bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of Dearomatised White Spirit in Brain, Blood, and Fat Tissue after Repeated Exposure of Rats
Authors: Löf Agneta , Lam Henrik Rye , Gullstrand Elisabeth , Øtergaard Grete , Ladefoged Ole
Published: March 2009

Abstract: Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg/l), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks'exposure. After 3 weeks of exposure the concentration of total white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n‐nonane, n‐decane, n‐undecane, and total white spirit in blood and brain were not affected by the duration of exposure. Two hours after the end of exposure the n‐decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n‐nonane, n‐undecane and total white spirit in blood and brain. In fat tissue the concentrations of n‐nonane, n‐decane, n‐undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady‐state concentrations is longer than 3 weeks. After the 3 weeks'exposure the fat tissue concentration of n‐nonane, n‐decane, n‐undecane, and total white spirit decreased very slowly compared with the rate of decrease in blood and brain suggesting that long‐lasting redistribution from fat to brain may occur. One week of exposure at 800 p.p.m. caused a statistically significant increase in whole brain dopamine concentration while the noradrenaline concentration was unaffected. Exposure at both exposure levels for 1 week caused a statistically significantly decreased concentration of 5‐hydroxytryptamine in whole brain. The reduction was related to the exposure concentration. These changes in neurotransmitter concentrations were normalised after 2 and 3 weeks'exposure. In conclusion, after 3 weeks of exposure the fat:brain:blood concentration coefficients for total white spirit were approximately 250:3:1, and redistribution from fat to brain is possible. As total white spirit behaved similarly to the n‐alkanes in blood, brain, and fat tissue, we suggest that the non‐n‐alkane white spirit components possess toxicokinetic properties similar to the n‐alkanes.
Effects of Propofol on Contractile Response and Electrophysiological Properties in Single Guinea‐Pig Ventricular Myocyte
Authors: Shigemura Toshiaki , Hatakeyama Noboru , Shibuya Nobuko , Yamazaki Mitsuaki , Masuda Akira , Chen Fu‐Shih , Momose Yasunori , Ito Yusuke
Published: March 2009

Abstract: Effects of propofol on contractile response, action potential, resting membrane potential and L‐type voltage‐dependent calcium channel current were examined in guinea‐pig single cardiac myocyte. Propofol (10−4 M) inhibited contractile response induced by electrical stimulation (83.6% of control, n=5), but did not change the resting membrane potential. On the other hand, propofol reduced the overshoot of action potential (10−4 M), and shortened the duration of action potential (10−5 and 10−4 M). Whole‐cell voltage clamp experiment showed inhibition of L‐type calcium channel current (ICa, 10−5 M: 90.8+1.39, 10−4 M: 83.4+1.53% of control, n=5). In addition, propofol showed use‐dependent block of ICa. It is concluded that negative inotropic effect of propofol is caused by suppression of action potential, and that inhibition of ICa plays a role in shortening of the duration of action potential.
Hydroxyl Radical Formation Following Methamphetamine Administration to Rats
Authors: Kita Taizo , Takahashi Masahiro , Kubo Kaoru , Wagner George C. , Nakashima Toshikatsu
Published: March 2009

Abstract:Administration of neurotoxic doses of methamphetamine (8 mg/kg, intraperitoneally x 4 times, at 2 hr intervals) caused a significant decrease in dopamine and 3,4‐dihydroxyphenylacetic acid and an increase in 3‐methoxytyramine levels in the striatum along with a decrease in serotonin and 5‐hydroxyindoleacetic acid levels in the striatum and hippocampus. In addition, the methamphetamine treatment caused an increase in rat rectal temperature. Intraventricular injection of salicylate 105 min. after the last injection of methamphetamine produced an increase in 2,3‐ and 2,5‐dihydroxybenzoic acid in the striatum and hippocampus. Moreover, the ratio of 2,3‐dihydroxybenzoic acid to salicylate was significantly increased in the striatum, but not in the hippocampus. These results indicate that the hydroxyl radical may play an important role in methamphetamine‐induced neurotoxicity in rat striatum and that its formation may be the result of methamphetamine‐induced release of dopamine.
Plasma and Brain Levels of Oxindole in Experimental Chronic Hepatic Encephalopathy: Effects of Systemic Ammonium Acetate and L‐Tryptophan
Authors: Bergqvist Peter B. F. , Carpenedo Raffaella , Apelqvist Gustav , Moroni Flavio , Bengtsson Finn
Published: March 2009

Abstract: It has previously been shown that the neurodepressant L‐tryptophan metabolite oxindole is increased in the blood and brain of rats with fulminant hepatic failure and in the blood of cirrhotic patients affected by chronic hepatic encephalopathy. In the present investigation, we found that oxindole levels were significantly increased in the blood and brain of portacaval‐shunted rats, an animal model of chronic hepatic encephalopathy, compared with sham‐operated controls. A further increase in plasma and brain oxindole content was found after oral administration of L‐tryptophan (300 mg/kg) to both portacaval‐shunted or sham‐operated animals, while intraperitoneal injection of the amino acid did not modify oxindole content either in brain or blood. Ammonium acetate administration (4.0 mmol/kg, intraperitoneal) reversibly deteriorated the neurological status of portacaval‐shunted animals, but did not modify, in a directly related manner, plasma and brain oxindole content. The present findings are in line with the possibility that oxindole may be an additional L‐tryptophan‐related candidate in the pathogenesis of chronic hepatic encephalopathy.
Chronic Carbon Monoxide Exposure in vivo Induces Myocardial Endothelin‐1 Expression and Hypertrophy in Rat
Authors: Loennechen Jan P. , Beisvag Vidar , Arbo Ingerid , Waldum Helge L. , Sandvik Arne K. , Knardahl Stein , Ellingsen Øyvind
Published: March 2009

Abstract: Smoking is associated with endothelial dysfunction and increased plasma levels of endothelin‐1. The component of tobacco smoke inducing these effects is unknown. Carbon monoxide induces hypoxia, and there is evidence of carbon monoxide acting as a local mediator in both endothelial and smooth muscle cells. The purpose of this study was to determine whether chronic carbon monoxide exposure similar to that experienced by smokers affects myocardial endothelin‐1 expression. Sprague‐Dawley female rats were exposed to carbon monoxide 100 ppm for one week or to 100 ppm for one week and 200 ppm for a second week. Carboxyhaemoglobin was 12+0.9% in the low and 23+1.1% in the high carbon monoxide exposure group. Endothelin‐1 expression was measured by competitive reverse transcriptase polymerase chain reaction. High carbon monoxide exposure increased endothelin‐1 mRNA by 54+12% (P<0.001) in the left ventricle and by 53+12% (P<0.001) in the right ventricle. In the low carbon monoxide exposure group corresponding changes were 43+14% (P=0.06) and 12+16% (P=0.29). Right ventricular weight increased by 18+7% (P=0.02) after high and by 16+5% (P=0.02) after low exposure. Left ventricular weight was elevated by 5+2% (P=0.05) when both exposure groups were compared to controls. We conclude that chronic carbon monoxide exposure leading to carboxyhaemoglobin levels similar to those observed in smokers increases endothelin‐1 gene expression and induces myocardial hypertrophy in the rat.
Influence of Hypoxia and Hyperoxia on the Cardiovascular and Lethal Effects of Ethanol
Authors: Strubelt Otfried , Younes Maged
Published: March 2009

The mutual potentiation of the hepatotoxic effects of ethanol and hypoxia raised the question of whether such an interaction also occurs in the cardiovascular system. Therefore, anaesthetized rats were infused intravenously with ethanol (25 mg/kgXmin.) over 90 min. to reach blood ethanol concentrations between 2.2 and 2.6 g/l and were ventilated artificially either with room air, 10% O2/90% N2 or 100% O2. Under normoxic conditions, ethanol produced a slow decrease of mean arterial blood pressure from 130 to 100 mmHg due to the decline in cardiac output and stroke volume (–20%) while heart rate and peripheral resistance remained unchanged. Hypoxia (arterial oxygen tension 35–38 mmHg) without ethanol produced immediate hypotension (–60 mmHg) without decreasing the cardiac output, i.e. by reducing peripheral resistance. In combination with ethanol, hypoxia produced an even stronger hypotension (–90 mmHg) due to reduction in both cardiac output and peripheral resistance. On the other hand, respiration with 100%) O2 (arterial oxygen tension about 500 mmHg) elevated peripheral resistance, attenuated ethanol‐induced cardiodepression and prevented ethanol‐induced hypotension. The lethal doses of ethanol evaluated by infusing 75 mg/kgXmin. ethanol until death amounted to 4.1 g/kg with 10% O2, to 5.5 g/kg with 20% O2 (room air) and to 6.9 g/kg with 100% O2. Thus decrease in vascular contractility induced by hypoxia combined with ethanol‐induced cardiodepression may result in lethal cardiovascular failure. Hyperoxia, on the other hand, counteracts ethanol‐induced cardiodepression and its acute toxicity by raising the vascular contractility.
Toxicity of Fructose‐1, 6‐Bisphosphate in Developing Normoxic Rats
Authors: Vexler Zinaida , Berrios Margarita , Ursell Philip C. , Sola Augusto , Ferriero Donna M. , Gregory George A.
Published: March 2009

Giving 500 mg/kg of fructose‐1, 6‐bisphosphate intraperitoneally decreases hypoxic/ischaemic CNS injury of neonatal rats. Before administering fructose‐1, 6‐bisphosphate to human neonates, its toxicity must be determined in neonatal animals. Thus, saline or 4,000, 6,000, or 8,000 mg/kg of fructose‐1, 6‐bisphosphate was given intraperitoneally to normoxic 7 days old rats. One, 2, and 24 hr and 7 days later, blood Ca2+, P043–, blood urea nitrogen, and creatinine concentrations, and aspartate aminotransferase activity were measured. Organ pathology was determined at necropsy. Pups receiving 4,000 mg/kg of fructose‐1, 6‐bisphosphate survived without evidence of injury or toxicity. All animals receiving 8,000 mg/kg and 27 percent of those receiving 6,000 mg/kg of fructose‐1, 6‐bisphosphate died. Surviving fructose‐1, 6‐bisphosphate‐treated animals grew at the same rates and had similar weights as saline‐treated animals. Nineteen percent of pups given 6,000 or 8,000 mg/kg of fructose‐1, 6‐bisphosphate had mild perivascular fluid cuffing and/or microscopic pulmonary haemorrhage, but none of the animals given 4,000 mg/kg of the compound had evidence of injury. No other organ pathology was found in any of the animals. Renal and hepatic function were normal in all animals. Fructose‐1, 6‐bisphosphate administration was associated with a significant increase in the fructose‐1, 6‐bisphosphate concentration of blood. Administering 4,000 to 8,000 mg/kg of fructose‐1, 6‐bisphosphate significantly decreased Ca2+ concentrations and increased P043– concentrations 1 and 2 hrs after fructose‐1, 6‐bisphosphate administration. Similar changes in Ca2+ and P043– concentrations occurred after the administration of 10 mmol/kg of sodium phosphate. The wide margin of safety for fructose‐1, 6‐bisphosphate (8 times the dose needed to prevent or reduce CNS injury) may render fructose‐1, 6‐bisphosphate safe for use in neonates.
Lack of Effect of Terfenadine on the Pharmacokinetics of the CYP3A4 Substrate Buspirone
Authors: Lamberg Tommi S. , Kivistö Kari T. , Neuvonen Pertti J.
Published: March 2009

Abstract:The effects of terfenadine, a non‐sedating antihistamine, on the pharmacokinetics and pharmacodynamics of buspirone, a CYP3A4 substrate, were investigated in a randomised, placebo‐controlled, two‐phase cross‐over study. Ten healthy volunteers took either 120 mg terfenadine or matched placebo orally once daily for 3 days. On day 3, 10 mg buspirone was taken orally. Plasma concentrations of buspirone were measured up to 18 hr and its pharmacodynamic effects up to 8 hr. Terfenadine slightly but not significantly increased plasma concentrations of buspirone. No psychomotor deterioration was observed during the terfenadine phase. In conclusion, terfenadine did not significantly affect the pharmacokinetics of buspirone, a CYP3A4 substrate shown to be very susceptible to interactions with CYP3A4 inhibitors. Thus, terfenadine is expected to have little effect on the pharmacokinetics of CYP3A4 substrates in general.
Effect of Some Psychotropic Drugs on the Activated Macrophage‐Induced Luminol‐Dependent Chemiluminescence
Authors: Hadjimitova Vera , Traykov Trayko , Goliysky Peter , Ribarov Stefan
Published: March 2009

Abstract: The effect of some psychotropic drugs on the activity of macrophages to produce superoxide radicals during phagocytosis was tested. Three‐cyclic antidepressants, imipramine and amitriptyline, and the thioxanthene neuroleptic, chlorprothixene, were studied. The superoxide production was measured by luminol‐dependent chemiluminescence. The drugs were investigated in the concentration range of 10−7–10−4 mol/1. It was seen that all tested drugs caused a concentration‐dependent decrease of the luminol‐dependent chemiluminescence. The inhibitory effect of imipramine and amitriptyline on the macrophage superoxide production was moderate, while the effect of chlorprothixene was significantly stronger (a decrease more than 100 times that of macrophage chemiluminescence). Essentially, the luminol‐dependent chemiluminescence reflects the level of superoxide radicals in the system. Therefore, the effect of drugs may be due to the possible activity for scavenging superoxide. In additional experiments with different systems of generations of O2− and different methods of registration, this possibility was discarded. Therefore, the effect of the drugs on the luminol‐dependent chemiluminescence seems to be due to drug‐induced decrease of the ability of activated macrophages to produce superoxide radicals.
Further Analysis of Cadmium Uptake from Apical Membrane of LLC‐PK1 Cells via Inorganic Anion Exchanger
Authors: Endo Tetsuya , Kimura Osamu , Sakata Masakatsu
Published: March 2009

Abstract: This study was undertaken to analyze Cd uptake via the inorganic anion exchanger (HCO3−/Cl−) by LLC‐PK1 cells cultured on permeable membranes. LLC‐PK1 cells were incubated at 37° with 1 μM CdCl2 added to the apical medium, and Cd accumulation in the cells was fractionated into a membrane‐bound (non‐internalized) Cd fraction and an internalized Cd fraction using ethyleneglycol‐bis‐(p‐aminoethylether)‐N, N, N', N'‐tetraacetic acid (EGTA), a chelating agent for Cd. Incubation at a lower temperature (4°) significantly decreased the membrane‐bound Cd fraction, and drastically decreased the internalized Cd fraction. Addition of NaHCO33 (a stimulator of Cd uptake via inorganic anion exchanger) to the apical medium significantly increased both membrane‐bound and internalized Cd fractions, and this increase was greater for the internalized fraction. Pretreatment of cells with 4, 4′‐diisothiocyanostilbene‐2, 2′‐disulfonic acid (DIDS), a specific inhibitor of inorganic anion exchangers, significantly decreased the internalized Cd fraction without changing the membrane‐bound Cd fraction. Addition of NaHCO3 did not effect both Cd fractions in DIDS‐pretreated cells. These results suggest that most of Cd binds non‐specifically to the apical membrane surface and then is internalized via simple diffusion and some Cd specifically binds to the inorganic anion exchanger and is internalized in a metabolism‐dependent manner.
Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers
Authors: Varis Tiina , Kivistö Kari T. , Backman Janne T. , Neuvonen Pertti J.
Published: March 2009

Abstract: A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double‐blind, randomized, two‐phase cross‐over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. Itraconazole increased the total area under the plasma methylprednisolone concentration‐time curve (AUC(0‐∞) 2.6‐fold) (P<0.001), while the AUC (12–24) of methylprednisolone was increased 12.2‐fold (P<0.001). The systemic clearance of methylprednisolone during the itraconazole phase was 40% of that during the placebo phase (P<0.01). The volume of distribution of methylprednisolone was not affected by itraconazole. The mean elimination half‐life of methylprednisolone was increased from 2.1±0.3 hr to 4.8±0.8 hr (P<0.001) by itraconazole. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hr after the administration of methylprednisolone, was only about 9% of that during the placebo phase (11.0±9.0 ng/ml versus 117±49.2 ng/ml; P<0.001). In conclusion, itraconazole decreases the clearance and increases the elimination half‐life of intravenously administered methylprednisolone, resulting in greatly increased exposure to methylprednisolone during the night time and in enhanced adrenal suppression. Care should be taken when itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with methylprednisolone.
Changes in Intestinal Absorption of 5‐Fluorouracil‐Treated Rats
Authors: Hirata Kohji , Horie Toshiharu
Published: March 2009

Abstract:5‐Fluorouracil chemotherapy is often accompanied by gastrointestinal toxicity. In this study, we investigated the effect of 5‐fluorouracil on the epithelial barrier function of rat small intestine by examining the absorption of a poorly absorbable marker, fluorescein isothiocyanate‐labelled dextran (molecular weight 4,400). We further evaluated the intestinal absorption of 5‐fluorouracil in rats treated orally with 5‐fluorouracil once daily for 4 days. The small intestinal absorption of fluorescein isothiocyanate‐labelled dextran and 5‐fluorouracil was tested usingin situclosed loop intestine technique andin vitroeverted intestine technique, respectively. After administration of 5‐fluorouracil to rats for 4 days, the body weight of rats decreased significantly and the fluorescein isothiocyanate‐labelled dextran concentration in plasma increased significantly, compared with that of control rats to which the saline solution alone was administered. Moreover, the intestinal absorption of 5‐fluorouracil in the 5‐fluorouracil‐treated rats was enhanced significantly, compared with that of control rats. The administration of 5‐fluorouracil to rats caused body weight loss and epithelial barrier dysfunction of the small intestine in rats as shown by the increased permeation of the high molecular weight compound, fluorescein isothiocyanate‐labelled dextran. The increased absorption of 5‐fluorouracil after this treatment suggest that the 5‐fluorouracil toxicity might be amplified by its treatment.
Clozapine: Dopamine D1Receptor Agonism in the Prefrontal Cortex as the Code to Decipher a Rosetta Stone of Antipsychotic Drugs
Authors: Ahlenius Sven
Published: March 2009

Abstract:A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D1and D2receptor families. The study of intrinsic efficacy at these receptors is less straightforward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D1receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg–1) in the rat is fully antagonised by either of the selective DA D1receptor antagonists SCH‐23390 (0.1 mg kg–1) or NNC‐687 (4 mg kg–1). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D1receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D1receptor agonist.
The Effect of Subcutaneous Tetrathiomolybdate Administration on Copper and Iron Metabolism, Including their Regional Redistribution in the Brain, in the Long‐Evans Cinnamon Rat, a bona fide Animal Model for Wilson's Disease
Authors: Sugawara Naoki , Ikeda Toshiko , Lai Yu‐Rong , Sugawara Chieko
Published: March 2009

Abstract: The present work was performed to examine the effect of tetrathiomolybdate on Cu and Fe metabolism, especially redistribution of Cu and Fe in the brains of Long‐Evans Cinnamon rats, with inherently abnormal Cu deposition in the liver. The drug was injected subcutaneously at 5 mg/kg of body weight twice a week for 65 days (total dose of 20 mg) into 40‐day‐old Long‐Evans Cinnamon rats. In Long‐Evans Cinnamon rats treated with tetrathiomolybdate, the hepatic Cu concentration was 60 μg/g wet weight, compared to 170 μg/g in untreated rats. In seven brain regions (cerebellum, medulla oblongata, hypothalamus, striatum, midbrain, hippocampus and cortex) of the Long‐Evans Cinnamon rats treated with tetrathiomolybdate, the Cu concentration (1.5 to 2.3 μg/g) was slightly lower (1.6 to 2.7 μg/g) than in untreated rats. A significant difference between the two groups was found only in the midbrain. Brain Fe concentrations in regions other than the striatum were not changed significantly by the tetrathiomolybdate injections. The hepatic Fe concentration was about 120 μg/g in Long‐Evans Cinnamon rats without tetrathiomolybdate. Tetrathiomolybdate injection further increased the concentration to about 250 μg/g. Our results indicated that subcutaneous tetrathiomolybdate injection did not have an effect that stimulated redistribution of Cu and Fe in the seven brain regions examined, although hepatic Cu was markedly decreased and the removed Cu was deposited in kidneys, spleen and testes. The increased hepatic Fe level should be taken into account when considering side effects of the compound.
In vitroCytotoxicity of the Nitric Oxide Donor,S‐Nitroso‐N‐acetyl‐peraciUamine, towards Cells from Human Oral Tissue
Authors: Babich Harvey , Zuckerbraun Harriet L. , Hirsch Shoshana T. , Blau Lea
Published: March 2009

Abstract:The cytotoxicity of the nitric oxide donor,S‐nitroso‐N‐acetyl‐penicillamine (SNAP), towards cultured human cells from oral tissue was evaluated. The toxicity of SNAP to Smulow‐Glickman gingival epithelial cells was correlated with the liberation of nitric oxide, asN‐acetyl‐D, L‐penicilIamine, the SNAP metabolites,N‐acetyl‐D, L‐penicillamine disulfide and nitrite, and preincubated (denilrosylated) SNAP did not affect viability. Comparing equimolar concentrations of various nitric oxide donors, cytotoxicity appeared to be inversely related to the relative stability (i.e., half‐life) of the test compound; the sequence of cytotoxicity for a 4 hr exposure was S‐nitrosoglutathione>>spermine NONOate> SNAP>DPTA NONOate>>DETA NONOate. Intracellular reduced glutathione (GSH) was lowered in S‐G cells exposed to SNAP. Pretreatment of the cells with the GSH depleter, 1, 3‐bis‐(chloroethyl)‐1‐nitrosourea (BCNU), enhanced the toxicity of SNAP. Similar findings of enhanced sensitivity to SNAP were noted with gingival fibroblasts and periodontal ligament cells pretreated with BCNU. The toxicity of SNAP towards the gingival epithelial cells was decreased by cotreatment with the antioxidants,N‐acetyl‐L‐cysteine, L‐ascorbic acid, and (+)‐catechin. Cells exposed to SNAP exhibited nuclear aberrations, including multilobed nuclei and multinucleation. SNAP‐induced cell death was apparently by apoptosis, as noted by fluorescence microscopy and DNA agarose gel electrophoresis.
The Neuronal Selective Nitric Oxide Inhibitor AR‐R 17477, Blocks some Effects of Phencyclidine, while Having No Observable Behavioural Effects when Given Alone
Authors: Johansson Christina , Deveney Aaron M. , Reif David , Jackson David M.
Published: March 2009

Abstract:We have previously shown that the non‐specific nitric oxide synthase inhibitor L‐NAME blocks the behavioural effects of phencyclidine, but not d‐amphetamine. To characterise the specificity of these effects, we used the specific neuronal nitric oxide synthase inhibitor AR‐R 17477 in two rat models of psychosis: the prepulse inhibition of the acoustic startle response and locomotor activity. In biochemical assays, AR‐R 17477 was shown to be selective for the neuronal nitric oxide synthase isoform. Test drugs were given subcutaneously. AR‐R 17477 (0.5, 1 and 5 mg/kg) antagonised phencyclidine‐induced hyperlocomotion, while higher doses (10 and 20 mg/kg) were less efficaceous. AR‐R 17477 (1 mg/kg) antagonised phencyclidine‐induced deficit in prepulse inhibition of the acoustic startle response, while a higher dose (15 mg/kg) was less active. AR‐R 17477 did not affect startle amplitude or prepulse inhibition of the acoustic startle response, did not affect locomotion and did not induce any changes in gross behaviour (sniffing, rearing, etc.) as determined in a subjective observation study. AR‐R 17477 (1 mg/kg) did not alter the effect of d‐amphetamine in prepulse inhibition of the acoustic startle response. Using radiotelemetry in rats, L‐NAME (10 mg/kg subcutaneously) increased blood pressure and decreased heart rate while AR‐R 17477 (10 mg/kg) did not have any significant effect on these parameters. The results show that a neuronal nitric oxide synthase inhibitor antagonises the effects of phencyclidine on prepulse inhibition of the acoustic startle response and locomotor activity, without exhibiting significant behavioural effects of its own and suggest that our earlier results with L‐NAME depended upon an inhibition of neuronal nitric oxide synthase and not on an inhibition of endothelial nitric oxide synthase or inducible nitric oxide synthase. The observed effects are unlikely to be related to an effect on cardiovascular function.
The Effect of Heavy Metal‐Induced Metallothionein on Zn, Cu and Cd Accumulation in Rat Kidney
Authors: Saito Shigeru , Okabe Masashi , Yoshida Katsumi , Kurasaki Masaaki
Published: March 2009

Abstract: To examine the role of metallothionein on heavy metal accumulation in kidneys of rats after Zn, Cd or Cu injection, the relative Zn, Cd or Cu‐binding capacity of heavy metal‐induced metallothionein in renal cytosol of rats after Zn, Cd or Cu injection was determined. The Zn or Cu increment in renal cytosol after Zn or Cu injection was attributable to low and high molecular weight proteins, while most of the Cd increment was attributable to a low molecular weight protein. The low molecular weight, metal‐binding protein was identified as metallothionein using a competitive ELISA. There was a close relationship between heavy metal contents in the renal cytosol and metallothionein of all heavy metal‐injected rats. In dose‐response and time‐course studies, approximately 45, 40 and 85% of the Zn, Cu and Cd increments in renal cytosol were bound to metallothionein after Zn, Cu and Cd injection, respectively. Therefore the order of relative binding capacities of Zn, Cu and Cd‐induced metallothionein in kidney was determined to be Cd>Zn Cu. These results suggest that the role of metallothionein in Zn or Cu accumulation in the kidney after Zn or Cu injection is different from that of metallothionein in Cd accumulation in the kidney after Cd injection.
The Acute Effect in Rats of 3, 4‐Methylenedioxyethamphetamine (MDEA, “Eve”) on Body Temperature and Long Term Degeneration of 5‐HT Neurones in Brain: A Comparison with MDMA (“Ecstasy”)
Authors: Colado Maria Isabel , Granados Raquel , O'Shea Esther , Esteban Blanca , Green A. Richard
Published: March 2009

Abstract:Administration of a single dose of the recreationally used drug 3, 4‐methylenedioxyethamphetamine (MDEA or “eve”) to Dark Agouti rats resulted in an acute dose‐dependent hyperthermic response. The peak effect and duration of hyperthermia of a dose of MDEA of 35 mg/kg intraperitoneally was similar to a dose of 3, 4‐methylenedioxymetham‐phetamine (MDMA or “ecstasy”) of 15 mg/kg intraperitoneally. Seven days later this dose of MDMA produced a marked (50%) loss of 5‐HT and its metabolite 5‐HIAA in cortex, hippocampus and striatum and a similar loss of [3H]‐paroxetine binding in cortex; these losses reflecting the MDMA‐induced neurotoxic degeneration of 5‐HT nerve endings. In contrast, administration of MDEA (15, 25 or 35 mg/kg), even at the highest dose, produced only a 20% loss in cortex and hippocampus and no decrease in striatum. The neurotoxic effect of MDEA was only weakly dose‐dependent. Neither MDEA (35 mg/kg) nor MDMA (15 mg/kg) altered striata! dopamine content 7 days later. MDEA appeared to have about half the potency of MDMA in inducing acute hyperthermia and 25% of the potency in inducing degeneration of cerebral 5‐HT neurones. However since higher doses of MDEA (compared to MDMA) are probably necessary to induce mood changing effects, these data do not support any contention that this compound is a “safer′’recreational drug than MDMA in terms of either acute toxicity or long term neurodegeneration.
Inhibitory Effects of Baicalein and Wogonin on Lipopolysaccharide‐Induced Nitric Oxide Production in Macrophages
Authors: Wakabayashi Ichiro
Published: March 2009

Abstract: In order to elucidate the mechanism of the antiinflammatory action of baicalein and wogonin, flavonoids from the root of Scutellaria baicalensis, the effects of these compounds were investigated on lipopolysaccharide‐induced nitric oxide production in a macrophage‐derived cell line, RAW 264.7. Baicalein (5–25 μM) and wogonin (5–50 μM) inhibited lipopolysaccharide‐induced nitric oxide generation in a concentration‐dependent manner. The inhibitory effect of these compounds was observed only when they were added at the start of cell incubation soon after the stimulation with lipopolysaccharide. Baicalein (25 μM) and wogonin (25 μM) also inhibited protein expression of inducible nitric oxide synthase. This inhibitory effect of wogonin was stronger than that of baicalein, which agrees with the result that wogonin showed stronger inhibition of nitric oxide production than baicalein. These results suggest that baicalein and wogonin attenuate lipopolysaccharide‐stimulated nitric oxide synthase induction in macrophages and thus may help to explain the antiinflammatory action of these flavonoid compounds.
Correlation between High Intake of Glycyrrhizin and Myolysis of the Papillary Muscles: An Experimental in vivo Study
Authors: Rossi Tiziana , Fano Rita Adriana , Castelli Mario , Malagoli Monica , Ruberto Antonio Ippazio , Baggio Giosuè , Zennaro Romeo , Migaldi Mario , Barbolini Giuseppe
Published: March 2009

Abstract The ingestion of large quantities of glycyrrhizin, whether as a drug or a sweetener, is known, in susceptible subjects, to induce a syndrome similar to hypermineralcorticoidism, with bouts of hypertension, hypokaliaemia and rabdomyolysis, sometimes associated with severe renal failure and hypokaliaemia‐induced arrythmias. Glycyrrhizin is also known to isomerize into the glycyrrhetic (or glycyrrhetinic) acids 18α‐ and 18β‐. In previous works, we reported that these metabolites cause bouts of hypertension and reduction in diuresis at low doses in the rat. In particular, the α isomer causes significant elimination of the calcium ion in the urine. The present findings confirm that 18α‐glycyrrhetic acid is more toxic than either glycyrrhizin or the β isomer. Histopathological study of tissue samples taken from rats treated with the α isomer also reveal selective damage to the myocardium with oedema, myolysis, apoptosis and blistering of the sarcoplasm. These effects begin to appear in the course of subchronic treatment, they manifest themselves in acute treatment and correlate closely with the electrocardiographic changes recorded in rats acutely treated with 18α‐glycyrrhetic acid.
Oxidative Injury Reproduces Age‐Related Impairment of Oxygen‐Dependent Drug Metabolism
Authors: Le Couteur David G. , Hickey Haruyo M. , Harvey Peta J. , McLean Allan J.
Published: March 2009

Abstract The Oxygen Diffusion Barrier Hypothesis states that aging in the liver is associated with restricted oxygen uptake that explains the age‐related impairment of phase I drug clearance observed in vivo with preservation of in vitro phase I enzyme activity and in vivo phase II drug clearance. Aging in the liver may be secondary to oxidative stress. Therefore we examined the effects of oxidative injury on oxygen uptake, and phase I and phase II drug metabolism in the liver. Oxidative stress was induced in the perfused rat liver with hydrogen peroxide. The intrinsic clearances of propranolol and morphine were used as markers of phase I and phase II activity, respectively. Oxidative injury was associated with a 14$pL9% (P=0.03) reduction in oxygen uptake. The decrease in the intrinsic clearance of propranolol was greater than that of morphine (57$pL14% vs 34$pL7% P<0.005). This result supports the concept of a restriction of oxygen supply constraining hepatic drug metabolism following oxidative stress. This has implications for aging and hepatic drug metabolism.
Rifampicin Treatment Greatly Increases the Apparent Oral Clearance of Qninidine
Authors: Damkier Per , Hansen Lone L. , Brøsen Kim
Published: March 2009

AbstractWe investigated the effect of cytochrome P450 induction by rifampicin on thein vivooxidative metabolism of quinidine. The pharmacokinetics of a 200 mg oral single dose quinidine were studied before and after one week of daily treatment with 600 mg rifampicin in six healthy young male volunteers. Biomarker reactions of cytochrome P450 isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. The median total apparent oral clearance and partial clearance by 3‐hydroxylation of quinidine increased 9 times. The partial clearance by N‐oxidation increased 6 times. The Cmaxand the elimination half life were reduced 3 times. No statistically significant changes were found for quinidine tmaxand renal clearance. The cortisol metabolic ratio increased 5 times, while no statistically significant effects were seen for other CYP marker reactions. The results indicate that the inductive effect of rifampicin is likely to be of clinical relevance particulary when used concomitantly with drugs metabolized by CYP3A4.
A Golgi PKD Activity Reporter Reveals a Crucial Role of PKD in Nocodazole‐Induced Golgi Dispersal
Authors: Fuchs Yannick F. , Eisler Stephan A. , Link Gisela , Schlicker Oliver , Bunt Gertrude , Pfizenmaier Klaus , Hausser Angelika
Published: March 2009

The protein kinase D (PKD) family comprises multifunctional serine/threonine‐specific protein kinases with three mammalian isoforms: PKD1, PKD2 and PKD3. A prominent PKD function is the regulation of basolateral‐targeted transport carrier fission from the trans‐Golgi network (TGN). To visualize site‐specific PKD activation at this organelle, we designed a molecular reporter consisting of a PKD‐specific substrate sequence fused to enhanced green fluorescent protein (EGFP), specifically targeted to the TGN via the p230 GRIP domain. Quantitative analyses using a phosphospecific antibody and ratiometric fluorescence imaging revealed that Golgi‐specific phosphorylation of the reporter was strictly dependent on stimulation of endogenous PKD or transient expression of active PKD constructs. Conversely, PKD‐specific pharmacological inhibitors and siRNA‐mediated PKD knockdown suppressed reporter phosphorylation. Using this reporter we investigated a potential role for PKD in the regulation of Golgi complex morphology. Interestingly, nocodazole‐induced Golgi complex break‐up and dispersal was associated with local PKD activation as measured by reporter phosphorylation and this was efficiently blocked by expression of a dominant‐negative PKD mutant or PKD depletion. Our data thus identify a novel link between PKD activity and the microtubule cytoskeleton, whereby Golgi complex integrity is regulated.
Sampling soil wood charcoals at a high spatial resolution: a new methodology to investigate the origin of grassland plant communities
Authors: Dutoit Thierry , Thinon Michel , Talon Brigitte , Buisson Elise , Alard Didier
Published: March 2009

Questions: (i) Can sampling of soil wood charcoals at high spatial resolution produce new evidence concerning the presence of chalk grassland before or during the Neolithic, Bronze and Iron Ages? (ii) Are there correlations between vegetation history and archeological data during these periods at this particular site?

Location: The chalk hillsides of Saint‐Adrien in the lower Seine Valley, Upper Normandy, northwest France.

Methods: The study was carried out at a high spatial resolution in chalk grassland using soil wood charcoal analysis, in which charcoals found in the soil were identified and dated in an area of several hundred square meters.

Results: Late‐successional woody species (Fagus sylvatica, Quercus sp.) were still present in the study site in an area inconsistent with the existence of large chalk grassland herbaceous plant communities (several hectares) in the Neolithic (6500–3800 BP) and Bronze Age (3800–2700 BP).

Conclusions: The presence of late‐successional woody species on the studied hillside suggests that fires in the Neolithic were linked to forest clearance for pastoral activities, as already demonstrated for similar ecosystems in eastern France and Germany. Nevertheless, our methodology clearly demonstrates that palaecological studies need to take into account the spatial organisation of plant communities as a complementary element to validate their potential existence in former times.
Plant population and community responses to removal of dominant species in the shortgrass steppe
Authors: Munson Seth M. , Lauenroth William K.
Published: March 2009

Question: What are the plant population‐ and community‐level effects of removal of dominant plant species in the shortgrass steppe?

Location: The Shortgrass Steppe Long‐Term Ecological Research site in northern Colorado, USA.

Methods: We annually measured plant cover and density by species for 10 years after a one‐time aboveground removal of the dominant perennial grass, Bouteloua gracilis. Removal and control plots (3 m × 3 m) were within grazed and ungrazed locations to assess the influence of grazing on recovery dynamics. Our analyses examined plant species, functional type, and community responses to removal, paying special attention to the dynamics of subdominant and rare species.

Results: Basal cover of B. gracilis increased by an average of 1% per year, but there was significantly less plant cover in treatment compared to control plots for 5 years following removal. In contrast to the lower cover in treatment plots, the plant density (number of plants m−2) of certain subdominant perennial grasses, herbaceous perennial and annual forbs, a dwarf shrub, and cactus increased after removal of the dominant species, with no major change in species richness (number of species per 1 m × 1 m) or diversity. Subdominant species were more similar between years than rare species, but dominant removal resulted in significantly lower similarity of the subdominant species in the short term and increased the similarity of rare species in the long term.

Conclusions: Removal of B. gracilis, the dominant perennial grass in the shortgrass steppe, increased the absolute density of subdominant plants, but caused little compensation of plant cover by other plants in the community and changes in species diversity.
Drug Use With Parents as a Relational Strategy for Incarcerated Female Adolescents
Authors: Lopez Vera , Katsulis Yasmina , Robillard Alyssa
Published: March 2009

Problems associated with poor quality parent‐child relationships are compounded for incarcerated girls. Using attachment theory as a framework, the present qualitative study examined how 18 incarcerated adolescent girls made meaning with regard to their parents’ drug use. We found that 8 of the 18 girls used drugs with their parents as a relational strategy to be close with them, particularly with their fathers, or as a means to share time together. The unique finding that girls used drugs together with their parents supports the need for relational parenting interventions that, whenever possible, support, encourage, and provide treatment and family strengthening services to parents who use drugs and their children.
Sexual Dysfunction in Men Who Abuse Illicit Drugs: A Preliminary Report
Authors: Bang-Ping Jiann
Published: March 2009

Introduction

Despite being seen as aphrodisiacs, illicit drugs are reported to have detrimental effects on male sexual function but most studies have been based on small case numbers with ambiguous results.

Aims

To assess the impact of illicit drugs abuse on male sexual function.

Main Outcome Measures

International Index of Erectile Function (IIEF) and global assessment questions.

Methods

Illicit drug abusers in a Drug Abstention and Treatment Center were recruited to complete the questionnaires and their data were compared with an age-matched control.

Results

The abusers (N = 701, mean age 33.8 years) had a lower mean IIEF score in each domain than that of the controls (N = 196, mean age 35.4 years). Heroin, amphetamine, and MDMA (“Ecstasy”) were the leading drugs used. Erectile dysfunction (ED) was reported in 36.4% of the abusers and the odds ratio of having ED (compared with the controls) in mono-users of heroin, amphetamine, and MDMA was 4.8 (P < 0.05), 3.2 (P < 0.05), and 1.4 (P > 0.05), respectively. Of the abusers, 38.6% reported to have decreased sexual desire with illicit drug use, more often seen in the heroin mono-users (46.7%), and 18.4% reported to have enhanced sexual desire, more often seen in the amphetamine mono-users (22.6%). Mean IIEF sexual desire domain score of the abusers was lower than that of the control, even for those who reported to have enhanced sexual desire. Increased and decreased ejaculation latency affected by illicit drugs was reported in 49.9 and 14.3%, respectively, of the abusers, showing no significant difference among the mono-users of three different drugs.

Conclusions

Illicit drug male abusers were prone to have ED, decreased sexual desire, and increased ejaculation latency. ED and decreased sexual desire were most commonly seen in heroin, followed by amphetamine and MDMA mono-users, while increased ejaculation latency occurred commonly in all of the abusers.
The Sexuality and Quality of Life of Hemodialyzed Patients—ASED Multicenter Study
Authors: Lew-Starowicz Michal , Gellert Ryszard
Published: March 2009

Introduction

Chronic kidney disease (CKD) strongly affects sexual function (SF) and quality of life (QoL). The relations between CKD, SF, mental health, and QoL remain poorly understood in dialyzed patients.

Aim

To correlate sexuality to QoL in hemodialysis patients.

Methods

One hundred twelve patients (69 males and 43 females) aged 20–60 years at six dialysis units were interviewed, and their medical records were reinvestigated and supplemented with completed Beck’s Depression Inventory, Self-Evaluation Questionnaire, Mell–Krat Scale, International Index of Erectile Function-5, Arizona Sexual Experience Scale, and health-related Quality of Life (Short Form [SF]-36) questionnaires.

Main Outcome Measures

Prevalence of different levels of measurable aspects of sexual life, mental health, QoL, as well as their correlations, was assessed.

Results

Only 55.4% of the patients were sexually active (79% in the age-matched general population) and 24.1% has ever before spoken to a doctor about their sexual life. The patients perceived sexual activity as important and were not satisfied with the performance. The predominant sexual dysfunctions were loss or diminished sexual needs (84.7% males and 48.8% females); in men, also erectile dysfunction (44.5%) and inhibited or lack of ejaculation (51.5%); in women, arousal dysfunction and anorgasmia (67.8% and 80.7%, respectively). The rate of depression was extremely high (80.5%). The patients self-assessed their QoL as low in both the physical and the mental health domains. Multiple regression analysis revealed that anxiety in men and depression in women independently predicted the lower quality of sexual life (P = 0.017 and 0.04, respectively). The general QoL, mental health, and physical health negatively correlated with the presence of depressive symptoms (P = 0.011, 0.013, and 0.011, respectively).

Conclusions

This pilot study is the first to present, in a multicenter design, the complex relations of sexuality and QoL in hemodialyzed patients, which are strongly underevaluated by medical professionals. It supports a thesis that sexual disability correlates with depression and anxiety, and seriously impacts the QoL in dialyzed patients.
Controversies in Sexual Medicine: Is There a Place for Conservative Treatment in Peyronie’s Disease?
Authors: Vardi Yoram , Levine Laurence A. , Chen Juza , Hatzimouratidis Konstantinos , Sohn Michael
Published: March 2009

Introduction

Peyronie’s disease (PD) is a relatively common disorder affecting middle aged men. Conservative nonsurgical treatments include oral, topical, and intra-lesional pharmacotherapies, vacuum stretching, and mechanical traction.

Methods

Four people with expertise and/or interest in the area of PD were asked to contribute their opinions with regard to the safety and efficacy of nonsurgical conservative treatments.

Main Outcome Measure

To provide food for thought, discussion, and possible further research in a poorly discussed area of sexual medicine.

Results

Of the four experts writing on the topic, one believes a combination of medical therapy and penile traction has positive potential for curvature. Another feels that although medical therapies have potential to alleviate pain, there is little evidence to show that they help with curvature or that penile traction helps. A third expert proposes dividing the disease into phases, where patients in the acute phase may benefit from conservative therapy, whereas patients whose disease is stable require surgical intervention. The last expert agrees that the therapy should depend on the stage of the disease, but believes like the first expert that there is a role for traction therapy for patients with stable disease.

Conclusion

There is a need for guidelines for nonsurgical therapies for patients with PD, but there is a paucity of evidence as to their efficacy.