bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Anaesthetic and Kinetic Properties of Thiobutabarbital, Butabarbital and Hexobarbital after Intravenous Threshold Doses in the Male Rat
Authors: Koskela Timo , Wahlström Göran
Published: March 2009

Abstract:Due to the exceptionally long duration of action of thiobutabarbital the anaesthetic properties of this barbiturate was reinvestigated with an intravenous threshold technique using butabarbital and hexobarbital as references. Adult male rats were used. The criterion of anaesthesia was a burst suppression in the EEG of 1 sec. or more (the “silent second” = SS). The dose which induced the criterion was used as a threshold. The barbiturates were infused with different rates to obtain dose rate curves. After induction of the threshold criterion the animals were either killed and different tissue concentrations were analyzed with a HPLC method or allowed to survive and duration of SS and duration of loss of righting reflex were recorded. With hexobarbital, duration of SS and of loss of righting reflex increased significantly with increasing dose rate. With increasing rates of thiobutabarbital and butabarbital there was in both cases a stepwise increase in duration of SS. At sacrifice, after induction of SS with slow rates brain concentrations of both thiobutabarbital and butabarbital were lower than values recorded after higher rates. The change between the two concentrations was abrupt and occured at a rate of 20 mg/kg/min. with thiobutabarbital and at the rate of 1.25 mg/kg/min. with butabarbital. This phenomenon was the reverse of acute tolerance which was recorded with hexobarbital and can thus be denoted acute supersensitivity. A kinetic analysis of serum, muscle and fat indicated considerable differences between the barbiturates. As indicated by mortality figures the induction of acute supersensitivity could be potentially dangerous.
Efficiency of Arsenic Clearance from Human Bloodin Vitroand from Dogsin Vivoby Extracorporeal Complexing Haemodialysis
Authors: Sheabar Fayad Z. , Yannai S. , Taitelman U.
Published: March 2009

Abstract:In vitrodialysis using human blood andin vivoextracorporeal haemodialysis trials with dogs, in the presence and absence of various chelating agents, showed that haemodialysis alone facilitated efficient removal of the metal, even in the absence of any of the chelating agents.In vitrohaemodialysis for 5 hr without chelating agents caused the removal of 85% of the arsenic (As) added to the blood 1 hr before the beginning of the treatment. Ten–33% of the single dose given to the dogs, were removed into the dialysate during the first treatment and 8–15% during the second. The amounts of As excreted in the urine of dogs given 0.25 mg As/kg b.wt./day for 6 days were 6.8–7.4 mg As/24 hr, while the same amounts of the metal were removed into the dialysate during haemodialysis for 5 hr. This demonstrates the advantage of employing haemodialysis over the conventional treatment for the enhanced removal of As from the body.
Dual Effects of Nicotine on Neuroleptic‐Induced Changes of Striatal Dopamine Metabolism in Mice
Authors: Haikala Heimo
Published: March 2009

Abstract:The effect of nicotine on the neuroleptic‐induced changes in striatal dopamine (DA) metabolism of mice was studied. To investigate the mechanism of action of nicotine, its interactions with apomorphine (APO) and γ‐hydroxybutyric acid (GHBA) were also investigated. Mice were given nicotine, (0.3–3 mg/kg subcutaneously) repeatedly (4 times) at 30 min. intervals. Haloperidol (HAL), (±)‐sulpiride (SUL), APO or GHBA were administered after the second nicotine dose. Hexamethonium was given to prevent the effects of nicotine on autonomic ganglia. The striatal contents of DA and of its metabolites homovanillic acid (HVA), 3,4‐dihydroxyphenylacetic acid (DOPAC) and 3‐methoxytyramine (3‐MT) were measured. The drug‐induced hypothermia in mice was controlled by increasing ambient temperature. At ambient temperature of 32–34° nicotine and HAL increased the striatal DOPAC and HVA contents additively, whereas APO counteracted the effects of nicotine at this ambient temperature. At 20–22° nicotine decreased the 3‐MT content which indicates reduced release of DA. In hypothermic mice nicotine inhibited better the HAL‐ and SUL‐induced increases of HVA content than those of DOPAC content suggesting that the neuroleptic‐induced increases in DOPAC and HVA contents are mediated partly by different mechanisms. In APO‐treated mice both the GHBA‐ and nicotine‐induced decreases of 3‐MT content fell further. GHBA did not alter the nicotine‐induced decrease of 3‐MT content and so this effect of nicotine may be mediated indirectly via GABAergic neurones. Unlike GHBA and APO nicotine decreased 3‐MT content only in hypothermic mice. Thus the mechanism of action of nicotine differs from that of GHBA and APO and could be a depolarization block perhaps in the striatal cholinergic interneurones.
Characterization of the Antinociception Induced by Intrathecally Administered Carbachol
Authors: Gillberg Per‐Göran , Jr. Torsten Gordh , Hartvig Per , Jansson Inger , Pettersson Jan , Post Claes
Published: March 2009

Abstract:The antinociceptive effect of intrathecally administered carbachol at the L1/L2 level in the rat was evaluated using the tail immersion test. A dose dependent increase in the nociceptive reaction times was evident following intrathecal carbachol in the dose range of 2.5–15 μg. At doses of 20 μg and above, although still effective in the test, motor impairment was pronounced. The antinociception was antagonized with atropine, and with either pirenzepine (PZ) or AFDX 116, which are selective M1 and M2 muscarinic receptor blocking drugs, respectively. Spinal cholinergic pain modulation was also studied in rats pretreated with DSP4 (N‐2‐chloroethyl‐N‐ethyl‐2‐bromobenzylamine), which causes a selective depletion of the noradrenergic nerve fibres in the CNS. The increased latency times after spinal carbachol were attenuated in animals depleted of spinal noradrenaline by DSP4. In conclusion, spinal analgesia by carbachol in the rat may therefore be mediated through both M1 and M2 muscarinic receptor stimulation in the spinal cord. It is also concluded that this spinal cholinergic pain modulation is interacting with spinal noradrenergic nerve terminals, but that the mechanism of the interaction remains to be established.
Central Sympathoinhibitory Effect of Ketanserin in the Spontaneously Hypertensive Rat
Authors: Gradin Kathryn , Pettersson Anders , Hedner Thomas , Persson Bengt
Published: March 2009

Abstract:The sympathoinhibitory effects of ketanserin were investigated in the spontaneously hypertensive rat. In conscious rats ketanserin (0.1–10.0 mg/kg intravenously caused dose‐related reductions in blood pressure and heart rate (carotid artery). The heart rate reduction was prevented by chemical sympathectomy (reserpine) and in anaesthetized rats the heart rate reduction was correlated to a reduction in the directly recorded preganglionic sympathetic activity in the left renal nerve. Ketanserin had no presynaptic effects on the sympathetic nerve terminals as evidenced by the lack of effect on the tachycardia induced by electrical stimulation of the sympathetic outflow in pithed rats. In rats, catecholamine‐depleted by reserpine, the heart rate reduction was prevented, and in atropine‐pretreated animals there was a partial blockade of the bradycardic effect. We conclude that the lack of reflexogenic tachycardia in response to the hypotension induced by ketanserin treatment is partly due to a preganglionic inhibition of sympathetic nerve activity.
Binding of Prazosin to α1‐Acid Glycoprotein and Albumin: Effect of Protein Purity and Concentrations
Authors: Sager Georg , Jæger Ragnhild , Little Clive
Published: March 2009

Abstract:Prazosin is extensively bound in human serum/plasma. In the present study a bound fraction of 93–95% was observed at 37° for therapeutic drug concentrations. Both α1‐acid glycoprotein (AAG) and albumin (HSA) are established as transport proteins for prazosin, but their individual contribution to the extent and variability of protein binding in serum/plasma is unclear. The present study showed that AAG possesses one binding site per molecule with high affinity (Kd≈0.8 μM) for prazosin. HSA, essentially globulin‐free, bound prazosin with lower affinity (Kd≈30 μM) with an average of 0.3 binding sites per molecule. However, less purified HSA, containing globulins, exhibited apparently higher affinity (Kd≈8 μM), but lower binding capacity (0.07 sites per molecule) for prazosin. In mixtures of highly purified proteins, the concentrations of AAG, and not HSA, determined the extent and variability of prazosin binding.
Biodistribution and Scintigraphy of 11C‐Toremifene in Rats Bearing DMBA‐Induced Mammary Carcinoma
Authors: Kangas Lauri , Haaparanta Merja , Paul Robert , Roeda Dirk , Sipilä Hannu
Published: March 2009

Abstract: A new antioestrogenic antitumour compound toremifene was labeled with 11C or 3H. The tissue distribution and tumour uptake of the compounds in DMBA induced breast tumour bearing rats was investigated. 11C‐toremifene was localized by gamma camera scintigraphy and tissue counting. 3H‐Toremifene was determined by liquid scintillation counting after oxidizing the tissue samples. Toremifene was distributed to several tissues due to the lipophilicity and was not taken up specifically by the tumours to any great extent. However, the radioactivity of the tumours increased as a function of time although it declined e.g. in the liver. The accumulation to the tumour was a slow process and cannot be followed up reliably by such short half‐life radionuclides as 11C. The tumour uptake properties of toremifene resemble those of tamoxifen and several other oestrogen receptor binding compounds. These substances have limited use in diagnosing and imaging oestrogen receptor rich breast tumours in man.
Rhythmic Jaw Movements Induced by Ethanol in Rats
Authors: Andersson Ulf , Lewander Tommy , Gunne Lars M.
Published: March 2009

Abstract: Intraperitoneal administration of an anaesthetic dose of ethanol, 3.0 mg/kg, produced rapid rhythmic jaw movements (RJM) in rats. The peak effect (90 RJM/min.) occurred after 5 min., and all movements ceased after about 15 min. Clozapine, (4.4 mg/kg intraperitoneally) completely abolished this RJM phenomenon, whereas halopridol (0.5 mg/kg intraperitoneally), apomorphine (1.0 mg/kg subcutaneously) and atropine (10 mg/kg intraperitoneally) reduced it. It is suggested that the postulated brain stem masticatory pattern generator is activated or released from inhibition during induction of ethanol anaesthesia. Apparently this masticatory movement pacemaker is amenable to pharmacological manipulation, as shown by the present experiments.
Trimipramine and Other Antipsychotics Inhibit Campylobacter Pylori in Vitro
Authors: Kristiansen Jette E. , Justesen Tage , Hvidberg Eigill F. , Andersen Leif P.
Published: March 2009

Abstract: A series of conventional anti‐ulcer drugs, tricyclic antidepressants and neuroleptics (and some CNS non‐active isomers) were tested in vitro for possible inhibition of Campylobacter pylori. These bacteria are claimed to play an etiological role in peptic ulcer disease, at least in gastritis B. While cimetidine, famotidine, ranitidine and pirenzepine were inactive, all the antipsychotic agents and their isomeric derivatives were active to various degrees with IC50 of 26–59 μM. Of special interest is trimipramine (Surmontil®) that has been demonstrated to be effective against duodenal ulcers in some trials. The activity of the non‐neuroleptic stereo‐isomers of clopenthixol and chlorprothixene may lead to investigation in patients with peptic ulcer disease of this kind of agents. However, a firm connection between the antimicrobial activity of these compounds, their possible anti‐ulcer effect and the etiological role of Campylobacter pylori in peptic ulcer disease must first be established.
Neurochemical Studies on Quinolone Antibiotics: Effects on Glutamate, GABA and Adenosine Systems in Mammalian CNS
Authors: Dodd Peter R. , Davies Les P. , Watson Wendy E. J. , Nielsen Birgitta , Dyer Jennifer A. , Wong Lisa S. , Johnston Graham A. R.
Published: March 2009

Abstract:Quinolone antibiotics, which can be proconvulsant in susceptible patients, were found to inhibit the specific binding of the adenosine receptor ligands L‐3H‐N6‐phenylisopropyladenosine (L‐3H‐PIA) and3H‐N‐ethylcarboxamidoadenosine (3H‐NECA) to rat brain synaptic membranes. The inhibitions were concentration dependent, and for both ligands the order of potency was rosoxacin > nalidixic acid > oxolinic acid ≥ ciprofloxacin > norfloxacin > enoxacin: IC20values (concentrations causing a 20% inhibition of specific binding) ranged from 30–35 μM to 1–3 mM. Hill coefficients were approximately 0.5, suggesting that the compounds are probably antagonists at these sites. Most of the compounds did not alter3H‐diazepam binding directly, although rosoxacin showed relatively strong, and enoxacin weak, concentration‐dependent inhibition. At 50 μM the compounds enhanced the maximal γ‐aminobutyric acid (GABA) activation of3H‐diazepam binding to varying degrees, without altering the EC50 of activation, whereas at 200 μM they tended to reduce GABA activation. Most noteworthy was the large increase in GABA‐stimulated3H‐diazepam binding caused by 50 μM nalidixic acid. The compounds did not alter the Ca2+/Cl−‐dependent binding of3H‐glutamate, nor of the binding of the glutamate site‐selective ligands3H‐kainate and α‐3H‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (3H‐AMPA); the uptake of the non‐metabolized glutamate analogue D‐3H‐aspartate by cortical homogenates was also unaffected. The CNS side effects of these antibiotics may result, in part, from interaction with sites which mediate the inhibitory neurotransmission of adenosine and, possibly, GABA.
Disposition Kinetics of Disopyramide in Human Healthy Volunteers Described by an Open Three Compartment Model
Authors: Bonde Jan , Jensen Niels Melchior , Pedersen Lars E. , Angelo Helle R. , Rasmussen Seren N. , Trap‐Jensen Jens , Kampmann Jens P.
Published: March 2009

Abstract:Disposition kinetics of disopyramide was examined in an open randomised cross‐over study in 8 healthy volunteers. Disopyramide was randomly administered as a single bolus injection (150 mg) over a period of 5 min. and as an infusion (28.2) mg/h to steady state. Disposition kinetics of disopyramide were most precisely described by an open three compartment model according to Akaike's information criteria. Significant positive correlations (0.909+/‐0.04, P<0.05 (injection study); 0.787+/‐0.11, P<0.05 (infusion study)) were observed between total serum concentrations of disopyramide and renal clearance while no significant correlation could be demonstrated between free serum concentrations and renal clearance. This implies a constant value of unbound renal clearance. The results are consistent with non linear kinetics (mainly caused by the variable free fraction of the drug), when based on total serum concentrations. The disposition of unbound disopyramide, however seems to be linear (i.e. the kinetic parameters are independent of dose) in the bolus injection study. Total elimination clearance (free and total), volume of distribution and elimination half‐life were significantly higher in the steady state experiment than in the bolus injection study.
Mercuric Chloride Activates Latent, Anion‐Dependent Cation Transport Systems in the Plasma Membrane of Ehrlich Ascites Tumour Cells
Authors: Kramheft Birte , Lambert Ian H. , Pedersen Rudi
Published: March 2009

Abstract: Electronic cell sizing of Ehrlich ascites tumour cells is presented as a biological test system for assessment of membrane associated effects of toxic compounds. Ehrlich ascites tumour cells readjust their cell volume after osmotic swelling in hypotonic media. This regulatory process (Regulatory Volume Decrease, RVD) involves a net loss of KCl from the cells. Addition of HgCl2(1 μM) results in a Cl−‐dependent acceleration of RVD in hypotonic medium. Cells in isotonic Cl−‐containing medium shrink upon addition of HgCl2 due to a Cl−‐dependent net loss of K+. In addition, a Cl−‐dependent net uptake of Na+ was also seen in the presence of HgCl2. It is concluded that HgCl2 activates a latent K+, Cl− cotransport as well as Na+, Cl− cotransport in Ehrlich cells.
Chronotropic Responses in Rats Implanted with an Acrylic Orthopaedic Cement
Authors: de Hurtado Maria C. Camilion , Gende Oscar A.
Published: March 2009

Abstract:The chronotropic and inotropic responses were studied in isolated atria and papillary muscles from rats who had carried a pellet of methyl methacrylate polymer for one week and from sham operated control rats. Right atria isolated from implanted rats were hyporesponsive to the positive chronotropic effects of isoproterenol and glucagon but not to dibutyryl cAMP or to CaC12. Inotropic response of left atria and papillary muscles to isoproterenol was unaltered. No change in the β‐receptor density or affinity was associated with these phenomena. The results indicate that methyl methacrylate exposure leads to a disruption in the signal transduction of chronotropic stimuli mediated by the adenylate cyclase system. The alteration occurs at some point after receptor binding and before cAMP action.
Extracorporeal Complexation Haemodialysis for the Treatment of Cadmium Poisoning. II.In VivoMobilization and Removal
Authors: Sheabar Fayad Z. , Yannal S. , Taitelman U.
Published: March 2009

Abstract:The purpose of this study was to apply our earlierin vitrofindings for extracorporeal complexation combined with haemodialysis toin vivoconditions, for the enhancement of cadmium (Cd) removal from dogs. The results showed that ethylenediaminetetraacetic acid (EDTA), glutathione (GSH) and combination of the two agents (EDTA+GSH) facilitated efficient elimination of cadmium. GSH, EDTA and EDTA+GSH treatments brought about the clearance of 2.2., 14.7 and 18.2 μg Cd/kg body weight/hr haemodialysis, respectively. Treatment with EDTA+GSH brought about the most rapid extravascular redistribution of the metal.
Chemical Structure and Toxicity of Diuretics in Isolated Hepatocytes
Authors: Higaki Junko , Harada Hiroshi , Tonda Kanya , Hirata Masaharu
Published: March 2009

Abstract:The effects of several diuretics, including tienilic acid and indacrinone, on isolated rat heaptocytes were examined. Addition of tienilic acid and indacrinone at 1 mM to a suspension of freshly isolated cells caused dose‐dependent loss of cell viability as judged by the LDH‐latency test. Survey of 19 structurally related compounds revealed that the extent of cell injury and chemical structure were correlated, and an intense adverse effect was attributed to the 2‐thienylcarbonyl moiety. Several other factors influencing cell viability are also disclosed. Further study revealed that tienilic acid and indacrinone were toxic to the primary culure of hepatocytes at a lower dose than that to freshly isolated hepatocytes. Thus, an isolated hepatocyte system can be used to select compounds displaying low hepatotoxicity, as for example is needed when screening diuretics.
Effects of Alaproclate, Potassium Channel Blockers, and Lidocaine on the Release of 3H‐Acetylcholine from the Guinea‐Pig Ileum Myenteric Plexus
Authors: Alberts Pēteris , Ögren Sven Ove
Published: March 2009

Abstract: The guinea‐pig ileum longitudinal muscle‐myenteric plexus preparation, preincubated with 3H‐choline or 3H‐noradrenaline, was mounted in an organ bath and superfused with Tyrode's solution. Alaproclate (2‐(4‐chlorophenyl)‐1,1‐dimethyl 2‐aminopropanoate) (0.01‐0.5 mmol/l) reduced (IC50 = 0.1 mmol/l) and at about 0.5 mmol/l completely blocked the electrically evoked 3H‐acetylcholine secretion. The depressing effect of alaproclate (0.2 mmol/l) was not counteracted by atropine (0.01, 1 or 10 μmol/l), hexamethonium (0.1 mmol/l), phentolamine (1 μmol/l) yohimbine (1 μmol/l), haloperidol (1 μmol/l), 8‐phenyltheophylline (10 μmol/l), cyproheptadine (1 μmol/l), metitepine (1 μmol/l), bicuculline (10 μmol/l), picrotoxinin (0.1 mmol/l), forskolin (25 μmol/l), 3‐isobutyl‐1‐methylxanthine (5 mmol/l), nifedipine (1 μmol/l), verapamil (1 μmol/l), dilitiazem (1 μmol/l), high calcium (6 mmol/l), high potassium (10 or 15 mmol/l), tetraethylammonium (2 mmol/l), 4‐aminopyridine (0.5 mmol/l), apamin (0.5 μmol/l), barium (0.5 mmol/l) or quinine (0.1 mmol/l). Among the potassium channel blockers tested only quinine (at 0.5 or 1 mmol/l), in the same manner as lidocaine, reduced the evoked secretion of 3H‐acetylcholine. The results are in agreement with the hypothesis that the effect of alaproclate on the evoked 3H‐acetylcholine secretion is not mediated by a neurotransmitter receptor, or a potassium channel sensitive to tetraethylammonium, 4‐aminopyridine, apamin, barium or quinine, but is due to a local anaesthetic effect. In contrast to the evoked secretion, the spontaneous release of 3H‐acetylcholine was enhanced by high concentrations of alaproclate (0.4‐1 mmol/l). The mechanism underlying the effect of alaproclate on the spontaneous release remains to be established. Alaproclate (0.25 or 0.5 mmol/l) also enhanced the spontaneous release and reduced the electrically evoked 3H‐noradrenaline secretion.
Glucuronidation of Amitriptyline in Manin Vivo
Authors: Dahl‐Puustinen Marja‐Liisa , Åberg‐Wistedt Anna , Bertilsson Leif
Published: March 2009

Abstract:The urinary excretion of amitriptyline (AT) as N‐glucuronide was studied in healthy volunteers after single oral doses of AT and in patients on continuous treatment with AT. In the volunteers, 8±3% of a 25 mg dose of AT was recovered in urine as glucuronide during 108 hr. No difference between slow and rapid debrisoquine hydroxylators with respect to the excretion of AT glucuronide was seen. 0.08 to 1.68% of the given AT dose was recovered in urine in unchanged form. The excretion of unchanged AT correlated with the debrisoquine metabolic ratio (rg=0.61; p<0.01). In 5 patients on continuous treatment with AT (125‐150 mg/day), 8 ± 5% of the daily dose was recovered in 24‐hr urine as AT glucuronide. The present study shows that direct glucuronidation is a minor metabolic pathway of AT in manin vivoboth after single low doses and during continuous treatment with therapeutic doses.
Comparative Study of Demethoxydaunorubicin with Other Anthracyclines on Generation of Oxygen Radicals and Clonogenic Survival of Fibroblasts
Authors: Grankvist K. , Stendahl U. , Henriksson R.
Published: March 2009

Abstract:Demethoxydaunorubicin was compared to other anthracyclines (daunorubicin, doxorubicin, epirubicin) on its ability to generate free oxygen radicals when mixed with Fe2+in solution and on its ability to reduce clonogenic survival of fibroblasts in culture. Oxygen electrode measurements of free radical generation showed that most of the consumed oxygen entered the monovalet oxygen reduction pathway. Catalase and superoxide dismutase additions inhibited oxygen consumption for all tested anthracyclines and diethylenetriaminepentacetic acid (DTPA) was also inhibitory except for demethoxydaunorubicin. Demethoxydaunorubicin and epirubicin dose‐dependently reduced the clonogenic survival of fibroblasts. Addition of catalase or superoxide dismutase was without effect, whereas metal chelators DTPA, desferrioxamine and EDTA all protected against epirubicin‐induced toxicity. Of the chelators, only desferrioxamine protected against demethoxydaunorubicin toxicity. Testsin vivowill further elucidate whether demethoxydaunorubicin also differs from the other anthracyclines in therapeutic effect as well as in side effects such as myocardial toxicity.
Neutral Red Changes Arginine‐Induced Glucagon and Insulin Response in the Rat
Authors: Poulsen H. E. , Hansen B. A. , Egeberg J. C.
Published: March 2009

Abstract: Rats were treated with neutral red (amino‐dimethyl‐amino‐toluaminozine hydrochloride, NR) twice weekly, 5 ml/kg b. wt.−1 of a 2% solution, for five weeks in order to investigate damage to pancreatic A‐cells. After 1‐5 weeks of treatment plasma glucagon levels were increased to about two times control values. Plasma glucose was maintained at control values. Following arginine stimulation, 8 μg intravenously 100 g b. wt.−1 min.−1 for 30 min., plasma glucagon and insulin concentrations increased 10‐fold in normal rats. After NR treatment for 1 and 2 weeks the arginine induced glucagon response was reduced to a two‐fold increase, after 5 weeks NR treatment arginine again increased glucagon concentrations 10‐fold. There was no change in the 10‐fold increase of insulin concentrations from arginine infusion during the NR treatment. Immunohistochemical examination of pancreas demonstrated unchanged number and size of Langerhans' islets. The insulin immunoreactivity of the B‐cells appeared constant 0‐5 weeks during NR treatment, while glucagon immunoreactivity appeared to lower in the A‐cells from animals treated for one or two weeks with NR. After three to five weeks of NR treatment, pancreatic glucagon immunoreactivity appeared restored. We conclude that NR leads to a release of glucagon from pancreatic A‐cells, with subsequent hyperglucagonaemia, maintained during repeated administrations. Such repeated administrations lead to a transient ≫glucagon insufficiency≪ on top of the hyperglucagonaemia, consisting of restricted ability to further release of glucagon, presumably because of pancreatic A‐cell glucagon depletion.
Actions and Interactions of Psychotropic Drugs on Human Performance and Mood: Single Doses of ORG 3770, Amitriptyline, and Diazepam
Authors: Mattila Marja , Mattila Mauri J. , Vries Maria Vrijmoed‐de , Kuitunen Tapio
Published: March 2009

Abstract: Actions and interactions of two antidepressants and diazepam on human skilled performance and mood were studied in a randomized double‐blind cross‐over trial with single oral doses of 50 mg amitriptyline (AMI), 15 mg Org 3770 (ORG) and placebo, given alone and in combination with 15 mg diazepam (DZ) to 12 young healthy subjects at one‐week intervals. Objective tests (digit substitution, tapping, flicker fusion, Maddox wing, tracking, choice reactions, body sway, memory) and subjective assessments (visual analogue scale) were performed at baseline and 1.5, 3, 4.5 and 6 hours after drug administration. Side‐effects were reported, blood pressure and heart rate measured and blood samples taken after each testing run. Placebo was nearly inert on performance and mood. DZ impaired some objective skills and showed sedative effects in the subjective tests. AMI produced sedation and impaired coordination as well as cognitive performance (digit substitution), most clearly at 3 to 4.5 hr. ORG resembled AMI in impairing objective and subjective performance, however, not necessarily in the same tests. Their combined effects with DZ were additive in objective tests but less additive in subjective tests. The drug combinations, but not any single drug, impaired learning acquisition. Plasma concentrations of the drugs given alone were about as expected, without important interactions. We conclude that the combinations of benzodiazepines with the antidepressants used impair skilled performance but may not cause major hazards.
Degradation of [Mercaptopropionic acid1, D‐arginine8] ‐ vasopressin (dDAVP) in Pancreatic Juice and Intestinal Mucosa Homogenate
Authors: Lundin S. , Bengtsson H.‐I. , Folkesson H. G. , Weström B. R.
Published: March 2009

Abstract: The degradation of the vasopressin analogue dDAVP was studied by reversed phase high‐performance liquid chromatography (HPLC) after incubations in pancreatic juice and intestinal mucosa homogenates. dDAVP remained stable in pancreatic juice for a period of 60 min. while the parent hormone arginine vasopressin (AVP) was completely degraded within 5 min. In intestinal mucosa homogenates dDAVP was degraded with half‐lives of 9 min. (fast phase) and 161 min. (slow phase), about four times slower than AVP. By amino‐acid analysis it was confirmed that the metabolite [Mpa1, Des‐D‐Arg8‐Gly9 NH2]‐vasopressin was gradually produced. No other breakdown products were observed. These findings may be of value for the further development of more stable peptide analogues which may be effective upon oral administration.
Growth Hormone Administration by Means of an Injection Pen
Authors: Jørgensen J. O. L. , Møller J. , Jensen F. S. , Jørgensen J. T. , Christiansen J. S.
Published: March 2009

Abstract: We have evaluated the pharmacokinetics, reliability and patient tolerability of a newly developed injection pen for cartridged growth hormone (GH). The cartridge contains 25 IU GH in 2 ml solvents. The pen, which is basically a needle, syringe and vial in one piece, is operated by a turning movement and allows doses from 0.25‐4 IU. Nine GH deficient patients were hospitalized twice for overnight bloodsampling following subcutaneous injections (at 8 p.m.) of GH: i.e. when using traditional syringe and vial and after 6 weeks of use of the pen. Serum GH antibodies were measured immediately prior to, and 3 and 6 months following pen treatment. GH containers were collected regularly from the patients for chemical analysis. A questionnaire was completed during and at the end of the study. The absorption rate and bioavailability of GH tended to be higher with syringe and vial (2 P = 0.07) but there were no differences in the profiles of IGF‐I, insulin, glucagon or pertinent metabolic parameters following the 2 injection modes. No GH antibodies occurred during 6 months of pen treatment. The content of polymeric GH was lower in the cartridges (2 P<0.001). Seven of the patients reported less injection pain when using the injection pen, which they all strongly preferred and wished to continue using. We conclude that the GH injection pen is a reliable tool which seems to be more convenient for the patients.
Inhibitory Effects of Sulfasalazine and Related Compounds on Superoxide Production by Human Polymorphonuclear Leukocytes
Authors: Carlin Gunnar , Djursäter Rickard , Smedegård Göran
Published: March 2009

Abstract: The inhibitory effects of sulfasalazine, some sulfasalazine‐related compounds and indomethacin on superoxide production by human polymorphonuclear (PMN) leukocytes were studied. The inhibition of the chemotactic peptide (FMLP)‐induced superoxide production, which is membrane receptor‐mediated, was strongly dependent on the concentration both of the secretory stimulus and of the test compounds, indicating an interaction between the receptor and the test compound. Furthermore, a positive correlation was found between the lipophilicity of the compound and the degree of inhibition. However, when the receptor was by‐passed by direct activation of the receptor‐linked G protein by the use of fluoride ions as secretory stimuli, the test compounds still inhibited superoxide production. On the other hand, superoxide production by cells stimulated with phorbol ester was not inhibited by the test compounds. Furthermore, the production of phosphatidic acid was decreased in the presence of sulfasalazine, indicating impaired phosphoinositide metabolism. The inhibition of this metabolism was not due to increased intracellular concentrations of cyclic AMP, although sulfasalazine did inhibit cyclic nucleotide phosphodiesterase. We conclude that sulfasalazine attenuates superoxide production by PMN leukocytes at a post‐receptor site of action at a step before the activation of protein kinase C, possibly by interfering with the phosphoinositide metabolism but independent of cyclic AMP.
Pharmacokinetics of Postoperative Intravenous Indomethacin in Children
Authors: Olkkola Klaus T. , Maunuksela Eeva‐Liisa , Korpela Reijo
Published: March 2009

Abstract:The disposition of indomethacin was studied in children aged one to four years. Indomethacin 0.35 mg/kg was administered as an intravenous infusion during 15 min. Venous blood samples were collected until 24 hr after infusion. Serum indomethacin was determined with gas chromatography. Using a non‐linear regression analysis, the individual data were fitted by a two‐compartment open mammillary model with central elimination. Calculated pharmacokinetic parameters were (mean±SD): α half‐life 25.2±11.3 min.; β half‐life 366±295 min.; steady‐state volume of distribution 0.74±0.75 l/kg; volume during elimination phase 1.53±1.27 l/kg; total body clearance 3.2±1.7 ml/min./kg. Accordingly, with respect to the pharmacokinetics of indomethacin, children seem to mature early, not later than at the age of one year.
Influence of Magnesium and Extracellular Calcium Reduction on Ouabain‐treated Sinoatrial Node Cells in Rabbit Heart
Authors: Miyamae Shun‐ichi
Published: March 2009

Abstract:The influence of the extracellular Mg on the slow regenerative potential induced by Ca removal was investigated by using rabbit SA node tissue treated with ouabain. When the SA node tissue was superfused with ouabain (10−5M), the preparation became quiescent. Further superfusion with Mg‐free and Ca‐free solution produced a small regenerative potential reaching 21±3 mV (n = 5). Superfusion with high Mg, Ca‐free solution containing 5.19 mM Mg inhibited the regenerative potential. Superfusion of the ouabain‐treated SA node tissue with Ca‐free (2 mM EGTA) solution containing normal Mg or Mg‐free, Ca‐free (2 mM EGTA) solution produced a slow regenerative potential reaching 45±2 mV (n = 5) or 44±3 mV (n = 5). Increasing the external Mg to 3.6 mM or 6.18 mM in the Ca‐free, EGTA solution caused a significant inhibition of slow regenerative potential. The addition of diltiazem (0.08 mM) blocked both normal action potential and slow regenerative potential induced by superfusion with Mg‐free, Ca‐free (2 mM EGTA) solution. These results suggest that Mg inhibits the development of the slow regenerative potential resulting from inward currents through the Ca channel.
The Interaction between Cyclosporin A and Erythromycin Studied by Means of an Isolated Perfused Rat Liver Model
Authors: Fabre Isabelle , Richard Bruno , Combalbert Jean , Fabre Gérard , Cano Jean‐Paul
Published: March 2009

Abstract:The isolated perfused rat liver model was successfully used to study the clinical interaction observed between cyclosporin A (CsA) and erythromycin (ER). Three experimental studies were performed. In a “Control group”, isolated rat livers were perfused with 60 μg3H‐CsA for 20 min. In an “ER group”, isolated rat livers were simultaneously perfused with 60 μg3H‐CsA and 6.0 mg ER. In an “ER ind group”, rats were treated with ER for 5 days, conditions under which the P450IIIA gene subfamily, principally involved in CsA metabolism, was specifically induced, and isolated rat livers were perfused with 60 μg3H‐CsA for 20 min. Biological parameters of the liver model such as biliary flow, oxygen consumption and pH were similar whatever group of animals. Biliary excretion of total radiolabel (sum of CsA and all the metabolites = CsAT) was similar in both the “Control” and “ER” groups but significantly higher in the “ER ind” group with respectively 8.05±0.81%, 8.45±1.93% and 14.54±2.12% of the entire amount of infused drug excreted during 2 hr. Using a high performance liquid chromatography method which specifically resolves unchanged CsA from its metabolites, we demonstrated that, although similar amounts of radiolabelled material were excreted in both the “Control” and “ER” groups, the CsA/metabolite ratio was lower than 1.0 in the “Control group” and higher than 1.0 in the “ER group”, suggesting an inhibition of CsA metabolism by ER in the “ER group”. These data could explain the increase in CsA blood levels observed in the clinic following administration of high ER doses and the reversing effect when ER administration is stopped.
Pharmacokinetic Interpretation of Toxicity Tests in Rats Treated with Oestradiol Valerate in the Diet
Authors: Kuhnz Wilhelm , Putz Barbara
Published: March 2009

Abstract: Oestrogen concentrations (oestradiol = E2 and oestriol = E3) were determined in plasma and liver tissue of female rats before, during and after treatment with two different doses (1.2 and 12.0 mg/kg/d) of oestradiol valerate (E2‐val) given in the feed over 27 days. The oral bioavailability of E2 was determined in a pharmacokinetic study in which rats received a single intramuscular administration of E2‐val. The aim of the present investigation was to support the evaluation of the results of a previous 90 weeks chronic toxicity and tumorigenicity study in rats where the same dosages were administered. The bioavailability was approximately 0.5%; the systemic body burden of exogenous E2 was 1.6 fold, the endogenous E2 burden at the low, and 9 fold at the high dose. Despite these low values, distinct systemic effects were noted. At 1.2 mg/kg/d a marked decrease in food consumption and body weight gain occurred in the 27 day study as well as in the chronic study. In addition, in the latter study mortality increased from the low dose onwards and was complete at the high dose after 72 weeks. The incidence of pituitary adenoma increased. The results indicate that theoretically rats are far more sensitive towards exogenous oestradiol treatment than humans.
The Enhanced Responsiveness of Hypophyseal DA Receptors in Female Rats Induced by Repeated Reserpine Treatment is Not Due to Decreased Oestrogen Secretion
Authors: Carlsson M. , Eriksson E.
Published: March 2009

Abstract: In a previous study we have demonstrated that repeated reserpine treatment markedly enhances the intrinsic activity of the partial dopamine (DA) agonist (‐)‐3‐PPP (preclamol) on pituitary DA receptors in female rats. This effect was attributed to the DA‐depleting action of reserpine. However, since reserpine may also decrease oestrogen secretion, and since this hormone is known to affect dopaminergic transmission, experiments with ovariectomized, oestrogen‐replaced female rats were undertaken. Ovariectomized rats were administered a depot preparation of oestradiol valerate in a dose that, according to literature data, yields physiological or slightly supraphysiological plasma concentrations of oestrogen. In spite of this treatment, repeated reserpine administration was found to substantially increase the intrinsic activity of (‐)‐3‐PPP, as well as that of the partial DA agonist TDHL (terguride), on female pituitary DA receptors. It was concluded that repeated reserpine treatment increases pituitary DA receptor responsiveness in female rats by depleting DA, rather than by decreasing oestrogen secretion.
Covalent Binding of Four DDD Isomers in the Mouse Lung: Lack of Structure Specificity
Authors: Lund Bert‐Ove , Ghantous Hanan , Bergman Åke , Brandt Ingvar
Published: March 2009

Abstract:Previous studies have shown that o,p'‐DDD is activated and covalently bound in the mouse lung. In order to examine the structure dependency of the selective lung binding, the14C‐labelled DDD isomers p,p'‐DDD, m,p'‐DDD and o,m'‐DDD were injected intravenously into female C57B1 mice and covalent binding was measured. Autoradiography of solvent‐extracted tape‐sections showed that all isomers were selectively and covalently bound in the lung alveolar region. As determined by exhaustive extraction of homogenized tissue, maximal binding was observed 4 hr after injection, although the lung/liver concentration ratio increased for 12 days. Covalent protein binding was also observedin vitro, implying that the activation of DDD to a reactive metabolite takes place in the target organ. Since the aryl‐chlorine substitution pattern did not change the selective lung binding, bioactivation of DDD may take place at the ethane side‐chain.
Increased Methylation of Chloroform Extractable Products and CTP: Cholinephosphate Cytidylyltransferase in Brain Membrane Preparations from Triethyltin‐Intoxicated Rats
Authors: Mages Françoise , Macovschi Olguta , Prigent Annie‐France , Fonlupt Pierre
Published: March 2009

Abstract: Rats were chronically intoxicated with triethyltin in the drinking water (0.002%) for a period of 15 days. Starting with day 5 of the intoxication period a decrease in the body weight was observed and, in parallel, the development of a cerebral oedema could be followed by measuring white matter density. At the same time, an increase of phosphatidyle‐thanolamine‐N‐methyltransferase and cholinephosphate cytidylyltransferase activities was noted. This increase might be a compensatory mechanism for counteracting the membrane damages induced by triethyltin.
Effects of Intravenous Bumetanide Administration on Renal Haemodynamics and Proximal and Distal Tubular Sodium Reabsorption in Conscious Rats
Authors: Shalmi Michael , Petersen Jørgen S. , Christensen Sten
Published: March 2009

Abstract:The renal effects of 0.02‐62.5 mg/kg bumetanide given as intravenous bolus injections were studied in water diuretic conscious rats. Clearances of14C‐tetraethylammonium,3H‐inulin and lithium were used as markers for renal plasma flow (RPF), glomerular filtion rate (GFR) and proximal tubular output, respectively. Bumetanide caused biphasic, transient and dose‐independent changes in the renal haemodynamics without significant alterations of the filtration fraction. At dose‐levels above 0.02 mg/kg bumetanide increased urine flow, absolute and fractional Na excretion as well as the indices for fractional output of Na from the proximal tubules (CLi/CIn) and the distal nephron segments (CNa/CLi). The changes in CLi/CInbecame maximal at doses above 0.5 mg/kg, whereas CNa/CLiwas increased with the dose up to 12.5 mg/kg. Paradoxically, doses above 12.5 mg/kg were less natriuretic due to a decrease of CNa/CLi. It is concluded that in rats bumetanide is an effective although short‐acting diuretic when administered intravenously. When comparing peak responses bumetanide is equipotent to furosemide but has a lower maximal efficacy. Judged from the changes in fractional lithium excretion, the natriuretic effect of bumetanide is effected by inhibition of Na reabsorption in the proximal tubule in addition to the well‐known effect on the distal nephron segment.
Impaired β‐Adrenergic Mediated Cerebral Blood Flow Response in Streptozotocin Diabetic Rats
Authors: Lass Piotr , Knudsen Gitte Moos , Pedersen Erik Vinholdt , Barry David I.
Published: March 2009

Abstract:The influence of intracarotic infusion of isoproterenol on cerebral blood flow, on cerebrovascular CO2‐reactivity, and on cerebral glucose metabolism were investigated in streptozotocin diabetic rats. Resting cerebral blood flow in diabetic rats decreased by 26% from a control value of 90 ml/100 g·min. to 66 ml/100 g·min. Intracarotid isoproterenol infusion leads to a significant increase in cerebral blood flow in both groups. The increase in cerebral blood flow in control rats (70%), significantly exceeded that in the streptozotocin diabetic rats (33%). Cerebrovascular reactivity to carbon dioxide was preserved after isoproterenol infusion in both groups and there was no significant difference in the relative cerebral blood flow increase in the two groups. Cerebral glucose metabolism was also unaffected by the isoproterenol infusion. The results indicate that impaired β‐adrenergic mechanisms may play a role for alterations in cerebral blood flow that is seen in diabetes mellitus.
Carcinogenic Potential of Cooked Food Mutagens (IQ and MeIQ) in Wistar Rats after Short‐Term Exposure
Authors: Kristiansen Eva , Clemmensen Steen , Olsen Preben
Published: March 2009

Abstract: Two potent cooked food mutagens, 2‐amino‐3‐methylimidazo/4,5‐f/quinoline (IQ) and 2‐amino‐3,4‐dimethylimidazo/4,5‐f/quinoline (MeIQ), were examined in an initiation‐promotion assay in the male Wistar rat. Fourteen doses of 10 mg IQ or 10 mg MeIQ/kg b. wt. were given during initiation, followed by promotion with 500 p.p.m. phenobarbital sodium (PB) in the drinking water up to week 58. A small number of tumours of Zymbal's gland were seen in all groups treated with IQ or MeIQ, irrespective of PB‐treatment. Though the promotional regimen failed to produce the expected number of liver tumours, it did induce a significant amount of gamma‐glutamyltranspeptidase (GGT) activity. These results suggest that even short exposures to low doses of IQ or MeIQ produce persistent procarcinogenic lesions in the rat, and that secondary factors, e.g. promoters or high cell turnover, may over time develop these lesions into cancer.
Neurophysiological and Behavioural Effects of Combined Exposure to 2,5‐Hexanedione and Acetone or Ethanol in Rats
Authors: Ladefoged O. , Hass U. , Simonsen L.
Published: March 2009

Abstract: Rats were dosed with 2,5‐hexanedione (2,5‐HD), acetone, ethanol or combinations of these for 6 weeks. Nerve conduction velocity (NCV) was measured in the tails of the rats once a week from the third week of dosing. Behaviour was monitored during the whole experiment as performance on a rotarod, in 30 sec. sessions. 2,5‐HD alone showed a significant effect on NCV and rotarod performance after 3 weeks of dosing. Acetone, but not ethanol, together with 2,5‐HD had an additional significant effect on NCV and rotarod performance of the rats. This additional effect was seen from the 4th dosage week. The mechanism behind this effect is partly unknown.
Pharmacokinetics of Etretinate in Psoriatic Patients with Liver Fibrosis
Authors: Larsen Frederik Grønhøj , Nielsen‐Kudsk Folmer , Jakobsen Preben , Kragballe Knud
Published: March 2009

Abstract: A study of the pharmacokinetics of etretinate in 7 psoriatic patients with liver fibrosis or liver cirrhosis is reported. Maximum plasma concentrations occurred within 1.5‐4.0 hr. Absorption lag‐times ranged from 0.3‐2.5 hr, whereas the apparent absorption first order half‐times (t1/2ka) were within the range of 0.3‐1.2 hr. As judged from the AUC‐values corrected for dose and body weight a six‐fold interindividual variation existed with regard to the systemic availability of etretinate. Absorption and disposition rates of etretinate in subjects with hepatic fibrosis increasing to cirrhosis were not significantly altered compared with previous results in psoriatic patients with normal liver function.
Regional Distribution of the Opioid Receptor Agonist N‐(methyl‐11C)pethidine in the Brain of the Rhesus Monkey Studied with Positron Emission Tomography
Authors: Hartvig Per , Eckernäs Sven Åke , Lindberg Bo S. , Lundqvist Hans , Antoni Gunnar , Rimland Annika , Långström Bengt
Published: March 2009

The regional distribution and kinetics in the brain of Rhesus monkeys of N‐(methyl‐11C)‐pethidine have been studied by positron emission tomography, PET.11C‐Pethidine reached the brain with peak radioactivities appearing within 6‐10 min. after administration. Highest radioactivities were measured in areas corresponding to the thalamus, the striatal area and also the lowest transection of the temporal lobes, with an uptake of 2.7‐3.1 times the homogenous dilution of the radioactive dose. Low radioactivities were seen in the cerebellum and the occipital lobes. This distribution corresponds to the regional density of opioid receptors usingin vitrobinding techniques. The11C‐pethidine derived radioactivity left the brain with an initial half‐life of 40‐60 min., followed by an elimination which paralleled the plasma elimination of unlabelled pethidine. After pretreatment of the monkey with a small dose of naloxone, the radioactivities decreased about 40% in areas corresponding to the thalamus, striatum and lowest section of the temporal lobes, indicating competition for the same binding sites. By the use of a three‐compartment model, it was possible to get an estimate of11C‐pethidine receptor binding characteristics in the brain. The ratio of Kon/Koff, equal to Bmax./Kd, was 0.06‐0.1. This indicates that pethidine is bound with low affinity to the opioid receptors and is a poor ligand for studies of opioid receptor function with PET. Brain kinetics of11C‐pethidine is mainly determined by its blood kinetics.