bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of St−587 on the α-adrenoceptors in the Bisected Rat Vas Deferens
Authors: Badia A , Sallés J
Published: April 2011

The effects of the α-adrenoceptor agonist St−587 have been studied on the twitch responses induced by field stimulation in the prostatic portion of rat vas deferens. Moreover the drug’s influence on the unstimulated prostatic and epididymal halves of rat vas deferens has also been determined. Alone and after addition of yohimbine (0·3 μM) it enhanced in a concentration-dependent manner the twitch responses in the prostatic half. Prazosin competitively antagonized (pA2 = 8·41 · 0·03) this effect. The enhancing effect of St−587 was not reduced in reserpinized animals. These results suggest that post-synaptic α1-adrenoceptors are involved in the potentiation of twitch responses induced by St−587. When α1-adrenoceptors were blocked by prazosin (0·1 μM), St−587 partially inhibited the twitch responses of the prostatic portion of rat vas deferens (Emax=49·5 ± 3·5%). Yohimbine completely reversed the inhibitory effects of both St-587 and Clonidine. Furthermore St−587 antagonized the inhibitory effects of Clonidine on twitch responses. Thus it appears that St−587 also behaves as a partial agonist of presynaptic α2-adrenoceptors in this portion of rat vas deferens, but it did not induce contractions in the unstimulated prostatic half of the vas deferens. However, it competitively antagonized the α1-adrenoceptor agonist phenylephrine by acting as an antagonist of prostatic postsynaptic α1 adrenoceptors. These α1-adrenoceptors are probably different from those that mediate the twitch enhancing response to St−587 in that portion. On the other hand, St−587 was a partial agonist of α1-adrenoceptors in the epididymal half. These results suggest that a different efficiency of stimulus-response mechanism is operating after postsynaptic α1-adrenoceptor activation in each one of the unstimulated portions of rat vas deferens.
Carbamoylated Enzyme Reversal as a Means of Predicting Pyridostigmine Protection Against Soman
Authors: Ellin Robert I , Kaminskis Andris
Published: April 2011

The inhibition of human and mammalian red blood cell (RBC) Cholinesterase (AChE) in whole blood in the presence of added pyridostigmine has been examined. After the addition of pyridostigmine to animal and human blood, red cells were separated from plasma at varying intervals and their enzyme activity measured. An apparent rate constant (ke) was derived for the reaction sequence in which carbamate is released from AChE inhibited by pyridostigmine. The constant is a complex of the rates of decarbamoylation and reinhibition of AChE in the blood sample. Rate constants were also determined for the spontaneous reactivation (ks) of carbamoylated AChE in the species studied. Values of ks were greater than ke in corresponding species but varied little between species. Pretreatment of animals with pyridostigmine is known to be an effective therapy against organophosphorus compounds, including soman. The ranking of ke values in mammalian blood was the same as that for the protection against soman in animals: monkey>guinea-pig>rabbit>rat (ke = 0·15, 0·07, 0·05, 0·02 h−1, respectively). Since ke for human blood (0·20 h−1) was greater than that of monkey, pyridostigmine pretreatment would be expected to be an effective prophylaxis for soman in humans.
The effect of repeated treatment with antidepressant drugs on the thyrotropin-releasing hormone (TRH)-induced hyperthermia in mice
Authors: Przegaliński Edmund , Baran Leokadia , Siwanowicz Joanna
Published: April 2011

The effect of acute (single dose) or repeated (twice daily, for 14 days) administration of 10 mg kg−1 p.o. of Imipramine, amitriptyline, Citalopram or mianserin has been examined on the hyperthermia induced by thyrotropin-releasing hormone (TRH) (40 mg kg−1 i.p., 2, or 2 and 72 h after single or last dose of antidepressants, respectively) in mice. Both imipramine and amitriptyline, given repeatedly, potentiated the TRH response, though the effect was observed 2 but not 72 h after the last dose of those drugs. Potentiation was also found after the single dose of imipramine or amitriptyline. On the other hand, Citalopram and mianserin, administered either acutely or repeatedly, did not affect the TRH-induced hyperthermia.
Bromocriptine-induced decrease in blood pressure in conscious spontaneously hypertensive rats: Evidence for a peripheral site of action
Authors: van den Buuse M , Lambrechts A C
Published: April 2011

The aim of the study was to discover whether the dopamine agonist bromocriptine has a central or peripheral site of action on blood pressure. An intraperitoneal injection of bromocriptine (0·5 mg kg−1) induced a long-lasting decrease in blood pressure in conscious spontaneously hypertensive rats (SHR). This effect was blocked by peripheral pretreatment with haloperidol or domperidone, but not by central treatment with haloperidol. A central injection of bromocriptine had only minor effects on blood pressure. These results suggest that primarily peripheral, rather than central, mechanisms are involved in the hypotensive effects of bromocriptine.
Absence of [3H]SCH 23390 binding sites in the rat adrenal gland
Authors: Zdilar D , Lacković Z
Published: April 2011

The binding of D2-dopamine receptor ligand [3H]spiperone and selective D1-ligand [3H]SCH 23390 to the rat adrenal gland and striatum has been compared. [3H]Spiperone showed specific binding in both tissues revealing a Bmax of 887 fmol mg−1 protein and KD of 0·38 nM, and B of 34 fmol mg−1 protein and KD of 0·66 nM in the striatum and adrenal gland, respectively. On the other hand, [3H]SCH 23390 showed a specific binding to the striatal tissue with Bmax of 747 fmol mg−1 protein and KD of 0·70 nM, while in the adrenal tissue no specific binding was observed. These results apparently indicated only D2-dopamine receptor binding sites being present in the rat adrenal gland.
Bioavailability of isradipine in young and old rats: Effect of mode of administration
Authors: Tse F L S , Jaffe J M , Hassell A E , Schran H F
Published: April 2011

The bioavailability of isradipine has been examined in 7-and 52-week-old rats after oral (12·5 mg kg−1) or intravenous (2·5 mg kg−1) doses as a solution and administration of various doses (1·8–85·5 mg kg−1) in the diet. Serial plasma samples were obtained from each rat and the drug concentration was determined by radioimmunoassay. Absorption from the dose given by gavage was rapid but when administered in a drug-diet mixture, isradipine appeared in the plasma slowly and in a manner reflecting the feeding pattern. Its absolute bioavailability from the drug-diet mixture averaged 3% over the dose range tested. By gavage its bioavailability was enhanced to 5% of dose with peak plasma values approximately 7 times higher than from a comparable dose in the diet. The low oral bioavailability of isradipine in the rat was most likely due to extensive first-pass metabolism. The decline in plasma concentrations was biexponential, with a mean terminal half-life of 3·6–3·7 h after oral or intravenous dosing. The pharmacokinetic characteristics of isradipine examined were independent of the age of the rat, except that its volume of distribution decreased with age. The older rats also showed a greater inter-animal variability in isradipine bioavailability from the drug-diet mixture.
Purification of Pluronic F-68 for perfluorochemical emulsification
Authors: Bentley P K , Davis S S , Johnson O L , Lowe K C , Washington C
Published: April 2011

A novel technique for purification of Pluronic F-68 has been developed involving passage through a silica-Amberlite resin column. Impurities present in commercial grade Pluronic could be readily removed, as confirmed by analysis of absorption and fluorescence emission bands. Intravenous injection of a 4% (w/v) unpurified Pluronic solution in male rats increased mean liver weight by 14% (P<0·05) after 24 h and increased spleen weight in female rats by 29% (P<0·01) after 7 days. No corresponding tissue weight changes occurred following injection of purified Pluronic solution. Haematocrit and red cell counts were also unchanged throughout. We propose that the use of purified Pluronic for perfluorochemical emulsification may reduce previously reported side-effects.
Permeability of Cellulose Polymers: Water Vapour Transmission Rates
Authors: Sprockel O L , Prapaitrakul W , Shivanand P
Published: April 2011

The water vapour transmission rates (WVTR) through solvent cast polymer films prepared from cellulose acetate, cellulose acetate propionate, and cellulose acetate butyrate have been determined. They were influenced by the relative humidity, the substituent type and the extent of substitution. Increasing the relative humidity from 32 to 90% increased the WVTR 3 to 5 times depending on the polymer used. The WVTR increased in the order of butyrate < propionate < acetate. An increase in the extent of substitution with acetyl and/or butyryl groups resulted in an exponential decline in the WVTR.
Decrease in Penbutolol Central Response as a Cause of Changes in its Serum Protein Binding
Authors: Jordá R Martínez , Aguirre C , Calvo R , Rodríguez-Sasiaín J M , Erill S
Published: April 2011

Penbutolol is a β-adrenoceptor antagonist that is extensively bound to α1-acid glycoprotein (α1-AGP), a protein that increases in inflammatory diseases thereby binding more drug in such conditions. Changes in serum binding can lead to modifications in the pharmacokinetics and pharmacodynamics of a drug, therefore, the central effect (as the anticonvulsant response) and brain uptake of penbutolol given intravenously to mice with experimental inflammation have been measured. A significant decrease of the central effect of penbutolol and its brain uptake was seen in diseased when compared with control animals (P < 0.01). A parallel decrease in free fraction of penbutolol in diseased vs normal animals was detected. These results suggest that there is an increase in serum binding of basic drugs related to increments in α1-AGP concentration, which reduces their central pharmacological effect.
Increased proliferation of phytohaemagglutinin (PHA)-stimulated human leucocytes after 8-methoxypsoralen treatment
Authors: Gawron A , Górski G , Glowniak K
Published: April 2011

The effect of 8-methoxypsoralen on human blood mono-nuclear cells cultured in darkness has been examined. 8-Methoxypsoralen (1 μg mL−1, 4.6 μM) added to (phytohaemagglutinin-stimulated cells induced a two-fold increase in the number of mitoses. The number of blastic cells also increased. There was no effect on the formation of micronuclei and there was no chromosomal breakage.
Enhancing effect of combining two pyrrolidone vehicles on transdermal drug delivery
Authors: Sasaki Hitoshi , Kojima Masaki , Nakamura Junzo , Shibasaki Juichiro
Published: April 2011

The enhancing effect of combining 1-methyl-2-pyrrolidone (MP) and 1-lauryl-2-pyrrolidone (LP) as the vehicles for transdermal penetration of phenolsulphonphthalein (phenol red) has been investigated by using an in-vitro technique with excised rat skin. LP had a higher enhancing effect on the penetration of phenol red than MP, but there was a long lag time before steady-state penetration was attained. A potent effect with a shorter lag time was obtained when MP and LP were used together. This potentiation was maintained when the concentration of MP was decreased by 95%. The combined vehicle also enhanced the skin accumulation of phenol red. MP promoted the rapid penetration of LP into the skin and potentiated the enhancing effect of LP on the penetration of phenol red and thereby shortened the lag time. The combined vehicle also enhanced the penetration of the hydrophilic anticancer agent, 5-fluorouracil.
Circadian phase dependent acute toxicity and pharmacokinetics of etidocaine in serum and brain of mice
Authors: Bruguerolle Bernard , Prat Marin
Published: April 2011

The aim of this study was to investigate the possible influence of the time of administration on etidocaine acute toxicity and kinetics in mice. Different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on 06.00–18.00) were injected at one of the following times: 10.00, 16.00,19.00,22.00,01.00 and 04.00 h with four doses of etidocaine at each time point to establish the acute toxicity (LD 50). To assess chronokinetics, a single 40 mg kg−1 i.p. dose of etidocaine was given to adult male NMRI mice at four fixed times: 10.00,16.00,22.00 and 04.00 h. Etidocaine serum levels were determined by GLC. The data showed significant 24 h variations of the Cmax only (highest value = 9.64 ± 1.31 μg mL−1 at 10.00 P < 0.05; amplitude, (maximum-minimum) mean × 100 = 84%) Vd, (amplitude = 59.7%), α and β phase elimination half-lives (amplitude = 52 and 35%, respectively), clearance (amplitude = 23%) and AUC°8 (amplitude = 22%) were not found to be significantly time dependent. Etidocaine kinetics in brain were determined similarly; a significant temporal variation was found for the elimination half life (amplitude, 161.9%) and AUC (amplitude, 133.2%) but not for Cmax. These data demonstrate a temporal pattern of etidocaine kinetics similar to those reported previously for other local anaesthetic agents, bupivacaine and mepivacaine. The temporal changes in etidocaine induced acute toxicity may result in part from its chronokinetic changes.
Hyperoxia and salicylate metabolism in rats
Authors: O'Connell Martin J , Webster Nigel R
Published: April 2011

Following the administration of aspirin to rats by gavage, both 2,3- and 2,5-dihydroxybenzoate appeared in the plasma. The concentration of the 2,3-dihydroxybenzoate was significantly higher in animals exposed to 100% O2 for 60 h than in air breathing controls. These data are evidence that increased salicylate hydroxylation is associated with oxidative stress.
Correlation of phenol sulphotransferase activities in the liver and platelets of rat
Authors: Nakamura Junko , Mizuma Takashi , Hayashi Masahiro , Awazu Shoji
Published: April 2011

Phenol sulphotransferase (PST) activity in rat platelet cytosol for p-nitrophenol (PNP) sulphation was found to have a similar dependence on PNP concentration and thermostability to that in rat liver cytosol. The activities of PST isoenzyme for the sulphation in the μM range of PNP in rat platelets and rat liver were significantly correlated. Thus, measurement of PST activity in platelets could be a useful and practical method for predicting this activity in liver.
Morphine and opioid peptides selectively inhibit the non-cholinergically mediated neurogenic contraction of guinea-pig isolated bronchial muscle
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

The experiments examine the actions of morphine and opioid peptides on the responses evoked by electrical field stimulation or by acetylcholine (ACh) and substance P (SP) in guinea-pig bronchial strip chain. Electrical field stimulation evoked a biphasic contraction, consisting of a cholinergically mediated fast contraction followed by a non-cholinergically mediated slow contraction. Morphine and opioid peptides caused a concentration-dependent inhibition in the height of the non-cholinergic contraction. The order of inhibitory activity was BW443C > dynorphin > morphine > β-endorphin > leucine-enkephalin > methionine-enkephalin. Cholinergically mediated contractions were less potently inhibited by these opioids. Submaximal contractions of bronchial muscle evoked by exogenous ACh (2 μM) or SP (02 μM) were not inhibited by morphine (100 μM) or opioid peptides (3–10 μM), rather, they were augmented. The results indicate that in guinea-pig isolated bronchial muscle, morphine and opioid peptides can selectively inhibit excitatory non-cholinergic neurotransmission via prejunctional opioid receptors.
Evidence for more than One Binding Site for Sulfonylureas in Insulin-secreting Cells
Authors: Verspohl E J , Ammon H P T , Mark M
Published: April 2011

Specific binding of both [3H]glibenclamide and [3H]gliquidone has been observed in a particulate fraction of insulin-secreting rat tumour (RIN m5F) cells. The binding of both the labels was time-dependent, of high affinity (including a low affinity binding site), saturable and reversible. The rank order of inhibition of [3H]glibenclamide binding was glibenclamide > gliquidone > AG-EE 388 = AG-EE 86 = AG-EE 319 > AG-EE 436 (AG coded drugs are benzoic acid derivatives which lack the sulfonylurea moiety of sulfonylureas). The KdS of high affinity binding for glibenclamide and gliquidone were 0.08 and 1.3 nM, respectively. When [3H]gliquidone was used as the labelled compound this rank order of binding and the affinities of drugs were different, e.g. glibenclamide was less potent than gliquidone. The Kd values of high affinity binding to the [3H]gliquidone binding site were 810 and 79 nM with respect to glibenclamide and gliquidone. The binding site labelled by [3H]gliquidone, in contrast to that labelled by [3H]glibenclamide, was not able to discriminate between the two enantiomers AG-EE 319 and AG-EE 436. The data indicate that there are different binding sites for glibenclamide and gliquidone in RIN m5F cells. In extension to data of other groups it is speculated that there exists more than one specific binding site for sulfonylureas and other related compounds, e.g. benzoic acid derivatives and that sulfonylureas behave differently not only in quantitative but in qualitative terms as well.
Inhibitory Effect of HSR-6071, A New Anti-allergic Agent, on Experimental Asthma in Rats and Guinea-pigs
Authors: Makino Eiichi , Ohashi Tetsuo , Takahashi Hiromi , Kato Hideo , Ito Yasuo , Nagai Hiroichi , Koda Akihide , Azuma Hiroshi
Published: April 2011

The experimental asthma caused by IgE antibody in rats was inhibited by HSR-6071 (6-(1-pyrrolidinyl)-N-(1H-tetrazol-5-yl)-2-pyrazinecarboxamide) (0.01-0.1 mg kg−1 i.v.) in a dose-dependent manner. The inhibitory activity of HSR-6071 was more potent than those of disodium cromoglycate and ketotifen, and equipotent with amlexanox. The bronchoconstriction mediated by IgE or IgG antibody in guinea-pigs was also prevented by HSR-6071 (0.3, 1 and 3 mg kg−1 i.v.), amlexanox (3, 10 and 30 mg kg−1 i.v.) and ketotifen (0.1 mg kg−1 i.v.) but not by disodium cromoglycate (10 mg kg−1 i.v.). HSR-6071 was more potent than amlexanox, but less potent than ketotifen. HSR-6071 suppressed antigen-induced histamine and SRS-A release from minced lung tissues of guinea-pigs sensitized passively with rabbit anti-EA serum and was a more potent inhibitor of the release of SRS-A than of histamine. On the other hand, histamine- or acetylcholine-induced bronchoconstriction in guinea-pigs was scarcely affected by HSR-6071 at doses sufficient to inhibit the experimental asthma, but LTD4-induced bronchoconstriction was dramatically inhibited. These results indicate that the inhibitory action on experimental allergic asthma of HSR-6071 may be due to suppression of antigen-induced histamine and SRS-A release from lung tissues and to antagonism of SRS-A action. In addition, HSR-6071 inhibited cyclic AMP phosphodiesterase activity and produced relaxation of the guinea-pig isolated trachea. These pharmacological actions may contribute to the production of the anti-allergic action of HSR-6071.
The effect of moisture content on the compression properties of maltodextrins
Authors: Li L C , Peck G E
Published: April 2011

The effect of moisture content on the compression properties of maltodextrin powders obtained by different degrees of hydrolysis (depolymerization) of corn starch has been studied using the yield pressure determined from the Heckel plot and the compact tensile strength measured by the diametrical compression method. An increase in the moisture content of the powder reduced the yield pressure and improved the densification for all five maltodextrins evaluated. At the same moisture level, the extent of densification which occurred during compaction was greater for maltodextrins with a lower degree of polymerization. Compacts produced by maltodextrins with a lower degree of polymerization also exhibited a greater tensile strength for a given pressure at a moisture content below 8 0%. However, further increase in moisture content resulted in a decrease in compact tensile strength for maltodextrins having a lower degree of polymerization. Despite the significant difference in compression behaviour, the five maltodextrins did not show noticeable differences in crystallinity as revealed by their x-ray powder diffraction pattern.
Lipid peroxidation effects of a novel iron compound, ferric maltol. A comparison with ferrous sulphate
Authors: Singh Rajiv K , Barrand Margery A
Published: April 2011

Lipid peroxidation effects of ferric maltol have been compared with those of ferrous sulphate both in lecithin liposomes and in brush border and mitochondrial membranes prepared from rat small intestine. Ferrous sulphate, but not ferric maltol, initiated peroxidation in liposomes as measured by conjugated diene production, but, with 500 μM ascorbic acid present, both caused intense peroxidation which was inhibitable by N2, tocopherol, maltol and ferrous chelators, but not by OH or H2O2 scavengers. The rate of peroxidation increased with ferrous sulphate concentration up to 100 μM but was independent of ferric maltol concentration between 5–500 μM. Material eluted from rat small intestine contained a reducing factor, similar in size to ascorbic acid, capable of generating ferrous ions from ferric maltol and initiating peroxidation. Peroxidation in mitochondrial membranes appeared unaffected by addition of iron whilst that in brush border membranes was detectable only in the presence of iron. At iron concentrations of 100 μM and above ferric maltol produced less liposomal peroxidation than ferrous sulphate. Maltol itself may delay recycling of Fe3+ to Fe2+. Thus ferric maltol could provide a less toxic alternative to ferrous salts in the oral treatment of iron-deficiency.
The importance of reductive mechanisms for intestinal uptake of iron from ferric maltol and ferric nitrilotriacetic acid (NTA)
Authors: Barrand Margery A , Hider Robert C , Callingham Brian A
Published: April 2011

Intestinal iron absorption is thought to proceed with iron mainly in the ferrous form, yet the novel iron complex, ferric maltol is an effective oral preparation. Although possessing a high oil: water partition coefficient, ferric maltol does not diffuse across the intestine but donates its iron to the endogenous uptake system. Reduction of the ferric iron in the gut lumen appears to precede iron uptake both from ferric maltol and from ferric nitrilotriacetic acid (NTA) which is a non-penetrating iron ligand. Uptake of radiolabelled iron (59Fe) into isolated fragments of rat small intestine was inhibited by the ferrous chelator, bathophenanthroline sulphonate (BPS) and enhanced at low concentrations by the reducing agent ascorbic acid. Spectrophotometric evidence was obtained that ferrous ions are generated from these ferric complexes in the presence of ascorbic acid and other reducing agents. The rate of ferrous ion formation was independent of ferric maltol concentration at low ascorbic acid levels and decreased with increasing ferric maltol concentration at higher levels of ascorbate. Maltol has a high affinity for ferric ions and may delay reduction at higher concentrations. By contrast, a higher rate of ferrous ion generation was seen with ferric NTA and this increased with iron ligand concentration. Washings from the intestinal lumen also brought about ferrous ion formation from these ferric ligands. Gel filtration revealed these reducing factors to be of low molecular weight. The washings, however, interfered with 59Fe uptake into the isolated fragments, but when reducing fractions only from the filtered washings were used, enhanced iron uptake was seen. There are thus additional, heat stable factors, unrelated to reduction, present in-vivo in the gut lumen that interfere with iron absorption. Intestinal absorption of iron from ferric maltol appears to occur as with other ferric chelates by initial reduction of the metal. Since maltol has a high affinity for ferric iron it may limit ferrous ion generation but it has a low affinity for the reduced form of the iron and so can donate the ferrous iron once formed immediately to the intestinal cell surface carrier. Ferric maltol may thus act as a relatively non-toxic reservoir for soluble iron in the intestinal lumen.
Increased dopamine turnover in the ventral striatum by 8-OH-DPAT administration in the rat
Authors: Ahlenius Sven , Hillegaart Viveka , Wijkström Agneta
Published: April 2011

The administration of the 5-HT1A agonist 8-OH-DPAT (0.8 μmol kg−1 s.c. — 40 min) produced an increase in dopamine (DA) turnover, estimated by the quotient (DOPAC + HVA) DA−1, in the ventral striatum of the rat. No statistically significant effects were obtained in the dorsal striatum. The accumulation of 3-MT in pargyline-treated animals (375 μmol kg−1 s.c.— 60 min) was not affected by 8-OH-DPAT treatment (0.15-2.4 μmol kg−1 s.c.-30 min). These findings indicate that 8-OH-DPAT has weak antagonist properties at striatal DA receptors in normal rats. Both the 5-HT1A agonist flesinoxan (0.06–17.8 μmol kg−1 s.c. — 50 min) and the mixed 5-HT1 and 5-HT2 agonist 5-MeODMT (1.6–26.0 μmol kg−1 s.c. −50 min) produced a decrease in forebrain 5-HTP accumulation (striatum and neocortex), following decarboxylase inhibition by means of NSD-1015 in reserpine treated rats, indicating stimulation of central 5-HT receptors by these two compounds. At the same time, the DOPA accumulation in the ventral striatum was decreased by flesinoxan and increased by 5-MeODMT treatment. These observations show that, under these conditions, the decrease in DA synthesis is not directly coupled to the decreased 5-HT synthesis produced by flesinoxan, as previously demonstrated for 8-OH-DPAT. Taken together with previous observations, the present results suggest that 8-OH-DPAT, depending on the experimental conditions, is an agonist or antagonist at striatal DA receptors, in all probability due to partial DA receptor agonist properties of the compound.
Effects of Verapamil, Nifedipine and Flunarizine on Haemodynamics and Regional Blood Flows in Pentobarbitone-anaesthetized Rats
Authors: Waite R P , Pang C C Y , Walker M J A
Published: April 2011

Representative calcium antagonists from proposed class I (nifedipine), class II (verapamil) and class III (flunarizine) have been examined for effects on blood pressure, heart rate, ventricular pressures, ECG, cardiac output and regional blood flow in pentobarbitone-anaesthetized rats. Flow was measured by the microsphere technique. Low and high infusion rates of each drug were chosen to decrease mean arterial pressure by 25 and 40 mmHg, respectively. At equi-depressor infusion rates, all drugs equally decreased total peripheral resistance and slightly increased cardiac output and stroke volume. Heart rate was decreased by verapamil and flunarizine, but increased by nifedipine. Verapamil markedly decreased dP/dtmax of ventricular pressure and prolonged the PR-interval. Flunarizine was similar. Nifedipine decreased dP/dtmax and had no effect on the PR-interval of the ECG. Similar effects on regional blood flow were seen with the three drugs; flow to lungs, heart, liver, skeletal muscle and stomach increased. Correction for blood pressure changes, i.e. conductance, showed that vasodilatation occurred in all regions, with all drugs, except for the skin. Therefore, representatives from three sub-classes of calcium antagonists had similar effects on blood flow but different effects on the heart.
A pattern recognition study of acyclic ureide anticonvulsants
Authors: Khalil Maged , Weaver Donald F
Published: April 2011

A pattern recognition structure-activity study employing topological, geometric and physicochemical descriptors was performed on 27 acyclic ureide anticonvulsants. Twelve numerical descriptors were used as variables in a discriminant function analysis which categorized the ureide analogues with respect to their bioactivity. The results from the discriminant function analysis were interpreted to support a model for antiepileptic activity.
Chronic administration of MK-801 and the NMDA receptor: Further evidence for reduced sensitivity of the primary acceptor site from studies with the cortical wedge preparation
Authors: Beart Philip M , Lodge David
Published: April 2011

Cortical slices removed from rats pre-treated with MK-901 0.5 mg kg−1 twice a day for 7 days had reduced responses to N-methyl-D-aspartate (NMDA) relative to quisqualate and glutamate compared with control animals. Potencies of competitive (CPMP) and non-competitive (ketamine) NMDA antagonists appeared unchanged. These changes are consistent with a reduced density of NMDA receptors.
Potencies of mioflazine and its derivatives as inhibitors of adenosine transport in isolated erythrocytes from different species
Authors: Baer Hans P , Haq Afrozul , El-Soofi Ali , Serignese Vincent , Paterson Alan R P
Published: April 2011

The potency of mioflazine and related drugs (Janssen Pharmaceutica, Belgium) as inhibitors of adenosine transport in isolated erythrocytes from several species were measured and compared with those of dilazep and 6-(4-nitrobenzylmercapto)purine ribonucleoside (NBMPR). [8−3H]Adenosine was used as the permeant at 1 μM and incubation times were 10 s, and assays were conducted in the presence and absence of varying doses of potential transport inhibitors. The species investigated included mouse, hamster, rabbit, baboon and man. Dilazep was the most potent compound throughout with an IC50 of about 2 nM. In the mouse and hamster mioflazine and its derivatives were considerably less potent (IC50 values > 200 nM) with the exception of R57974 with IC50 values of about 150 and 60 nM in mouse and hamster, respectively. In the man and baboon the derivatives had IC50 values in the same order of magnitude as NBMPR (< 100 nM), and in the rabbit they had potencies close to that of NBMPR, ranging between 10–60 nM. Nucleoside transport inhibitors are of potential importance as host protectors during treatment of parasitic infections with cytotoxic nucleosides. Present data indicate that mioflazine and its derivatives are not very potent in some of the preferred animal models for parasitic infections (mouse, hamster) but are more effective in primates such as man and baboon.
Kynurenic acid blocks chemogenic nociception
Authors: Hajós Mihály , Engberg Göran
Published: April 2011

Previous studies have suggested a role of excitatory amino acids (EAA) in nociception. In the present study the effects of two antagonists of EAA-receptors on capsaicin-induced eye wipings were investigated. Intracisternally administered kynurenic acid, in contrast to intravenously administered MK-801, was found to effectively block the induced eye wipings. It is proposed that EAA, by activating non-NMDA receptors, are involved in the transmission of chemogenic nociception.
Stability of Liposomes on Long Term Storage
Authors: Hernández-Caselles T , Villalaín J , Gómez-Fernández J C
Published: April 2011

The effect of the lipid composition of liposomes on their storage for up to one year under different environmental conditions has been examined using 5,6-carboxyfluorescein as a model drug. When cholesterol and/or α-tocopherol were included in the liposomes, a significantly greater amount of dye was retained. The presence of α-tocopherol decreased the breakdown of phosphatidylcholine to lysophosphatidylcholine and also reduced the level of peroxidation. Carboxyfluorescein retention was further enhanced when liposomes were stored at 4°C or at room temperature (20°C) in an O2-free atmosphere. Lysophosphatidylcholine formation also slowed when the liposomes were kept at 4°C, or in an O2-free atmosphere. It is concluded that egg yolk lecithin liposomes may be stored for long periods at low temperature in an O2-free atmosphere or with added stabilizers such as cholesterol and α-tocopherol.
Normal Phase HPLC as a Model System of Specific Benzodiazepine-receptor Binding
Authors: Gilli Gastone , Pietrogrande Maria Chiara , Borea Pier Andrea
Published: April 2011

The hypothesis that benzodiazepines interact with their receptors in the CNS via hydrogen bonding mediated by the carbonyl and imine groups has been studied by correlating a physicochemical parameter affected by hydrogen bonds potentially accepted or donated by benzodiazepines with their binding constants to synaptosomal rat brain membranes. The reference physicochemical system chosen was normal phase high-performance liquid chromatography on μ-Bondapack NH2 (propylamine groups chemically bonded to porous silica) eluted with mixtures of n-hexane and 2-propanol. A strong correlation has been found for binding of the implicated groups to the column and to the receptor.
Augmented Potentiation of Renal Vasoconstrictor Responses by Thromboxane A2 Receptor Stimulation in the Alloxan-diabetic Rat
Authors: Hodgson W C , King R G , Boura A L A
Published: April 2011

Dose-response curves were obtained to bolus injections of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in blood and Krebs-perfused kidneys of male Wistar rats. Vasoconstrictor responses to both NA and 5-HT were significantly attenuated in blood-perfused kidneys of alloxan-treated 14 day diabetic rats compared with non-diabetic animals. Responses to low doses of NA were also significantly attenuated in Krebs-perfused kidneys from diabetic rats but responses to 5-HT were augmented. Dose-dependent potentiation of vasoconstrictor responses to NA and 5-HT in Krebs-perfused kidneys of both non-diabetic and diabetic rats occurred during infusion of the thromboxane A2 (TxA2)-mimetic U46619 ((15S)-hydroxy-11α, 9α-(epoxymethano) prosta-5Z, 13E-dienoic acid). The potentiation by U46619 (11 ng mL−1) was inhibited in both groups during infusion of the thromboxane receptor antagonist AH23848 ([1α(Z), 2β, 5α]-(±)-7-[5[[(1,1′-biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid). Infusion of 5-HT in Krebs-perfused kidneys of non-diabetic rats, causing a rise in perfusion pressure of similar magnitude to that produced by infusion of 111 ng mL−1 U46619, did not significantly affect responses to bolus injections of NA. Potentiation of vasoconstrictor responses to low concentrations of 5-HT by U46619 was significantly greater in Krebs-perfused kidneys of diabetic rats than kidneys from non-diabetic animals. Activation of vascular TxA2 receptors augments the vasoconstrictor effects of 5-HT in Krebs-perfused diabetic rat kidneys to a greater extent than in non-diabetic kidneys.
The effect of fatty acids on the rectal absorption of acyclovir in rats
Authors: Yamazaki Masaru , Itoh Soichi , SawanoI Masayoshi , Kobayashi Miki , Suzuki Sayaka , Komatsu Toshiaki , Tanabe Kazuhisa
Published: April 2011

The enhancing effect of fatty acids on the rectal absorption of acyclovir has been evaluated in rats. Acyclovir proved to be absorbed to the extent of 3 to 9% after oral administration. After rectal administration in the absence of absorption-promoter, the bioavailability of acyclovir was 37%. Its rectal administration with 4% sodium caprate resulted in enhanced bioavailability (81 ± 3%).
Effect of Recombinant Human Erythropoietin on New Anaemic Model Rats Induced by Gentamicin
Authors: Nagano Nobuo , Koumegawa Jun-Ichi , Arai Hirofumi , Wada Michihito , Kusaka Masaru
Published: April 2011

The effects of recombinant human erythropoietin (r-HuEPO) on haematological parameters were studied in rats in which uraemia and anaemia had been induced by gentamicin, an aminoglycoside antibiotic and a nephrotoxic agent. After the occurrence of slight polycythaemia, the red blood cell count, haematocrit and haemoglobin concentration decreased by 20–30% compared with those of the control (saline-injected) rats. At the end of gentamicin treatment, the endogenous serum EPO level had decreased to about 40% compared with that of control rats. Gentamicin-treated rats showed marked elevation of blood urea nitrogen, extensive tubular necrosis in the kidney and haemosiderin deposition in the spleen. In the osmotic fragility test, the fragility of erythrocytes significantly increased compared with that of control rats. These findings indicate that the anaemia induced by gentamicin is due not only to a deficiency of EPO but also to an enhancement of fragility of erythrocytes in an azotaemic environment. The administration of r-HuEPO during anaemia markedly increased red blood cell count, haematocrit and haemoglobin concentration. It is suggested that a gentamicin-treated rat is a useful and convenient anaemic model and r-HuEPO is useful for treatment of anaemia in acute renal failure.
α-Adrenoceptor Involvement in Swim Stress-induced Antinociception in the Mouse
Authors: Oluyomi Ademola O , Hart Stephen L
Published: April 2011

Three different intensities of swim stress produced stress-induced antinociception (SIA) in mice which was assessed either by the reduction in the number of abdominal constrictions produced by acetic acid or by an increase in reaction time on a hot-plate. The involvement of α-adrenoceptors in the three models of SIA was investigated using selective antagonists. SIA produced by the mild stress of a 30 s warm water swim was attenuated by idazoxan (0.5-1 mg kg−1), and by yohimbine at a dose (1 mg kg−1) which reduced antinociception produced by clonidine (12.5–50 μg kg−1). Indoramin (1–2 mg kg−1) did not affect this model of SIA, but reversed phenylephrine induced inhibition of the constrictions. A 3 min room temperature swim increased reaction times on the hot-plate and this naloxone-sensitive SIA was reduced significantly by prazosin (1–2 mg kg−1), idazoxan (0.5-1 mg kg−1) and yohimbine (0.5-1 mg kg−1) but enhanced by clonidine (0.5 mg kg−1) and noradrenaline (NA) (10 μg i.c.v.). Mice treated with 6-hydroxydopamine (60 + 60 μg i.c.v.) were hypersensitive to the hot-plate and did not develop SIA. Levels of noradrenaline in the brain (minus the cerebellum) were decreased after the room temperature swim SIA. The most severe stress of a cold water swim produced SIA on the hot-plate which was initially naloxone-insensitive. Both components of the cold water swim SIA were enhanced by NA (10 μg i.c.v.) and reduced by yohimbine (5 μg i.c.v.) whilst prazosin (5 μg i.c.v.) inhibited only the later naloxone-sensitive component; and these adrenoceptor agents potentiated cold water swim hypothermia induced by the cold water swim. These results show the differential involvement of α1-and α2-adrenoceptors in SIA in the mouse.
A disintegration test for vaginal tablets: comparison with BP test
Authors: Yamaguchi Masatoshi , Tanno Keiki , Sucibayashi Kenji , Morimoto Vasunori
Published: April 2011

To improve the disintegration test for vaginal tablets described in the British Pharmacopoeia (BP), a monitoring apparatus was added, and tested with seven effervescent and five non-effervescent tablets. A tablet was placed on the metal disc of the BP disintegration apparatus, and the guided plate was placed on the tablet. The guided plate moved downward smoothly in a cylinder as the tablet disintegrated. The movement was recorded by using a kymograph. The end-point and process of disintegration of the tablet were automatically recorded and the results obtained suggest that the modified test is a useful tool for the quality control of vaginal tablets.
Phenytoin-bupropion interaction: effect on plasma phenytoin concentration in the rat
Authors: Tekle A , Al-Khamis Khalil I
Published: April 2011

The effect of coadministration of bupropion (50 mg kg−1, p.o.) on the disposition profile of phenytoin has been studied in the rat. Plasma phenytoin concentration was measured serially for 10 h by HPLC. Bupropion had little or no effect on the pharmacokinetic parameters of an acutely administered dose of phenytoin. Following multiple doses of phenytoin however (i.e. steady state) the coadministration of bupropion resulted in significant increases in the elimination half-life (t 1/2), the area under the plasma concentration-time curve (AUC) and the time to maximum plasma concentration (tmax). Allowing for the limitations of single dose studies, these results point to a possible pharmacokinetic interaction between bupropion and phenytoin—the clinical significance of which needs to be assessed.
Susceptibility of bacterial isolates from AIDS patients to six fluoroquinolones
Authors: Lewin C S , Naden M , Watt B , Amyes S G B
Published: April 2011

The susceptibilities to ciprofloxacin, DR-3355 (S-(—)-ofloxacin), enoxacin, lomefloxacin, ofloxacin and PD127,391 of 69 significant bacterial isolates from HIV-positive patients at the City Hospital, Edinburgh have been determined. With the exception of the enterococci, most of the strains tested (including staphylococci, Escherichia coli and Pseudomonas aeruginosa) were susceptible to the fluoroquinolones. Ciprofloxacin was the most active of the clinically available drugs followed by ofloxacin, lomefloxacin and enoxacin. PD127,391 and DR-3355, the new fluoroquinolones tested, were at least as active as ciprofloxacin. Hence bacterial infections in AIDS patients should respond to fluoroquinolone therapy.
Dependence of the Renal Excretion of Theophylline on its Plasma Concentrations and Urine Flow Rate in Asthmatic Children
Authors: Agbaba D , Pokrajac M , Varagić V M , Pešić V
Published: April 2011

The dependence of the renal excretion of theophylline on its plasma concentration and urine flow rate has been investigated in asthmatic children of either sex. One group (age 12.25 ± 0.80, mean ± s.d. n = 8) was given aminophylline intravenously (i.v.), while another (age 10.00 ± 3.64 n = 14) was given a sustained release preparation of theophylline orally (single dose and repeated doses). Unchanged drug (11.6% ± 1.75) was excreted in the urine corresponding to a renal clearance of 10.6 ± 1.6 mL h−1 kg−1. Time dependence of the renal clearance of theophylline was found only after i.v. administration. Dependence of the renal clearance on urine flow rate was found both after i.v. administration and at steady state, but not after a single oral dose of theophylline. After oral administration, renal clearance of theophylline was higher at steady state than after a single dose (0.58 ± 0.06 L h−1 kg−1 vs 0.23 ± 0.03 L h−1 kg−1), while urine flow rate was lower (1.1 ± 0.5 mL min−1 vs 1.8 ± 0.9 mL min−1). High correlation of theophylline plasma concentration and theophylline excretion rate was obtained in 10 of 14 patients after administration of a single oral dose of the preparation (r = 0.8567 to 0.9830). There was no dose dependence of the renal clearance of the drug either after a single dose, or at steady state.
Regulation of Sympathetic and Parasympathetic Receptor Responses in the Rat Trachea by Epithelium: Influence of Mechanical and Chemical Removal of Epithelium
Authors: Doelman Cees J A , Oosterom Willem C , Bast Aalt
Published: April 2011

Removal of the epithelial layer of rat tracheal tissue did not affect the methacholine-induced contraction of the tracheal smooth muscle, but attenuated the (—)-isoprenaline induced relaxation (expressed as percentage of the methacholine contraction). In this way the epithelial layer seemed to play a role in the maintenance of an autonomic balance between sympathetic and parasympathetic receptor responses. Incubation of rat tracheal tissue with cumene hydroperoxide (3 × 10−5-10−3 M) resulted in a dose-dependent destruction and (partial) removal of the epithelial layer. Cumene hydroperoxide diminished muscarinic receptor responses of the rat trachea. Moreover, the autonomic balance between muscarinic and β-adrenoceptor responses was affected. The effects of cumene hydroperoxide on receptor responses were more pronounced after epithelium removal. The protective role of the epithelial layer of pulmonary tissue against oxidative stress has therefore been emphasized.
Effect of Anti-inflammatory Drugs on the Cardiotoxin-induced Hind-paw Oedema in Rats
Authors: Wang Jih-Pyang , Teng Che-Ming
Published: April 2011

Cardiotoxin, isolated from Naja naja atra venom, induced rat hind-paw oedema. This effect was suppressed by the pretreatment with dexamethasone or BW 755C, or subplantar co-injection with FPL 55712. Pretreatment with aspirin alone did not affect this response, while a significant reduction of cardiotoxin-induced paw oedema was achieved with aspirin in combination with diphenhydramine and methysergide. Subplantar co-injection of PAF antagonist, BN 52021 or L 652731, with cardiotoxin had no effect on paw oedema, whereas superoxide dismutase/catalase reduced this oedematous response. Cardiotoxin-induced paw oedema was also suppressed by pretreating the rats with isoprenaline. Pretreatment with rat anti-platelet plasma, which greatly reduced peripheral platelet count, did not affect cardiotoxin-induced paw oedema. Cardiotoxin did not trigger platelet aggregation or release reaction either in platelet-rich plasma or in washed platelet suspension. The oedematous response after subplantar co-injection of cardiotoxin with basic or acidic phospholipase A2 appeared to be only an additive effect. These results suggest that arachidonate metabolites, in which leukotrienes are most important, participated in cardiotoxin-induced paw oedema. Superoxide radical was also involved, while PAF and platelets showed little influence in this oedema effect.
Measurement of Protein Synthesis by the Phenylalanine Flooding Dose Technique: Effect of Phenylalanine and Anaesthesia on Plasma Electrolyte, Enzyme and Metabolite Levels
Authors: Preedy Victor R , Hammond Barry , Bottiglieri Teodoro G , Marway Jaspaul S , Peters Timothy J
Published: April 2011

Ten minutes after an intravenous flooding dose of phenylalanine to rats, plasma sodium and calcium concentrations were slightly reduced (by 2–7%) but no effects on potassium or phosphate were observed. Creatine kinase activities were significantly increased by phenylalanine injection (by 39%), but alkaline phosphatase, alanine aminotransferase, lactate dehydrogenase and aspartate aminotransferase activities were unaltered. Plasma concentrations of total proteins, albumin, cholesterol, triglycerides, urea, creatinine and glucose were also unaffected. In the presence of anaesthesia, phenylalanine injection had almost identical effects, although the increase in creatine kinase activities did not reach statistical significance. Anaesthesia for 10 min reduced plasma potassium concentrations (by 27%), and calcium (by 5%), though phosphate and sodium were unaltered. The activities of lactate dehydrogenase, creatine kinase and aspartate aminotransferase were reduced by between 36–52%, but alkaline phosphatase and alanine aminotransferase activities were unaltered by anaesthesia. Plasma concentrations of total proteins and albumin were also reduced (both by 9%), but glucose concentrations were increased (by 33%). Anaesthesia had no other significant effects on cholesterol, triglycerides, urea or creatinine concentrations. The qualitative effects of anaesthesia in the presence of raised free phenylalanine concentrations were similar. It was concluded that, except for creatine kinase, determinations of plasma constituents in phenylalanine-injected rats could be made without overt interpretational errors. However, caution is required in interpreting data on plasma constituents from anaesthetized rats.
The Disposition of a Histidine Decarboxylase Inhibitor (S)-α-Fluoromethylhistidine in Rats
Authors: Sakurai Eiichi , Niwa Hiroshi , Yamasaki Seiji , Maeyama Kazutaka , Watanabe Takehiko
Published: April 2011

An amino acid analyser method using ninhydrin was developed for (S)-α-fluoromethylhistidine (FMH) with a minimum quantitation limit of 0.2 μg mL−1. The assay was used to study the kinetics of FMH in rat. After bolus intravenous administration of FMH hydrochloride hemihydrate (50 mg kg−1), plasma concentration decreased biexponentially with half-lives of 4.4 and 32.7 min. The distribution volumes of the central and peripheral compartments were 127.4 and 166.3 mL kg−1, respectively. The tissue concentration of FMH was highest in the kidney and also decreased biphasically. The FMH concentrations in other tissues were lower, but their tissue/plasma ratios of FMH increased continuously after FMH injection, indicating that FMH partitioned into these tissues and was lost from them very slowly.