bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects ofEscherichia coliHeat‐Stable Enterotoxin in Renal Sodium Tubular Transport
Authors: Lima Aldo A. M. , Monteiro Helena S. A. , Fonteles Manasses C.
Published: March 2009

Abstract:To compare the function of sodium transport between intestine and renal tubule, we studied the effect ofE. coliSTa enterotoxin and 8‐bromo cyclic GMP in perfused rat kidneys. Infusion of STa enterotoxin (0.017 and 0.1 μg/ml) caused a dose and time dependent decrease in total renal sodium tubular transport. The major site of STa effect was at the renal proximal tubule. Similar to Sta enterotoxin, 8‐bromo cyclic GMP (10–5M) caused a significant decrease of fractional renal sodium proximal tubule transport. In contrast to STa enterotoxin, infusion of 8‐bromo cyclic GMP resulted in a significant but short lasting (30 min.) increase in glomerular filtration rate. STa enterotoxin also decreased significantly the renal tissue potassium. This STa effect was related to a significant decrease in renal potassium tubular transport, resulting also in an increase of urinary potassium excretion. These studies demonstrate the specific functional effect of STa enterotoxin in promoting the decrease in renal proximal tubular sodium transport, similar to 8‐bromo cyclic GMP. In perfused rat kidneys STa also decreased tissue potassium, mainly by a decrease in potassium transport and increase in urinary potassium excretion. These effects suggest the existence of an endogenous peptide resembling STa enterotoxin, that regulates the function of renal sodium tubular transport.
Experimentally Induced Lipid Peroxidation after Exposure to Chromium, Mercury or Silver: Interactions with Carbon Tetrachloride
Authors: Rungby Jorgen , Ernst Erik
Published: March 2009

Abstract: Chromium, along with other heavy metals, induces an increased production of malondialdehyde (MDA), an indicator of lipid peroxidation, in liver and kidney tissue of NMRI male mice. After acute intoxications MDA levels remain high for 60 min. and thereafter return to normal in the kidney whereas MDA levels in liver are still increased 48 hr after exposure. Exposure of mice to chromium, mercury, or silver and another stimulator of lipid peroxidation, carbon tetrachloride, showed synergism between inorganic mercury and CCl4. Pre‐exposure to chromium, organic mercury, or silver at selected doses did not enhance CCl4‐toxicity as measured by organ content of MDA.
Clinical Pharmacology of Potassium Channel Openers
Authors: Andersson Karl‐Erik
Published: March 2009

Abstract:Opening of K+channels in cell membranes with resulting increase in K+conductance, shifts the membrane potential in a hyperpolarizing direction towards the K+equilibrium potential. Hyperpolarization reduces the opening probability of ion channels involved in membrane depolarization and excitation is reduced. K+channel openers are believed to hyperpolarize smooth muscle cells by a direct action on the cell membrane. The best known members of the group are cromakalim, nicorandil and pinacidil, but several new compounds are being evaluated. In addition, it has recently been shown that also clinically well‐known drugs like, e.g. diazoxide and minoxidil exhibit K+channel opening properties. Nicorandil and new compounds containing nitro groups have a dual mechanism of action, also activating guanylate cyclase, an effect that contributes to their cardiovascular effect profile. K+channel openers have a wide range of effects. Some of their properties and actions are summarized, and their present applications and/or potential for future application, in e.g. hypertension, angina pectoris, asthma, bladder instability, and several other disorders are discussed. It is concluded that K+channel openening represents an interesting pharmacological principle with many potential clinical applications. However, most available drugs do not seem to have a sufficient tissue selectivity to be useful therapeutic alternatives. Before the potential of the new members of the group on clinical trials can be properly evaluated, clinical experiences are needed.
Syntheses of 14C‐Ochratoxin A and 14C‐Ochratoxin B and a Comparative Study of their Distribution in Rats Using Whole Body Autoradiography
Authors: Breitholtz‐Emanuelsson Anna , Fuchs Radovan , Hult Karl , Appelgren Lars‐Erik
Published: March 2009

Abstract: Methods for preparation of labelled ochratoxin A and B are described. The method for preparation of labelled ochratoxin B involves the synthesis of the azide of ochratoxin β via the mixed anhydride and subsequent conjugation to labelled phenylalanine to yield 14C‐ochratoxin B. The labelled ochratoxins were injected into male Wistar rats and after different survival times they were sacrificed and subjected to whole body autoradiography. The distribution pattern of ochratoxin A in the rat did not differ from that earlier registered for mouse. The previously known, high susceptibility of rats (and not mice) to ochratoxin A‐induced cancer could thus not be explained by an accumulation of the toxin in specific cells or organs. The distribution patterns of ochratoxin A and B were almost congruent – the only apparent difference being a much longer retention of the labelled ochratoxin A in the blood compared to ochratoxin B, which was much faster excreted. When analyzing tissue extracts for labelled metabolites only the extracts from the rats injected with ochratoxin B were found to contain easily detectable concentrations, while no metabolites of ochratoxin A were seen.
Protection Against Acetaminophen Hepatotoxicity by Ribose‐Cysteine (RibCys)
Authors: Roberts Jeanette C. , Charyulu Rajeev L. , Zera Richard T. , Nagasawa Herbert T.
Published: March 2009

Abstract:2(RS)‐D‐ribo‐(1′, 2′, 3′, 4′‐Tetrahydroxybutyl)thiazolidine‐4(R)‐carboxylic acid (Ribose‐Cysteine, RibCys), a latent form of L‐cysteine, releases the sulfhydryl amino acidin vivoby non‐enzymatic ring opening and solvolysis. The liberated L‐cysteine then stimulates hepatic glutathione biosynthesis. In the present studies, the efficacy of hepatoprotection by RibCys was evaluated to explore its potential utility as an acetaminophen (APAP) antidote. Protection was evaluated in the Swiss‐Webster mouse model both by survival data as well as by quantitative histological criteria of hepatic damage. A dose‐response study showed increased protection with increased intraperitoneal doses of RibCys ranging from 0.5 to 8.0 mmol/kg. RibCys administration 30 min. prior to and up to four hours after the APAP dose showed varying degrees of protection; however, the best protection was seen when RibCys was given shortly after APAP administration. A single RibCys dose given by the intraperitoneal or intravenous route gave better protection than when administered orally; however, RibCys given in three doses, one hour apart, regardless of the mode of administration, offered the best protection after an LD90dose of APAP. Overall, RibCys continues to exhibit promising protective capabilities against APAP hepatotoxicity, which may be capitalized upon in clinical overdose situations.
Thyroid Status and Hepatic Thyroxine Deiodinating Activity under High‐Dose Long‐Term Nitrendipine
Authors: Wieberneit J. , Wolf Ch.‐F. , Keck F. S.
Published: March 2009

Abstract: The influence of high doses of oral nitrendipine on the hypophyseal‐thyroid axis and on peripheral thyroxine metabolism was studied in baboons. Administration of 320 mg oral nitrendipine per kg body weight (b.wt.) for three months caused a hypothyroid state with decreased values for thyroxine and reverse triiodothyronine, elevated TSH, but unchanged triiodothyronine; the lower doses investigated (24 and 48 mg/kg b.wt.) were without any effect. High doses of nitrendipine concomitantly increased hepatic 5′‐deiodinating activity by a rise in Vmax, which could be attributed to an increase in the deiodinating enzyme content. Normal T3 serum levels in the presence of low T4 serum concentrations under high dose nitrendipine can be ascribed, at least in part, to the enhanced peripheral 5′‐deiodination.
Accumulation of Potassium and Calcium in Rat Myocardium Exposed to α‐1‐Adrenoceptor Stimulation
Authors: Hanem Sigrid , Skomedal Tor , Osnes Jan‐Bjørn
Published: March 2009

Abstract:Net fluxes of potassium, calcium, sodium and chloride were examined in isolated perfused rat hearts during α‐1‐adrenoceptor stimulation. The ion measurements were performed in the non‐recirculating perfusate. Hearts were exposed to α‐1‐adrenoceptor stimulation (phenylephrine 5×10–5mol/1 in the presence of the β‐blocker timolol 10–6mol/1). During α‐1‐adrenoceptor stimulation perfusate potassium fell relatively rapidly by about 0.10 mmol/1 after approximately 100 sec. followed by a slower rise. About 180 sec. after onset of α‐1‐adrenoceptor stimulation, the potassium level was about 0.06 mmol/1 below the control concentration level. This reduction was eliminated by the α‐1‐adrenoceptor blocker prazosin (10–7mol/1). The effects on net calcium fluxes were measured at two different calcium concentrations. For both concentrations we found a small but statistically significant reduction of the calcium concentration in the perfusate after α‐1‐adrenoceptor stimulation. Neither sodium nor chloride perfusate concentrations showed statistical significant changes compared to control values. The present observations revealed the existence of α‐1‐adrenoceptor regulated mechanisms related to a net uptake of both potassium and calcium in rat heart.
The Influence of Detergents on Skin Barrier Properties
Authors: Pr̂íborský Jan , Takayama Kozo , Pr̂íborská Zuzana , Mühlbachovà Elfa , Nagai Tsuneji
Published: March 2009

Abstract: The influence of surfactants on the changes in skin barrier properties was investigated in rats. Various ionic and non‐ionic surfactants were assessed using indomethacin as a model penetrant. The surfactants appeared to either increase or decrease the skin permeability, due to the properties of both compound and surfactant. Ionic surfactant sodium dodecylsulfate was the most powerful and exceeded controls by approximately 10 times measured by means of serum levels of indomethacin. Other surfactants caused concentration increase or decrease of indomethacin in serum.
Effect of Various Antidotes on Biliary Excretion of Arsenic in Isolated Perfused Livers of Guinea Pigs after Acute Experimental Poisoning with As2O3*
Authors: Reichl F. X. , Mückter H. , Kreppel H. , Forth W.
Published: March 2009

Abstract: The effect of the dithiols British Anti‐Lewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuc‐cinic acid (DMSA) and a new metal binding agent 2, 3–bis‐(acetylthio)‐propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs after acute experimental poisoning with As2O3 was investigated. Guinea pigs received As2O3, 10.0 mg/kg subcutaneously at 9 a. m. as a single injection. One hour after the injection the livers were perfused (2.5 mix min.–1 x g–1 liver) with Krebs‐Henseleit buffer and glucose for 80 min. After 40 min. of saline perfusion (control) 0.1 or 0.7 mmol/1 BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effluent perfusate was measured. The biliary excretion of arsenic in control livers between 40 and 80 min. was 0.7% of the total arsenic liver content before perfusion (= arsenic liver content after perfusion + portion excreted in the bile + perfusate). After antidote addition (0.1 mmol/l) the excretion was 0.2% for livers perfused with BAL, 6.8% for DMSA, 10.6% for DMPS, and 11.1% for BAPSA, respectively. After 0.7 mmol/l antidote the excretion of arsenic was 0.1% in livers perfused with BAL, 9.6% for DMSA, 12.3% for DMPS, and 13.3% for BAPSA, respectively. Except BAL, all compounds and most effectively BAPSA increased biliary excretion of arsenic. This indicates that excretion of arsenic which normally is mainly renal is shifted towards faecal excretion by the dithiols.
Human Fibroblasts Lacking Trans‐Stilbene Oxide Active Glutathione Transferase Exhibit Increased Cell Death when Exposed to Polycyclic Aromatic Hydrocarbons*
Authors: Pessah‐Rasmussen Hélène , Stavenow Lars , Seidegård Janeric , Berglund Anna
Published: March 2009

Abstract: Glutathione transferases (GST) are detoxifying enzymes who act with many endogenous and exogenous substances such as polycyclic aromatic hydrocarbons (PAH). The GST activity towards trans‐stilbene oxide (GST‐tSBO) is inherited in an autosomal dominant fashion and can be separated in high (GST‐positive) and low (GST‐negative) phenotypes when measured in blood. Human fibroblast cultures were established from males matched for age, smoking habits and clinical manifestations of atherosclerosis. Matched pairs of GST‐negative and GST‐positive fibroblasts were studied. There was a very strong correlation between the levels of GST‐tSBO in peripheral blood and in cultured fibroblasts within the same individual. When fibroblasts were exposed to benzo(a)pyrene (BP) or dimethylbenzanthracene (DMBA) GST‐negative cells produced relatively more collagen than GST‐positive cells. GST‐negative fibroblasts showed a greater cell death than GST‐positive fibroblasts as well among controls as after exposure to PAH. It is concluded that lack of GST‐tSBO is easily discriminated in cultured skin fibroblasts. GST‐negative and GST‐positive fibroblasts showed different susceptibility towards some toxic stimuli that might be of importance in atherogenesis.
Isradipine Dynamics and Pharmacokinetics in the Isolated Rabbit Heart
Authors: Mellemkjær Søren , Bang Lone , Nielsen‐Kudsk Folmer
Published: March 2009

Abstract:The cardiac effects of increasing concentrations of isradipine (racemic) from 1.64 pM to 232 nM were studied in isolated spontaneously beating rabbit hearts. Inhibitory responses with regard to contraction amplitude, contraction velocity and oxygen consumption exhibited a biphasic progressive course at increasing drug exposure. Computer derived inhibitory Emax‐values of the second phase were 104, 103 and 87% (IC50: 7.1, 6.3 and 28.7 nM), respectively, whereas those of the initial phase were 24.7, 25.9 and 19.5% (IC50: 0.012, 0.038 and 0.026 nM). A progressive inhibition of frequency reached a maximum of only 21%. The ECG‐derived PQ‐interval showed a rapid increase (maximum 46%) at drug concentrations above 1 nM. Complete AV‐block and ventricular asystolia occurred in half of the hearts at the second highest (99 nM) and in all except one at the highest concentration. SA‐node activity was retained in 9 of 10 hearts at the second highest and in 3 at the highest drug exposure. The QRS‐ and the frequency‐corrected QT‐interval did not increase significantly. Coronary flow‐rate showed no initial increase, but a decrease to 70% of control at the highest concentration. Supplementaryin vitrostudies on rabbit coronary artery ring‐preparations contracted with 124 mM K+showed, however, an relaxant Emax‐value for isradipine of about 100% and an inhibitory EC50–value of 0.63 nM with a ‘Hill’ coefficient of 1.1. At toxic concentrations isradipine showed a kinetic monophasic accumulation in the rabbit heart of about 44‐fold with a half‐time of 10.6 min. The myocardial disposition of the drug was three‐phasic with half‐times of 4.3, 13.8 and 75 min., respectively. These findings seem compatible with a biphasic and only partial reversibility of the dynamic effects within 30 min. after termination of drug exposure.
Intoxications with Anticholinesterases: Effect of Different Combinations of Antidotes on the Dynamics of Acetylcholine in Mouse Brain
Authors: Nordgren I. , Karlén B. , Kimland M. , Palmér L. , Holmstedt B.
Published: March 2009

Abstract: Intoxications with organophosphorus compounds are normally treated with a mixture of atropine and an enzyme regenerating oxime. The addition of diazepam to the conventional drug therapy is reported to greatly improve the antidotal effect. The implication of the cholinergic system in such intoxications prompted us to study the effect of different combinations of antidotes on the acetylcholine (ACh) synthesizing system in mouse brain in vivo. The antidotes studied in this paper are diazepam, HI‐6 and 1–hyoscyamine, the active enantiomer of atropine. Diazepam decreases the synthesis rate of ACh both when administered separately and in combination with 1–hyoscyamine and HI‐6. This is in contrast to 1–hyoscyamine which, in addition to blocking muscarinic receptors, also increases the release and rate of synthesis of ACh, which probably is an unfavourable effect of the antidote. This might at least partly explain the advantage of combining 1–hyoscyamine and an oxime with diazepam in intoxications with anticholinesterases. Mice administered soman (0.75 x LD50), after pretreatment with the three‐drug combination of antidotes, show no cholinergic symptoms despite a 50% increase in endogenous ACh. The rate of synthesis of ACh in these mice is in the same range as in animals administered diazepam alone. Mice administered the same dose of soman with no antidotal pretreatment suffer from severe tremor and salivation, and have a strongly reduced synthesis rate of ACh.
Interactions between Substance P and Norepinephrine in the Regulation of Nociception in Mouse Spinal Cord
Authors: Eide Per Kristian , Hole Kjell
Published: March 2009

Abstract:This study examined interactions between effects of the undecapeptide substance P and norepinephrine and the α‐adrenoceptor agonist clonidine in the mouse spinal cord. All compounds were injected into the lumbar subarachnoid space, and effects on the tail‐flick reflex and the behavioural response to intrathecal substance P were evaluated. The tail‐flick response latencies were markedly increased 5–20 min. after intrathecal application of norepinephrine (0.0125–0.1 μg) or clonidine (0.0125–0.1 μg). The actions of both intrathecal norepinephrine (0.025 μg) and intrathecal clonidine (0.025 μg) were significantly attenuated when substance P (5 μg) was given intrathecally 55 and 45 min. before the agonists. There was a significant relationship between the tail‐flick response latencies and the tail skin temperature. However, the tail‐flick results were not due to changes in the skin temperature. Intrathecally applied substance P (10 ng) produced a response consisting of biting of the caudal part of the body and a few hindlimb scratches. The number of bites was significantly reduced 5 min. after injection of norepinephrine (0.1 μg) or clonidine (0.05–0.1 μg), but the number of scratches was unchanged. The data show that increased stimulation of spinal α‐adrenoceptors inhibits a spinal nociceptive reflex as well as the action of substance P in the spinal cord. Substance P modulates the action of α‐adrenoceptor agonists on the tail‐flick reflex, which may tentatively be explained by downregulation of α‐adrenoceptors by substance P.
Effect of Phosphamidon and Obidoxime on the QT‐RR Relationship of Isolated Rat Heart
Authors: Ben‐Haim Shlomo A. , Ben‐Ami Haim , Hayam Gal , Taitelman Uri , Edoute Yeouda
Published: March 2009

Abstract: We studied the effects of phosphamidon (an organophosphate compound), obidoxime (a cholinesterase reactivator), and their combination, phosphamidon/obidoxime (PD/OB) on cardiac cycle length (RR), QT interval, and on QT‐RR relationship of isolated rat heart. Cardiac cycle length did not change significantly following perfusion with phosphamidon or obidoxime alone; however, following perfusion with PD/OB, RR significantly increased at high concentrations (10–3 M) of both drugs. The QT interval lengthened by 5% following perfusion with phosphamidon, did not change following perfusion with obidoxime, and increased by 10% following perfusion with PD/OB. The QT‐RR relationship without drugs was positive and linear. Following perfusion with phosphamidon alone, the slope of the relationship decreased significantly, while perfusion with obidoxime alone did not change the QT‐RR relationship. Perfusion with PD/OB at low concentrations decreased the slope of the relationship; however, at the highest concentration (10–3 M) the QT‐RR relationship was inverted and became negative. Ventricular arrhythmias as premature ventricular beats, or bigeminies, were noted with increasing frequency following perfusion with increasing doses of phosphamidon. Perfusion with obidoxime did not cause arrhythmias, whereas perfusion with PD/OB caused premature ventricular beats, bigeminies, and ventricular tachycardias at high doses. We suggest that obidoxime modulates the direct effects of phosphamidon on the cardiac repolarization process. PD/OB at high concentrations invert the normal depolarization‐repolarization coupling and may therefore potentiate arrhythmias.
Ouabain Enhancement of Compound 48/80 Induced Histamine Secretion from Rat Peritoneal Mast Cells: Dependence on Extracellular Sodium
Authors: Knudsen T. , Bertelsen H. , Johansen T.
Published: March 2009

Abstract:Purified populations of rat peritoneal mast cells were used to study the effect of ouabain on compound 48/80‐induced histamine secretion and on86Rb+uptake.86Rb+was used as a tracer for extracellular K+. The calculated value of the ouabain‐sensitive uptake of K+and86Rb+was considered a measure of the Na+–K+pump activity of the cells. Ouabain caused an immediate inhibition of the pump activity and a time‐dependent increase in histamine secretion in the absence of extracellular calcium. No effect on the secretion was observed in the presence of calcium. The effect of ouabain on the secretion occurs in the presence of sodium but not when sodium was replaced by lithium. Preservation by ouabain of a high intracellular sodium content in sodium‐loaded cells was associated with preservation of the secretory response in a calcium‐free medium. In the presence of lanthanum in a calcium‐free medium, the pump activity was inhibited and the enhancement by ouabain of the secretion of histamine was blocked. A less marked inhibition of the pump was found in a calcium‐free medium containing magnesium. The inhibition exerted by magnesium was concentration‐dependent (0–5 mM) as was the counteraction of magnesium of the enhancement of ouabain of the secretion of histamine. These observations indicate that the enhancement by ouabain of the secretory response of mast cells preincubated in a calcium‐free medium is associated with accumulation of sodium inside the cell. In addition to a decreased rate of sodium‐calcium exchange caused by a decreased inward directed sodium gradient, the mechanism by which ouabain enhances the secretory response is likely to involve an increased binding of calcium to membrane binding sites.
Effects of Androgen Treatment on Adenylate Cyclase System in Rat Hepatic Membranes
Authors: Shima Sumio
Published: March 2009

Abstract:Effects of androgen treatment of young female rats on glucagon‐ and catecholamine‐sensitive adenylate cyclase activity and adrenergic receptors of hepatic membranes have been studied. Injections of testosterone propionate for 7 days showed a significant decrease in the adenylate cyclase activity responding to isoproterenol and glucagon. The decrease in hormonal stimulation of the enzyme was accompanied with the fall in activation by non‐hormonal stimuli, such as forskolin, sodium fluoride, Gpp(NH)p and Mn, without any changes in the number and the affinity of p‐adrenergic receptors of the membrane. These results suggest that androgens exert post‐receptor effects by inhibiting the activity of the catalytic unit of adenylate cyclase system in rat hepatic membranes.
The Fate of Altered Hepatocytic Foci as a Result of Treatment with Oxodipine, a Calcium Channel Blocker
Authors: Nyska Abraham , Waner Trevor , Galiano Alvaro , Klein Baruch
Published: March 2009

Abstract: The dietary administration of the calcium channel blocker oxodipine to Fischer (F344) rats for 12 and 30 months resulted in increased incidence of altered hepatocytic foci (AHF). As the Environmental Protection Agency (EPA) regards AHF as potentially precancerous it is important to accumulate experimental evidence which may negate this theory. In the case of oxodipine we proved that with dosages close to maximum tolerated dose (MTD) for prolonged periods no hepatic neoplasms were produced. The possible nature of such AHF is discussed.
Class III Antiarrhythmic Action and Inotropy: Effects of Almokalant in Acute Ischaemic Heart Failure in Dogs
Authors: Mortensen Elin , Yang Tao , Refsum Helge
Published: March 2009

Abstract:We studied the haemodynamic and metabolic effects of the novel class III antiarrhythmic agent almokalant (H 234/09) in acute ischaemic heart failure at a dose prolonging ventricular repolarization. In pentobarbital anaesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular end‐diastolic pressure (LVEDP) of 32 ± 2 mmHg was achieved. Embolization depressed LV dP/dtmax, LV dP/dtmin, left ventricular systolic pressure (LVSP) and cardiac output. After intravenous infusion of almokalant (0.35 μg/kg) LV dP/dtmaxand LV dP/dtminwere not significantly changed at paced cycle length of 300 msec, whereas LVSP and aortic pressure decreased both at spontaneous and paced cycle length of 300 msec. LVEDP remained unchanged. Heart rate decreased from 185 ± 7 to 167 ± 5 beats/min., and corrected QT‐time (QTc) increased from 9.5 ± 0.3 to 10.4 ± 0.5 msec. Arterial concentration and net myocardial uptake of glucose, lactate and free fatty acids were not significantly influenced by almokalant. In conclusion, almokalant at a dose prolonging ventricular repolarization had no negative inotropic effect in acute ischaemic heart failure.
Antithrombotic Activity of a New Pyrazine Derivative Determined by the Mouse Antithrombotic Assay
Authors: Petrusewicz Jacek , Yilinkou Rene Garni , Pilarski Boguslaw , Kaliszan Roman
Published: March 2009

Abstract:A model of pulmonary microembolization in the mouse induced by infusion of epinephrine and collagen was used to determine antithrombotic activity of indomethacin and acetylsalicylic acid and of two newly synthesized pyrazine derivatives. One of the new agents provided marked protection of mice from thrombotic challenge with epinephrine and collagen. Its effectiveness was higher than acetylsalicylic acid (especially at small doses) but smaller than that of indomethacin. The same compound was similar to acetylsalicylic acid with respect to the inhibition ofin vitrohuman blood platelet aggregation. The new class of pyrazine derivatives (the so‐called pyrazine CH‐ and NH‐acids) appears interesting from the view‐point of the studies of platelet aggregation and may yield potential antithrombotic drugs.
Recent Developments in Peptide Drug Delivery to the Brain
Authors: Pardridge William M.
Published: March 2009

Abstract:Peptide‐based therapeutics are highly water‐soluble compounds that do not readily enter brain from blood owing to poor transport through the brain capillary endothelial wall, i.e., the blood‐brain barrier (BBB). Strategies available for peptide drug delivery to brain include: (a) neurosurgical‐based (intraventricular drug infusion, hyperosmotic opening of the BBB); (b) pharmacological‐based (peptide lipidization, liposomes); and (c) physiological‐based (biochemical opening of the BBB, chimeric peptides). Chimeric peptides are formed by the covalent coupling of a pharmaceutical peptide (that is normally not transported through the BBB) to a brain transport vector that undergoes absorptive‐mediated or receptor‐mediated transcytosis through the BBB. The most efficient brain transport vector known to date is a monoclonal antibody to the transferrin receptor, and this vector achieves a brain volume of distribution approximately 18‐fold greater than the plasma space by 5 hr after a single intravenous injection of antibody. The chimeric peptides are formed generally with chemical‐based linkers. However, avidin/biotin‐based linkers allow for high yield coupling of drug to vector, and for the release of biologically‐active peptide following cleavage of the chimeric peptide linker. These strategies may also be used for the delivery of antisense oligonucleotide‐based therapeutics to brain. In conclusion, the development of efficacious neuropharmaceuticals in the future will require the development of both drug delivery and drug discovery strategies that operate in parallel.
The Influence of Mercury on the Secretion of Human Chorionic Gonadotropin in Superfused Young Placental Tissue
Authors: Boadi W. Y. , Shurtz‐Swirski R. , Barnea E. R. , Urbach J. , Brandes J. M. , Yannai S.
Published: March 2009

Abstract: The effect of mercury (Hg), as HgCl2, in levels ranging from 0.75 to 12 μg/ml medium, on the secretion of human chorionic gonadotropin (hCG) was examined in first‐trimester placental explants, after 6 or 24 hr incubation, employing both static and dynamic systems (the latter by superfusion). Later the unbound Hg was washed for 45 min. with fresh medium devoid of Hg, followed by superfusion with the latter medium for 75 min., during which time samples were collected for hCG assay. For the superfusion experiments the parameters used for evaluating the hCG secretion pattern were: mean peak amplitude, pulse frequency and the area under the hCG secretion curve (AUC). The results observed after 24 hr incubation indicate that in the dynamic system the hCG secretion increased significantly, and this increase was dose‐dependent. There was also a dose‐related increase in mean total hCG secreted by the explants exposed to Hg. Maximal hCG secretion was observed after 24 hr exposure of explants to 6 μg of the metal/ml. Both the mean peak amplitude and AUC parameters showed a statistically‐significant increase for this dose level. At 12 μg/ml, the pulsatile secretion of hCG decreased, but the value for the mean hCG secretion was still higher than that observed for 0.75 and 3 μg/ml. After 6 hr incubation, however, there were no significant changes from the control, as judged by all of the above parameters. The levels of hCG secreted by the explants into the media in the static system were not significantly different from their respective controls, for both incubation periods and Hg levels. These results may reflect an altered de novo synthesis, or increased production of hCG granules, resulting in enhanced hCG secretion, brought about by exposure to Hg.
5‐Hydroxytryptamine1AReceptor Agonists in Animal Models of Depression and Anxiety
Authors: Kostowski Wojciech , Dyr Wanda , Krzascik Pawel , Järbe Torbjörn , Archer Trevor
Published: March 2009

Abstract:The effects of different doses of buspirone, 3‐dipropyl‐amino‐5‐hydrochromar (NDO 008) and 8‐hydroxydipropyl‐aminotetralin (8‐OH‐DPAT) (administered intraperitoneally) were studied in tests of anxiolytic and antidepressant action in rats. These tests included the elevated plus maze test, the forced swim test, stress‐induced suppression of open‐field behavior, and the differential‐reinforcement‐of‐low‐rates‐of‐behaviour‐72 sec (DRL 72 s) test. Buspirone (0.125 mg/kg) and NDO 008 (1.0 to 2.0 mg/kg) produced anxiolytic activity in the elevated plus maze, whereas 8‐OH‐DPAT did not in the doses employed. All three compounds increased activity in the forced swim test, although buspirone did so at a lower dose than NDO 008 and 8‐OH‐DPAT. In the stress‐induced suppression test of open field activity all three compounds induced an antidepressant‐like effect at different doses dependent on whether footshock (stressor) was presented 24 hr before or just prior to the open‐field test. All three compounds even caused some reduction of activity in the non‐shocked rats. 8‐OH‐DPAT (1.0 mg/kg) produced a significant and reliable increase in the Reinforcement/Response rate quotient in the DRL 72s test. These diverse results may provide an indication of potential clinical efficacy of the 5‐HT1Aagonists in the treatment of anxiety and depression.
Chrononephrotoxicity in Rat of a Vancomycin and Gentamicin Combination
Authors: Fauconneau B. , Lemos E. De , Pariat C. , Bouquet S. , Courtois Ph. , Piriou A.
Published: March 2009

Abstract:The effect of time of administration on excretion of two brush border enzymes ‐ alanine aminopeptidase (AAP) and gamma‐glutamyl transferase (γGT), and a lysosomal enzyme, N‐acetyl‐β‐D‐glucosaminidase (NAG) with a single high dose of vancomycin, gentamicin or a combination of vancomycin and gentamicin was studied in male Wistar rats and compared with elimination of a control group. The rats received vancomycin intraperitoneally (200 mg·kg‐1), gentamicin intramuscularly (100 mg·kg‐1) or the combination of the drugs by the same route. A control group received isotonic NaCl solution. The four groups of animals received a single injection at 8 a.m., 2 p.m., 8 p.m. and 2 a.m. and urine excretion values for AAP, γGT and NAG were determined 24 hr later. The results show that the nephrotoxicity of gentamicin + vancomycin is greater than that observed with gentamicin, which again is greater than that observed with vancomycin. Furthermore, circadian variations in renal toxicity were observed, the least occurring at 8 a.m.
In VitroTachyphylaxis to Isoprenaline in Guinea‐Pig Trachea: Influence of Theophylline?
Authors: Bergendal A. , Lindén A. , Lötvall J. , Ullman A. , Skoogh B. E. , Löfdahl C. G.
Published: March 2009

Abstract:We used frontally opened tracheal rings, contracted with 10 μM of histamine to produce β‐adrenoceptor tachyphylaxis by isoprenaline incubation and to evaluate whether theophylline can prevent this tachyphylaxis. Two concentration‐response experiments with isoprenaline were performed in each ring. Between the concentration‐response experiments the rings were incubated using four different treatments, isoprenaline (3 μM), theophylline (1 mM), theophylline + isoprenaline or vehicle for 60 min. Tachyphylaxis was evaluated as the difference in pD2(‐log EC50) during the first and second concentration‐response experiment. Isoprenaline incubation produced a shift to the right of the concentration‐response curve. The shift was small (approximately 0.2 log units) but significantly different from the control group. Theophylline failed to influence the process either alone or in combination with isoprenaline. In conclusion, β‐adrenoceptor tachyphylaxis after isoprenaline incubation in isolated guinea‐pig trachea proved to be a very small effect and we observed no influence by theophylline.
Active and Passive Electrical Properties of Isolated Canine Cardiac Purkinje Fibers under Conditions Simulating Ischaemia: Effect of Diltiazem
Authors: Nánási Péter P. , Knilans Timothy K. , Varró András , Murphy Anne M. , Fujiki Akira , Schwartz Arnold , Lathrop David A.
Published: March 2009

Abstract: The effect of a calcium channel blocker diltiazem on the electrical properties of canine Purkinje fibers superfused in a milieu similar to that occurring in acute myocardial ischaemia was studied. Action potential parameters, passive electrical properties, and conduction velocity were measured using conventional microelectrode techniques. Superfusion with glucose‐free Tyrode's solution containing 9 mM K+, gassed with 100% N2 at pH = 6.5 (‘ischemic solution') significantly reduced the maximal diastolic potential, action potential duration, maximal upstroke velocity, conduction velocity and length constant, while input resistance and longitudinal resistance were elevated and membrane resistance remained unchanged. Diltiazem (1 μM) alone reduced only the action potential duration, while all other parameters were unaffected. Pretreatment with diltiazem did not fully prevent the effects of ischemic superfusion; however, the ischaemia‐induced decrease in length constant was not significant in the presence of diltiazem. In addition, the increase in longitudinal resistance during ischaemia was significantly reduced following diltiazem pretreatment. This decrease in longitudinal resistance may contribute to the improvement of ischaemia‐induced conduction delay observed in intact animals and may be related to a reduction of ischaemia‐induced increase in intracellular free Ca2+.
Effects of Hydrocarbons on Transformation and Intercellular Communication in Syrian Hamster Embryo Cells
Authors: Rivedal E. , Mikalsen S.‐O. , Roseng L. E. , Sanner T. , Eide I.
Published: March 2009

Abstract: The ability of 18 different hydrocarbons to induce and promote morphological transformation and to inhibit intercellular communication in primary Syrian hamster embryo cells in culture have been studied. The compounds were: the n‐alkanes octane, nonane, decane, undecane, dodecane and tridecane; the iso‐alkanes 2‐methylheptane, 2‐methyloctane and 2‐methylnonane; the naphthenes 1,2‐dimethylcyclohexane, 1,2,4‐trimethylcyclohexane and tert‐butylcyclohexane; the aromates 1,2‐dimethylbenzene, 1,2,4‐trimetylbenzene and tert‐butylbenzene; and the alkenes 1‐octene, 1‐nonene and 1‐decene. None of the hydrocarbons induced morphological transformation of Syrian hamster embryo cells. When the hydrocarbons were incubated together with benzo(a)pyrene, enhancement of the transformation frequency was observed for the naphthene 1,2‐dimethylcyclohexane and the iso‐alkanes 2‐methylheptane and 2‐methyloctane. None of the n‐alkanes, alkenes or aromates enhanced the transformation frequency induced by benzo(a)pyrene. The alkane tridecane and the iso‐alkanes 2‐methyloctane and 2‐methylnonane reduced intercellular communication in the primary Syrian hamster embryo cells.
Effects of Central and Peripheral Type Benzodiazepine Ligands on Growth Hormone and Gonadotropin Secretion in Male Rats*
Authors: Männistö Pekka T. , Laakso Maija‐Lüsa , Järvinen Asko , Rägo Lembit
Published: March 2009

Abstract:The action of central and peripheral type benzodiazepine ligands on growth hormone, luteinizing hormone and follicle stimulating hormone levels in serum were studied in male rats. Graded doses of Ro 5‐4864, that binds to the peripheral type benzodiazepine receptors, clonazepam, a fairly pure central type agonist and diazepam, a mixed‐type agonist, were given intraperitoneally. Also a benzodiazepine partial inverse agonist, FG 7142, was investigated. Clonazepam increased growth hormone levels at 0.2 mg/kg while higher doses were not active. Diazepam (5‐25 mg/kg) was not effective. FG 7142 (15 mg/kg) and Ro 5‐4864 (25 mg/kg) decreased growth hormone levels. Flumazenil, a central‐type antagonist, reversed at least partially the effects of clonazepam and FG 7142, suggesting an effect through GABA‐benzodiazepine complex. Elevation of growth hormone could be associated with anxiolysis and decrease of growth hormone with enhanced anxiety. Clonazepam (0.2‐5 mg/kg) and diazepam (5‐25 mg/kg) increased luteinizing hormone concentrations, but only the effects of 1 mg/kg of clonazepam and 5 mg/kg of diazepam reached statistical significance. Even FG 7142 caused a modest increase of luteinizing hormone at 5 mg/kg, but Ro 5‐4864 rather decreased luteinizing hormone, although not significantly. Flumazenil (25 mg/kg) antagonized partially the effects of diazepam and clonazepam. Effects of Ro 5‐4864 and FG 7142 were not modified by flumazenil or PK 11195, a peripheral‐type mixed antagonist/agonist. Luteinizing hormone stimulation by benzodiazepine ligands may be a pituitary action while inhibition could be caused by the activation of the central GABAergic system. Serum follicle stimulating hormone levels were not significantly altered by central or peripheral type benzodiazepine agonists or antagonists.
Reward and Abuse of Opiates
Authors: Ramsey Nick F. , Van Ree Jan M.
Published: March 2009

Abstract:The dependence creating properties of drugs are mediated by structures in the brain. The mesolimbic system seems to play a crucial role in the behaviourally reinforcing effects of opiates and other drugs of abuse. The significance of dopamine in opiate reinforcement is still a matter of debate, in spite of the large number of studies on this subject. Dopamine appears to be involved in conditioning processes and in drug self‐administration behaviour only once it has been established. Neuropeptides, centrally active fragments of hormones, may play a role in the individual vulnerability for the development of drug dependence. Administration of a number of wellknown neuropeptides attenuates the acquisition of drug self‐administration behaviour. The virtues and flaws of some widely used animal models for drug dependence are discussed.
GEA 857, A Putative Blocker of Potassium Conductance, Enhances Muscarinic Agonist‐Evoked Responses: Dissociation from an Action on 5‐HT Mechanisms
Authors: Ögren Sven Ove , Bartfai Tamas , Hedlund Britta , Lindberg Ulf Henrik
Published: March 2009

Abstract:GEA 857 [2‐(4‐chlorophenyl)‐1,1‐dimethylethyl 2‐amino‐3‐methylbutanoate], a structural analogue of the 5‐HT uptake blocker alaproclate, was tested for its ability to modify tremor and salivation induced by muscarinic agonists (oxotremorine, arecoline) and acetylcholinesterase inhibitors (physostigmine, THA) in the male rat. These agents were employed at submaximal doses. GEA 857, similarly to alaproclate (Ögrenet al.1985a & b), produced a dose‐dependent, statistically significant (in the 5‐20 mg/kg dose range) enhancement of the tremor response induced by all four cholinergic stimulants. However, unlike alaproclate, GEA 857 failed to enhance salivation in a consistent manner. GEA 857 itself did not produce tremor in the absence of the muscarinic agonists or the acetylcholinesterase inhibitors. The potentiation of oxotremorine tremor by GEA 857 could be fully blocked by atropine (1 mg/kg intraperitoneally). Unlike alaproclate, GEA 857 failed to affect 5‐HT uptake or 5‐HT metabolism in the 10‐20 mg/kg dose range. However, similarly to the action of alaproclate, the potentiating effect of GEA 857 on muscarinic responses could be explained neither by actions on serotonergic mechanisms nor by actions on muscarinic receptor mechanisms in the striatum. Evidence is presented suggesting that the ability of GEA 857 to enhance responses evoked by muscarinic agonists involves inhibitory properties of GEA 857 at certain membranal Ca2+‐dependent K+channels, the blockade of which can potentiate or prolong muscarinic cholinergic actions.
Elimination of PCB Congeners via Milk in Rabbits Administered Fenclor 64
Authors: Montesissa C. , Lauro F. Di , Fadini L. , Pompa G.
Published: March 2009

Abstract:A single dose of 100 mg per kg body weight of a commercial mixture of polychlorinated biphenyls (PCB), Fenclor 64 was given intraperitoneally to pregnant rabbits. The distribution in dams and foetuses and excretion in milk was investigated for six of the congeners by quantifying them in fat from maternal adipose tissue, from whole foetuses and newborn bodies and from newborn gastric contents. The cytochrome‐P‐450 induction after Fenclor 64 in foetuses and suckling off‐spring was followed by measuring the following hepatic mixed function oxidase (MFO) activities: p‐nitroanisole‐demethylase, ethoxyresorufin‐deethylase, ethoxycoumarin‐deethylase and NADPH cytochrome‐C reductase. At the 28th day of pregnancy PCB fat concentrations in foetuses were similar to those in mothers (126.4 ± 7.1 and 152.6 ± 28.1 μg/g of fat, respectively). By the 5th day of life fat concentrations in the youngs were double those of foetuses (216.81 ± 8.12 μg/g) and remained high until weaning (142.2 ± 15.5 μg/g at the 20th day). PCB concentrations in mothers'fat decreased during lactation (104.1 μg/g at the 20th day) but at the end of the experiment they were still high (95.5 μg/g). The cytochrome‐P‐450 concentration and MFO activities in young rabbits'livers from treated dams were significantly higher than controls from the 5th (P<0.01) to the 10th (P<0.01) day of life, with the exception of NADPH‐cyt‐C‐reductase (P<0.05). By the 20th day the differences between control and treated animals were smaller but significant (P<0.05), except for ethoxycoumarin deethylase; by the 40th day all the MFOs and the cytochrome‐P‐450 concentration reached the values of control animals.
Inhalation Kinetics of C6 to C10 Aliphatic, Aromatic and Naphthenic Hydrocarbons in Rat after Repeated Exposures
Authors: Zahlsen K. , Eide I. , Nilsen A. M. , Nilsen O. G.
Published: March 2009

Abstract: The toxicokinetic properties of C6 to C10 n‐alkanes, aromates and naphthenes have been investigated in rats during inhalation of 100 p.p.m. of the single hydrocarbons for 3 days, 12 hr/day. The concentration of hydrocarbon was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat at days 1, 2 and 3, immediately after termination of exposure and 12 hr after exposure on day 3. The main conclusions drawn from the study were: a) Aromatic hydrocarbons show high concentrations in blood and low concentrations in organs. b) Naphthenic hydrocarbons show low concentrations in blood and high concentrations in organs. c) n‐Alkanes show very low concentrations in blood, relatively high concentrations in brain and a high potential for accumulation in fat with repeated exposures. d) Biological concentrations of hydrocarbons within one class increase in general with increasing molecular weight, though with specific exceptions. e) Accumulation is obviously influenced by differences in metabolism and enzyme induction potential. f) Lipid solubility is not the only parameter relevant for the evaluation of hydrocarbon accumulation.
Single Dose Pharmacokinetics of Trazodone in Healthy Subjects
Authors: Nilsen Odd G. , Dale Ola
Published: March 2009

Abstract: Eight healthy subjects were administered trazodone‐HCl orally (100 mg) with and without food and by infusion in a three way cross‐over study. Unchanged trazodone was determined in serum and urine by high performance liquid chromatography after an alkaline extraction. Absorption of trazodone was irregular in fasting subjects and improved after food intake. Food intake significantly decreased the maximum serum concentrations of trazodone from 1.88 ± 0.42 to 1.47 ± 0.16 μg/ml, and increased the time for reaching maximum concentration from 1.3 ± 0.8 hr to 2.0 ± 1.5 hr. No differences were observed in the total amount of trazodone absorbed with or without food with bioavailability values of 65 ± 6 and 63 ± 4 per cent, respectively. The apparent volume of distribution and total body clearance for trazodone were estimated to 0.84 ± 0.16 1/kg and 5.3 ± 0.9 1/hr, respectively. The terminal elimination half‐life of 7.3 ± 0.8 hr showed no significant differences between the different ways of administration. Urinary excretion of unchanged trazodone during 26 hr was less than 0.13 per cent of the administered dose, suggesting a high degree of trazodone metabolism. Earlier statements of enterohepatic circulation of trazodone and pharmacokinetic differences between males and females were not confirmed by the present study. Due to the irregular absorption in fasting subjects, trazodone should preferably be administered after food.
In Vitro and In Vivo Evaluation of the Genotoxicity of N‐Nitrosooxprenolol
Authors: Martelli Antonietta , Canonero Roberta , Allavena Alessandra , Sottofattori Enzo , Brambilla Giovanni
Published: March 2009

Abstract: N‐nitrosooxprenolol (NO‐oxprenolol) might be formed in the stomach of patients taking the β‐adrenergic blocking drug, oxprenolol. This nitroso derivative has previously been shown to induce DNA damage and repair in both rat and human cultured hepatocytes. The results of the present study show that in the presence of co‐cultured rat hepatocytes, 0.03 mM NO‐oxprenolol produced a significant increase in the frequency of 6‐thioguanine‐resistant but not of ouabain‐resistant mutants. No mutagenic activity was detected in the absence of metabolic activation. In mice, NO‐oxprenolol (1 g/kg) increased the incidence of micronucleated cells in the liver but not in the bone marrow and the spleen. These results suggest that NO‐oxprenolol, consistent with its chemical nature of nitrosamine, is biotransformed into short‐lived reactive species.