bluuebunny/crossref_metadata_2025 huggingface dataset:
An Improved Foot‐Shock Titration Procedure in Rats for Centrally Acting Analgesics
Authors: Neil A. , Terenius L.
Published: July 2010

Abstract:A foot‐shock titration method for the measurement of antinociceptive activity in the rat has been developed. A new grid design is described which makes the use of scrambled shocks unnecessary. Thresholds for responses elicited at different levels of integration within the central nervous system are measured: Detection threshold, flexor reflex, coordinated jumping and vocalisation. These thresholds were found to be stable over time in saline‐treated rats. The two opioid analgesics morphine and d‐propoxyphene increased these thresholds, each in a characteristic way. Morphine was more selective in its action and significantly more effective in increasing the vocalisation threshold than the threshold for jumping, whereas d‐propoxyphene increased both these thresholds to the same extent. Neither drug affected the detection threshold in low to moderate doses. The difference in pharmacodynamic profile is discussed in terms of heterogeneity of opioid receptor‐effector mechanisms at different levels of the neuroaxis.
Studies of Foetal Death and Foetal Weight in Guinea Pigs Fed Polychlorinated Biphenyls (PCB)
Authors: Brunström Björn , Kihlström Ingemar , Lundkvist Ulrika
Published: July 2010

Abstract: Pregnant guinea pigs were fed a total dose of 100 mg of the commercial PCB preparation Clophen A50 during days 16 to 60 of gestation. This treatment caused severe foetal, but no maternal, death. Contrarily, a total dose of 25 mg or 100 mg of 2,2′,4,4′,5,5′‐hexachlorobiphenyl (HCB) did not cause foetal death in the guinea pig. The prenatal growth rate was increased by a total dose of 25 mg, but not by 100 mg, of HCB.
Pharmacokinetics and First‐pass Metabolism of Levomepromazine in the Rat
Authors: Hals Petter‐Arnt , Dahl Svein G.
Published: July 2010

Abstract:The time course of the blood concentrations of levomepromazine and its two major non‐polar metabolites in man were studied in the rat after single oral and intraarterial doses of levomepromazine hydrochloride. The blood levels of N‐monodesmethyl levomepromazine were on average 179% of the levomepromazine levels after oral doses, but only 15% of the levomepromazine levels after intraarterial doses. The blood levels of levomepromazine sulfoxide, relative to the levomepromazine levels, were also generally higher after oral doses than after parenteral doses, on average 65% and 25%, respectively. Large interindividual variations were observed in the blood levels of levomepromazine and in the systemic availability of the drug after oral doses. The distribution phase lasted for about 8 hrs, the mean apparent volume of distribution was 16.6 l/kg, and the total body clearance was on average 12.3 ml/min. It is concluded that the rat provides a suitable model for the kinetics of levomepromazine in man, and that the sulfoxide and N‐monodesmethyl metabolites of the drug are mainly formed by first‐pass metabolism after oral doses in the rat, either in the liver or in the gut.
The Influence of Physostigmine on Respiratory and Circulatory Changes Caused by Overdoses of Orphenadrine or Imipramine in the Rat
Authors: Zandberg P. , Sangster B.
Published: July 2010

Abstract:Orphenadrine or imipramine were given intravenously as an infusion to spontaneously breathing, anaesthetized rats until respiratory arrest, the primary cause of death for both drugs. Intravenous injections of physostigmine did not prolong survival. Artificial ventilation prolonged survival for orphenadrine and imipramine by about a factor 3 and the rats died from cardiogenic shock. The cardiotoxic properties of orphenadrine and imipramine express themselves as a progressing disturbance in stimulus formation and conduction, a decrease in dP/dt max and increase in left ventricular end‐diastolic pressure and a decrease in cardiac output caused by the progressing decrease of heart rate. An intravenous injection of physostigmine did not prolong survival and had no favourable effect on the cardiotoxicity caused by orphenadrine and imipramine. Although physostigmine may be useful in the treatment of the anticholinergic syndrome it has, at least in the rat, no favourable effect on the respiratory insufficiency, due to overdoses of orphenadrine and imipramine. Moreover it is not effective in antagonizing the cardiotoxic effects of orphenadrine or imipramine.
The Absorption and Excretion of Methyldopa Ingested Concomitantly with Amino Acids or Food Rich in Protein
Authors: Stenbæk Ørnulf , Myhre Erik , Rugstad Hans Erik , Arnold Elisabeth , Hansen Tage
Published: July 2010

Abstract:Absorption and urinary excretion of 2‐14C‐L‐α‐methyldopa (αMD) were investigated in 5 healthy human volunteers. The drug was administered alone, with a mixture of amino acids and with a meal consisting of roast beef. The radioactivity in plasma and urine was not decreased significantly by either treatment, and it was concluded that the overall absorption of the drug was virtually unchanged. The amount of unconjugated αMD in plasma and urine, however, was significantly decreased following administration of the drug with roast beef. As the acid labile conjugates of αMD were practically unchanged an increased biotransformation to other metabolites owing to the protein rich meal was suggested more probable than competition between αMD and amino acids in the specific transport systems.
Progesterone and Oestrogen Concentrations in Plasma during Blastocyst Implantation in Mice Exposed to Triethyl Lead
Authors: Odenbro Agneta , Örberg Jan , Lundqvist Eva
Published: July 2010

Abstract:Female mice were injected intraperitoneally with triethyl lead chloride (3.0 or 6.0 mg/kg body weight, respectively) once a day on days 3–4 after mating. At the time of blastocyst implantation the plasma level of progesterone was significantly lower in females given 3.0 mg/kg body weight and the plasma levels of 17β‐oestradiol and progesterone were significantly lower in females given 6.0 mg/kg body weight than in control females.
Pharmacology of B‐HT 920 in some Isolated Smooth Muscles of the Guinea‐pig
Authors: Wikberg Jarl E. S. , Grundström Nils , Visnovsky Peter , Andersson Rolf G. G.
Published: July 2010

Abstract:The effects of B‐HT 920 were investigated on four isolated preparations from the guinea‐pig, namely the aorta, trachea, ileum and vas deferens. The latter three preparations were studied during electrical field stimulation, which induced contractions by activating cholinergic neurones (trachea and ileum) or adrenergic neurones (vas deferens), respectively. Comparative studies were also made with clonidine and noradrenaline. In ileum and trachea B‐HT 920 was almost equipotent with noradrenaline to inhibit the electrically induced contractions. In these tissues, B‐HT 920 also displayed almost the same maximal effect as noradrenaline. Clonidine also inhibited the contractions in ileum and trachea; the drug was slightly more potent than noradrenaline. However, in contrast to the intrinsic activity of B‐HT 920 that of clonidine was only submaximal. In vas deferens both B‐HT 920 and clonidine induced inhibition of contractions on electrical field stimulation at low concentrations. In this organ, both drugs were capable of inducing complete inhibition of the contractile response. In aorta B‐HT 920 as well as clonidine were only weak agonists in comparison to noradrenaline. The α2‐blocker, yohimbine, completely blocked the effect of B‐HT 920 in ileum at low concentrations (1 × 10−7M). Remarkably, however, the inhibitory action of B‐HT 920 in trachea was only marginally affected even by high concentrations of yohimbine (1 × 10−6M). It is suggested from the present results that B‐HT 920 can induce inhibition of both cholinergic and adrenergic neurotransmission presumably by inducing selective stimulation of prejunctional α2‐receptors. In fact, the selectivity of B‐HT 920 seems to be comparable to that of clonidine for the α2‐receptor. However, the mode of action of B‐HT 920 in trachea may be somewhat uncertain since its effect was not inhibited by yohimbine.
Inhibition of Paranitroanisole and Antipyrine Monooxygenation in Isolated Rat Hepatocytes by Compounds Interacting with Mitochondrially Related Carbohydrate Metabolism
Authors: Holme Jørn A. , Eek‐Hansen Arne , Jervell Kristian F.
Published: July 2010

Abstract:The monooxygenation of paranitroanisole (PNA) and antipyrine (AP) were measured in isolated rat hepatocytes incubated with compounds interacting with mitochondrially related carbohydrate metabolism. Phenylpyruvate, an inhibitor of pyruvate carboxylase, reduced the rate of PNA and AP metabolism to about 60 and 20%, respectively, in hepatocytes both from fasted and fed rats. Inhibition of amino acid transaminase with aminooxyacetate, decreased the metabolism of both PNA and AP to 60–70% of control values in hepatocytes from fasted rats, whereas this effect was not seen in fed rats. n‐Butylmalonate, an inhibitor of mitochondrial malate/phosphate exchange, had only minimal effects on PNA and AP monooxygenation in both the nutritional states. The simultaneous presence of glyoxylate and pyruvate, known to inhibit the NADPH specific isocitrate dehydrogenase, reduced the metabolism of both PNA and AP in hepatocytes from fasted rats to about 60 and 35% of control values respectively, while the effect was not so marked in hepatocytes from fed rats. The metabolism both of PNA and of AP in hepatocytes from fasted rats was reduced to 50–60% of control values with the addition of NH4Cl. This effect could be blocked either by incubating the hepatocytes with pyruvate or by using hepatocytes isolated from fed rats. The addition of various carbon intermediates generally reduced the effect of the inhibitors used. Phenobarbital‐treatment did not change the effects observed with cells from uninduced animals. The inhibitors did not alter PNA or AP metabolism in microsomal incubations, and therefore most likely reduced the monooxygenation in intact cells by affecting NADPH generation pathways.
Uptake of51Cr‐Chromate by Human Erythrocytes – A Role of Glutathione
Authors: Aaseth Jan , Alexander Jan , Norseth Tor
Published: July 2010

Abstract:Hexavalent chromium (Cr‐VI), as Na2CrO4in an aquous solution, was reduced rapidly to the trivalent form (Cr‐III) in the presence of glutathione, GSH (0.3–3.0 mM). Such GSH‐dependent reduction of Cr‐VI can take place in the cytosolic space of Cr‐VI‐exposed cells, since GSH is found in reactive concentrations in this compartment. The reduction makes chromium essentially impermeable through the cell membrane, explaining the observation that Cr‐VI, when added to red cell suspensions, is bound quantitatively intracellularly after a few hours. Diethylmaleate conjugation of the SH‐group of the intracellular GSH preventing the oxidation to GSSG, lowered the chromium‐uptake significantly, showing that reduced GSH plays a role for the chromium binding. In healthy red cells chromium is partially bound to haemoglobin and partially to small molecular weight substances, probably in the trivalent form. This intracellular chromium cannot be removed to the extracellular space by addition of chelating agents as long as the cell membrane is intact.
Monooxygenase Activities of Human Liver, Lung, and Kidney Microsomes – A Study of 42post mortemCases
Authors: Jakobsson Sten W. , Okita Richard T. , Mock Nell I. , Masters Bettie Sue S. , Buja L. Maximilian , Prough Russell A.
Published: July 2010

Abstract:The cytochrome P‐450‐dependent monooxygenase system was examined in microsomal fractions prepared from 42post mortemhuman livers and 9 lungs and kidneys. Electron microscopy studies indicated that the human liver samples were relatively free of mitochondrial and plasma membrane contamination, but samples of kidney and lung were less pure. The microsomal fractions from all organs were judged to be relatively free of haemoglobin and methaemoglobin. The specific enzyme activities for several drug substrates for the monooxygenase, NADPH‐cytochromecreductase activity and the content of the microsomal cytochromes were measured. The values of the biochemical parameters studied were found to be quite variable and the values for the human liver were appreciably lower than those obtained with liver microsomes from laboratory rodents. The enzyme activities of the human kidney and lung microsomal fractions were 1–10% of those seen for human liver samples, except for NADPH‐cytochromec(P‐450) reductase activity. In order to evaluate anypost mortemchanges in human liver, correlations between drug metabolism activities and either cytochrome P‐450 or NADPH‐cytochromec(P‐450) reductase content were examined. Strong correlations (r>0.91) were seen only between aminopyrine or ethylmorphine demethylase activity and cytochrome P‐450 content in samples obtained within 4 hours of death. Longerpost mortemtimes gave poorer correlation between activity and cytochrome content. These studies document several conditions required in order to obtain human microsomal fractions representative of the activities in fresh, viable tissue.
Vascular Smooth Muscle Relaxation by Nitro Compounds: Reduced Relaxation and cGMP Elevation in Tolerant Vessels and Reversal of Tolerance by Dithiothreitol
Authors: Axelsson Krister L. , Andersson Rolf G. G. , Wikberg Jarl E. S.
Published: July 2010

Abstract:Smooth muscle preparations obtained from bovine mesenteric artery were incubated with high concentrations of nitroglycerin (NG) or nitroprusside (NP) at elevated pH. This treatment was found to make the vessels tolerant towards both the relaxant and cGMP elevating action of a challenging dose of nitrocompounds when tested on the histamine contracted vessels. Also, some cross‐tolerance between NP and NG could be found since pretreatment of the vessels with NP caused a reduction in both the relaxant and the cGMP elevating action of NG. The NG induced tolerance could be partly reversed by treatment with the disulfide reducing agent dithiothreitol (DTT). These results are suggested to strenghten the evidence for cGMP as a mediator of vascular smooth muscle relaxation induced by nitrocompounds. The ability of DTT to partly reverse this tolerance indicates the existence of critical tissue sulfhydryl groups with which the nitrocompounds interact. There also seemed to exist certain differences in the mechanism of action between NG and NP since the tolerance induced against NG was much more pronounced than was the case for NP.
Actions and Interactions of Diazepam and Alcohol on Psychomotor Skills in Young and Middle‐aged Subjects
Authors: Palva E. S. , Linnoila M. , Routledge P. , Seppälä T.
Published: July 2010

Abstract: Healthy pretrained men participated in three separate controlled double‐blind and cross‐over trials. There were 10 students in Trial I, 11 army officials or policemen aged 38–59 years in Trial II, and 11 students in Trial III. After single oral doses of diazepam 10 mg (D), placebo, alcohol 0.5 g/kg (A) or D + A, given at one‐week intervals in balanced order, the psychomotor skills (choice reaction, tracking, attention, flicker fusion) were repetitively measured up to 2.5 hrs. Serum D concentrations were measured by gas chromatography. D alone impaired flicker fusion in trials I and II, and also reactive and coordinative skills in trial III. A alone slightly impaired skills and failed to potentiate D effects. Increasing age rendered the performance worse but this was due to increased base‐line errors rather than to enhanced responses to D. Serum D concentrations tended to rise in the presence of A suggesting an inhibition of D demethylation by alcohol. Both total and free concentrations of D were similar in both age groups. The results suggest that in spite of unaltered sensitivity to D, middle‐aged subjects have a lowered margin of safety when driving or using machinery under D treatment.
Studies of the Contracting Mechanism Induced by Slow Reacting Substance of Anaphylaxis (SRS‐A): Interaction with Calcium
Authors: Hedman Susan E. , Andersson Rolf G. G.
Published: July 2010

Abstract:The present study demonstrates the Ca2+dependency of the contractions elicited by egg albumin and SRS‐A in isolated tracheal preparations from sensitized guniea‐pigs. The egg albumin contraction consisted of a rapid, initial and a long lasting, tonic phase; the first phase independent and the latter dependent of extracellular Ca2+. The SRS‐A contraction was completely dependent of extracellular Ca2+ions. On the other hand, the egg albumin contraction of the parenchymal strips was not influenced by extracellular Ca2+. SRS‐A released Ca2+from a microsomal fraction of sensitized lung tissue. This effect was, however, absent in microsomes from desensitized lung tissue. It is suggested that the Ca2+‐mobilizing effect of SRS‐A is of utmost importance for the initiation of contraction of the tracheal smooth muscle.
Dissociation between the Effects of some Xanthine Derivatives on the Tracheal Smooth Muscle and on the Skeletal Muscle
Authors: Jeppsson A.‐B. , Johansson U. , Waldeck B.
Published: July 2010

Abstract:The ability of some xanthine derivatives to relax the trachea, contracted by pilocarpine, and to increase the force of contraction of directly stimulated skeletal muscles from the guinea‐pig was studiedin vitro.No relationship was found between these two effects. Relaxation of the trachea occurred at lower concentrations and with a different order of potency as compared with the effects on the slow‐contracting soleus muscle or on the fast‐contracting extensor digitorum longus. One of the compounds, IBMX, 1‐methyl‐3‐isobytylxanthine, showed an isoprenaline‐like effect on the soleus muscle i.e. it depressed the force and fusion of subtetanic contractions. The relaxing effect of theophylline and IBMX on the trachea was additive to that of terbutaline but no clear potentiation was observed. The depression of the contractions of the soleus muscle elicited by terbutaline was reinforced by IBMX but not by theophylline. Theophylline in concentrations which used alone enhanced the contractions of the soleus muscle inhibited the effect of terbutaline. We conclude that the relative contribution of the various effects of xanthine derivatives differs from compound to compound.
Dependence of Lung Uptake of Lidocainein Vivoon Blood pH
Authors: Post Claes , Eriksdotter‐Behm Kristina
Published: July 2010

Abstract:Lung uptake of lidocaine was studied in anaesthetized Swedish landrace pigs using the double indicator dilution method with indocyanine green dye as i ntravascular marker. The pigs were given infusions of sodium bicarbonate or hydrochloric acid to arterial blood pH in the range 7 to 8. Lung uptake of lidocaine was found to correlate statistically significant (P < 0.05) with pH. Lung uptake in the first injection before the infusion of acid or base, was 42 ± 4 (X̄ ± S.E.M.)%. The uptake was not found to correlate to cardiac output. The conclusion from this work is therefore that lung uptake of xenobiotic amines in part is dependent on blood pH.
Thallium‐201: Autoradiography in Pigmented Mice and Melanin‐bindingin Vitro
Authors: Tjälve Hans , Nilsson Monica , Larsson Bengt
Published: July 2010

Abstract:Autoradiography with201T1+in C57B1 mice showed a strong labelling of the eye melanin and of pigmented hair follicles. An analysis of the affinity of thallium for pigment from cow eyes indicated a binding to three groups of sites and showed a marked sensitivity to the addition of H+‐ions. The results are consistent with the conception that a binding of thallium occurs to the free carboxyl groups of the melanin and that the structure of the polymer has a marked influence on the affinity. Similar results have previously been obtained with other cations. There was no indication that the strongin vivoaffinity of thallium to melanin is due to a more firm binding than for other cations which do not localize on melaninin vivo.Instead, the ability of cations to pass the melanocyte membranes and reach the melanin granules is probably decisive for whether a melanin binding will take placein vivo.Toxic effects on the eye and epilation are symptoms of thallium intoxication which may be related to its melanin binding. The fate of201Tl+in some other tissues is also described and discussed.
Renal Tubular Secretion and Effects of Chlorothiazide, Hydrochlorothiazide and Clopamide: A Study in the Avian Kidney
Authors: Odlind Bo , Lönnerholm Gudmar
Published: July 2010

Abstract:The relationship between renal tubular secretion and saluretic effects of two thiazides (chlorothiazide and hydrochlorothiazide) and clopamide was studied using a modified Sperber technique. The distribution of carbonic anhydrase in the avian kidney was studied by a histochemical method. The modified Sperber technique allows an absolute estimation of the tubular excretion efficiency of a substance, as determined by its True Tubular Excretion Fraction (TTEF). The TTEF values were for chlorothiazide 59%, hydrochlorothiazide 22% and clopamide 10%. Thus, they were all actively secreted by renal tubular cells; most likely through organic anion transport since novobiocin markedly reduced the TTEF values. After infusion of the diuretics into the renal portal system on one side there was only a small ipsilateral excess natriuresis and chloruresis, in spite of their different tubular excretion efficiencies. For hydrochlorothiazide, and especially for chlorothiazide the saluretic effect therefore appears to be largely independent of the tubular fluid concentration of the diuretic and primarily evoked from the peritubular side of the avian nephron. This is in sharp contrast to the primarily luminally induced saluretic effects of furosemide, ethacrynic acid and piretanide. Only chlorothiazide caused an ipsilateral excess excretion of potassium and bicarbonate, probably due to inhibition of carbonic anhydrase since similar effects were seen after acetazolamide. This effect was coupled to tubular secretion of the diuretic, and probably reflects an inhibition of carbonic anhydrase in cortical distal tubules, where the enzyme is present in the apical region of most cells and could be reached by chlorothiazide present in the tubular fluid.
Inhibition of Human Lung Cyclic Nucleotide Phosphodiesterases by Proxyphylline, Theophylline and their Metabolites
Authors: Selvig Kirsten , Bjerve Kristian S.
Published: July 2010

Abstract:Inhibition of cAMP and cGMP hydrolysis in human lung tissue by proxyphylline and its main metabolite 1‐methyl‐7‐(β‐hydroxypropyl)xanthine was compared with theophylline and its metabolite 3‐methylxanthine. The apparent inhibition constant of proxyphylline was 0.6–0.7 mmol/l at low cAMP concentrations and at both low and high cGMP concentrations, while it was 1.0 mmol/l at high cAMP concentrations. This is 1.2–1.7 times higher than the corresponding values for theophylline. Both metabolites were slightly weaker inhibitors than their parent drugs, the theophylline metabolite relatively weaker than the proxyphylline metabolite. The differences in the observed inhibition constants agree with previous clinical studies indicating that the potency of theophylline is approximately twice that of proxyphylline.
Autoradiographic Studies on the Distribution of Arsenic in Mice and Hamsters Administered74As‐Arsenite or ‐Arsenate
Authors: Lindgren A. , Vahter M. , Dencker L.
Published: July 2010

Abstract:Whole‐body autoradiography in combination with other determinations of tissue levels of74Asarsenic in mice, 5 min. to 30 days after intravenous injections of74As‐arsenite (As III) or ‐arsenate (As V), showed higher organ concentrations and whole‐body retention of arsenic in the As III mice as compared to the As V mice. Only the kidneys (at short time intervals) and the skeleton had higher levels in the As V mice as compared to the As III mice. The skeletal accumulation of As V is probably due to the resemblance of the arsenate to phosphate, so that arsenate may substitute for phosphate in the apatite crystal. The long‐term retention of arsenic was most apparent in hair and skin, squamous epithelium of the upper gastrointestinal tract (oral cavity, oesophagus, and the oesophageal part of the stomach mucosa), the epididymis, thyroid, lens and skeleton. The accumulation in hair, skin and the upper gastrointestinal tract may be ascribed to a binding to keratin, the content of which is high in squamous epithelia. The distribution of arsenic in golden hamsters was similar to that found in mice. The significance of the findings in relation to reported adverse effects of inorganic arsenic is discussed.
Interaction of Hydroflumethiazide and 2,4‐Disulfamyl‐5‐trifluoromethylaniline with Cyclic AMP Phosphodiesterase and Carbonic Anhydrase
Authors: Brørs O. , Braut G. S. , Braut S. , Jacobsen S.
Published: July 2010

Abstract:The inhibitory effect of hydroflumethiazide (HFT) and its metabolite, 2,4‐disulfamyl‐5‐trifluoro‐methylaniline (DTA) on cyclic AMP phosphodiesterase and the binding of HFT and DTA to carbonic anhydrase was studiedin vitro. Significant inhibition of rat kidney low‐Kmcyclic AMP phosphodiesterase was observed with DTA concentration above 2.5 × 10−4mol/1 and with HFT concentration above 1 × 10−4mol/1. 50% inhibition was observed at a DTA concentration of 1 × 10−3mol/1. Binding of DTA and HFT to commercially obtained bovine erythrocyte carbonic anhydrase was demonstrated by equilibrium dialysis. Data were consistent with one class of binding sites. The product of n (number of binding sites) and Kass(association constant) was 5 × 105M for DTA and 3.3 × 104M for HFT at 2°. In human bloodin vitroat 37°, the equilibrium erythrocyte/plasma concentration ratio was 18 for DTA and 1.6 for HFT. It is concluded that HFT and DTA have approximately the same potency as cyclic AMP phosphodiesterase inhibitors, whereas DTA is more extensively bound by erythrocyte carbonic anhydrase.
Toxic Effects of Free and DNA‐linked Daunorubicin on Isolated Rat Cardiac Myocytes
Authors: Paul Christer , Tomingas Allan , Rajs Jovan , Anundi Iréne , Högberg Johan , Peterson Curt
Published: July 2010

Abstract: Isolated cardiac myocytes from adult rats were used as a model to study the cardiotoxicity of free and DNA‐linked daunorubicin. The toxic effects on the myocytes were evaluated by studying morphological changes, trypan blue exclusion and cell membrane permeability to NADH, as determined by LDH‐activity. At a concentration of 100 μM daunorubicin caused an increased plasma membrane permeability within 30 min. Using light microscopy, the myocytic injury induced by daunorubicin could be distinguished from that induced by anoxia or elevated pH. In contrast to the effect of the free drug, no toxic effects could be demonstrated after incubation with DNA‐linked daunorubicin (100 μM) for 5 hours. The higher toxicity of the free drug was related to a much higher intracellular accumulation of daunorubicin. No fluorescent metabolites of daunorubicin could be detected in the myocardial cells. Daunorubicin did not induce lipid peroxidation, as judged by the absence of malondialdehyde production and evolution of ethane. It is concluded that daunorubicin exerts toxic effects on rat cardiac myocytes by mechanisms that do not involve lipid peroxidation. Isolated cardiac cells from adult rats seem to be a useful model for the further study of such mehanisms.
Reversal of Enterotoxic Diarrhoea by Anaesthetic and Membrane‐stabilizing Agents
Authors: Lönnroth Ivar , Jennische Eva
Published: July 2010

Abstract:The effect of membrane‐stabilizing and sedative drugs on enterotoxic diarrhoea was studied in mice. Fluid secretion was induced in ligated loops of the small intestine by challenge with cholera toxin (CT), heatlabile enterotoxin (LT) fromEscherichia colior dibuturyl‐cyclic AMP (dB‐cAMP). Chlorpromazine, melperone, diazepam, mebumal, ketamine and ethanol all inhibited CT‐induced hypersecretion, ED50 being 1.5, 4, 4, 35, 70 and 1500 mg/kg, respectively. The drugs also blocked CT‐stimulation of adenylate cyclase, which mediates the action of CT. Concomitant with the antisecretory effect a sedative effect was induced, as judged by the motility and righting reflex of the animals. Hypersecretion byE. coliand LT was also totally blocked by chlorpromazine, diazepam, ketamine and ethanol. In contrast, the secretion by dB‐cAMP which bypasses adenylate cyclase in its action, was not affected by diazepam and was only partly reversed by chlorpromazine, ketamine and ethanol. The reversal of dB‐cAMP‐secretion is probably due to enhanced absorption, rather than inhibition of adenylate‐cyclase. The use of membrane‐stabilizing drugs may represent a new principle for pharmacological treatment of diarrhoea.
The Distribution and Fate of14C‐Chloramphenicol in the New‐born Pig
Authors: Appelgren L.‐E. , Eberhardson B. , Martin K. , Slanina P.
Published: July 2010

Abstract:The distribution of14C‐chloramphenicol has been studied in new‐born pigs with the aid of whole‐body autoradiography. In the lung, liver, adrenal cortex, kidney, myocardium, pancreas, thyroid, spleen and skeletal muscle the amounts of radioactivity were higher than that of the blood short time after injection and remained higher than the blood up to 8 hrs. After 4 and 8 hrs the brain concentration of14C was also higher than that of the blood. In the bone marrow, however, the concentration did not reach that of the blood during the whole experiment. In the organs more than 90% of the radioactivity was represented by chloramphenicol; the excretory organs, thyroids, and adrenals being exceptions.
Some Problems Encountered in the Evaluation of New Bronchodilating β‐Adrenoceptor Agonists
Authors: Andersson P. , Olsson O. A. T. , Waldeck B.
Published: July 2010

Abstract:A series of phenylethanolamine derivatives were examined with respect to their bronchospasmolytic effect and their ability to depress the contractions of the soleus muscle in cat and guinea‐pig. One group of compounds including D2343 (1‐(4‐hydroxyphenyl)‐2‐[1,1‐dimethyl‐3‐(2‐methoxyphenyl) propylamino]‐ethanol HCl), a new β2‐adrenoceptor agonist, appeared to be more effective in combating bronchospasm induced by histamine than in depressing the contractions of the soleus muscle in anaesthetized cat. This difference disappeared when serotonin was used to induce bronchospasm. Terbutaline antagonized histamine and serotonin equally well. Experimentsin vivoandin vitrowith guinea‐pigs gave ambiguous results. Slowly developing effects was a common feature of the compounds showing the apparent effect separation. None of the available β‐adrenoceptor agonists appears to distinguish between the adrenoceptors in the airway smooth muscle mediating bronchial relaxation and those in the skeletal muscle associated with tremor.
Relaxant β‐Receptors in the Trachea, but not Prejunctional α2‐Receptors in the Tracheal Cholinergic Neurones, are Subjected to Homologous Desensitization
Authors: Visnovsky Peter , Andersson Rolf G. G. , Grundström Nils , Wikberg Jarl E. S.
Published: July 2010

Abstract:Guinea‐pigs were pretreated with either isoprenaline, terbutaline or the α2agonist B‐HT 920 in order to asses the hypothesis that β‐ and α2receptors in trachea are subjected to homologous desensitization. In these experiments the β receptor activity was investigated on tracheal ring preparations contracted with carbacholine. Both in the isoprenaline and the terbutaline pretreated group the relaxant responses to β agonists were diminished. Pretreatment with B‐HT 920 did not affect the sensitivity of the trachea to β stimulation. In order to asses the responsiveness of α2receptors the trachea was contracted by electrical field stimulation in the presence of propranolol. During these conditions contractions were mediated by activation of cholinergic neurones and inhibitory effects of alpha stimulation were due to inhibition of the cholinergic neurotransmission by stimulation of prejunctional α2receptors. In these tests neither isoprenaline, terbutaline nor B‐HT 920 pretreatment affected the responsiveness of α stimulation to inhibit the electrically induced contractions.
Uptake, Conjugation and Transport of Laxative Diphenols by Everted Sacs of the Rat Jejunum and Stripped Colon
Authors: Sund Reidar Bredo , Hillestad Brit
Published: July 2010

Abstract: Phenolphthalein (PHEN), desacetylbisacodyl (DES) and oxyphenisatin (OXY) were incubated with everted sacs of the rat jejunum and stripped descending colon; the mucosal and serosal fluid were analysed with respect to free and conjugated diphenol by means of HPLC. Conjugates were measured as the amount of free diphenol in completely hydrolyzed samples less the amount before hydrolysis. A study with double‐sided administration of PHEN revealed that diphenol uptake from and conjugate output to both sides followed a rectilinear course for 15–90 min. A standard incubation time of 60 min. was chosen for the subsequent experiments, in which the diphenols were administered at the mucosal side at a low and a high concentration. Diphenol uptake, i.e. the amount of free diphenol administered less the amount recovered at the mucosal side, varied in an order (PHEN>DES>OXY) which seems to be inversely related to the order of water solubility of the compounds. Tissue accumulation and conjugate output relative to uptake varied with the dose, and from one compound to another. At low initial concentration (20 nmol/ml), the compounds were transferred to the jejunal and colonic serosal fluid almost entirely as conjugates (≥95%); the transfer rates followed, qualitatively, the same order as above. In jejunum, more conjugates were released to the mucosal than to the serosal side; in colon the distribution was reversed. Increasing the dose to 100 nmol/ml caused a corresponding increase in uptake, but relative output decreased and tissue accumulation increased; thus demonstrating capacity limitation. With PHEN, the ratio of conjugated:free diphenol on the serosal side remained essentially unchanged; with DES in particular, but also with OXY the ratio decreased. These findings may be interpreted to mean that in case of PHEN capacity limitation is linked to conjugate efflux, while DES and OXY may be poor substrates for glucuronide formation as well. Experiments with serosal side administration like the double‐sided PHEN experiments verified the dissimilar conjugate distribution in jejunal and colonic sacs; the phenomenon is to some extent discussed in the text. Identity tests gave evidence that the conjugates were mainly monoglucuronides.
Intestinal Handling of Bisacodyl and Picosulphate by Everted Sacs of the Rat Jejunum and Stripped Colon
Authors: Hillestad Brit , Sund Reidar Bredo , Buajordet Marit
Published: July 2010

Abstract:Bisacodyl (BIS) is the acetic acid di‐ester of the laxative diphenol 2‐(4,4′‐dihydroxydiphenyl)methylpyridine. A HPLC‐method which permits the simultaneous determination of BIS and its monodesacetylated (MONO) as well as totally desacetylated (DES) form, has been used to study the intestinal handling of BIS (20 nmol/ml), when the compound was incubated for 60 min. at the mucosal side of the preparations specified. In the jejunal mucosal fluid, BIS disappeared completely in short time, and there was a nearly equivalent rise in DES. MONO was transitory present. Hydrolysis was also rapid in mucosal fluid which had been in contact with jejunal sacs for 30 sec., but BIS was stable in blank incubations. Hydrolysis of BIS was slower by colonic than by jejunal sacs, and all three molecular forms were present during incubation. It seemed still slower in mucosal fluid which had been in contact with colonic sacs for 5 min. BIS just as DES accumulated in the jejunal and colonic serosal fluid mainly as conjugates (>95%), and DES was in all cases the only unconjugated metabolite present. Drug accumulation in jejunal serosal fluid was the same whether BIS or DES was added. However, more drug seemed to accumulate on the serosal side of colonic sacs when incubated with BIS instead of DES. In similar experiments with picosulphate, which is the sulphuric acid di‐ester analogue of BIS, free DES was not detected in the mucosal fluid during incubation. The amounts of laxative accumulating in the serosal fluid were less than 1/10 of those observed with BIS.
The Influence of Age and Sex on Weight Variation in Rats Treated Chronically with Lithium Chloride
Authors: Teixeira N. A. , Karniol I. G.
Published: July 2010

Abstract: Weight increase is a common side‐effect after chronic lithium salt treatment in man. This effect has not always been found in animal models using the rat. The possibility that the age and sex of animals might interfere with the results was studied, using groups of male and female rats, 2, 5, and 12 months old, injected intraperitoneally twice daily for 28 days with a solution of lithium chloride, or sodium chloride as control. The dose used was 1.5 meq./kg body weight (total daily dose of 3.0 meq./kg). In 2 month old animals, lithium induced an increase in weight significantly greater than that of the controls in the female group, while the weight of the male rats in this age group remained indistinguishable from the control rats. The 5 and 12 month old lithium treated female rats showed no differentiation in weight. Lithium treatment of the males in these two age groups caused a large number of deaths and, considering only those animals which survived, average weights were significantly less than those of control in the 5 month olds rats, and equal to control in the 12 month olds. It is concluded that age and sex have to be taken into consideration when studying the effects of chronic lithium treatment on the weight of rats.
Muscarinic Receptor Binding in the Guinea Pig Urinary Bladder
Authors: Nilvebrant Lisbeth , Sparf Bengt
Published: July 2010

Abstract:The muscarinic receptors in the guinea pig urinary bladder and the longitudinal muscle of the guinea pig ileum were studied by means of a receptor‐binding technique.l‐Quinuclidinyl[phenyl4‐3H] benzilate ((‐)3H‐QNB) was employed as radio‐ligand and the separation of bound from free (‐)3H‐QNB was performed by microcentrifugation. Under conditions of equilibrium (‐)3H‐QNB was specifically bound with high affinity to a limited number of sites, 0.32 and 1.62 pmol/mg protein in the bladder and ileum, respectively. The binding appeared to represent a single population of non‐interacting binding sites. The apparent dissociation constants were 2.6±10−10M in the bladder and 1.2±10−9M in the ileum, whereas the KD‐values, estimated by extrapolation to an infinitely low receptor concentration were 1.1±10−10M (bladder) and 3.1±10−10M (ileum). The binding of (‐)3H‐QNB appears to represent an interaction with muscarinic receptors, as it was effectively inhibited by muscarinic antagonists and agonists, but not by a variety of non‐cholinergic drugs.
Preclinical Studies on Human Insulin. II. General pharmacological Studies
Authors: Jørgensen Karin Damm , Wolffbrandt Knut Hafstein , Weis Jan Ulrik
Published: July 2010

Abstract:Human insulin was tested for pharmacological effects in variousin vitroandin vivomodels. The effects were compared with the effects of porcine insulin. No significant differences were observed between the two insulins. Human and porcine insulins had comparable blood glucose lowering effects in diabetic rats. Sedation was seen after high doses of either insulin due to hypoglycaemia. Diuretic effects were observed after high doses (25 U/kg) of the insulins. No other pharmacological effects were observed.
Drug Metabolism Activities of Isolated Rat Hepatocytes in Monolayer Culture
Authors: Holme Jørn A. , Søderlund Erik , Dybing Erik
Published: July 2010

Abstract:The levels of cytochrome P‐450 in hepatocytes cultured as monolayers for 22 hrs in Dulbecco's modified Eagle medium supplemented with serum and insulin was reduced to approximately 40% of initial values of freshly isolated hepatocytes. In correspondance with this the activities of the cytochrome P‐450 monooxygenases aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) and ethylmorphine (EM) N‐demethylase were reduced to 40 and 22% of their initial activities, respectively. Modifying the culture medium through omission of cysteine and cystine, and adding dexamethazone and delta‐amino levulinic acid, increased the content of cytochrome P‐450 to 59 % and EM N‐demethylase to 46 % of initial values, but was without effect on AHH activity. However, further modifications by adding high concentrations of asparagine and leucine increased AHH activity to 62% of initial values, but did not further enhance the total content of cytochrome P‐450 or the EM N‐demethylase activity. The activities of cytochrome P‐450 reductase, flavin containing monooxygenase, epoxide hydrolase and glutathione S‐transferase decreased less (to about 70–80% of initial values) than cytochrome P‐450 associated monooxygenase activities, whereas UDP‐glucuronyl transferase decreased to about 50% of initial values. In contrast to what was observed regarding cytochrome P‐450 and associated monooxygenase activities, modification of the incubation conditions did not affect the non‐cytochrome P‐450 enzymatic activities.
The Binding of Thiopental to Human Serum Albumin at Variable pH and Temperature
Authors: Christensen J. Heslop , Andreasen F. , Jensen Eva Bjørn
Published: July 2010

Abstract:The binding of thiopental was studiedin vitroby equilibrium dialysis over the concentration range 0.8–80 μg/ml in solutions with 45 g albumin (HSA) per litre. The binding at 37° was from 79% to 67.6% at pH 6 while it was 94.5% to 93.0% at pH 9. At intermediate values of pH the observed values for binding were compatible with the assumption of a gradual transition of an N‐form of HSA present exclusively at pH 6 to a B‐form present exclusively at pH 9. The variation in binding could not be explained by changes in the balance between ionised and unionised drug (pK2=7.6). An increase in r (number of thiopental molecules bound per HSA molecule) was demonstrated when the temperature was lowered to 2°. Graphs showing the relation between drug concentrations and percentual binding all showed a very modest slope and it was concluded that a traditional binding model with calculation of the number of binding sites and association constants was of little use in the evaluation of our binding studies of thiopental. The binding between thiopental and albumin may be characterized best by the solubility of thiopental in hydrofobic areas in the albumin solutions.
The Inhibitory Effect of Some Chlorinated Hydrocarbon Pesticides on the ATP‐Dependent Ca2+ Binding of the Particulate Fraction of the Eggshell Gland Mucosa Cells
Authors: Lundholm C. E. , Mathson K.
Published: July 2010

Abstract: The pesticide p‐p'‐DDT and its persistent metabolite p‐p'‐DDE cause thinning of the eggshells in several species of birds. In earlier investigations on ducks this thinning was found to be associated with a reduction of the ATP‐dependent Ca2+ binding to a homogenate of the shell gland mucosal cells by DDE. The activity of a Ca2+‐Mg2+‐activated ATPase in the homogenate was also decreased on administration of DDE in vivo. We have therefore investigated the in vitro effects of some other chlorinated hydrocarbon pesticides of ecotoxicological interest on the ATP‐dependent Ca2+ binding and the Ca2+‐Mg2+‐activated ATPase activity in a homogenate of the eggshell gland mucosa of the hen and determined the molar concentrations that produced 50% inhibition (= IC50). Several of the investigated compounds, namely toxaphene, chlordane, p‐p'‐DDD, o‐p'‐DDE, p‐p'‐DDT, methoxychlor and PCB (Arochlor 1242), had a similar IC50 to inhibit the Ca2+ binding as p‐p'‐DDE. Lindane, p‐p'‐DDA and biphenyl had an IC50 3.3–4 times higher and that of 2.4 D was 13.5 times higher than that of p‐p'‐DDE. When the IC50 of some of the compounds (p‐p'‐DDE, PCB, toxaphene, Lindane) was determined that decreased the Ca2+‐Mg2+‐activated ATPase of the homogenate it was found to be only 18 to 29 per cent of that needed to inhibit the Ca2+ binding by the homogenate. It is therefore probable that some other effect than inhibition of this enzyme is also involved in the Ca2+‐binding process and affected by the compounds.
Tolerance and some Circulatory Effects of Intravenous and Oral Enprofylline in Healthy Volunteers
Authors: Lunell E. , Andersson K.‐E. , Persson C. G. A.
Published: July 2010

Abstract: Enprofylline (3‐propylxanthine), a novel bronchodilating xanthine derivative that seems to lack adenosine antagonistic potency was given intravenously to eight recumbent healthy male volunteers in the doses 0.5, 1 and 1.5 mg/kg body‐weight and to six of them also orally in the doses 2,4 and 6 mg/kg. Mean enprofylline plasma levels ranged between 1.6 and 4.4 mg/l (8.2–22.2 μmol/l) after intravenous, and between 1.9 and 5.5 mg/l (9.8–27.9 μmol/l) after oral adminstration. Enprofylline was rapidly and completely absorbed and had an elimination half‐life of approximately 2 hrs. About 90% of the dose given by either route was recovered as unchanged drug in the urine. A slight but significant increase in heart rate was seen at peak plasma levels after each of the highest intravenous and oral doses. At these dose levels the heart rate response to orthostatic tests was significantly increased by enprofylline. Adverse reactions were mild and short‐lasting and occurred most frequently after the two highest intravenous and oral doses. Headache and nausea were noted in 5 of the 24 intravenous experiments and in 9 of the 17 times that enprofylline was given orally. In conclusion, the circulatory effects of enprofylline were small and the adverse reactions mild. Further clinical studies with enprofylline seem warranted.
Comparative Ototoxicity of Dibekacin and Netilmicin in Guinea Pigs
Authors: Parravicini L. , Forlani A. , Marzanatti M. , Arpini A.
Published: July 2010

Abstract:The cochleo‐ and vestibulotoxicity of dibekacin and netilmicin were compared in a guinea pig model. Both aminoglycosides were administered subcutaneously for 21 days at the dose level of 150 mg/kg/day. Control animals were injected with saline. Dibekacin‐treated animals showed a significant (P<0.05) increase in the thresholds of the Preyer pinna reflex and the VIIIth nerve compound action potential in response to sound click stimulation. Moreover, a deterioration of the electrophysiologic auditory response and an almost complete suppression of the post‐rotatory nystagmus were detected. In contrast, netilmicin did not induce any significant change in auditory and vestibular functions as compared to the control group. Our results demonstrated that netilmicin was devoid of ototoxicity in the guinea pig, while dibekacin provoked mild cochlear and severe vestibulotoxicity.
Utilization of Adenosine Triphosphate in Rat Mast Cells during and after Secretion of Histamine in Response to Compound 48/80
Authors: Johansen Torben
Published: July 2010

Abstract:The adenosine triphosphate (ATP) content of rat mast cells and their lactate production were measured during and after secretion of histamine induced by compound 48/80. Antimycin A and oligomycin were used to block oxidative ATP synthesis, and 2‐deoxyglucose (2‐DG) was used to block glycolytic ATP synthesis. Histamine secretion was completed after 10 sec. exposure of the cells to compound 48/80. During that time period there was an increased ATP‐utilization of 0.15 pmol/103cells. After completion of the secretory process there seemed to be an enhanced utilization of ATP of 0.40 pmol/103cells/min., which may be associated with recovery of the cells.
Placental Transfer of Diethylhexyl Phthalate in the Guinea‐pig Placenta Perfusedin Situ
Authors: Kihlström Ingemar
Published: July 2010

Abstract:Placental transport of diethylhexyl phthalate (DEHP) in guinea‐pigs has been studied with a placental perfusion technique. This transfer was shown to be independent of perfusion flow rate within 1.5–2.3 ml/min. when heparinized blood was used as perfusion media. When dextran solution (Macrodex®) or dextran solution with the addition of Intralipid®was used as perfusion medium there was no transport of DEHP from the maternal to the foetal compartment. The placental transport of DEHP was shown to be dependent on the albumin concentration in the perfusion media, up to an albumin concentration of 54 mg/ml. With γ‐globulin solution as perfusion medium there was no placental transfer of DEHP.