nitroanisole in rat liver microsomes (9‐fold and 6‐fold, respectively), whereas 3‐methylcholanthrene alone was able to enhance the aryl hydrocarbon hydroxylase activity (13‐fold). When the inducers were administered to rats in combination, the enhancement inp‐nitroanisole 0‐demethylase activity was greater and in aryl hydrocarbon hydroxylase was smaller than when administered singly. Both 3‐methylcholanthrene and phenobarbital also enhanced the microsomal UDP glucuronyltransferase activity when measured afterin vitroactivation of the latent enzyme. The pretreatment of rats with the combination brought about no additional effect, when calculated on a microsomal protein basis. If calculated on 100 gram of body weight basis, however, an additive effect was observed in UDP glucuronyltransferase activity due to the effects of the inducers on the liver weight‐body weight ratio.
The Effect of Diethyldithiocarbamate on Biliary Transport, Excretion and Organ Distribution of Mercury in the Rat after Exposure to Methyl Mercuric Chloride
Authors: Norseth Tor
Published: July 2010

Abstract: Diethyldithiocarbamate (DDC) and disulfiram decrease the biliary excretion of methyl mercuric compounds. The biliary mercury excretion returns to normal after a time period which is dependent on the dose of the inhibiting compound. For some doses of DDC the excretion of mercury increases above control values following the period of inhibition. DDC treatment increases brain, muscle and fur content of mercury. There is an increased retention of mercury in the liver, but decreased amounts of mercury in the kidney. Mercury in red cells is not affected. Faecal excretion of mercury decreases as expected because of decreased biliary excretion. The urinary excretion of mercury also decreases, but the mechanism is not clear. Changes in the excretion and organ distribution pattern indicate similar mechanisms for DDC treatment as for bile duct ligation, but DDC probably also changes the organ distribution and excretion by complex formation with some methyl mercuric compound.
An Experimental Study of the Effects of Daily Cannabis Smoking on Behaviour Patterns
Authors: MILES C. G. , CONGREW G. R. S. , GIBBINS R. J. , MARSHMAN J. , DEVENYI P. , HICKS R. C.
Published: July 2010

Abstract: Six male volunteer subjects were studied for 70 days in a high security hospital setting under a token economic (micro‐economic) system. A 42‐day regimen of free purchase and compulsory marijuana smoking was established, using one gram cigarettes with 8.5 mg Δ‐9THC. This period was preceded and followed by two weeks when marijuana was not available. Subjects were paid only for goods produced. Earnings could be saved or spent to satisfy subjects' needs and consumer desires. All economic transactions were recorded. Data was collected every half hour of each subject's dominant activity. The subjects demanded, and recieved, two wage raises. Introduction of cannabis resulted in lower productivity; reduction of intake raised productivity. A fall in productivity was matched by a fall in time spent working, but not in efficiency. Subjects spent more time resting awake and in entertainment during periods when more marijuana was smoked. Some indications of “amotivational syndrome” were present but no evidence of physiological damage was yielded by clinical medical examinations. Certain relationships between alcohol and rnarijuana were noted.
Theophylline Increased Sensitivity to Nociceptive Stimulation and Regional Turnover of Rat Brain 5‐HT, Noradrenaline and Dopamine1
Authors: Paalzow Gudrun , Paalzow Lennart
Published: July 2010

Abstract:Theophylline is able to decrease the thresholds of nociceptive stimulation (motor response, vocalisation and vocalisation afterdischarge), the effects being maximal at 30 minutes after administration. At this time theophylline was found to increase the endogenous level of dopamine in the telencephalic cortex and decrease the level of noradrenaline in regions including the diencephalon and the striatum. After inhibition of tyrosine hydroxylase with α‐methyl‐p‐tyrosine, theophylline was found to decrease the depletion of dopamine brought about by the inhibitor in the telencephalic cortex, indicating a decreased turnover of dopamine in this region. Theophylline was able to accelerate the decrease in noradrenaline concentration in the diencephalon‐striatum region induced by the enzyme inhibition, indicating an increased turnover of nordarenaline. The 5‐HIAA content in the telencephalic cortex was found to be decreased by theophylline and increased in the mesencephalon‐pons‐medulla oblongata region. After pre‐treatment with probenecid the latter increase was more pronounced while the decrease in the cortical structures was abolished by the pretreatment. It was furthermore found that probenecidper sewas able to increase the thresholds for nociceptive stimulation and was able to counteract the effect of theophylline on these thresholds, and inpreliminaryexperiments probenecid was found to affect the brain concentrations of noradrenaline. Inhibition of tyrosine hydroxylase was also found to counteract the decrease in the threshold of vocalisation afterdischarge produced by theophylline. From the experiments it seems possible that there is a relationship between a reduced turnover of dopamine and serotonin in the telencephalic cortex and the theophylline‐induced decrease of the threshold for vocalisation afterdischarge (affective component of the pain reactions) while the modulation of the vocalisation response may be related to the serotonin metabolism in lower brain stem structures.
The Effect of Practolol, Atropine and Phenoxybenzamine on Contractile Force of Isolated Rat Atria at Threshold and Suprathreshold Stimulation
Authors: Refsum Helge , Landmark Knud
Published: July 2010

Abstract:Isolated left rat atria were stimulated at a frequency of 180 per min. An increase in the strength of electrical stimulation from threshold (11±2mA) to suprathreshold values (50 mA) caused an initial decrease followed by an increase in the amplitude of the contractions. On the basis of experiments with an adrenergic β‐receptor blocker, practolol 5±10−6M, and atropine 1.43 ± 10−6M, it was shown that suprathreshold stimulation released noradrenaline as well as acetylcholine (ACh) within the myocardium. The effect of phenoxybenzamine, an adrenergic α‐receptor blocker with an atropine‐like activity, was also tested. At threshold stimulation this drug (2.5±10−6M) caused no changes in contractile force, while at suprathreshold values a pronounced increase in the amplitude of the contractions was observed. This effect was probably, at least partly, due to a blockade of the ACh‐induced depression of atrial contractile force. It is concluded that the interpretation of drug effects on isolated atrial preparations depends on the design of the experiments such as the strength of the electrical stimulation.
Effects of Phenformin and Phenformin‐Ethanol Synergism on the Perfused Rat Liver
Authors: Olsen Christian , Krarup Niels
Published: July 2010

Abstract:The metabolic effects of phenformin and phenformin‐ethanol were studied in isolated perfused liver preparations from fed rats. Whether phenformin was given alone or together with ethanol, the hepatic oxygen consumption decreased and the lactate production increased. Phenformin caused a decrease in ethanol elimination. The mitochondrial redox level was reduced by phenformin in all types of experiments, but a significant reduction of the cytoplasmic redox level was seen only when phenformin and ethanol were given together. The findings indicate that phenformin, in addition to an inhibitory effect on oxidative phosphorylation, impairs the transport of reducing equivalents across the mitochondrial membrane. This effect may be secondary to a lack of energy in the transport system.
Comparison of α‐ and β‐Receptor Stimulation in the Circular and Longitudinal Muscle of the Oestrogen and Progesterone Dominated Rabbit Uterus
Authors: Nesheim Britt‐Ingjerd
Published: July 2010

Abstract:Longitudinal and circular muscle strips from the progesterone‐dominated rabbit uterus were stimulatedin vitrowith the α‐ and β‐adrenergic agents noradrenaline and isoprenaline, and the effects were compared with results obtained from the oestrogen‐dominated uterus. The spontaneous activity in oestrogen‐ and progesterone‐dominated strips was the same. Noradrenaline caused an increase in frequency and basal tone in all strips. In the oestrogen‐dominated strips the force of the induced contractions exceeded the force of the spontaneous contractions. In the progesterone‐dominated strips the force of the contractions subsequent to the addition of noradrenaline was usually a little reduced. No difference between the circular and longitudinal strips was observed. Reserpine‐treatment of the oestrogen‐dominated animals substantially reduced the force of the noradrenaline‐induced contractions. In progesterone‐dominated animals reserpine treatment had no such effect. Isoprenaline produced a reduction in the force and the frequency of the spontaneous contractions. In the circular strips, the spontaneous activity was less inhibited by isoprenaline in the progesterone than in the oestrogen‐dominated strips. As to the longitudinal strips, the dose‐response curves were quite similar. The circular strips were much less inhibited by isoprenaline than were the longitudinal ones. It is concluded that the different reactions to adrenergic nerve stimulation in oestrogen‐ and progesterone‐dominated rabbit uteri reported previously by other investigators, might depend on the different reactions of the muscle to α stimulation, this difference being partly explained by the higher catecholamine content of the oestrogen‐dominated tissue.
Investigation of the Mechanism by which L‐DOPA Induces Gnawing in Mice
Authors: Molander Lars , Randrup Axel
Published: July 2010

Abstract:Stereotyped behaviour including gnawing was elicited in mice by L‐DOPA given after various doses of the decarboxylase inhibitor Ro 4–4602, The gnawing was estimated quantitatively. The effect of various drugs including reserpine, FLA‐63, spiramide and α‐methyltyrosine on the gnawing was studied and it is concluded that the gnawing is influenced by both dopamine and noradrenaline in the brain. The relation of noradrenergic brain mechanisms to gnawing seems to be complicated.
Increased Utilization of Endogenous ATP in Isolated Rat Mast Cells during Histamine Release Induced by Compound 48/80
Authors: Peterson Curt , Diamant Bertil
Published: July 2010

Abstract:In order to investigate whether the energy dependence of histamine release induced by compound 48/80 from isolated rat mast cells reflects an increased utilization of ATP during the release process, the ATP content in samples of mast cells was determined 5 sec. before and 25 sec. after the addition of compound 48/80. No change in the ATP content was found when histamine release was induced from cells with an intact energy metabolism. However, when the cells had been preincubated for 1 min. with antimycin A to inhibit oxidative production of ATP, histamine release was accompanied by a greater reduction (P < 0.005) in the ATP content than that observed in the control samples. In contrast, when corresponding experiments were performed with chlorpromazine or n‐decylamine as releasing agent, the ATP content was not lower in the samples in which histamine release had been induced than in the controls, regardless of whether antimycin A was present or not. The results indicate that histamine release from rat mast cells induced by compound 48/80, but not by chlorpromazine or n‐decylamine, is accompanied by an increased utilization of ATP in the cells.
Human and Animal Study on Elimination from Plasma and Metabolism of Diazepam after Chronic Alcohol Intake
Authors: Sellman R. , Kanto J. , Raijola E. , Pekkarinen A.
Published: July 2010

Abstract: Very significantly lower concentrations of diazepam at 15 minutes and 1 hour after 10 mg intravenous diazepam injection were found in chronic alcoholic patients in comparison to healthy controls. Compared to 13 healthy controls a more rapid elimination of diazepam from the plasma of 14 chronic alcoholic patients during their alcohol‐free period was observed. The alcoholics had a smaller concentration of the diazepam main metabolite, N‐demethyl‐diazepam, and at 3 hours this difference was significant. The concentrations of free plasma oxazepam as a metabolite of diazepam, were not observed after a single dose of diazepam either in the alcoholics or in volunteers. A more rapid elimination of diazepam after 5 mg/kg intraperitoneally in the plasma of rats pretreated with ethyl alcohol (15% in drinking water for 3 weeks) was found than in the control rats. Pretreatment of rats with ethyl alcohol increased significantly the concentration of the hydroxylated metabolite, free oxazepam, in the plasma, but not of the demethylated metabolite, N‐demethyldiazepam.
Comparison of the Activities of Drug‐metabolizing Enzymes in End‐term Foetal and Maternal Livers of the Rabbit
Authors: Vainio Harri
Published: July 2010

Abstract:The components of drug biotransformation complex in the microsomal membranes of end‐term foetal and maternal livers were compared. The end‐term foetal liver was found to possess NADPH cytochromecreductase and cytochrome P‐450 at levels of 38 and 18% of the maternal level, respectively. The foetal liver also hadp‐nitroanisole O‐demethylase activity of 29% of that in maternal hepatic microsomes. However, the aryl hydrocarbon hydroxylase activity was very low in foetal liver (only about 5% of that in maternal liver). UDPGlucuronosyltransferase (p‐nitrophenol as aglycone) activity in the foetal liver was at the level of 36% of that in maternal liver, when measured in “native” microsomes. The measurable glucuronosyltransferase activity in foetal liver could be increased 10‐fold by digitonin, 5‐fold by trypsin and 2‐fold by phospholipase A treatments, as compared to 6‐fold by digitonin and 3‐fold by both trypsin and phospholipase A in maternal liver microsomes.
Effects of Morphine Infusion in Maternal Rats at Near‐term on Ribosome Size Distribution in Foetal and Maternal Rat Brain
Authors: Steele William J. , Jóhannesson Torkell
Published: July 2010

Abstract:Timed‐pregnant (day 21–22) Sprague‐Dawley rats were administered morphine, 5 mg/kg/hr, or saline in equivalent volumes, by continuous intravenous infusion for periods up to 4 hrs. The brain of maternal and foetal rats was collected and analyzed for ribosome size distribution and morphine content. A marked increase of the disome component of the free ribosome fraction of foetal and maternal brain, and a corresponding diminution of the monosome and polysome components, was observed after infusion of morphine. Ratios of disomes to monosomes and of disomes to polysomes were maximal after 3 hrs of infusion. At the same time, the morphine concentration in the brain of foetal and maternal rats was maximal and nearly equivalent when expressed on DNA basis. The changes in morphine concentration and disome formation occurred virtually in parallel in both the foetal and maternal brain. The results indicate that morphine administration may in a dose‐dependent way cause a derangement of cerebral protein synthesis, possibly by interfering with the availability of mRNA.
Tissue Distribution of14C‐Rifampicin II. Accumulation in Melanin‐containing Structures
Authors: Boman Gunnar
Published: July 2010

Abstract:The tissue distribution of14C‐rifampicin was investigated by whole body autoradiography in brown mice surviving up to 30 days after a single intravenous injection. In contrast to the findings in albino mice a long‐term retention was observed in the uveal tract, the inner ear and the skin. Similar results were obtained in pigmented rats. Sections of organs from a human foetus incubated in14C‐rifampicin showed selective accumulation in the pigment epithelium of the eye. Quantitative determinations of radioactivity were performed of the blood, liver, lung, kidney and eye of mice up to 4 days after a single intravenous injection of14C‐rifampicin. A 15‐fold difference was found between the pigmented and the albino eye after 4 days. The findings were interpreted as evidence for a melanin affinity of rifampicin and discussed in relation to its possible ocular and otological side effects, which seem to be mostly unverified and very infrequent even during long‐term therapy. However, the accumulation of transplacentally transferred drug in the eye and the inner ear provides a further reason for restricting its use during pregnancy.
Tricyclic Antidepressant Agents. I. Comparison of the Inhibition of the Uptake of3H‐Noradrenaline and14C‐5‐Hydroxytryptamine in Slices and Crude Synaptosome Preparations of the Midbrain‐Hypothalamus Region of the Rat Brain
Authors: Ross Svante B. , Renyi Anna L.
Published: July 2010

Abstract:The simultaneous uptake of3H‐I‐noradrenaline (NA) and14C‐5‐hydroxytryptamine (5‐HT) in slices from the midbrain‐hypothalamus region of the rat brain was compared with the corresponding uptake in crude synaptosome preparations of the same brain region. In both preparations the uptake of the two amines was selective at the concentration used (1 x 10‐7M or lower). The KMvalues for the amines (NA: 2 x 10‐7M in synaptosomes and 5 x 10‐7M in slices; 5‐HT: 8 x 10‐8M in synaptosomes and 6 x 10‐7M in slices) and the inhibitory concentrations (IC50) of the antidepressant agents were lower in the synaptosome experiments than in the slices experiments. Moreover the order of the inhibitory activities differed between the two preparations. In the slices experiments the NA uptake was inhibited most markedly by desipramine followed by imipramine > chlorimipramine = nortriptyline ≥ amitriptyline ≥ chlordesipramine whereas in the synaptosome experiments the order was desipramine > nortriptyline ≥ chlordesipramine ≥ imipramine > amitriptyline ≥ chlorimipramine. For the 5‐HT uptake in slices the order of activity was: chlorimipramine > imipramine ≥ amitriptyline ≥ chlordesipramine = desipramine ≥ nortriptyline whereas in the synaptosome preparations the order was: chlorimipramine > imipramine ≥ amitriptyline ≥ chlordesipramine > nortriptyline = desipramine. The role of protein binding and diffusion barriers in the causation of the difference in the results obtained with the two preparations is discussed.
Tricyclic Antidepressant Agents. II. Effect of Oral Administration on the Uptake of3H‐Noradrenaline and14C‐5‐Hydroxytryptamine in Slices of the Midbrain‐Hypothalamus Region of the Rat
Authors: Ross Svante B. , Renyi Anna L.
Published: July 2010

Abstract:The inhibition of the simultaneous uptake of3H‐l‐noradrenaline (NA) and14C‐5‐hydroxytryptamine (5‐HT) in slices of the midbrain‐hypothalamus region of the rat brain after oral administration of desipramine, imipramine, nortriptyline, amitriptyline, chlordesipramine and chlorimipramine was determined. All compounds were more active in inhibiting the NA uptake than the 5‐HT uptake. This difference was very marked for desipramine, imipramine, nortriptyline and chlordesipramine. Chlorimipramine was almost as active on the 5‐HT uptake (ED50= 35 mg/kg orally) as on the NA uptake (ED60= 20 mg/kg orally) and amitriptyline had low activity on both uptake mechanisms (ED50> 50 mg/kg orally). Desipramine and imipramine were the most active compounds on the NA uptake (ED50= 8 mg/kg orally for both compounds) and the duration of the action was very long. The ED50values for nortriptyline and chlordesipramine in inhibiting the NA uptake were about 20 mg/kg orally for both compounds. The inhibition of the 5‐HT uptake was less than 50% at 50 mg/kg orally for all compounds except for imipramine (ED50= 50 mg/kg orally) and for chlorimipramine. The role of the biotransformation for the inhibitory activities of imipramine, chlorimipramine and amitriptyline was investigated in animals pre‐treated with SKF 525 A. The inhibitory potency of imipramine was increased by the same factor for both uptake mechanisms probably due to the large increase in the concentration of imipramine in the rat brain, which was demonstrated after the administration of14C‐imipramine. The inhibitory activity of chlorimipramine was somewhat more increased for the 5‐HT uptake than for the NA uptake. The low activity of amitriptyline seems to be mainly due to poor resorption, since pretreatment of the animals with SKF 525 A only slightly increased the potency whereas intraperitoneal injection of amitriptyline had a rather marked effect on the NA uptake (ED50= 11 mg/kg intraperitoneally).
The Kinetics of the Splanchnic Elimination of Ethanol and Glycerol
Authors: Krarup N. , Larsen J. A. , Olsen C.
Published: July 2010

Abstract:The kinetics of the splanchnic ethanol‐ and glycerol‐elimination were studied in fasting cats by simultaneous estimation of the splanchnic elimination rate and the average splanchnic concentration of these substances. Ethanol elimination followed Michaelis kinetics with a maximal elimination rate of 27 μmol/kg/min. and apparentin vivoKmof 0.25 mM. In contrast, the kinetic constants in glycerol elimination could not be determined, probably due to a splanchnic production of glycerol and/or a diffusion barrier for glycerol from blood to hepatic cytosol.
Effect of Reserpine, Desipramine and Phenytoin on Digoxin Induced Arrhythmias and Myocardial Uptake of Digoxin in Guinea Pigs
Authors: Allonen H. , Iisalo E. , Nuortio L.
Published: July 2010

Abstract:Digoxin was infused intravenously 27.5 μg/min. to guinea pigs. By means of the ECG doses of digoxin needed to cause ventricular extrasystoles (VES), ventricular fibrillation (VF), and asystole (AS) were determined in a control group without any premedication. Three groups were given a pre‐treatment with desipramine, phenytoin and reserpine. After AS digoxin concentrations in the heart muscle and in the kidneys were determined by radioimmunoassay. The concentrations of adrenaline and noradrenaline were also determined in these tissues. After reserpine and phenytoin the doses of digoxin needed to induce VF and AS were increased. Desipramine had no effect on digitalis‐induced arrhythmias. The relative uptake of digoxin in the heart muscle was decreased after all of the three premedications; there was no change in the kidney. The tissue catecholamine concentrations were decreased after reserpine and desipramine, but remained unchanged after phenytoin. The lethal dose of digoxin seemed not to correlate to the myocardial digoxin concentration after different premedications. The mechanism of the uptake in the heart muscle seemed to be different from that in the kidney. There was no correlation between the catecholamine concentration in myocardium and the ar‐rhythmogenic effect of digoxin in the different groups.
Placental and Foetal Metabolism of Acetaldehyde in Rat I. Contents of Ethanol and Acetaldehyde in Placenta and Foetus of the Pregnant Rat during Ethanol Oxidation
Authors: Kesäniemi Y. A. , Sippel H. W.
Published: July 2010

Abstract: Following the administration of ethanol to pregnant rats, the ethanol content of the maternal aortic blood was compared with that of the intact placenta and whole foetuses. The results support previous observations that ethanol is present in the placenta and foetus in about the same amount as in the maternal circulation. In contrast, only 25 % of the acetaldehyde content present in the maternal aortic blood could be found in the intact placenta and no acetaldehyde was found in the intact foetal tissue. These findings suggest that during maternal ethanol oxidation there is no accumulation of acetaldehyde in the foetal tissue.
Plasma Half‐lives and the Excretion into Egg‐white and ‐yolk of Three Sulphonamides and Pyrimethamine after Medication of Laying Hens
Authors: Blom Lars
Published: July 2010

Abstract:The concentration of drugs in blood plasma and the excretion into egg‐white and ‐yolk were studied after continuous administration for 8 days in the drinking water of 0.1 % sulphanilamide, 0.2 % and 0.1 % sulphadimidine, 0.04 % sulphaquinoxaline and 0.01 % pyrimethamine. During the last two thirds of this period of treatment a state of equilibrium was reached between the drug concentration in the blood plasma and that in egg‐white. No such equilibrium was established between blood plasma and egg‐yolk. Some physical and chemical constants of the drugs (i. e. lipid solubility at pH 7.4 and 6.0 and per cent protein‐bound in blood plasma and egg‐white) have been measured together with some pharmacokinetic parameters in hens (t1/2α, t1/2β, Vd). By using these results the experimental and theoretical distribution ratios between the ultrafiltrate of egg‐white and blood plasma have been calculated. This has not provided any conclusive evidence of the passage of the investigated drugs from blood plasma to egg‐white following the passive diffusion concept; however, the possibility still exists. With regard to the passage of drugs from blood plasma to egg‐yolk, the amount of drug excreted into the egg‐yolk mainly depends on the lipid solubility of the drug in use.
Central and Peripheral Catecholamine Levels after Pyrazole Treatment
Authors: MacDonald Ewen , Marselos Marios , Nousiainen Unto
Published: July 2010

Abstract:Pyrazole (50 to 300 mg/kg intraperitoneally) given to male rats produced a decrease in body weight. A dose dependent fall in the noradrenaline content of the brain was observed, but no changes occurred in the central levels of dopamine or 5‐hydroxytryptamine. Even a single dose of pyrazole (100 mg/kg) decreased the noradrenaline content by 20 %. Successive doses had an additive effect which was maximal 24 hrs after the final dose. Recovery was quite rapid, but 3 days after the final administration the levels were still lower than in the controls. The noradrenaline content of the heart and spleen was also slightly reduced. The adrenaline content of the adrenals seemed unaffected by the treatment. It is concluded that pyrazole administration in the dose and time schedules used, markedly reduces the noradrenaline content of the central nervous system. This should be kept in mind when this substance is combined with ethanol in similar studies.
Urinary Kallikrein Excretion in Normotensive and Spontaneously Hypertensive Rats
Authors: Arrigoni‐Martelli E. , Nielsen Chr. Kærgård
Published: July 2010

Abstract:Using single animals and repeated determinations at one week intervals the urine output, and sodium and kallikrein urinary excretion have been measured in normotensive, “moderate” spontaneously hypertensive (BP 150–179 mmHg) and “elevated” spontaneously hypertensive rats (BP > 180 mmHg). Both the groups of spontaneously hypertensive rats show higher water, sodium and kallikrein excretions than the normotensive animals. The group of “elevated” hypertensive rats shows the highest values. The results are discussed in the light of the interrelation between the kallikrein‐kinin system and the prostaglandis.
The Kinetics of Propylthiouracil in Hyperthyroidism
Authors: Kampmann J. , Skovsted L.
Published: July 2010

Abstract:The kinetics of propylthiouracil have been estimated in 10 hyperthyroid subjects according to a two‐compartment model by giving the drug initially by the intravenous and subsequently by the oral route. The apparent half‐life was 77 ± 34 min. (mean ± S.D.). This value and other pharmacokinetic parameters were compared with the corresponding values obtained in a previous study in normal subjects. No significant differences were found. A table showing studies in humans correlating drug metabolism and thyroid status is presented.
Comparison between Narcotic “Receptors” in the Guinea‐pig Ileum and the Rat Brain
Authors: Terenius Lars
Published: July 2010

Abstract:The receptors, i.e., specific binding molecules, for narcotic analgesics in the guinea‐pig ileum and rat brain have been compared. The relative affinities of a number of narcotics for the two receptors were very similar and discrimination between stereoisomeric agents was identical. The dissociation constants for dihydromorphine binding were 0.78 nM for the ileum and 1.4 nM for the brain receptor, respectively. There was a good correspondance between receptor affinities on the ileum preparation and the literature data on biologic activity on the isolated ileum. Codeine, diphenoxylate, difenoxine and loperamide, which are used clinically for the treatment of diarrhoea showed no selectivity against the ileum receptor. The two latter drugs had a very high receptor affinity and their lack of narcotic activity after oral administration is probably attributable to lack of penetration of the CNS. Receptor binding in both ileum and brain preparations was inhibited by N‐ethylmaleimide, Triton X‐100, trypsin and phospholipase C. There were small quantitative differences in sensitivity to these agents but it is difficult to assess whether this is because of real differences between the receptor molecules or attributable to secondary effects. As previously described for the brain receptor, the ileum receptor appeared to be present in a fraction enriched in plasma membranes.
Biliary Excretion of Diazepam and its Metabolites in Man
Authors: Sellman R. , Kanto J. , Pekkarinen J.
Published: July 2010

Abstract:Ten mg diazepam was given intravenously to 12 patients with a T‐tube in the common bile duct after choledochotomy (Group I) and to 10 patients after cholecystectomy (Group II). The concentrations of diazepam, of its main metabolite, N‐demethyldiazepam, and of free oxazepam in the plasma of both groups and the conjugated and free concentrations of diazepam, N‐demethyldiazepam, and oxazepam in the bile in the Group I were measured by gas chromatography. In Group I significantly lower plasma diazepam concentrations were obtained as compared with Group II indicating an enterohepatic circulation of diazepam. There was no significant difference in the concentrations of N‐demethyldiazepam in the plasma between the two groups. In Group I the patients had frequently more free oxazepam in their plasma than in Group II. The main conjugated metabolite in the bile was N‐demethyldiazepam (about 74 %). Traces of diazepam were in the conjugated form, but no conjugated oxazepam was found in the human bile. The enterohepatic circulation of diazepam and its metabolites may be partly responsible for the prolonged effects of diazepam.
Growth Hormone and Cortisol Secretion after Oral and Intravenous Administration of Methyldopa
Authors: Syvälahti E. , Seppälä P. O. , Iisalo E.
Published: July 2010

Abstract:The effect of oral administration of methyldopa for two to three weeks on growth hormone and Cortisol secretion was studied in untreated hypertensive patients in an insulin stimulation test. In addition, the effect of an acute intravenous infusion of methyldopa on these hormones was studied in normotensive patients. In an insulin‐hypoglycaemia test the levels of serum growth hormone did not differ significantly after treatment with methyldopa (750 mg daily) from the levels obtained before treatment. The levels of plasma Cortisol tended to be slightly lower after the treatment than before treatment up to 90 minutes, although the difference was statistically significant only at 30 minutes. The decrease in blood pressure after treatment was significant. An acute infusion of methyldopa (250 mg intravenously) induced no significant changes in blood pressure in normotensive patients. The concentration of plasma Cortisol decreased slightly but significantly after the infusion. However, there were no significant changes in the secretion of growth hormone after the infusion. It is concluded that treatment of hypertension with methyldopa does not cause any clinically important alterations in the anterior pituitary function.
The Effect of Calcium, Practolol, Atropine and Phenoxybenzamine on the Rat Atrial Action Potential at Threshold and Supra‐threshold Stimulation
Authors: Landmark Knud , Refsum* Helge
Published: July 2010

Abstract:An increase in the concentration of calcium in the Ringer's solution increased the maximum rate of rise (dv/dt) and shortened the duration of the action potential of rat left atriain vitro. Supra‐threshold stimulation increased dv/dt at low Ca++concentration (2.0 meq./l). This increase was completely abolished by pretreatment with an adrenergic β‐receptor blocker, practolol 5 × 10‐6M. At this concentration the drug is devoid of a quinidine‐like effect. The duration of the action potential was decreased by an increase in the strength of the electrical stimulation. This decrease was completely blocked by pretreatment with atropine 1.43 × 10‐6M and phenoxybenzamine 2.5 × 10‐6M, an adrenergic α‐receptor blocker with an atropine‐like activity. At threshold stimulation neither practolol 5 × 10‐6M nor atropine 1.43 × 10‐6M nor phenoxybenzamine 2.5 × 10‐6M caused any changes in the shape or the duration of the intracellularly recorded rat left atrial action potential. It is concluded that the possible liberation of autonomic mediators as well as the calcium concentration of the Ringer solution, should be taken into consideration in the interpretation of the results of experiments which involve the effects of antagonists on intracellularly recorded atrial action potentials.
The Effect of a Calcium‐antagonistic Drug, Nifedipine, on the Rat Atrial Action Potential at Different Calcium Levels
Authors: Refsum* Helge
Published: July 2010

Abstract:Increasing concentrations of calcium in the Ringer solution, [Ca++]O, increased the maximum rate of rise (dv/dt) of the intracellularly recorded action potential of electrically stimulated, isolated rat left atria; while a drug with calcium‐antagonistic activity, nifedipine 100 μg/l, reduced dv/dt. The duration of the action potential was shortened with increasing [Ca++]O. A further reduction in the time for 50 and 90 per cent of the repolarization was observed after the administration of nifedipine. All effects of nifedipine on the action potential were most pronounced at the lowest [Ca++]Ostudied (2.0 meq./l). At the highest [Ca++]Oused (8.0meq./l) the effects of this drug were negligible. It is concluded that in the presentin vitroexperiments, a Ca++current seems to influence the rapid phase of depolarization of the rat left atrium.
Induction Effect of Diazepam on its Own Metabolism
Authors: Sellman R. , Kanto J. , Raijola E. , Pekkarinen A.
Published: July 2010

Abstract:In the 7 psychiatric patients 10 mg diazepam administered intravenously, during continuous therapy, caused a significantly lower increase of diazepam concentrations in the plasma (at 15 min. P < 0.01; 1 hour P < 0.001; 3 and 6 hours P < 0.05; 24 hours P < 0.001) than in 13 healthy volunteers as an indicator of the increased elimination rate of diazepam. As a sign of the increased formation of the main metabolite, the increase in the concentration of N‐demethyldiazepam was significantly higher in the psychiatric patients on continuous diazepam therapy (at 15 min. P < 0.05; 1 hour P < 0.01) than in healthy volunteers. The intravenous injection of 10 mg diazepam caused in 7 psychiatric patients on continuous diazepam therapy a significantly lower mean increase of diazepam concentrations in the plasma (at 15 min., 1 hour, 3 and 6 hours P < 0.01; 24 hours P < 0.001) than in 12 psychiatric patients treated without diazepam and significantly higher increase in the concentrations of N‐demethyldiazepam (at 1 hour P < 0.05). No measurable amounts of free oxazepam was found in the plasma.
Calcium‐antagonistic and Anti‐arrhythmic Effects of Nifedipine on the Isolated Rat Atrium
Authors: Refsum* Helge
Published: July 2010

Abstract:Increasing concentrations of calcium in the Ringer solution, [Ca++]o, increased the rate and amplitude of contractions of spontaneously beating, isolated rat atria. Nifedipine 100 μg/l had negative chronotropic and inotropic effects when [Ca++]owas 2.0 and 5.0 meq./l, and atrial arrest occurred in some experiments at these calcium concentrations. The sinus node recovery time decreased with increasing [Ca++]o, but was increased by nifedipine 100 μg/l. All the effects of nifedipine were most pronounced at the lowest [Ca++]ostudied (2.0 meq./l), while these effects were negligible at the highest [Ca++]oused (8.0 meq./l). Nifedipine 100 μg/l did not influence the threshold for electricall) induced atrial fibrillation. However, pretreatment with the drug completely protected the atria against calcium‐induced arrhythmias. It is concluded that the anti‐arrhythmic activity of nifedipine is due to its calcium‐antagonistic effect.
Age and Exposure Factors in Drug Metabolism
Authors: Hänninen Osmo
Published: July 2010

Abstract:The development of drug metabolism in the foetal and postnatal periods varies in different species. It is also different in different tissues. The capacity of tissues to catalyze drug hydrolysis, oxidation and reduction as well as the conjugation reactions appears to mature in different phases. The human foetus seems to be better equipped than the foetuses of other species, since both drug hydroxylation and e.g. salicyluric acid synthesis take place sooner than in other species. Glucuronide synthesis can also be detected early in human foetal tissues. During adulthood the drug metabolism decreases with age at least in the rat. The exposure of the organism to foreign compounds often results in an increase in the rate of drug metabolism. This can also be detected in foetal tissues. In the liver similar responses to successive exposures to inducing chemicals can be found at least in the young adult rats, providing they have had sufficient time to recover from previous loadings. In old rats the drug metabolizing enzymes are poorly induced. The diseased state of organs responsible for the detoxication reactions show a lower capacity to handle drugs. The mucosal cells of the intestine serve as a special model for studies on drug biotransformation, since their life span is short and cells at different developmental phases are available at the same time.
The Antigonadotropic Activity of an Organosiloxane in the Male Rat: 2,6‐cis‐Diphenylhexamethylcyclotetrasiloxane
Authors: Le Vier R. R. , Boley W. F.
Published: July 2010

Abstract:An organosilicon compound, 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane, was investigated as an orally active estrogenic antigonadotropin in the male rat and compared to subcutaneously administered estradiol benzoate. The cyclosiloxane lowered serum LH and FSH in association with sex accessory tissue atrophy. Serum LH declined to 50% of the control level within 5 hrs. of a single dose of the cyclosiloxane; FSH declined more slowly. Gonadotropin levels were further decreased to 15–20% of the control level after one week of treatment. A direct anterior pituitary block was demonstrated in LRH challenged animals 8 hrs. after a single dose of the cyclosiloxane; estradiol blocked the pituitary as early as 1 hr. after estrogen administration. The cyclosiloxane decreased available releasing hormone activity at 24 hrs. This action was associated with an increase in the median eminence content of dopamine and anin vivodecrease in the rate of synthesis of dopamine from14C‐tyrosine. Estradiol had a similar but weaker effect. On the basis of these data it was postulated that this unusual nonsteroid structure exerts its effects at the level of the anterior pituitary and on the hypothalamus.
A survey of the pharmacological properties of metoprolol in animals and man
Authors: Åblad Bengt , Borg Karl Olof , Carlsson Enar , Ek Lars , Johnsson Gillis , Malmfors Torbjörn , Regårdh Carl‐Gunnar
Published: July 2010

Abstract:Studies in both animals and man have shown that metoprolol is a β1‐selective adrenergic receptor antagonist devoid of betamimetic activity. The cardiac stimulant effect of isoprenaline is markedly inhibited by metoprolol in doses that only slightly influence the vasodilator and bronchodilator effects of isoprenaline. Metoprolol markedly inhibits the cardiac response to exogenous or neuronally released noradrenaline. This action is probably the main determinant of the acute general hemodynamic effects of the compound. Metoprolol differs from propranolol in being a very weak inhibitor of the peripheral vasodilator effect of adrenaline. The two blockers may therefore produce differential hemodynamic effects in situations in which endogenous adrenaline contributes to cardiovascular control.

Metoprolol has a preventive antihypertensive action in rats with genetically determined hypertension. This effect is associated with an impaired vasoconstrictor fibre control, the mechanism of which is discussed.

The results of the toxicological and general pharmacological studies indicate that metoprolol is a highly specific β‐blocker.

The pharmacokinetic studies indicate that metoprolol is completely absorbed after oral administration. The first pass elimination in man is about 55% and independent of dose in the therapeutic dose range. Metoprolol is eliminated from human blood plasma with a half‐life of 3–4 hours. The main metabolites have been isolated and characterized pharmacologically. Unchanged metoprolol appears to be responsible for the β‐blocking action.

The pharmacological characterization of metoprolol gave results that warranted reformulation of the β1—β2‐receptor classification of Lands et al. (1967). This modified adrenergic β‐receptor concept is described and its implications are discussed.
Combined pharmacokinetic and pharmacodynamic studies in man of the adrenergic β1‐receptor antagonist metoprolol *
Authors: Johnsson Gillis , Regärdh Carl‐Gunnar , Sölvell Lennart
Published: July 2010

Abstract: The adrenergic β1‐receptor antagonist metoprolol was given orally and intravenously in varying doses to healthy volunteers. The effect on the heart rate during exercise was linearly related to the logarithm of the dose and the plasma concentration. The most pronounced effect was obtained during the first exercise test after administration (one hour after oral and 20 minutes after intravenous administration). The effect declined linearly with time (zero‐order kinetics) and at virtually the same rate for all doses investigated. The time for 50% reduction of the maximally registered effect was 6.4 hours after 100 mg metoprolol orally and 5.0 hours after 50 mg.

The plasma concentration of metoprolol declined mono‐exponentially with time at a rate corresponding to an elimination half‐life of about three hours. The relationship between the areas under the plasma concentration curves after oral and intravenous administration indicated a bioavailability of 40–50% for the two highest oral doses. In accordance with this the ratio between equipotent oral and intravenous doses was about 2.5.
Comparative bioavailability and effect studies on metoprolol* administered as ordinary and slow‐release tablets in single and multiple doses
Authors: Regärdh Carl‐Gunnar , Johnsson Gillis , Jordö Lars , Sölvell Lennart
Published: July 2010

Abstract: The bioavailability, plasma levels and pharmacological effects of 100 mg of metoprolol tartrate administered as an ordinary tablet and as two different slow‐release (SR) preparations were compared in healthy volunteers after single and multiple doses in one series of experiments. In another the urinary excretion of metoprolol and total radioactivity during 72 hours were determined after single doses of 50 mg of metoprolol‐(3H) tartrate in solution and in two SR tablets with different dissolution rates. Administration of metoprolol in SR form reduced the peak plasma levels and delayed the time to reach the peak in comparison with the ordinary tablet. The areas under the plasma concentration curves (AUC) after single doses and between two doses in steady state were almost identical for the SR tablets and the ordinary one. Administration of metoprolol in SR form did not significantly influence the urinary recovery of metoprolol (about 3% of the dose) or the fraction of the radioactive dose excreted via the kidney (>97% for each preparation).

The elimination half‐life determined from the post‐absorptive phase of the ordinary tablet was 4.0±0.6 hours. The effect on the exercise heart rate and the blood pressure declined at the same constant rate in the post‐absorptive phase and the rate was virtually identical for the different types of tablets. The time for 50% reduction of the maximum effect was about 8 hours. Both of the effect variables were linearly related to the log plasma concentration for the ordinary tablet and the relationships could be described by the same regression line. No significant correlation between the effects and the plasma levels was obtained for the SR tablets. Despite substantial differences between the peak plasma levels of the ordinary tablet and the SR preparations, both types of tablets induced about the same maximum effects on exercise heart rate and systolic blood pressure and only slightly higher effects were recorded at the end of the dosage interval for the SR tablets.
Toxicological studies on metoprolol *
Authors: Bodin Nils‐Olof , Flodh Hans , Magnusson Göran , Malmfors Torbjörn , Nyberg Jan‐Anders
Published: July 2010

Abstract:This paper presents a review of the toxicological studies in animals on metoprolol ‐ a cardioselective β‐blocking agent. Studies after single administration were performed in mice, rats and dogs. LD50‐values were calculated for the rodents while maximum tolerated dose was estimated for the dogs. Studies after repeated administration for up to 6 months were performed in rats and dogs. Reproduction studies were performed in rats and rabbits.

The studies performed on metoprolol so far have not revealed any toxic effect other than the acute effects observed after administration of single, high doses.