bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of magnesium chloride on the contractile response of uterus to several agonists in Ca-free solution
Authors: D'Ocon M P , Anselmi E , Villar A
Published: April 2011

The effects of MgCl2 on the oestrogen-dominated rat uterus have been examined. Tissues were preincubated in a Ca2+- and Mg2+-free medium containing 3 mM EDTA. Most experiments were subsequently performed in a similar medium containing either no EDTA or EDTA (1 mM). When MgCl2 was added cumulatively (1–32 mM) no contractile responses were obtained in Ca,Mg-free medium or in Ca,Mg-free high K+ solution. When 2 mM CaCl2 as added, a sustained contraction was obtained. Subsequent addition of cumulative concentrations of MgCl2 caused concentration-dependent relaxation. Oxytocin, 2 μM, produced a small and sustained contraction in a Ca,Mg-free medium. Addition of MgCl2, 2 mM, increased this contraction. In a Ca,Mg-free medium vanadate (8 times 10−5 M) did not evoke spasm of uterine smooth muscle. After addition of MgCl2 in cumulative amounts (1–32 mM) in the presence of vanadate, a concentration-dependent contraction was obtained. The present work shows that in Ca-free solution, maintained contractions induced by oxytocin and vanadate are augmented by Mg2+.
Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups
Authors: Heptinstall S , Groenewegen W A , Spangenberg P , Loesche W
Published: April 2011

It has been suggested that extracts of feverfew may inhibit platelet behaviour via effects on platelet sulphydryl groups. In the present study we have obtained evidence for such a mode of action. (i) Compounds that contain sulphydryl groups such as cysteine and N-(2-mercaptopropionyl)glycine prevented the inhibition of platelet behaviour by feverfew. (ii) Feverfew and parthenolide (one of the active components of feverfew) dramatically reduced the number of acid-soluble sulphydryl groups in platelets. This effect occurred at concentrations similar to those that inhibited platelet secretory activity. (iii) Feverfew itself did not induce the formation of disulphide-linked protein polymers in platelets but polymer formation occurred when aggregating agents were added to feverfew-treated platelets. (iv) Feverfew evoked changes in the metabolism of arachidonic acid that were similar to those observed in glutathione-depleted platelets.
The activity of compounds extracted from feverfew on histamine release from rat mast cells
Authors: Hayes N A , Foreman J C
Published: April 2011

An extract of the plant feverfew (Tanacetum parthenium) produces a dose-dependent inhibition of histamine release from rat peritoneal mast cells stimulated with anti-IgE or the calcium ionophore A23187. Greater inhibition of anti-IgE-induced histamine release was achieved with feverfew compared with the inhibition of A23187-induced release. Inhibition of anti-IgE-induced histamine release by feverfew extract was observed when the drug was added simultaneously with anti-IgE and the inhibitory activity increased only slightly when the drug was preincubated with the cells for 5 min before anti-IgE stimulation. In this respect feverfew differs from cromoglycate and quercetin. Feverfew extract inhibited anti-IgE-induced histamine release to the same extent in the absence and presence of extracellular glucose. It is concluded that feverfew extract contains a novel type of mast cell inhibitor.
Physicochemical investigations of dipolar aprotic solvents as potential cholelitholytic agents
Authors: Kennelly P , Corrigan O I
Published: April 2011

A number of dipolar aprotic solvents have been examined as potential co-solvents for gallstone dissolution. The power of these agents to solubilize such gallstone components as cholesterol, calcium carbonate, calcium palmi-tate and palmitic acid was determined and compared with that of monooctanoin (Capmul), using the synthetic solubility method. The solubilities of cholesterol and palmitic acid were greater in the N-methyl, N-ethyl and N-butyl-pyrrolidone derivatives than in monooctanoin. In contrast, the solubilities of the calcium salts were very low (<0ṁ25% w/w) in all solvents examined. The influence of N-methylpyrrolidone (NMP) on both the in-vitro dissolution of cholesterol from gallstones and the decrease in stone weight with time was determined. NMP proved to be a better solvent than monooctanoin for human stones. NMP, which is miscible with water and monooctanoin, may have potential as a co-solvent in the design of solvent systems for gallstones.
Studies on thyrotropin-releasing hormone-induced micturition in cats
Authors: Beleslin Dušan B , Jovanović-Mićić Danica , Samardžić Ranka , Terzić Branka
Published: April 2011

In unanaesthetized cats micturition produced by thyrotropin-releasing hormone (TRH) was investigated after its injection into the cerebral ventricles through chronically implanted cannulae. TRH in doses from 0ṁ1 to 1ṁ0 mg evoked dose-dependent micturition. In cats treated with intracerebroventricular (i.c.v.) reserpine and 6-hydroxy-dopamine, but not with i.c.v. 5,6-dihydroxytryptamine and hemicholinium, the micturition caused by i.c.v. TRH was abolished. Chlorpromazine and antazoline injected into the cerebral ventricles prevented the micturition induced by i.c.v. TRH. On the other hand, mecamylamine, yohimbine, propranolol, atropine and methysergide injected i.c.v. had virtually no effect or partially antagonized the micturition evoked by TRH similarly injected. It is apparent therefore that centrally induced TRH micturition could be related to central catecholaminergic mechanisms.
Antiarrhythmic effect of desethylamiodarone in conscious rats
Authors: Varró András , Bódi Ilona , Rabloczky George
Published: April 2011

The effect of desethylamiodarone, a metabolite of amiodarone, was studied in the early phase of arrhythmias induced by coronary artery ligation in conscious rats. Desethylamiodarone pretreatment improved survival without altering the occurrence of different types of arrhythmias during the first 20 min after coronary ligation. It was concluded that desethylamiodarone may contribute to the antiarrhythmic effect seen after chronic amiodarone treatment.
The influence of drug sorption on pharmacokinetic studies of chlormethiazole and lignocaine
Authors: Upton Richard N , Mather Laurence E , Runciman William B
Published: April 2011

The influence of drug sorption on the measurement of dose and blood concentrations during pharmacokinetic studies of chlormethiazole and lignocaine in a chronically catheterized sheep preparation has been examined. There was no sorption to soda glass tubes, borosilicate glass volumetric flasks or soda glass microlitre syringes but minor sorption to polypropylene syringes, polypropylene pipette tips and rubber bottle stoppers after 240 min contact. During infusions through administration sets including either polyvinyl chloride or polyethylene catheters, no significant loss of lignocaine occurred, but only 41ṁ7–63ṁ9% of the chlormethiazole dose was delivered. No significant decreases in either drug occurred from blood sampled through an intravascular catheter and stopcock system. There was negligible degradation of the samples over 4 h. Sorption of chlormethiazole or lignocaine to the laboratory equipment used was not a significant source of error but polyvinyl chloride infusion catheters could result in significant reductions in chlormethiazole dose.
A gamma scintigraphic evaluation of the precorneal residence of liposomal formulations in the rabbit
Authors: Fitzgerald P , Hadgraft J , Wilson C G
Published: April 2011

Multilamellar liposomes were prepared from dipalmitoyl phosphatidylcholine or egg lecithin in combination with cholesterol and either dicetyl phosphate or stearylamine. The size and charge of the colloidal preparations were characterized before labelling with [111In]8-hydroxyquinoline. Freshly labelled liposomes were instilled into the eyes of unanaesthetized NZW rabbits and their disposition and drainage followed using gamma scintigraphy. A positive surface charge was found to affect significantly liposomal drainage rate, whereas an increase in size restricted drainage from the inner canthal region. Drainage of the suspending medium was directly compared with liposomes by labelling the medium with [99mTc] sodium pertechnetate and following the simultaneous change in removal of 99mTc and 111In from the precorneal area. Slower drainage rates were obtained for the suspending medium compared with solutions of the isotopes suggesting that the liposomes restricted solution drainage.
Stimulant action of pethidine on the pregnant rat uterus in-vitro
Authors: Fazackerley J , Pleuvry B J
Published: April 2011

Pethidine's stimulant action on the 22-day pregnant rat isolated uterus does not involve receptors sensitive to methysergide and is unlikely to involve the synthesis and release of endogenous prostaglandins. The sensitivity of pethidine-induced contractions to verapamil suggests that mobilization of extracellular calcium is necessary for pethidine's action.
A comparative investigation of glycinebetaine and dimethylsulphoxide as liposome cryoprotectants
Authors: Higgins J , Hodges N A , Olliff C J , Phillips A J
Published: April 2011

The release of streptomycin from lecithin liposomes following a freeze-thaw cycle was used to measure the cryoprotective activities of glycinebetaine and dimethylsulphoxide (DMSO). At concentrations between 4 and 8% w/v in the external solution, glycinebetaine was superior to DMSO at freezing rates faster than 50 °C min−1. At lower rates their activities were similar, and drug loss ranged between 10 and 20% depending upon freezing rate and cryoprotectant concentration. The pattern of streptomycin loss when the concentrations of cryoprotectants inside and outside the liposome were varied indicated that glycinebetaine, in contrast to DMSO, does not diffuse across the liposome membrane. The activity of glycinebetaine was not impaired by the presence in the membrane of cholesterol or charged lipids.
The influence of viscosity on the migration of chloramphenicol and 4-hydroxybenzoic acid through glycerogelatin gels
Authors: Armstrong N Anthony , Gebre-Mariam Tsige , James Kenneth C , Kearney Patrick
Published: April 2011

Migration of chloramphenicol and 4-hydroxybenzoic acid from solutions in 1-octanol into Glycerol Suppository Base, BP and soft gelatin capsule shells is reported. Rates of migration through the gels, quantified in terms of diffusion coefficients, are given. An electron spin resonance probing technique was used to determine the microscopic viscosity. The latter, rather than the bulk viscosity, was shown to be the major rheological influence on the rate of diffusion.
Effect of moderate haemodilution with Fluosol-DA or normal saline on indocyanine green and (+)-propranolol kinetics
Authors: Shrewsbury Robert P , Lewis Lee M , Oliver Sharon R , Womble Catherine L
Published: April 2011

Indocyanine green (ICG) and (+)-propranolol kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol-DA or 0ṁ9% NaCl (saline). Rats received an intravenous ICG dose (5 mg kg−1) before an intravenous dose of (+)-propranolol (2ṁ5 mg kg−1) 0ṁ5, 24, 48 or 72 h after haemodilution and were compared with non-exchanged controls. Haemodilution with Fluosol-DA reduced the ICG elimination rate constant during the first 24 h while a significant reduction was seen 48 h after normal saline exchange. ICG clearances tended to be less than the control value, and were significantly reduced only at 24 h after Fluosol-DA exchange due to a reduced Varea. (+)-Propranolol half-life was significantly increased 48 and 72 h after saline exchange; (+)-propranolol clearance was only significantly reduced 72 h after Fluosol-DA exchange. ICG clearance may be reflecting a hypovolaemic change which occurs after haemodilution, which would reduce the hepatic blood flow. However, (+)-propranolol clearance was not altered, suggesting that the hepatic blood flow is not changed. It is possible that ICG clearance is changed due to alterations in its extraction ratio instead of hepatic blood flow changes.
Alcuronium pharmacodynamics in dogs: effect-concentration relationships in the diaphragmatic and limb muscles
Authors: Walker Judy S , Shanks Colin A , Borton Christopher , Brown Kenneth F
Published: April 2011

Previous studies suggest that the muscles of the diaphragm are less sensitive to neuromuscular blocking agents than the limb muscles. However, this difference has not been characterized directly in terms of relaxant drug plasma concentrations. The pharmacodynamics of the non-depolarizing muscle relaxant alcuronium were therefore investigated in nine dogs using a constant-rate infusion regimen with simultaneous measurement of muscle paralysis in the limb and diaphragm. Maximum paralysis between 95 and 100% was achieved in both muscle groups, within approximately the same time interval. However, during onset of and offset of effect, the pharmacodynamic parameters ECp50 and ECp95 for the limb muscle were lower than in the diaphragm. From a pharmacodynamic effect model it was also predicted that Css(50) and Css(95) for the limb muscles are half those values for the diaphragm. Thus, the diaphragm is less sensitive to the action of alcuronium than are limb muscles. The half-time for equilibration of alcuronium between plasma and the effect site was two-fold lower for the diaphragm, and the rate of recovery from paralysis in diaphragmatic muscles was twice that observed in limb muscles. Collectively, these data suggest that there is a greater margin of safety in the diaphragmatic muscles and that the response of the peripheral limb muscles to nerve stimulation provides only a conservative index of recovery from competitive neuromuscular block in the diaphragmatic muscles.
Fundamental properties of metronidazole formulations in relation to tableting
Authors: Itiola O A , Pilpel N
Published: April 2011

A study has been made of the effects of polyvinylpyrrolidone, gelatin and methylcellulose binding agents on the fundamental and tableting properties of a metronidazole-lactose-starch formulation. A material constant, α, was derived from the measured values of tensile strength of the materials. The values of a for the formulations are lower than that for metronidazole and depend on the nature and concentration of binder present. In terms of tableting properties, α supplements the information obtained from the ratios of elastic recovery to plastic compression (ER/PC) and from the brittle fracture index values (BFI) of the materials, although its influence appears to be limited at low values of ER/PC.
The presence of mucosa reduces the contractile response of the guinea-pig urinary bladder to substance P
Authors: Maggi Carlo Alberto , Santicioli Paolo , Parlani Massimo , Astolfi Mara , Patacchini Riccardo , Meli Alberto
Published: April 2011

The contractile response to substance P in-vitro is greater in strips of guinea-pig bladder freed of mucosa than in normal strips, while the response to field stimulation, histamine or KCl is unaffected by the presence of mucosa. Substance P has no inhibitory effect on histamine-induced contractions of the guinea-pig bladder. These findings support the possibility that the presence of mucosa may reduce accessibility of substance P to the muscle layer.
Liquid chromatographic determination of ampicillin and its metabolites in human urine by postcolumn alkaline degradation
Authors: Haginaka Jun , Wakai Junko
Published: April 2011

A high-performance liquid chromatographic method has been developed for the determination of ampicillin (I) and its metabolites ((5R, 6R)-penicilloate (II), the (5S, 6R)-epimer (III), and piperazine-2,5-dione (IV)) in human urine. The assay was based on the measurement of the absorbance at 300 nm following the postcolumn alkaline degradation with 0.75 M sodium hydroxide, 2 × 10−3 M mercuric chloride, and 1 × 10−2 M ethylenediaminetetraacetic acid disodium salt in solution. The limits of accurate determination were 0.5 μg mL−1 for I, 2.0 μg mL−1 for II and III, and 1.0 μg mL−1 for IV in neat urine samples with a 10 μL injection. At concentrations of compounds I-IV of 5 μg mL−1, within- and between-run precisions were 1.10–4.03% and 0.93–2.34%, respectively. The urinary levels of I and its metabolites were quantified by the proposed method.
Changes in glutathione and its metabolizing enzymes in human erythrocytes and lymphocytes with age
Authors: Al-Turk Walid A , Stohs Sidney J , El-Rashidy Fatma H , Othman Sadeq
Published: April 2011

The levels of glutathione (GSH) and the activities of glutathione S-transferases (GST) and glutathione reductase (GSR) in human erythrocytes and lymphocytes were determined in three age groups (5–12, 25–40, 65–83 years). The levels of GSH in lymphocytes increased with age, however, its levels in erythrocytes reached a maximum in the middle age group. The activity of GST in erythrocytes and lymphocytes changed as a function of age in a pattern similar to the changes found for GSH levels. GSR activity increased from young to middle age in both erythrocytes and lymphocytes, but decreased again in the old age group.
Solubilization kinetics of n-alkanes by a non-ionic surfactant
Authors: Donegan Ann C , Ward Anthony J I
Published: April 2011

The rates of solubilization of a homologous series of n-alkanes (CnH2n + 2; n = 8–16) into micellar solutions of n-dodecyl hexaoxyethylene glycol ether (C12E6) have been measured at 298 K. A mechanism involving a micellar dissociation-association process previously proposed was found to give an adequate description of the data. Proportionality between the micellar solubilization capacity in the kinetic process and that found at equilibrium could be inferred for such a series of solubilizates which have the same locus of solubilization and packing requirements.
Lipid vehicles for intestinal lymphatic drug absorption
Authors: Cheema M , Palin K J , Davis S S
Published: April 2011

The lipoprotein fractions in mesenteric lymph were monitored following intraduodenal administration of arachis oil and oleic, linoleic and linolenic fatty acids to rats. An increase in the chylomicron fraction, but not the VLDL or LDL fraction, was observed with each lipid. The greater the degree of unsaturation of the fatty acid, the more rapid the onset of chylomicron synthesis. The administration of linoleic acid and arachis oil produced the highest concentration of chylomicrons in the lymph. These results reflect differences in the rate of absorption and biochemical metabolism of the lipids and have implications for the selection of vehicles for the delivery of drugs by the lymphatic route.
Effects of dimethyl sulphoxide (DMSO) on aggregation of human blood platelets
Authors: Lehuu B , Curtis-Prior P B
Published: April 2011

The effects were examined of the universal solvent dimethyl sulphoxide (DMSO) on human platelet aggregatory activity, in-vitro, of the endogenous mediators ADP, adrenaline, arachidonic acid, collagen and PAF-acether which are believed to play important roles in cardiovascular diseases in man. DMSO inhibited aggregation induced by all of the mediators in the order ADP > adrenaline = arachidonic acid = PAF-acether > collagen. Since DMSO is widely used as a solvent for drug substances, an awareness of its intrinsic activity in any such evaluations is essential.
Involvement of Prostaglandin E-like Material in the Purgative Action of Rhein An throne, the Intraluminal Active Metabolite of Sennosides A and B in Mice
Authors: Yagi Teruyo , Miyawaki Yoshie , Nishikawa Tomoyo , Yamauchi Kazuko , Kuwano Shigeaki
Published: April 2011

Intracaecal administration of rhein anthrone, the intraluminally active metabolite of sennosides A and B, to mice quickly induced severe diarrhoea. Pretreatment with the prostaglandin (PG) biosynthesis inhibitor, indomethacin, and PGE2 antagonist, SC-19220, prevented the onset of diarrhoea induced by rhein anthrone, but the PGE2 antagonist polyphoretin phosphate (PPP) showed only a weak inhibitory effect. Rhein anthrone stimulated the production of PGE-like material only in the colon and its large intestinal propulsive activity was depressed by indomethacin and SC-19220, but not by PPP which suggests that the release of PGE-like material has some role in its purgative action.
Pharmacological Profile of New Histamine H2-Receptor Antagonists Related to Cimetidine, Ranitidine and Lamtidine
Authors: Orsetti M , Sorba G
Published: April 2011

New compounds structurally related to cimetidine, ranitidine and lamtidine have been prepared and tested for their histamine H2-receptor blocking activity on guinea-pig atria, rat perfused stomach and frog isolated gastric mucosa. These derivatives contain as a polar group, a diaminofurazan moiety, a 3-amino-4-methylfurazan or a 3-amino-4-phenylfurazan moiety. Ranitidine and lamtidine analogues display strong H2-antagonist activity in-vitro (KB on atria 0.037 μM and 0.0039 μM, respectively) and in-vivo on the lumen-perfused stomach of the anaesthetized rat (ID50 0.13 μmol kg−1 and 0.023 μmol kg−1 i.v., respectively). However, lamtidine analogues are ineffective in blocking the histamine-induced increase of H+ output in the frog isolated gastric mucosa. On the basis of the anomalous results in the frog, it is concluded that caution must be exercised in extrapolating information from amphibian to mammalian tissues with regard to the structure and the function of histamine receptors.
The inhibitory effect of liposome-encapsulated indomethacin on inflammation and platelet aggregation
Authors: Gürsoy Aylâ , Akbuğga JÜLi̇de , Eroğglu LÜTfi̇ye , Uluti̇n şengün
Published: April 2011

A comparison has been made between liposome-encapsulated and free indomethacin for their anti-inflammatory activities in the carrageenan paw oedema test in rats, and their inhibitory effect on platelet aggregation induced by adenosine 5-diphosphate (ADP) in-vitro. Free indomethacin, 3 mg kg−1, strongly inhibited carrageenan-induced oedema and a similar inhibitory activity was shown by 0.3 mg kg−1 of encapsulated drug. For the inhibition of platelet aggregation, the threshold concentration of free drug was 0.559 mM. At this concentration, at least 5 min incubation was needed to achieve 12.5% and 45 min for 50% inhibition. The inhibition was much stronger with encapsulated drug, and pre-incubation of 28 μM encapsulated drug for 10 min with platelet-rich plasma before addition of ADP completely inhibited platelet aggregation.
Myoclonic seizures in the mouse induced by alphaxalone and related steroid anaesthetics
Authors: File Sandra E , Simmonds Michael A
Published: April 2011

The anaesthetic steroids alphaxalone. 5β-alphaxalone and pregnanolone each caused myoclonic jerks in mice in a dose-related manner between 4 and 16 mg kg−1 i.v. There was no loss of righting reflex at these doses. The veterinary product Saffan, which contains alphaxalone and alphadalone, also caused myoclonic jerks at 2 mg kg−1 i.v., and a loss of righting reflex at doses of 4 mg kg−1 and above. These effects appear to be unrelated to the wide spectrum of potencies at the GABAA receptor complex of the three individual steroids as potentiators of muscimol, or as attenuators of picrotoxin.
Eudistomin derivatives, novel phosphodiesterase inhibitors: synthesis and relative activity
Authors: Kobayashi Jun'ichi , Taniguchi Mikio , Hino Tohru , Ohizumi Yasushi
Published: April 2011

The preparations of novel phosphodiesterase inhibitors, 8-acetoxy-5-iodo-6-methoxypy rido[3,4-b]indole, 5,7-dibromo-6-hydroxypyrido[3,4-b]indole, 5,7-dichloro-6-hydroxypyrido[3,4-b]-indole and 8-acetoxy-5-bromo-6-methoxypyrido[3,4-b]indole, are described together with concentrations giving 50% inhibition against cyclic AMP phosphodiesterase, i.e. 3 × 10−6, 3 × 10−6, 7 × 10−6 and 1 × 10−5 M, respectively. The relative potency of these eudistomin derivatives is discussed in terms of the chemical structures compared with those of other inactive eudistomins and derivatives.
Bunitrolol metabolism and its inhibition by cimetidine
Authors: Ishida Ryozo , Fujita Shoichi , Suzuki Tokuji
Published: April 2011

A simple fluorometric assay method as well as a sensitive HPLC method for determination of bunitrolol, a β-adrenoreceptor blocking drug, and its 4-hydroxylated metabolite is described. More than 90% of bunitrolol metabolized was accounted for by the formation of 4-hydroxybunitrolol in rat hepatic microsomes. Bunitrolol 4-hydroxylation required NADPH, and was inhibited by CO, proadifen and metyrapone, indicating that this reaction is mediated by cytochrome P450. This reaction was also inhibited by cimetidine competitively, and the inhibition constant, Ki, was 40 ± 11.5 μM (mean ± s.e. n = 3).
Effects of minaprine, a novel antidepressant, on prolactin secretion in the rat
Authors: Matsuo N , Yamada K , Kumacai M , Nagashima M , Matsumoto S , Shirakawa K , Furukawa T
Published: April 2011

The effect of minaprine, a novel psychotropic drug with antidepressant properties, on prolactin secretion has been investigated in the rat. On intraperitoneal administration (10 and 20 mg kg−1) it significantly decreased basal prolactin levels. In contrast, both haloperidol (1 mg kg−1 i.p.) and morphine (20 mg kg−1 i.p.) increased serum prolactin levels and daily treatment with oestradiol (100 μg kg−1 s.c.) for 4 days also elevated the levels. Minaprine at a dose of 20 mg kg−1 failed to antagonize the elevation of serum prolactin levels induced by these drugs. The results imply that minaprine may not exert a direct inhibitory action on prolactin secretion at the pituitary gland.
Effects of AN-132 and quinidine, antiarrhythmic agents, on plasma digoxin concentrations in rats
Authors: Sakai Kazushige , Yamazaki Tamotsu , Hinohara Yoshikazu
Published: April 2011

The effects of AN-132, 3-(diisopropylaminoethylamino)-2′,6′-dimethylpropionanilide.2H3PO4, on chloroform-induced arrhythmias and plasma digoxin concentrations have been compared with those of quinidine in rats. AN-132 (0.01–3 mg kg−1) administered orally significantly inhibited the incidence of cardiac arrhythmias in a dose-related fashion. A single dose of digoxin (1 mg kg−1) given orally for 7 consecutive days was followed, on day 8, orally by digoxin alone, or together with AN-132 (50, 100 and 200 mg kg−1) or quinidine (25 and 50 mg kg−1). The AUC0-24 and Cmax of plasma digoxin were enhanced significantly by co-administration of quinidine, but not by AN-132.
Influence of adrenocorticotrophic hormone on the behaviour in the swim test of rats treated chronically with desipramine
Authors: Volosin M , Cancela L , Molina V
Published: April 2011

Chronic desipramine (DMI) administration induced a dose-dependent reduction in the immobility time of the swim test in rats. A combined treatment of ACTH (50 iu kg−1 s.c.) and DMI (5 or 10 mg kg−1 i.p.) for 7 days potentiated the anti-immobility effect of DMI. ACTH 4–10, a fragment peptide with little corticotrophic activity, mimicked ACTH-induced potentiation. No stimulating effect on locomotor activity was observed following seven daily co-administrations of ACTH or ACTH 4–10 and DMI (10 mg kg−1). This behavioural evidence indicates that ACTH potentiation involves a central mechanism and demonstrates a functional interaction between ACTH and DMI at the behavioural level.
Compatibility of Intravenous Fat Emulsions with Prodrug Amino Acids
Authors: Ishii F , Takamura A , Ogata H
Published: April 2011

Three prodrugs, N-α-acetyl-L-arginine, N-α-acetyl-L-histidine and N-α-acetyl-L-lysine have been examined to see if they could induce significant changes in the stability of an intravenous fat emulsion, the stability being evaluated in terms of physicochemical measurements such as particle size distribution, surface tension, pH and zeta potential. The acetyl amino acids had an excellent stabilizing effect on the emulsion compared with amino acids without acetyl groups.
Differential Retention of Doxorubicin in the Organs of Two Strains of Rats
Authors: Chauffert Bruno , Dumas Monique , Dubuet Aleth , D'Athis Philippe , Olsson Nils Olivier
Published: April 2011

Fluorescence microscopy and high pressure liquid chromatography were used to study the decrease of doxorubicin (DXR) concentrations in the liver, spleen, heart, lung, kidney and skeletal muscle of two strains of rats at various times after a single intravenous injection of the drug (8 mg kg−1). DXR was located within the cell nucleus and was mostly undegraded, it persisted, especially in heart, lungs and spleen where it was detectable 10 days after injection. The DXR/DNA ratio, was used as an index of nuclear fixation of the drug. A major difference in the DXR/DNA ratio between the two strains were observed in heart and spleen results; the DXR/DNA ratio was significantly higher in heart and spleen compared with lung, liver and kidney in both strains.
Dose-dependency in the Exsorption of Theophylline and the Intestinal Dialysis of Theophylline by Oral Activated Charcoal in Rats
Authors: Arimori Kazuhiko , Nakano Masahiro
Published: April 2011

The elimination half-life of theophylline in serum after intravenous (i.v.) administration of aminophylline increased with increase in dose. Exsorption of theophylline from blood to the gastrointestinal tract was investigated after i.v. administration of aminophylline (10–50 mg kg−1) to rats by the in-situ single-pass perfusion technique. The exsorption rate of theophylline into the intestinal lumen also increased with increase in dose. When the dose of aminophylline was increased five-fold from 10 to 50 mg kg−1, the amount of theophylline exsorbed in 120 min was proportionally increased from 450 to 2300 μ g. The average extent of theophylline exsorbed into the intestinal lumen was 12–15% after doses from 10–50 mg kg−1, while the extent of the drug excreted into the bile varied from 0.17–0.30% after doses from 10–50 mg kg−1. However, intestinal and biliary clearance of theophylline did not change significantly in the range 10 to 50 mg kg−1. Oral administration of multiple doses of activated charcoal reduced the serum theophylline levels after i.v. administration of aminophylline (50 mg kg−1) to rats. The serum half-life and the area under the serum concentration-time curve of theophylline were decreased to 52 and 50% by the charcoal treatment, respectively, while the total body clearance of the drug was increased to 188% compared with the corresponding control experiments. The volume of distribution was not significantly different between treated and control rats. As the total body clearance after a high dose is less than after a low dose, because there is a decreased endogenous clearance (as observed in theophylline overdose), clearance after a high dose may be more enhanced by oral activated charcoal than that after a low dose.
Involvement of Prostaglandins in Histamine-induced Fluid and Electrolyte Secretion by Rat Colon
Authors: Hardcastle Jacqueline , Hardcastle P T
Published: April 2011

Histamine increased the transmural potential difference across rat colon in-vivo and induced a net secretion of fluid. Both effects were inhibited by indomethacin. Histamine increased the potential difference and short-circuit current, and reduced tissue resistance in colonic sheets in-vitro. This response was reduced in the absence of chloride in the bathing medium or in the presence of serosal frusemide, suggesting that histamine stimulated electrogenic chloride secretion by the colon. The rise in short-circuit current induced by histamine was calcium-dependent since it was reduced in the absence of serosal calcium or in the presence of serosal verapamil. Indomethacin, a cyclo-oxygenase inhibitor, and mepacrine, a phospholipase inhibitor, both caused a dose-dependent inhibition of the electrical response of colonic sheets to histamine, without affecting the rise in short-circuit current induced by prostaglandin E2. The stimulation of chloride secretion induced by histamine in rat colon therefore appears to be mediated by an increased production of prostaglandins.
The Effect of Metoclopramide on the Absorption and Pharmacology of Chlorpromazine in the Rat
Authors: Imamura Y , Harada S , Okano Y , Miyata T , Otagiri M
Published: April 2011

The mechanism of interaction between metoclopramide (MCP) and chlorpromazine (CPZ) has been examined in rats. MCP given intraperitoneally 30 min before orally administered CPZ significantly enhanced the cataleptic and hypothermic effects of CPZ, and also initially increased its plasma and brain concentrations. However, MCP had no effect on the plasma and brain concentrations of CPZ given as an intravenous bolus, indicating that MCP interacts with CPZ during its intestinal absorption. Furthermore, co-administration of MCP (i.p.) with CPZ (p.o.) markedly accelerated gastric emptying compared with CPZ alone, and MCP (i.v.) did not alter the uptake of CPZ by the intestinal membrane. Therefore, it is concluded that MCP causes an increase in the rate of CPZ absorption, by accelerating the gastric emptying.
Different Ability of Trifluoperazine to Inhibit Agonist-induced Contraction of Lung Parenchyma Strips from Control and Sensitized Guinea-pigs
Authors: Sanz Celia , Cortijo Julio , Perpin̄á Miguel , Esplugues Juan , Morcillo Esteban J
Published: April 2011

There is increasing interest in the therapeutic potential of calcium antagonists in asthma. Among them the use of calmodulin antagonists deserves consideration. In the present work the effect of trifluoperazine on contractions generated by different mechanisms (CaCl2, KCl, acetylcholine, histamine and 5-hydroxytryptamine) in lung parenchyma strip isolated from control and actively sensitized guinea-pigs has been studied. Trifluoperazine produced both in unsensitized and sensitized lung strips, a concentration-dependent, right, downward displacement of the concentration-response curves to the agonists used, although the sensitization procedure resulted in a potentiation in the ability of trifluoperazine to inhibit agonist-induced contractions. The basis for this greater potency of trifluoperazine in sensitized tissues remains to be elucidated but raises attention to the future use of selective calmodulin antagonists in the management of asthma.
The permeability of grafted human transplant skin in athymic mice
Authors: Scott Robert C , Rhodes Christopher
Published: April 2011

Human skin has been transplanted onto athymic mice and its permeability properties assessed to see if this in-vivo model would be of benefit in predicting accurately absorption of drugs or toxic chemicals through human skin. The permeability properties of the skin alone, and grafted and athymic mouse skin were assessed by measuring in-vitro absorption of tritiated water and a permanently charged cationic penetrant, paraquat. The grafted skin and athymic mouse skin had similar permeability to the tritiated water. However, the grafted skin was less permeable to paraquat but was more permeable to it than normal human skin, indicating that although histologically, the transplanted skin appeared normal, its barrier properties were impaired. The model was not, therefore, useful for assessing human percutaneous absorption.
Transport Characteristics of Propantheline Across Rat Intestinal Brush Border Membrane
Authors: Saitoh Hiroshi , Kawai Shinji , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

The transport mechanism of propantheline, an anti-acetylcholine quaternary ammonium compound, has been studied using brush border membrane vesicles isolated from rat small intestine. The uptake of propantheline was facilitated by the transmembrane electrical potential difference (cell interior negative) induced by NaSCN, NaI or valinomycin. But this effect was a secondary action; in the initial phase of propantheline uptake (< 5 min), there was no facilitating effect. When the transmembrane potential difference was induced after propantheline uptake had reached a steady state, there was an overshoot of the drug. Therefore, it is suggested that the transport of propantheline across the brush border membrane consists of at least two processes. In the first, propantheline rapidly binds to the brush border membrane, in the second it enters into epithelium driven by the negative transmembrane electrical potential difference. Cationic tertiary amines such as chlorpromazine, imipramine and promethazine markedly inhibited propantheline uptake. These results suggest that there is a common absorption process for tertiary amines and quaternary ammonium compounds.
Depolarizing Effect of Various Local Anaesthetics on the Helix aspersa Neurons: Dose-response Relationship
Authors: Cardi P , Lartigue M , Meunier J M
Published: April 2011

The depolarizing effect of various local anaesthetics (LA) on the membrane potential of Helix central neurons has been examined. There is a relation between depolarizing effect and concentration of LA in the bath that is linear over a range of concentrations. The slope of the curve is significantly higher for amethocaine (tetracaine) than for procaine while for dibucaine the dose-response relation is not linear. The blockade of a response to acetylcholine (ACh) is about two fold higher for dibucaine and amethocaine than for procaine. These results suggest that both amethocaine and procaine act at the ACh-site in addition to their binding with specific sites located within the ionic channel lumen; dibucaine appears to act through another mechanism.
The Anxiolytic and Anxiogenic Actions of Ethanol in a Mouse Model
Authors: Costall B , Kelly M E , Naylor R J
Published: April 2011

The administration to mice of ethanol in the drinking water for 7 days modified exploratory activity (rearings/line crossings) in an anxiety testing box separated into white and black sections with an interconnecting door. During ethanol intake mice exhibited reduced anxiety responding, shown as increased rearings and line crossings in the white section, to which the mice are normally averse, with corresponding decreased behaviour in the black section. When naive mice were presented with a choice between normal drinking water and drinking water containing ethanol, they consumed sufficient of the latter to secure a full anxiolytic response, making up the total volume of fluid required by also drinking the former. A 48 h withdrawal from a 14 day treatment with ethanol caused a reversed profile of exploratory behaviour, directed preferentially at the black section of the test box, and indicative of an anxiogenic response. Diazepam, tiapride or clonidine given twice daily during withdrawal from ethanol could each secure a reduction in the withdrawal anxiogenesis. It is concluded that the simple model of anxiety described in the mouse may be useful for eludicating the mechanisms involved in the anxiolytic and anxiogenic potential of ethanol and may aid the search for novel agents having potential to suppress withdrawal anxiogenesis.
Interfacial tensions and partition coefficients in water/heptane systems containing 2,6-diisopropylphenol, n-alkylphenols and cycloalkanols
Authors: Runyan A , Perrin J H , Vilallonga F A
Published: April 2011

The free energies of absorption, dehydration, and transfer in a heptane-water system for a set of phenolic compounds and a series of cycloalkanols have been investigated. The free energy of adsorption depends only upon the molecular surface area of the hydrophobic fraction of the molecule, whereas the free energy of dehydration is independent of this fraction.
Modulation of cyclic AMP and autoregulation of renal blood flow, analysed by the use of forskolin and 1-methyl-3-isobutylxanthine
Authors: Ogawa Nobuyuki , Ono Hiroshl
Published: April 2011

We have examined the effects of forskolin and 1-methyl-3-isobutylxanthine (IBMX) in relation to cyclic (c)AMP metabolism and renal blood flow autoregulation in anaesthetized dogs. Control observations usually showed excellent autoregulation of renal blood flow over the renal perfusion pressure range of 120–200 mmHg, when the perfusion pressure was changed, stepwise, between 60 and 200 mmHg. Renal blood flow was increased by the infusion of forskolin (10 μg min−1) and IBMX (100 μg min−1) at the basal perfusion pressure of 100 mmHg, and maintained an increased level while the infusion was continued. Forskolin and IBMX did not inhibit autoregulation, though they shifted the perfusion pressure range evoking autoregulation. These data indicate that vasodilators which may produce the activity through modulating the cAMP level in vascular smooth muscle do not influence the establishment of autoregulation of renal blood flow.
In-vivo studies with the opioid antagonist, 16-methylcyprenorphine
Authors: Birch Phillip J , Hayes Ann G , Sheehan Michael J , Tyers Michael B
Published: April 2011

The effect of the opioid antagonist, 16-methylcyprenorphine (RX8008M), on the antinociceptive action of the μ-selective agonist, morphine, and the κ-selective agonist, U50488H, has been investigated in the mouse abdominal constriction test. RX8008M produced a dose-dependent antagonism of the antinociceptive effect of morphine, but did not antagonize the response to U50488H. RX8008M should prove a useful probe for the in-vivo characterization of the receptor selectivity of opioid drugs.
A modified transmembrane migration method for evaluating the spermicidal potency of some nonoxynol compounds
Authors: Gadd A L , Curtis-Prior P B
Published: April 2011

The transmembrane migration technique, a simple method in-vitro for quantitatively assessing the effects of a drug on human sperm motility, has been evaluated. The original method has been modified to include a preincubation step, and the incubation time has been reduced to 90 min. In semen samples possessing sperm concentrations of < 75 × 126 spermatozoa mL−1 the volume of the lower reservoir has been reduced to 1 mL. This modified method has been used to compare the spermicidal potency of the widely employed non-ionic surfactant nonoxynol-9, with nonoxynol-5 and nonoxynol-15 (containing, respectively, fewer and more ethylene oxide units per molecule). The rank order of spermicidal potency of the compounds evaluated was nonoxynol-9 = nonoxynol-5 > nonoxynol-15.
The effect of repeated oral doses of azelastine hydrochloride on antipyrine half-life in normal volunteers
Authors: Johnston A , Warrington S J , Turner P , Aurlch R
Published: April 2011

Treatment with azelastine 4.4 mg twice daily for 21 days did not produce any change in salivary antipyrine elimination in 8 normal volunteers.
Strategy to Assess the Role of (Inter)active Metabolites in Pharmacodynamic Studies In-vivo: a Model Study with Heptabarbital
Authors: Dingemanse Jasper , Thomassen David , Mentink Bert H , Danhof Meindert
Published: April 2011

The purpose of this investigation was to develop a universal experimental strategy by which the role of (inter)active metabolites in in-vivo pharmacodynamic studies can be examined. Heptabarbital was chosen as a model drug and several pharmacokinetic variables which may affect in-vivo concentration-pharmacological response relationships were examined. Adult female rats received an i.v. infusion of the drug at one of three different rates (0.225–1.50 mg min−1) until the animals lost their righting reflex (after 11 ± 1 to 88 ± 8 min of infusion). The serum concentration of the drug at onset of loss of righting reflex (LRR) increased slightly with increasing infusion rate. The drug concentrations in brain tissue and cerebrospinal fluid (CSF), (mean ± s.d.: 67 ± 5 mg kg−1 and 24 ± 4 mg L−1, respectively, for the lowest infusion rate) were not affected by the infusion rate. The possible contribution of (inter)active metabolites to the pharmacological response of heptabarbital was determined by administration of different i.v. bolus doses (14.1–22.5 mg) resulting in widely differing sleeping-times (7 ± 3 to 119 ± 20 min). The concentrations of heptabarbital in serum, brain tissue and CSF at offset of LRR (mean ± s.d.: 77 ± 8 mg L−1, 76 ± 7 mg kg−1 and 29 ± 5 mg L−1, respectively, for the highest dose) were not affected by the administered dose. Kinetic analysis of the relationship between dose and the duration of the pharmacological response revealed an elimination half-life of heptabarbital of 2.8 ± 0.2 h, which is in close agreement with the value determined on the basis of the plasma concentration vs time profile following administration of 22.5 mg i.v. (2.8 ± 0.4 h). In a separate investigation no statistically significant differences were observed in heptabarbital concentrations at onset of LRR during an i.v. infusion (0.563 mg min−1) and at offset of LRR following an i.v. bolus dose (22.5 mg; sleeping time: 100 ± 20 min). These results show that (a) there is a rapid equilibration between the concentrations of heptabarbital (heptabarbitone) in CSF and those at the site of action (i.e. the CSF compartment is pharmacokinetically indistinguishable from the site of action), (b) metabolites do not interfere with the pharmacological effect of heptabarbital and (c) within the time-frame of the experiments there is no development of ‘acute’ tolerance to the anaesthetic effect of heptabarbital. It is concluded that a combination of determination of the concentrations at offset of a certain pharmacological effect following administration of different drug doses, and evaluation of the dose vs duration of pharmacological response relationship, can be a powerful tool in examining the role of unknown (inter)active metabolites.
Cardiovascular Effects of Fibrinopeptide B
Authors: Moore P K , Hussaini I , Bhardwaj R
Published: April 2011

The effect of fibrinopeptide B (FpB) on isolated blood vessels and in the intact rat has been investigated. FpB contracted the rabbit superfused aorta preparation (EC50 = 7.5 nmol) and was some 20 times less potent than noradrenaline. Similarly, FpB (0.2–10 nmol) injected into the rat perfused kidney caused dose related, short-lived increases in perfusion pressure and potentiated the vasoconstrictor effect of injected noradrenaline. These effects were associated with increased efflux of PGE2 (but not TxB2) and were reduced but not abolished by indomethacin (10 μM). FpB injected intravenously into the urethaneanaesthetized rat exhibited vasoconstrictor activity (EC50 = 2.5 μg kg−1) but was less potent than noradrenaline (EC50 = 0.9 μg kg−1). The doses of FpB required to contract the rabbit isolated aorta and to constrict the vasculature of the rat kidney occur naturally in the bloodstream of patients with thrombotic disease. FpB released at the site of thrombus formation may play a part in regulating local blood vessel calibre.
Effect of Levonorgestrel and Ethinyloestradiol on Vasoconstriction in Rat Isolated Vasculature
Authors: Byrne K Bruce , Stanton Bryan J , Coupar Ian M , Burcher Elizabeth
Published: April 2011

Female Sprague-Dawley rats were injected s.c. with 0.2 μg day−1 ethinyloestradiol (EE2) or 2.0 μg day−1 levonorgestrel (NG), procedures previously shown to increase systolic blood pressure. Increases in perfusion pressure to clonidine, phenylephrine, noradrenaline (NA) and angiotensin II (AII) were observed in rat isolated tail arteries, and to NA in the isolated mesenteric vasculature from steroid and vehicle-treated rats. NG treatment for four weeks produced increases in sensitivity to phenylephrine and NA in rat tail arteries; at 6 weeks the increases in sensitivity had largely disappeared but the maximum responses to clonidine and phenylephrine were increased. No change in sensitivity to AII was observed with NG. In contrast, EE2 treatment for six weeks produced increases in sensitivity to AII, and a decrease in sensitivity and maximum response to clonidine but not to phenylephrine or NA, in tail arteries. Responses to NA in the mesenteric vasculature were increased after 6 weeks NG treatment but unaffected after 12 weeks EE2 treatment. It is concluded that NG treatment stimulates α-adrenoceptor number, affinity or receptor-linked Ca2+ events which may contribute to its previously demonstrated hypertensive effect. The increased responsiveness to AII but not the decrease in α2-adrenoceptor responsiveness may be associated with the chronic hypertension induced by EE2.
The effect of the shape of fine particles on the formation of ordered mixtures
Authors: Wong L W , Pilpel N
Published: April 2011

A study has been made of the effects of the shape of fine particles on the formation and stability of some ordered mixtures using a specially constructed Y mixer. Irregular particles adhere to indentations on the surface of the carrier particles and form stable ordered mixtures.