bluuebunny/crossref_metadata_2025 huggingface dataset:
The Bioavailability of a New Sustained‐Release Preparation of Proxiphylline (Neofyllin Retard®) in the Guinea Pig
Authors: Larsen Jens‐Jørgen
Published: July 2010

A bstract: The bioavailability of a new sustained‐release preparation of proxiphylline (neofyllin retard®) has been compared with that of the conventional tablet. The antagonistic action on histamine induced bronchoconstriction in the guinea pig has been used as effect parameter. The results indicate that the release of proxiphylline from the conventional tablet occurred within 85 min. with a maximum antagonistic action of 95 % reached after 70 min., whereas that of the sustained‐release preparation was effected more slowly over a period of at least 190 min., resulting in a stable antagonistic action of about 40 % during most of the experimental period. A quantitative analysis of tablets placed in the duodenum for different lengths of time and of the residual amount of proxiphylline in the intestinal content has confirmed that the different shape of the time effect curves obtained with the two tablet formulations is due to a slower release of proxiphylline from the sustained‐release tablet than from the conventional tablet. The describedin vivomodel in the guinea pig has proved useful for the evaluation of the release‐ and absorption pattern of new sustained‐release formulations of anti‐asthmatic drugs.
The Influence of Emulsifying Agents and of Lipid Soluble Drugs on the Fractional Removal Rate of Lipid Emulsions from the Blood Stream of the Rabbit
Authors: Jeppsson Roland , Rössner Stephen
Published: July 2010

Abstract:The fractional removal rate of intravenously injected fat emulsions prepared with various emulsifiers, was studied in rabbits. The emulsions were made with soya bean oil and addition of egg yolk phosphatides, acetylated monoglycerides or polyoxypropylene‐polyoxyethylene condensates (Pluronic). In some studies lipid soluble drugs were also added to the emulsions. The fractional removal rates of the emulsions from the blood stream were determined by means of an intravenous fat tolerance test. Addition of phosphatides slightly promoted the elimination of the fat emulsions, whereas the surface active agent Pluronic F 108 considerably impaired the fractional removal rate. Addition of cyclandelate or nitroglycerin increased the fractional elimination rate, whereas diazepam and chlorprozamine had the opposite effect. The half‐life of secobarbital in plasma was unaffected whether administered as emulsion or water solution, but the half‐life of thiopental was slightly longer when given as an emulsion. The pharmacological effect of barbiturates measured as duration of sleep in mice was not affected whether these agents were dissolved in slowly or rapidly eliminated emulsions. The results support the concept that the emulsifying agent is of major importance for the fractional removal rate of the emulsion from the blood stream, and further that the pharmacological effect of barbiturates dissolved in emulsions of different types is not related to the removal rate of the emulsion particles.
On the Affinity of Aminotriazole to Cells of the Haemopoietic System in Mice
Authors: Beran Miloslav , Slanina Premysl , Tjälve Hans
Published: July 2010

Abstract:The uptake and distribution of14C‐aminotriazole (3‐amino‐1,2, 4‐triazole) in the haemopoietic tissues were studied in mice, and thein vitroeffect of aminotriazole on the formation of mature granulocytes from the mouse bone marrow progenitor cells was also investigated. For the distribution studies whole‐body autoradiography was applied both to the normal and to the supra‐lethally irradiated mice injected with bone marrow cells from syngeneic donor mice. In the latter mice erythrocytic and granulocytic cell‐colonies are formed in the spleen. For a certain period of time these colonies appear separated in the spleen and may be identified with a suitable staining. Upon the injection of the labelled aminotriazole a high radioactivity was found in the bone marrow of the normal mice and in the haemopoietic colonies of the spleen of the irradiated mice. Both the erythrocytic and the granulocytic colonies were found to be labelled. In spite of this aminotriazole was found to be without influence on the formation of granulocytic coloniesin vitro. The combination of spleen colony assay and whole‐body autoradiography may be a useful method when the uptake and distribution of drugs in the haemopoietic tissues are studied.
Potentiation by β‐Adrenoceptor Blocking Agents of the Inhibitory Effect of Adrenaline on Carrageenin‐Induced Rat Paw Oedema
Authors: Briseid Kjell , Korbu Astri , Arntzen Finn Cato , Baksaas Ingebjørg
Published: July 2010

Abstract:The β‐adrenoceptor blocking agents (±)‐practolol, (±)‐propranolol, (—)‐propranolol and (±)‐sotalol were found toreducethe adrenaline induced inhibition of carrageenin‐induced rat paw oedema during the first hour of development and thenpotentiateadrenaline for at least 3 hours. Experiments carried out with (+)‐propranolol indicated that both effects depended on the levoisomers of the substances and accordingly on some kind of β‐blockade. It has previously been suggested that normal stores of endogenous catecholamines might be essential for the development of carrageenin‐induced rat paw oedema (ARNTZEN & BRISEID 1973). Under the experimental conditions used in the present work (—)‐propranolol did not counteract the increase in the catecholamine content of the spleen caused by adrenaline injection, more than (+)‐propranolol. It is suggested that the marked potentiation of the oedema inhibition caused by adrenaline might be due to a combined effect of increased adrenaline stores and β‐adrenoceptor blockade.
Metabolic Interaction of Ethanol and Alprenolol in Isolated Liver Cells
Authors: Grundin R.
Published: July 2010

Abstract:Metabolism of ethanol and alprenolol was studied in isolated rat liver cells. At low ethanol concentrations, where the rate of ethanol metabolism seemed to be limited by the rate of re‐oxidation of NADH, ethanol metabolism was markedly stimulated by the addition of alprenolol, propranolol or hexobarbital. At higher concentrations of ethanol no stimulation by added alprenolol was observed. Alprenolol‐stimulated ethanol metabolism was more sensitive to low concentrations of the ADH inhibitor 4‐CH3‐pyrazole, than unstimulated ethanol metabolism. Alprenolol metabolism in isolated liver microsomes and isolated liver cells was inhibited by addition of ethanol; however, at very low ethanol concentrations a slight stimulation of alprenolol metabolism was observed in isolated liver cells. The increased lactate/pyruvate ratio caused by ethanol metabolism in isolated liver cells was decreased by the addition of alprenolol. The present findings indicate that during simultaneous metabolism of ethanol and alprenolol, at low concentrations of ethanol, electrons can be diverted from the greatly reduced NADH/NAD+ couple by the microsomal monooxygenase reaction.
Ethanol Induced Alteration of Microsomal Membrane Bound Enzymes of Rat Liverin Vitro
Authors: Marniemi Jukka , Aitio Antero , Vainio Harri
Published: July 2010

Abstract:Ethanol appeared to inhibit more readily the 0‐demethylation of p‐nitroanisole than the activity of arylhydrocarbon hydroxylase. Arylhydrocarbon hydroxylase was more sensitive to the inhibition by ethanol in control or phenobarbital pretreated rats than in rats administered 3,4‐benzpyrene. Ethanol was shown to activate the glucuronidation of p‐nitrophenol at 2.45 mol/l, which was followed by inhibition at higher ethanol concentrations. A similar activation could also be demonstrated in rats pretreated with phenobarbital or 3,4‐benzpyrene. This activation was not seen in microsomes pretreatedin vitrowith detergents like digitonin and cetylpyridinium chloride. Glucose 6‐phosphatase was not clearly inhibited until the ethanol concentration was as high as 4 mol/l. Digitonin and trypsin treatments of the microsomal membranein vitroappeared to activate the measurable glucose 6‐phosphatase activity.
The Pain Aggression Induced by Bronopol in the Rat
Authors: Nieminen L. , Möttönen M.
Published: July 2010

Abstract:Bronopol in doses of 7–25 mg/kg given intraperitoneally almost immediately releases a transitory aggressive behaviour in rats. The painful state caused by bronopol‐induced chemical peritonitis probably brought about this behavioural phenomenon. The age of the animal and also the reserpine treatment play some role in this behavioural pattern.
The Levels of Serum Growth Hormone and Immunoreactive Insulin after Administration of Antipyretic Analgetics
Authors: Syvälahti E.
Published: July 2010

Abstract:The effects of indomethacin (100 mg) and phenylbutazone (250 mg) suppositories and acetylsalicylic acid (1000 mg) as well as placebo tablets on serum growth hormone, serum immunoreactive insulin and blood glucose concentrations were studied in young male volunteers after an overnight fast. Peak drug concentration in serum was reached 60, 120, and 180 minutes after indomethacin (2.1 ± 0.3 μg/ml), acetylsalicylic acid (88.0 ± 13.4 μg/ml) and phenylbutazone (30.8 ± 2.2 μg/ml), respectively. Blood glucose rose from 4.2 ± 0.1 mmol/l to 5.0 ± 0.1 mmol/l (P < 0.001) (n = 21) at 120 minutes after indomethacin and the rise was significant throughout the study. No significant changes in blood glucose were seen after the administration of the other drugs. The levels of serum growth hormone were also significantly increased after indomethacin throughout the study, but not after the other drugs. The mean of the peak serum growth hormone concentration of the subjects (11.7 ± 1.2 ng/ml) (n = 19) was significantly higher after indomethacin than after the other drugs, which did not not differ from each other significantly. There were no significant changes in serum immunoreactive insulin levels after the drugs. However, after acetylsalicylic acid the levels tended to increase and the serum immunoreactive insulin remained significantly higher at 30, 60, and 120 minutes after acetylsalicylic acid (18.5 ± 1.6, 19.1 ± 3.4, and 20.2 ± 3.2 μU/ml) (n = 13) than after placebo (11.2 ± 2.2, 10.1 ± 2.0, and 10.6 ± 1.5 μU/ml) (n = 13) (P < 0.05).
Oxidation of Phenethylamine Yielding Tyramine by Rat Liver Microsomes
Authors: Jonsson John , Lindeke Björn , Cho Arthur K.
Published: July 2010

Abstract:Phenethylamine was oxidized at the aromatic p‐position by rat liver mixed function oxidase. The identity of the product as tyramine (p‐hydroxyphenethyl amine) was unequivocally established by gas chromatography‐mass spectrometry using deuterium labelled 1‐phenyl[1,2‐2H2]ethylamine as substrate. The hydroxylation reaction proceeded at a relatively low rate, Vmax, 0.2 nmol × mg protein‐1× min.‐1and with a Kmof 2.3 × 10‐4M. The reaction kinetics were linear as against substrate at low concentrations but above 0.5 mM, substrate inhibition was apparently induced.
ETHANOL METABOLISM IN THE LIVER
Authors: Thieden Herluf I. D.
Published: July 2010

Summary:Ethanol elimination by the liver, a relatively constant process, may be increased at high concentrations of ethanol, when certain substances like fructose or pyruvate are metabolized together with ethanol or after prolonged exposure for ethanol. The metabolic effects on the liver are different at high and at low concentrations of ethanol. A number of enzymes or enzyme systems, – liver alcohol dehydrogenase, catalase and mixed‐function oxidase – canin vitrocatalyze the oxidation of ethanol, but little is known about the actual role of each enzyme at different metabolic conditions. The existence of more than one pathway for ethanol metabolism in the liver is now becomming increasingly evident, but whether the non‐ADH mediated ethanol oxidation occurs via catalase, or mixed‐function oxidase system, or both, cannot at present be decided.

The activity of liver alcohol dehydrogenase cannot be induced by continuous use of ethanol. The ADH‐mediated ethanol oxidation may be increased when the steady state concentration of free NADH in the cytoplasm is lowered. The rate of ethanol oxidation underin vivoconditions seems not to be determined by the rate of acetaldehyde elimination, although acetaldehyde is a product of ethanol metabolism. The reoxidation of NADH may proceed by NADH‐linked substrate system, by transhydrogenation to NADP+or by transporting reducing equivalents into mitochondria where they are oxidized.

In this review an attempt is made to examine the effects of a number of substrates or metabolic conditions which may enhance ethanol oxidation (concentration of ethanol, fructose, pyruvate, D‐glyceraldehyde, oxygen, CO2and 2,4‐dinitrophenol) and to discuss the mechanisms involved in this action. It is concluded that the effect of pyruvate and fructose (maybe also CO2and D‐glyceraldehyde) proceeds via ADH‐mediated pathway (possibly involving the so‐called “malic enzyme shuttle”) whereas the acceleration in ethanol metabolism, observed in rat liver preparations when high concentrations of ethanol are metabolized, is associated with the participation of non‐ADH pathway (s) in ethanol metabolism.
Forty Days Oral Toxicity of 2,6‐cis‐Diphenylhexamethylcyclotetrasiloxane (KABI 1774) in Beagle Dogs with Special Reference to Effects on the Male Reproductive System
Authors: Albanus Lennart , Björklund Nils‐Erik , Gustafsson Börje , Jönsson Monica
Published: July 2010

Abstract:The oral toxicity of KABI 1774**, a siloxane compound with estrogen‐like effect, was studied for 40 successive days in 20 male and female beagle dogs. The test compound was dissolved in soy bean oil and dosed at the levels of 10 or 250 mg/kg. Controls received soy bean oil only.

Increased WBC count, mainly due to increased neutrophils, and enhanced alkaline phosphatase activity were evident at 250 mg/kg. No death occurred.

The treatment with KABI 1774 caused marked effects on the reproductive system which is the target for the principal pharmacological effects. One typical feature was an adverse influence on the ability to ejaculate. In spite of pelvic movements and rhythmic contractions of penis as in normal ejaculation the dogs delivered a very small amount of semen or no semen at all (‘dry ejaculate’). The ejaculate volume and the total number of sperm per ejaculate decreased gradually. Other striking changes were pathological sperm motility, high frequency of sperm tail abnormalities and increased occurrence of distal cytoplasmic droplets. At the end of the experiment all males presented arrested spermatogenesis to the degree of complete degeneration of all germ cells, epithelial atrophy and fibrosis in epididymis and prostate. In the latter also epithelial metaplasia was displayed. The weights of the testes were decreased in the high dose group.

In females receiving 250 mg/kg the findings were hypertrophy of the lining epithelium in the endometrium of uterus, dilatation of uterine glands, oedema of the stroma and hypertrophy of the stratified squamous epithelium in vagina.

In pars anterior of the hypophysis small tinctorial changes in chromophobic and basophilic cells and some hypertrophy and hyperplasia of acidophilic cells were observed in all the dosed animals.

Single as well as repeated administration of 10 and 250 mg/kg gave peak plasma levels of 1–5 μg/ml at 2–4 hours and 30–60 μg/ml at 2 hours, respectively. Urinary excretion of KABI 1774 was extremely low.

A series of low molecular‐weight linear and cyclic phenylmethylsiloxanes have been shown to cause suppression of the male endocrine system, including testicular atrophy and inhibition of spermatogenesis (Palazzoloet al.1972,Le Fevreet al.1972). The most active member of these siloxanes was 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane (Bennettet al.1972), hereafter referred to as KABI 1774. The purpose of the present study was to investigate the subacute oral toxicity of KABI 1774 in dogs and to evaluate the effects of the drug on the sexual behaviour and on the semen characteristics.
Influence of metoprolol* and propranolol on hemodynamic effects induced by adrenaline and physical work
Authors: Johnsson Gillis
Published: July 2010

Abstract:The influence of intravenously administered metoprolol (10 mg), propranolol (5 and 10 mg) and saline on hemodynamic effects induced by adrenaline and physical work were studied in healthy volunteers. In the doses used the two β‐blockers were approximately equipotent in reducing the heart rate and systolic blood pressure during exercise.

Adrenaline induced an increase of the heart rate, systolic blood pressure and forearm blood flow, while the mean blood pressure, diastolic blood pressure and vascular resistance in the forearm decreased.

The two β‐blockers interacted differently with adrenaline. When adrenaline was infused after propranolol the mean and diastolic blood pressure increased as did also vascular resistance in the forearm. Adrenaline now had no significant effect on the forearm blood flow, while the heart rate decreased.

After metoprolol, adrenaline still induced a decrease of the diastolic blood pressure and an increase of the forearm blood flow, but the effect of adrenaline on these variables seemed to be inhibited to a great extent. The decrease of the mean blood pressure after adrenaline was blocked by metoprolol, while the effect on the vascular resistance in the forearm and the heart rate was not significantly changed.

The difference in interaction of the two β‐blockers with adrenaline is interpreted as being caused by a much less pronounced effect of metoprolol on the adrenergic vascular β2‐receptors compared to propranolol in the doses studied.
Influence of metoprolol and propranolol on hemodynamic effects induced by physical work and isoprenaline
Authors: Johnsson Gillis , Nyberg Gunnar , Sölvell Lennart
Published: July 2010

Abstract: The effects of metoprolol (40 and 80 mg orally as hydrochloride) and propranolol (40 mg orally as hydrochloride) were compared on the increase of heart rate and systolic blood pressure induced by physical exercise and infusion of isoprenaline.

The two β‐blockers seemed to be equipotent in reducing heart rate and systolic blood pressure during exercise, while they differed considerably in their interaction with isoprenaline. Thus, the isoprenaline‐induced increase of the heart rate was blocked to a considerably greater extent after propranolol than after metoprolol. The reason for this is discussed and can be explained by the selectivity of metoprolol for β‐receptors.
Effects of metoprolol and propranolol on some metabolic responses to catecholamines in the anaesthetized dog
Authors: Åblad Bengt , Börjesson Inger , Carlsson Enar , Johnsson Gillis
Published: July 2010

Abstract:The effects of metoprolol (0.5 mg/kg i.v.) and propranolol (0.2 mg/kg i.v.) on the plasma FFA response to i.v. infused adrenaline and noradrenaline and on the blood glucose and lactate responses to adrenaline were studied in anaesthetized dogs. Both β‐blockers markedly reduced the plasma FFA response to noradrenaline. Metoprolol differed from propranolol by inhibiting the plasma FFA response to adrenaline significantly less than that to noradrenaline. The lactacidemic effect of adrenaline was somewhat reduced by metoprolol and abolished by propranolol. The slight increase of blood glucose concentration produced by adrenaline was not significantly affected by either blocker. Adrenaline elicited a marked increase of the arterial blood pressure after propranolol treatment, whereas a slight hypotensive effect was observed after administration of metoprolol or in control experiments.

It is suggested that the effects of metoprolol could be ascribed to inhibition of adrenergic β1‐receptor mediated actions, while those of propranolol were due to combined β1and β2‐receptor blockade.
Pharmacokinetic studies of metoprolol‐(3H) in the rat and the dog
Authors: Borg Karl Olof , Fellenius Erik , Johansson Rustan , Wallborg Marita
Published: July 2010

Abstract:This paper describes the gastrointestinal absorption, the renal, biliary and faecal excretion and blood/plasma levels of metoprolol‐(3H) in the rat and the dog. The compound was well absorbed in both species, about 70–100% of the given dose being recovered from the urine within 24 hours irrespective of the route of administration. Low radioactivity was found in faeces and bile. The drug was rapidly and extensively distributed to extravascular tissues, the half‐life of the distribution process being 5–10 minutes. The half‐life for the elimination phase in the rat was about 0.6 hours and independent of dose and route of administration. The corresponding figure in the dog was about 1.5 hours. The systemic bioavailability of metoprolol‐(3H) was about 4% in the rat and in the range 20–40% in the dog. The peak concentrations of metoprolol after oral administration were approximately proportional to the dose given. Short‐term treatment with metoprolol had no effects on the pharmacokinetics of the drug.

Since the pharmacokinetic characteristics, obtained by interpreting the blood/plasma curve in terms of a two‐compartment open model, were rather similar in the dog and in man (Regårdh et al. 1974,Johnsson et al. 1975) it is concluded that the dog can serve as a better model for human experiments with this drug than the rat.
Tissue distribution of metoprolol‐(3H) in the mouse and the rat
Authors: Bodin Nils‐Olof , Borg Karl Olof , Johansson Rustan , Ramsay Carl‐Henrik , Skånberg Inger
Published: July 2010

Abstract:The tissue distribution of specifically tritium‐labelled metoprolol was studied in mice by whole‐body autoradiography and in rats by determination of unchanged drug and the total pool of metabolites in pre‐selceted tissues. The distribution after intravenous administration was characterized by a rapid localization to various tissues e.g. liver, kidney, gall bladder, urinary bladder, salivary glands, Harder's gland, spleen, lungs and adrenals. In the pregnant mouse the drug and/or its metabolites crossed the blood‐placenta barrier and moderate concentrations were found in the foetus. Metoprolol was metabolized to a large extent in the rat and after oral administration the total pool of metabolites exceeded the concentration of unchanged drug in the tissues studied.
Effects of Four Local Anaesthetics on the Membrane Stability of Isolated Rat Liver Lysosomes
Authors: Mörck E. , Friberger P. , Åberg G.
Published: July 2010

AbstractThe effects of the local anaesthetics bupivacaine, lidocaine, mepivacaine and prilocaine on lysosomal membrane stability have been studied on isolated rat liver lysosomes. The lysosomal membranes were stabilized by the local anaesthetics only within a very narrow range of concentration (around 0.001 M). In lower concentrations there was no effect of the substances while in higher concentrations there was a marked labilizing effect on the lysosomal membranes. The phlogistic effect of an injected suspension of lysosomes in the rat paw was increased by mepivacaine in concentrations of 1 % (0.04 M) and higher. The labilizing effects of local anaesthetics on lysosomes were probably due to precipitation of lysosomal membrane proteins by the local anaesthetics.
Influence of the Diet on the Metabolism of Acetaldehyde in Rats
Authors: Marchner H. , Tottmar O.
Published: July 2010

AbstractThe acetaldehyde dehydrogenases of rat liver, the hepatic output of acetaldehyde and the rate of ethanol elimination were studied in two groups of female Sprague‐Dawley rats fed on two different commercial standard diets (diet 1 and diet 2). The activity of the mitochondrial low‐Kmenzyme was 2–3 times lower in rats fed on diet 1 as compared to rats fed on diet 2, whereas only slight differences were found in the activities of the high‐Kmenzymes in the mitochondrial, the microsomal and the cytosol fractions. No differences were observed between the two groups in the activities of alcohol dehydrogenase, glutamate dehydrogenase, glucose‐6‐phosphatase or malic enzyme. The rate of ethanol elimination was 15 % lower, and the acetaldehyde level in the blood was 2–4 times higher in rats fed on diet 1 as compared to rats fed on diet 2. When the diets were interchanged between the two groups, the activity of the low‐Kmenzyme increased or decreased twofold within 12 hrs. Starvation increased the activity of the low‐Kmenzyme in rats fed on diet 1, but had no effect on the activity in rats fed on diet 2. The results suggest that diet 1 contains an inhibitor of the low‐Kmenzyme, and that dietary factors may be of importance in the regulation of the hepatic output of acetaldehyde during ethanol metabolism.
Effects of Catecholamine Receptor Blocking Agents on Toxicity and Thermal Responses Induced by Amphetamine Isomers in Adult and Developing Mice
Authors: Alhava Eeva
Published: July 2010

AbstractThe toxicity of d‐amphetamine was greater than that of 1‐amphetamine in adult mice with intraperitoneal dosage range of 10–50 mg/kg. In these doses neither isomer was toxic to developing mice aged 12–16 days. Both isomers of amphetamine induced a dose‐dependent hyperthermia in adults, and the response was stronger after the d‐ than the 1‐form. Ten mg/kg of d‐amphetamine increased the temperature of developing mice, while 50 mg/kg of both isomers was markedly hypothermic; p‐OH‐amphetamine (10 and 50 mg/kg) was not lethal and lacked the thermal effect in adult and developing mice. Phenoxybenzamine (20 mg/kg) completely protected adult mice against the toxicity of 50 mg/kg of d‐amphetamine. It also attenuated the d‐amphetamine‐induced hyperthermia in adult as well as hypothermia in developing mice. Propranolol (10 mg/kg) partially protected adult mice against d‐amphetamine toxicity and clearly antagonized the hyperthermia. In combination with propranolol d‐amphetamine was toxic to developing mice and potentiated the hypothermia. Metoclopramide (40 mg/kg) partially protected adult mice against d‐amphetamine toxicity and diminished the hyperthermia. In developing mice, metoclopramide increased d‐amphetamine toxicity, but decreased the hypothermia. It is suggested that amphetamine preferentially affects noradrenergic mechanisms in adult mice and dopaminergic mechanisms in developing mice. Central noradrenaline receptors seem to be mainly responsible for the mediation of amphetamine toxicity. Amphetamine‐induced disturbances in thermoregulation play a minor role in amphetamine toxicity in both adult and developing mice.
Serum Growth Hormone, Serum Immunoreactive Insulin and Blood Glucose Response to Intravenous Tolbutamide in Postmenopausal Women with and without Natural Oestrogen Therapy
Authors: Syvälahti E. , Erkkola R. , Punnonen R. , Rauramo L.
Published: July 2010

Abstract The response of serum growth hormone, serum immunoreactive insulin and blood glucose to intravenously administered tolbutamide was studied in twenty non‐obese and four obese healthy volunteer postmenopausal women with or without oestrogen therapy. Fasting blood glucose and the maximal fall in blood glucose during the test (44 % and 45 %) was normal in the non‐obese control and oestrogen groups, and the two groups did not differ significantly from each other. Even the four obese women, two on oestrogen therapy and two without, showed a normal blood glucose response to tolbutamide. Moreover the response of serum immunoreactive insulin to tolbutamide was normal in subjects both with and without oestrogen therapy and there were no significant differences between the two groups. The response of serum growth hormone to tolbutamide was small in both groups, but slightly more pronounced in the non‐obese women undergoing oestrogen therapy than in the controls. It is concluded that a postmenopausal period of five years leads to no impairment in carbohydrate metabolism in healthy women, and an oestrogen therapy for 3–7 years has no effects on glucose tolerance in healthy postmenopausal subjects.
Chlorpromazine and Hormonal Elevation of Cyclic AMP Contents in Turkey Erythrocytes and in Perfused Rat Heart and Liver
Authors: Osnes Jan‐Bjørn , Christoffersen Thoralf , Mørland Jørg , Øye Ivar
Published: July 2010

AbstractAn investigation was carried out to determine whether chlorpromazine (CPZ) affected the elevation of cyclic AMP by isoprenaline in turkey erythrocytes and perfused rat hearts, and by glucagon in perfused rat liver. In the perfused heart the incorporation of14C‐adenine (in the perfusate) into the cyclic AMP pool, was also measured. In turkey erythrocytes exposed to isoprenaline the cyclic AMP accumulation was markedly inhibited by CPZ at concentrations above 5 × 10‐5M, whereas lower concentrations caused slight reduction of cyclic AMP elevation. In the perfused rat heart and liver CPZ, at concentrations compatible with the integrity of the organ, did not reduce or change the cyclic AMP increase after isoprenaline and glucagon, respectively. The results indicate that inhibition of adenylate cyclase activation is not a general feature of the membrane stabilizing effects of CPZ. The loss of cyclic AMP response in turkey erythrocytes exposed to high concentrations of CPZ may be related to impairment of the cell membrane. CPZ could not be used as a tool in an attempt to discriminate between cyclic AMP‐mediated and cyclic AMP‐independent hormone effects. The present results compared to results obtained by other investigators indicate that caution is needed in extrapolating from experiments done on cell fractions to intact tissue.
Bumetanide Induced Increase of Renal Blood Flow in Conscious Dogs and its Relation to Local Renal Hormones (PGE, Kallikrein and Renin)
Authors: Olsen Uffe Bang , Ahnfelt‐Rønne Jan
Published: July 2010

AbstractBumetanide (0.25 mg/kg intravenously) increases renal blood flow (RBF) for 40–60 min. in conscious dogs with chronically implanted flow probes. The time of maximum increase in RBF (10–15 min. after administration) proceeds maximum diuresis (20–30 min. after administration). A several fold increase in urinary PGE‐output occurs during the first 20 min. after bumetanide administration. Urinary PGE excretion is not increased during the later course of the increase in RBF. Urinary kallikrein excretion increases and this is highly correlated with the diuretic volume. Plasma renin activity (PRA) increases initially concomitantly with the increase in renal blood flow. Indomethacin treatment (5 mg/kg orally) lowers RBF and urinary PGE excretion. Bumetanide in indomethacin pretreated dogs does not modify RBF or urinary PGE output. The diuretic effect of bumetanide is reduced as is also the urinary kallikrein excretion, while the initial increase of PRA is absent. The results support the conclusion that the increase of RBF and PRA after bumetanide administration is dependent on an increased prostaglandin/kinin activity.
Kinetics of Phenytoin in Pregnant and Non‐pregnant Rats
Authors: Gutová Marcela , Borgå Olof , Rane Anders
Published: July 2010

AbstractThe plasma kinetics of phenytoin were studied in pregnant and nonpregnant rats after a single intravenous dose. The apparent volume of distribution was greater in the pregnant rats resulting in lower plasma concentrations in these rats within the first hour of injection. The beta half‐life in pregnant rats (5.0 hours) was prolonged compared to the non‐pregnant rats (2.2 hours). The plasma clearance values which take the altered volume of distribution into account, showed a smaller but still significant difference between the two groups of rats. This indicates a lower capacity of the pregnant rats to metabolize the drug.
The Effect of Nifedipine on the Isolated Rat Heart
Authors: Refsum Helge , Glomstein Anders , Landmark Knud
Published: July 2010

AbstractThe mode of action of a calcium‐antagonistic drug, nifedipine, on the spontaneously beating, isolated, perfused rat heart was studied at two different calcium concentrations of the Ringer solution, [Ca++]o, (2.0 and 5.0 meq./l). The sinus node discharge, the aortic pressure amplitude and hence the work index were greater at 5.0 than at 2.0 meq./l. Nifedipine 100 μg/1 caused a reduction in these parameters, the effects being most pronounced at the lowest [Ca++]ostudied. ECG tracings demonstrated that the PR‐interval was longer at 2.0 than at 5.0 meq./l of calcium. The AV conduction time further increased after the addition of nifedipine. This effect was enhanced at the lowest [Ca++]oused, where varying degrees of AV block occurred in several experiments. The drug also reduced the R‐wave voltage and the RT‐interval. Calcium‐induced ventricular tachyarrhythmias were produced, which were suppressed by nifedipine. Nifedipine 100 μg/l produced a small and transient increase in the coronary flow, but a tremendous increase in the ratio coronary flow/work index was observed. This indicates improvement of the cardiac energy balance caused by an increase in the coronary oxygen supply in relation to the myocardial oxygen demand.
Reduction of Sulphonated Water‐soluble Azo Dyes by Caecal Microorganisms from the Rat
Authors: Larsen J. Chr. , Meyer T. , Scheline R. R.
Published: July 2010

AbstractThe degradation of Fast Red E, Amaranth, Ponceau 4R and Ponceau 6R in anaerobic incubates of rat caecal extract was studied by spectrophotometric scanning. The compounds underwent reduction of the azo linkage and thus loss of colour. The reaction rates seem to depend on the number rather than position of the sulphonate groups in the molecule.
Uptake and Retention of14C‐Bretylium in Degenerating Postganglionic Sympathetic Nerves of the Rat
Authors: Almgren Olle , Lundberg Dag
Published: July 2010

AbstractThe uptake and retention of14C‐bretylium was studied in rat salivary glands and iridesin vivoat different time intervals after sympathetic denervation or decentralization. The uptake of bretylium was increased on the denervated side during a time period which precedes the degeneration release of sympathetic transmitter, but was later on reduced. On the other hand, the retention of bretylium on the denervated side was already markedly reduced during the time period preceding the onset of the degeneration transmitter release. In experiments with chronically denervated salivary glands, or glands atrophied by means of excretory duct ligation, a pronounced extraneuronal accumulation was observed. The extraneuronal accumulation of bretylium may partly mask the changes in disposition of the drug induced by the sympathetic denervation. The results are in accordance with the hypothesis that bretylium must be associated with special sites at the adrenergic nerve terminals in order to exert its degeneration delaying effect.
Effect of Acetylated Derivatives of some Sympathomimetic Amines on the Acute Toxicity, Locomotor Activity and Barbiturate Anaesthesia Time in Mice
Authors: Marvola Martti
Published: July 2010

AbstractIn order to study how acetylation affects the activity of sympathomimetic amines the effects of tyramine, amphetamine, ephedrine, phenylephrine, orciprenaline and their O‐ and N‐acetyl derivatives on acute toxicity, locomotor activity and barbiturate anaesthesia time were studied. N‐acetylated derivatives were always significantly less toxic whereas O‐acetylated derivatives except O‐diacetylphenylephrine were more toxic than the parent compounds. Amphetamine > ephedrine > tyramine increased locomotor activity of mice. O‐acetylephedrine had a similar though weaker effect in this respect than ephedrine. O‐acetyltyramine and N‐acetylated derivatives of tyramine, amphetamine and ephedrine reduced the locomotor activity of mice. Phenylephrine and its O‐ and N‐acetyl derivatives reduced the locomotor activity of mice to about the same degree. Amphetamine > ephedrine > O‐acetylephedrine > tyramine reduced the duration of barbiturate anaesthesia, whereas this was prolonged by adrenaline, N‐acetyltyramine, N‐acetylamphetamine and N‐acetylephedrine. The results show that N‐acetylation decreased or even reversed the action of the parent compound. O‐acetylation increased toxicity but reduced the other effects of the drugs studied. It is probable that the effects of O‐acetyl derivatives are at least partly due to deacetylation.
Biochemical and Behavioural Effects of Thiothixene: Relation to Tissue Levels of the Drug
Authors: Mjörndal Tom , Wiesel Frits‐Axel , Oreland Lars
Published: July 2010

AbstractMale Sprague‐Dawley rats were given a single intraperitoneal dose of a thioxanthene neuroleptic, thiothixene. The effect on the spontaneous motor activity and the level of homovanillic acid in the striatum and the olfactory tubercle were studied at various times after the injection of the drug. The concentration of thiothixene in the blood and brain was also followed. The rats showed a significant decrease in motor activity from 15 min. to 12 hours after the injection. The HVA‐levels in the striatum and olfactory tubercle were significantly elevated from 0.5 to 18 hours, the effect on the striatum being relatively more pronounced. No clear relation between drug levels and changes in motor activity of HVA‐levels was found.
Stoichiometric Interaction of a β‐Receptor Blocking Drug with Fraction of Liver Cytochrome P‐450 as a Possible Cause for its Dose‐dependent Availability
Authors: von Bahr Christer , Vadi Helena , Norlin Allan , Moldéus Peter
Published: July 2010

AbstractThe liver's ability to bind and metabolize “first‐pass” drugs is a major factor responsible for their blood concentrations on oral administration. Therefore we have characterized the binding of such a drug, the adrenergic β‐receptor antagonist alprenolol, to rat liver. The microsomal fraction accounted for almost all the liver binding capacity. On titration of microsomes with alprenolol, the induced type I spectral change, reflecting alprenolol‐cytochrome P‐450 interaction, showed a high and a low affinity binding phase with identical “optical capacity”. The spectral dissociation constant for the high affinity binding was 0.17 μM. By use of spectral methods we found that 13–14 per cent of the total microsomal cytochrome P‐450 participated in the alprenolol binding at the end of the first phase and 27 per cent at the end of the second phase. Spectral titrations showed that SKF 525‐A and imipramine interact with the same sites of cytochrome P‐450 as alprenolol. Binding studies with radioactive alprenolol showed the presence of a minimum of three classes of microsomal binding sites. The last had a very high capacity. The first phase caused a marked non‐linearity in the overall microsomal binding of the drug, and it had almost identical capacity (0.12 mol alprenolol/mol P‐450) and affinity (Ks= 0.21 μM) as the first type I spectral binding phase. This strongly indicates that this first “overall” binding phase reflects selective binding to P‐450, which is further strengthened by the fact that SKF 525‐A and imipramine markedly influenced this phase. Moreover, this phase was not present in plasma membranes, which do not contain cytochrome P‐450. Hence we conclude that a stoichiometric (1:1) interaction of alprenolol with a 12–14 per cent fraction of rat liver microsomal cytochrome P‐450 causes a non‐linear overall microsomal binding. Such a phenomenon probably explains this drug's dose‐dependent availability. We suggest that when this high affinity site is saturated the low affinity site of cytochrome P‐450 oxidizes a large fraction of the alprenolol escaping ‘first pass’ liver extraction.
Effect of Bendroflumethiazide on Na+and Ca++Transport in Rat and Guinea Pig Jejunum
Authors: Jørgensen F. Schønau , Rask–Madsen J.
Published: July 2010

AbstractThe effect of therapeutic bendroflumethiazide (BHFT) concentrations on transepithelial Na+and Ca++transport in the rat and guinea pig jejunum was studied by the Ussing technique. In the rat a relative depression of Na+and Ca++fluxes from the mucosa to serosa as well as a relative increase of the opposite Na+flux was observed. These effects suggest an inhibition of BHFT on Na+and Ca++absorption, which may prevent the development of a positive Ca++balance during long–term thiazide administration. No consistent changes were found in the guinea pig – either in Na+or in Ca++transport.
Physiological Disposition of Ibuterol and Terbutaline in the Isolated Perfused Rat Lung
Authors: Ryrfeldt Ake , Nilsson Elisabeth
Published: July 2010

AbstractThe absorption from the airways, uptake from the vascular compartment and biotransformation of3H–ibuterol (diisobutyrate ester of terbutaline) and3H–terbutaline have been studied using isolated perfused and ventilated rat lungs. After endotracheal instillation, ibuterol was more rapidly absorbed than terbutaline (P < 0.01 at 5 and 10 min. after administration) at doses of 55 and 550 nmol/lung. No difference was noted at 5.5 nmol/lung. When the drugs were added to the perfusion medium the calculated lung uptake for ibuterol was about 30 times that for terbutaline. Ibuterol was shown to be rapidly hydrolyzed to terbutaline. No or minor biotransformation of terbutaline was noted.
Tolerance to Marijuana–Induced Tachycardia in Man
Authors: Gibbins Robert J. , McDougall Janet , Miles C. G. , Marshman Joan A.
Published: July 2010

AbstractTwenty–seven days exposure of 10 male volunteers to marijuana cigarettes containing a total dose of 16 mg of Δ9–tetrahydrocannabinol resulted in a significant reduction in the effect of the drug on heart rate. The results are consistent with and best explained by the hypothesis of tolerance development.
Human Pharmacokinetics of Sotalol
Authors: Anttila Markku , Arstila Matti , Pfeffer Morris , Tikkanen Risto , Vallinkoski Virve , Sundquist Hannu
Published: July 2010

Abstract The pharmacokinetics of sotalol were studied in healthy volunteers after a single dose and in hypertensive patients after chronic administration. A single 160 mg and two 80 mg socator® tablets were compared and found to be bioequivalent in terms of relative total bioavailability. Sotalol was well absorbed, about 73 % of the dose being excreted in the urine within 72 hours. The absolute bioavailability on oral administration was 100% indicating that both first–pass hepatic metabolism and metabolic destruction are negligible. There was no protein binding and the distribution volume was 171 1 after oral administration. The graphical fit of the plasma levels after a single oral dose was compatible with a two–compartment open model. The curve consisted of a distribution phase with a t1/2 of 6 hrs followed by a disposition phase with a t1/2 of 9.5 hrs. After chronic administration the t1/2 during the disposition phase was 10 hrs. Computer fitting of the data gave a terminal body half–life of 17.2 hrs which corresponded well with the terminal body half–life of 15 hrs calculated manually from urinary excretion rate data. In the computer analysis the steady–state plasma levels to be expected after long–term oral dosing were simulated and found to be in good agreement with experimental data, indicating that there is no induction of sotalol metabolism or increase in efficiency of excretion during long–term sotalol administration.
Effect of Body Temperature on Cardiotoxicity of Isoprenaline in Rats*
Authors: Harri Mikko N. E.
Published: July 2010

Abstract The acute subcutaneous toxicity of isoprenaline was found to depend on body temperature. Since isoprenaline increases both heat production and heat loss, its effect on body temperature was influenced by the thermoregulatory capacity of an animal. An increased hyperthermic action of the drug following a rise in ambient temperature by 4° was associated with 10 times increased toxicity. Increased heat production capacity following cold acclimatisation resulted in increased toxicity at room temperature but no more than in a cold environment. The higher body weight to body surface ratio in bigger rats diminished the isoprenaline–induced hypothermia. On the other hand, hypothermia reduced tachycardia and pulse pressure responses to isoprenaline. However, cardiomegaly and myocardial lesions produced by small and repeated doses of isoprenaline (5 mg/kg daily for 4 days) were independent of whether the animals were hypo– or hyperthermic after the injections. In addition, the extent of cardiac enlargement was as great in small rats as in the larger rats. It is concluded that hypothermia protects the heart from acute failure but not from hypoxia, which may be the main reason for cardiomegaly and myocardial lesions after isoprenaline.
Induction of the Drug Metabolizing System in Rainbow Trout (Salmo gairdnerii) Liver by Polychlorinated Biphenyls (PCBs)
Authors: Lidman Ulf , Förlin Lars , Molander Olof , Axelson Gösta
Published: July 2010

AbstractClophen A50 is shown to enhance the O–demethylation of p–nitroanisole to p–nitrophenol and to elevate the cytochrome P–450–content of the rainbow trout liver. Three days after feeding, the O–demethylating activity had increased about 4–fold while the cytochrome P–450–concentration was unchanged. This suggests that the process is divided into two or more steps, with an initial lag in the cytochrome P–450 formation. From 7 days and throughout the experiment a concomitant increase in the O–demethylating activity and the cytochrome P–450–content can be observed. The increased activity can not, however, be solely correlated to the increase in cytochrome P–450 content.
Modification of Microsomal Membrane Components and Induction of Hepatic Drug Biotransformation in Rats on a High Cholesterol Diet
Authors: Lang Matti , Laitinen Matti , Hietanen Eino , Vainio Harri
Published: July 2010

AbstractThe effect of cholesterol on the microsomal membrane components and the induction of drug–metabolizing enzymes was studied in rats after feeding with a two per cent cholesterol diet and administration of phenobarbitone or 3–methylcholanthrene intraperitoneally. The results revealed that cholesterol affected both the amount and the binding properties of protein, phospholipid and cholesterol in microsomes. Cholesterol also modified the effects of phenobarbitone and 3–methylcholanthrene on microsomal membranes. The administration of inducers increased the liver–body weight ratio significantly. Phenobarbitone enhanced NADPH cytochromecreductase activity in native microsomes by about 2–fold. The aryl hydrocarbon hydroxylase activity was increased markedly by both phenobarbitone and 3–methylcholanthrene. The UDPglucuronosyltrans–ferase activity was also enhanced by both inducers. After trypsin digestion of microsomes UDPglucuronosyltransferase activity was significantly higher in rats on a high cholesterol diet than in those on standard diet. After treating the microsomesin vitroby various membrane perturbants it was found that 3–methylcholanthrene made the enzyme proteins less soluble than phenobarbitone. The results support the idea that cholesterol affects the activities of drug metabolizing enzymes, due to changes in the structure of microsomal membranes.
Experimental Data on the Neurotoxicity of Fenitrothion
Authors: Lehotzky Kornélia , Ungváry Gy.
Published: July 2010

Abstract Fenitrothion, the indirect cholinesterase inhibitor organophosphorus insecticide, caused alteration in the conditioned avoidance reflex of rats. In trained rats (treated with 10 and 100 mg/kg fenitrothion) the number of conditioned responses diminished the latency period leghtened, and the tendency towards extinction was slower. The whole blood cholinesterase activity showed marked inhibition during the toxic effects. In rabbits, treated with 10 and 25 mg/kg fenitrothion daily, the conduction velocity of the sciatic nerve became slower. At the same time rabbits, poisoned with the higher dose, had marked signs of intoxication while others showed no signs at all. The histological findings showed destruction of the myelinated fibres of the sciatic nerve. Our results indicate that fenitrothion has a neurotoxic effect but the type and the mechanism of action is still obscure.