bluuebunny/crossref_metadata_2025 huggingface dataset:
Cephaloridine resistance in Gram-negative bacteria isolated in Scotland
Authors: Reid Alison J , Simpson Iain N , Harper Paul B , Amyes Sebastian G B
Published: April 2011

The incidence of cephaloridine resistance (minimum inhibitory concentration, MIC > 8mg L−1) in isolates from urinary tract infections was 45.1 % in Glasgow, 22.6% in Dundee and 25.9% in Edinburgh. The incidence of ampicillin resistance (MIC > 8 mg L−1) was even higher:- being 45.2% in Dundee and 48.5% in Edinburgh. In Glasgow, the incidence was 71.9% which is the highest proportion of ampicillin resistance reported in the United Kingdom. The cephaloridine resistant strains were examined for β-lactamase production. Amongst these strains 50.8% produced only a chromosomal β-lactamase, whereas 47.9% produced β-lactamases which were potentially plasmid-mediated on the basis of biochemical tests. Only 1 % of the resistant strains produced no detectable β-lactamase.
Frequency-dependent autoinhibition of histamine release from rat cortical slices: a possible role for H3 receptor reserve
Authors: van der Vliet A , van der Werf I F , Bast A , Timmerman H
Published: April 2011

The inhibition of histamine release after depolarization of rat cerebral cortex slices by electrical stimulation and mediated by the postulated presynaptic autoreceptor (H3) depends strongly on the conditions of stimulation. Using electrically stimulated slices of the cortex a rightwards shift of the concentration-response curve of histamine (an H3 agonist) was observed on increasing the frequency of stimulation. The pA2 value of the H3 antagonist impromidine was, however, not altered at different stimulation frequencies; for a partial agonist only the maximal effect was influenced. These results indicate the existence of a receptor reserve at the H3autoreceptor.
Determination of the Critical Stress Intensity Factor (KIC) of Compacted Pharmaceutical Powders by the Double Torsion Method
Authors: Mashadi A B , Newton J M
Published: April 2011

The critical stress intensity factor KIC has been determined for compacts prepared at different pressures from both Avicel PH101 and sorbitol ‘Instant’, by means of a double torsion method. This method avoids the need for displacement measurement and the introduction of notch into the specimens, both of which present problems with pharmaceutical materials. Measurements of fracture loads for such specimens were reproducible. The values of KIC derived for both materials were found to increase linearly with increase in compaction pressure and linearly with decrease in specimen porosity. Extrapolation of the latter relationship to zero porosity gave values of 1.81 and 0.09 MN m−3/2 for the KIC of Avicel PH101 and sorbitol ‘Instant’, respectively.
Properties of a Semicarbazide-Sensitive Amine Oxidase in Human Umbilical Artery
Authors: Precious Elaine , Lyles Geoffrey A
Published: April 2011

The metabolism of some aromatic amines by amine oxidase activities in human umbilical artery homogenates has been studied. The inhibitory effects of clorgyline showed that 5-hydroxytryptamine (5-HT) and tryptamine, 1 mM, were predominantly substrates for monoamine oxidase (MAO) type A, whereas MAO-A and B were both involved in the metabolism of β-phenylethylamine (PEA), 100 μM, and tyramine, 1 mM. About 20–30% of tyramine and PEA metabolism was resistant to 1 mM clorgyline, but sensitive to inhibition by semicarbazide, 1 mM, indicating the presence of a semicarbazide-sensitive amine oxidase (SSAO). Benzylamine, 1 mM, appeared to be metabolized exclusively by SSAO with a Km (161 μM) at pH 7.8 similar to that found for SSAO in other human tissues. Tyramine and PEA were relatively poor substrates for SSAO, with very high apparent Km values of 17.6 and 13.3 mM, respectively, when determined in the presence of clorgyline, 10−3 M, added to inhibit any metabolism of those amines by MAO activities. However, kinetic studies with benzylamine indicated that clorgyline, 10−3 M, also appears to inhibit SSAO competitively such that the true Km values for tyramine and PEA may be about 60% of those apparent values given above. No evidence for the metabolism of 5-HT or tryptamine by SSAO was obtained. The aliphatic amine methylamine was recently shown to be a specific substrate for SSAO in umbilical artery homogenates. We have used benzylamine and methylamine as SSAO substrates in histochemical studies to localize SSAO in tissue sections. Both amines promoted tissue staining which occurred predominantly over the medial layers of the vessel wall, and this staining was prevented by the presence of semicarbazide, 1 mM, but not by pargyline, 1 mM, in the reaction medium. The results support the notion that smooth muscle cells are an important site of SSAO activity in human blood vessels, and reinforce the possibility that methylamine, an endogenously-occurring amine, may be a better candidate as a physiological substrate for SSAO in man, than several aromatic biogenic amines so far examined.
Effect of tiopronin on prostaglandin synthesis in rabbit kidney medulla slices
Authors: Fujita Tadashi , Fujimoto Yohko , Wada Kohichiro , Kaneko Mika , Sakuma Satoru , Iso Tadashi
Published: April 2011

The effect of 2-mercaptopropionylglycine (tiopronin), which is widely used for the treatment of various hepatic disorders, on the generation of medullary prostaglandins (PG) E2 and F2α has been examined. Tiopronin had a potent inhibitory effect on PG E2 formation. Simultaneously, PG F2α production was increased. In the presence of tiopronin the net increased amount of PG F2α was much smaller than the net decreased amount of PG E2 (6–20%). These results suggest that tiopronin has the potential to modulate PG E2 and F2α synthesis by affecting endoperoxide E2 isomerase or endoperoxide reductase and that this effect may represent some pharmacological action of the drug.
Antihistaminic and anticholinergic activities of mequitazine in comparison with clemizole
Authors: Martinez-Mir I , Estañ L , Rubio E , Morales-Olivas F J
Published: April 2011

The antihistamine and anticholinergic properties of mequitazine have been investigated and compared with those of clemizole. Both mequitazine and clemizole antagonized the effect of histamine in guinea-pig ileum competitively, the pA2 values calculated by Schild plot were 9.95 ± 0.44 for mequitazine and 10.54 ± 0.44 for clemizole. Mequitazine at 10−7 M produced a parallel shift of the dose-response curve to acetylcholine in the rat duodenum, clemizole and the lower doses of mequitazine failed to modify the effect of acetylcholine. The potency of mequitazine and clemizole as H1-histamine blockers is similar, but only mequitazine at highest concentration used showed anticholinergic activity.
A comparison of the effects of oxodipine and nifedipine on rat vas deferens
Authors: Martin Isabel , Alfaro Maria José , Tamargo Juan
Published: April 2011

The effects of oxodipine, a new dihydropyridine, were studied and compared with those of nifedipine in the complete vasa deferentia and in the prostatic and epididymal halves of the rat vas deferens. Oxodipine and nifedipine, 10−9–10−6M, produced a dose-dependent inhibition of the contractile responses induced by single pulse stimulation, noradrenaline (3 × 10−5M) and high-K (50 mM). The inhibitory effects of oxodipine were significantly reduced in high Ca media. From these experiments it is concluded that oxodipine, like nifedipine, produced a similar and potent inhibitory effect of the contractile responses induced in the rat vas deferens.
An assay procedure to compare sorptive capacities of activated carbon dressings: the detection of impregnation with silver
Authors: Schmidt Richard J , Shrestha Tirtha , Turner Terence D
Published: April 2011

A semiquantitative assay procedure for the estimation of uptake of diethylamine by activated carbon dressings has been developed. The procedure involves the use of Nessler’s reagent as a comparative indicator. The use of diethylamine allows the concomitant detection of silver with which the dressings may be impregnated. The implications of silver/amine complex formation during dressing use are discussed. Quantification of the silver content of one such fabric was carried out by atomic absorption spectrophotometry. A silver content of 2770 ppm was found. It is suggested that this method might be suitable for adoption as the basis for a pharmacopoeial assay procedure for activated carbon dressings.
Concentration and Time-dependent Inter-relationships for Cytotoxicities of Nitrogen Mustard Drugs against Lymphoblasts In-vitro
Authors: Ehrsson Hans , Wallin Inger , Ringborg Ulrik
Published: April 2011

Peripheral lymphoblasts were exposed either to different initial concentrations of the alkylating agents (melphalan, chlorambucil or phenylacetic acid mustard) using a fixed incubation time or a constant initial concentration with variable exposure times. The cytotoxic activity was evaluated as the inhibition of [3H]methylthymidine incorporation into the trichloroacetic acid-insoluble fraction of the cells. The concentration-time relationships were evaluated by calculating the amount of drug which had chemically reacted in the incubation system. Melphalan showed lower cytotoxicity at short exposure times and high drug concentrations, while chlorambucil exhibited higher cytotoxicity at longer exposure times. In the latter case the effect could be accounted for by the cytotoxic activity of monohydroxy chlorambucil which was formed in the incubation system.
Effects of Various Ginseng Saponins on 5-Hydroxytryptamine Release and Aggregation in Human Platelets
Authors: Kimura Yoshiyuki , Okuda Hiromichi , Arichi Shigeru
Published: April 2011

The effects of various ginseng saponins isolated from red ginseng roots, on aggregation and 5-hydroxytryptamine release (5-HT) human platelets have been investigated. Among the six saponins tested, only ginsenoside Rg1 inhibited adrenaline- and thrombin-induced platelet aggregation and 5-HT release dose-dependently, at concentrations of 5 to 500 μg mL−1. Ginsenoside Rg1 had no effect on adrenaline- and thrombin-induced arachidonic acid release and diacylglycerol production. But it did reduce the elevation of cytosolic free calcium concentration (Ca2+)i shown in the second phase induced by adrenaline and thrombin, at concentrations of 10 to 500 μg mL−1. Those data suggest that the inhibitory effects of ginsenoside Rg1 on 5-HT release from, and aggregation of, platelets might be due to the reduction of (Ca2+)i elevation at the second phase induced by adrenaline and thrombin. The results suggest that ginsenoside Rg1 in red ginseng roots may be active as a drug in the treatment of artheroscleorosis and thrombosis.
The Effect of Acute and Chronic Administration of Morphine and Morphine Withdrawal on Intestinal Transit Time in the Rat
Authors: Brown Nicola J , Coupar Ian M , Rumsey R David E
Published: April 2011

The effects of acute and chronic morphine administration and of morphine-withdrawal on intestinal transit time of a liquid meal were investigated using rats. Many experiments have assessed the effects of acute morphine administration on intestinal transit, but the intestinal effects of chronic morphine administration have been neglected. Our results showed no significant differences between morphine-dependent and control animals when assessing the leading edge of the liquid meal infusion, its distribution and geometric centre (G.C.). However, during naloxone-precipitated withdrawal from morphine, the leading edge of the infusion and its G.C. were significantly distal to values obtained from other groups. Acute morphine administration caused delayed intestinal transit of a meal infusion, an effect partly caused by significant retention of the infusion in the stomach and duodenum. The leading edge of the meal infusion and G.C. were significantly proximal to values obtained from other groups of animals. The results show that morphine-dependent rats develop complete tolerance to the delayed intestinal transit of a meal observed after acute morphine administration and that withdrawal from morphine accelerates intestinal transit of a liquid meal.
Effect of Alkylxanthines on Gentamicin-induced Acute Renal Failure in the Rat
Authors: Kellett R , Bowmer C J , Collis M G , Yates M S
Published: April 2011

Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg−1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF.
Enhanced bioavailability of morphine after rectal administration in rats
Authors: Katagiri Yoshihiro , Itakura Tadanori , Naora Kohji , Kanba Yasuhiro , Iwamoto Kikuo
Published: April 2011

Plasma morphine levels and the area under the plasma concentration-time curve (AUC) after i.v. (10 mg kg−1), p.o. (100 mg kg−1) and rectal (unrestricted or restricted to 1.5 cm from the anus, 10 mg kg−1) administration of morphine hydrochloride were determined in 10 or 11-week-old male Wistar rats to compare bioavailability of morphine after the rectal dosage with that after oral administration. The AUC value after oral administration (15 μg min mL−1), which was normalized by the dose, was only one-tenth of that after i.v. dosing (151 μg min mL−1). In contrast, the AUC after rectal administration (unrestricted, 133 μg min mL−1; restricted, 142 μg min mL−1) was almost comparable with that after i.v. administration. From the comparison of these AUC values, the extent of systemic availability of morphine after rectal (unrestricted or restricted) and p.o. administration was estimated to be approximately 90 and 10%, respectively.
Reversal of neuroleptic-induced catalepsy by novel aryl-piperazine anxiolytic drugs
Authors: McMillen Brian A , Scott Sara M , Davanzo Elizabeth A
Published: April 2011

The novel anxiolytic drug, buspirone, reverses catalepsy induced by haloperidol. A series of aryl-piperazine analogues of buspirone and other 5-hydroxytryptaminergic agonists were tested for their ability to reverse haloperidol induced catalepsy. Those drugs with strong affinity for 5-hydroxytryptamine1a receptors were able to reverse catalepsy. Drugs with affinity for other 5-HT receptors or weak affinity were ineffective. However, inhibition of postsynaptic 5-HT receptors neither inhibited nor potentiated reversal of catalepsy and leaves open the question as to the site or mechanism for this effect.
The influence of urotensin II on calcium flux in rat aorta
Authors: Gibson A , Conyers S , Bern H A
Published: April 2011

The fish neuropeptide urotensin II (UII, 10 nM) caused a 51% increase in uptake of 45Ca by segments of rat aorta; this increase was abolished by the Ca channel blocking drug nitrendipine (200 nM). 45Ca efflux was unchanged in the presence of UII, but was significantly increased following washout of the peptide; again, this increase was not observed in the presence of nitrendipine. The results provide direct evidence that the nitrendipine-sensitive component of the contractile response of rat aorta to UII involves mobilization of extracellular Ca, with subsequent activation of a Ca-induced, Ca-release process intracellularly. The mechanisms responsible for the nitrendipine-resistant component of the contractile response to UII remain to be established.
The Disposition of The Enantiomers of Warfarin Following Chronic Administration to Rats: Relationship to Anticoagulant Response
Authors: Pratt S K , Winn M J , Park B K
Published: April 2011

A model of chronic anticoagulation has been used to investigate the whole liver and subcellular disposition of the individual enantiomers of warfarin in the Wistar rat in relation to anticoagulant response. Consistent pharmacodynamic responses were achieved by dosing daily with R-warfarin (0·4, or 0·8 mg kg−1 day−1 i.p.) or S-warfarin (0·1 mg kg−1 day−1 i.p.). After the administration of increasing doses of R-warfarin, prothrombin times were dose-dependent (16·3 ± 0·5 s, 0·1 mg kg−1 day−1; 21·6 ± 1·7 s, 0·4 mg kg−1 day−1; 55·1 ± 9·0 s, 0·8 mg kg−1 day−1; results all measured 24 h after the final dose). Increasing doses of R-warfarin also produced increases in plasma, whole liver, and cytosolic concentrations of warfarin. However, there were no significant differences between the microsomal concentrations of R-warfarin in the three groups. The dose of S-warfarin required to produce a consistent and significant increase in the prothrombin time was four-fold lower than the dose of R-warfarin required to cause a similar effect. Plasma concentrations of S-warfarin were not significantly different from those seen after 0·4 mg kg−1 day−1  R-warfarin. Whole liver and cytosolic concentrations of the S-enantiomer were lower than those observed after a dose of 0·4 mg kg−1 day−1  R-warfarin. However, consistent with microsomal concentrations following increasing doses of R-warfarin, there was no significant difference between microsomal concentrations of R(+)- and S(—)-warfarin. Thus, in contrast to plasma, whole liver or liver cytosol, microsomal concentrations of warfarin do not appear to be related to either dose or pharmacological response. Our results appear consistent with the possibility of there being a saturable binding site in the microsomal fraction of the liver, with a capacity of approximately 4·0 μg g−1 protein.
Excitatory Effect of Morphine and Opioid Peptides in the Rat Isolated Colon
Authors: Laniyonu Adebayo , McCulloch Cameron , Pollock David
Published: April 2011

Morphine and the opioid peptides cause isolated segments of rat colon to contract and relax rhythmically. This study re-examines two hypotheses to explain this phenomenon: Release of 5-hydroxytryptamine (5-HT)/acetylcholine by morphine or inhibition of a tonically active non-adrenergic, non-cholinergic (NANC) inhibitory mechanism. Rhythmic contractions induced by morphine (5 × 10−6 M) were naloxone sensitive (10−6 M) but unaffected by methysergide (10−6 M), atropine (10−6 M) or pretreatment of rats with p-chlorophenylalanine (200 mg kg−1 i.p. for four days) which lowered the 5-HT level in the colon from 3·73 ± 0·83 mg g−1 in controls to 0·41 ± 0·06 mg g−1 (P < 0·001). The pattern of rhythmic contractions produced by morphine was unlike those produced by 5-HT (5 × 10−6 M), acetylcholine (5 × 10−6 M) or potassium chloride (30 mM). Tetrodotoxin (10−6 M), apamin (10−8 M), clonidine (2 × 10−8 M), phentolamine (10−5 M) or oxprenolol (10−5 M) caused rhythmic contractions which were unaffected by naloxone. Clonidine contractions were inhibited by yohimbine (10−7 M) but not by prazosin (10−6 M). Electrical field stimulation at the peak of a contraction induced by morphine, apamin or Clonidine, produced an inhibitory response which was unaffected by atropine, phentolamine, propranolol and guanethidine (all 10−5 M). It persisted in colon segments from rats pretreated with reserpine or 6-hydroxydopamine. These results suggest that neither the 5-HT/acetylcholine hypothesis nor inhibition of the NANC mechanism adequately explains the excitatory effect of morphine in the rat colon.
On the Relevance of Non-steroidal Anti-inflammatory Drugs in the Prevention of Paralytic Ileus in Rodents
Authors: Pairet Michel , Ruckebusch Yves
Published: April 2011

In the mouse, the gastrointestinal transit of a charcoal marker, halved following the intraperitoneal administration of acetic acid, was no longer inhibited after pretreatment with the nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin, ketoprofen, piroxicam or ximoprofen (0·25–2·5 mg kg−1 orally). In the fasted rat, the migrating myoelectric complex pattern of the small intestine which was disrupted for about one hour by acetic acid was unaltered by pretreatment with indomethacin or ximoprofen (0·5 mg kg−1 i.p.). In the anaesthetized rat, the inhibition by about 50% of the gastrointestinal transit due to laparotomy, did not occur following treatment with NSAIDs. It is concluded that NSAIDs prevent the occurrence of chemically-induced and postoperative ileus in rodents, an effect probably related to the analgesic properties of NSAIDs.
Blood Pressure, the Renin-angiotensin System and Neurogenic Vasoconstriction in Pithed Rats
Authors: Henrion D , Eglème C , Criscione L , Wood J M
Published: April 2011

The influence of changing baseline blood pressure by various means, both related or unrelated to the renin-angiotensin system, on the pressor responses to spinal cord stimulation has been examined in the pithed rat. Mean arterial pressure and neurogenic vasoconstriction were higher in pithed rats with intact kidneys (2-kidney rats) than in nephrectomized pithed rats. Increasing blood pressure by infusion of vasopressin increased the pressor response to nerve stimulation in both 2-kidney and nephrectomized pithed rats. Decreasing blood pressure produced by administration of enalaprilat or hydralazine in 2-kidney pithed rats or by administration of hydralazine in nephrectomized pithed rats, decreased the pressor responses to nerve stimulation. Our results showed a positive correlation between the mean arterial blood pressure and the response to nerve stimulation in pithed rats. Therefore, we conclude that the pithed rat is an animal model which should be used with caution to study the interaction between the sympathetic nervous system and drugs which change baseline blood pressure.
The plasma disposition of sheep antibody (Fab) Fragments in the guinea-pig and rabbit
Authors: Timsina M P , Ostenfeld T , Hewick D S
Published: April 2011

The plasma elimination of sheep digoxin-specific Fab (fragment antigen-binding) antibody fragments has been studied after intravenous injection (1 mg kg−1) in guinea-pigs and rabbits using an enzyme-linked immunosorbent assay. The log concentration versus time profiles were best described by biexponential and triexponential functions for the response in the guinea-pig and rabbit, respectively. However, the elimination half-lives and apparent volumes of distribution were similar in both species (about 140 min and 120 mL kg−1, respectively). The value for the Fab distribution volume suggests that the antibody fragments distribute out of the vascular compartment but do not fully occupy the extracellular space. Our estimates of the latter, using thiocyanate as a marker, ranged from 220 to 327 mL kg−1 (rabbits and guinea-pigs, respectively). The distribution of Fab fragments in these two species differs significantly from that in the rat, where our earlier studies have shown that these antibody fragments are confined to the intravascular compartment with a distribution volume approximately equivalent to that of plasma (about 40 mL kg−1).
Brain tyrosine increases after treating with prodrugs: comparison with tyrosine
Authors: Topall Guy , Laborit Henri
Published: April 2011

After mice had been treated with L-tyrosine, O-phospho-L-tyrosine, L-tyrosine methyl ester or N-acetyl-L-tyrosine, tyrosine was assayed by HPLC coupled with fluorometric detection. O-Phospho-L-tyrosine behaved as a tyrosine prodrug after its hydrolysis by acid and alkaline phosphatases. After the intraperitoneal administration of O-phospho-L-tyrosine or the methyl ester, there was a substantial increase in bioavailability in terms of the effect of tyrosine. The two prodrugs were as powerful as tyrosine following oral administration. N-Acetyl-L-tyrosine was the least effective prodrug tested. The stability, solubility and bioavailability of O-phospho-L-tyrosine are consistent with proposing it for use as a tyrosine prodrug. In addition, it can be used parenterally. The use of a tyrosine aminotransferase inhibitor is necessary for limiting the hepatic breakdown of tyrosine and for increasing its bioavailability.
The effect of monoamine depletors on metrazol induced convulsions and brain γ-aminobutyric acid (GABA) contents in rats
Authors: Abed Wadie T
Published: April 2011

The thresholds for metrazol (pentylenetetrazol) clonic convulsions and brain γ-aminobutyric acid contents were significantly reduced after treatment with the monoamine depletors reserpine, tetrabenazine and p-chlorophenylalanine. Moreover, α-methyltyrosine, and α-methyl-m-tyrosine also lowered metrazol threshold seizures, but had no effect on brain α-aminobutyric acid contents. Furthermore, neither 5-hydroxytryptophan nor tranylcypromine had a significant effect on metrazol threshold seizures or brain α-aminobutyric acid contents, but blocked the changes previously induced by p-chlorophenyl alanine and reserpine.
Albumin Microspheres as Vehicles for the Sustained and Controlled Release of Doxorubicin
Authors: Jones C , Burton M A , Gray B N
Published: April 2011

Biodegradable albumin microspheres have been prepared with the intention of targeting doxorubicin preferentially to tumour tissue. A high-yielding microsphere manufacturing process has been developed that involved the denaturation of an aqueous protein emulsion by chemical and/or thermal crosslinking methods. Microspheres can be closely sized to a diameter of 25·3 ± 2·6 μm with the aid of microsieves. The in-vitro release of doxorubicin from albumin microspheres was measured using a continuous flow system. Doxorubicin release can be sustained for up to 10 days and the rate of release could be controlled by manipulating protein denaturation conditions between the temperatures 110–135°C in the presence of 0–2% gluturaldehyde. Release of doxorubicin was significantly faster in human plasma compared with isotonic saline.
An In-vitro Study of the Interactions Between Intravenous Induction Agents and the Calcium Antagonists Verapamil and Nifedipine
Authors: Bunting P , Ramsay T M , Pleuvry B J
Published: April 2011

Thiopentone, propofol and etomidate inhibit the contractions of the rat isolated atria and portal vein. The actions of thiopentone and propofol summate with those of verapamil and nifedipine. Verapamil potentiates the action of etomidate on both preparations. The depressant actions of thiopentone and propofol on the portal vein are associated with a reduced response to calcium. Etomidate does not reduce the response to calcium in this preparation.
Increased influence of endothelium in obese Zucker rat aorta
Authors: Auouet M , Delaflotte S , Braquet P
Published: April 2011

The ability of endothelium to alter contractile events in phenylephrine (PE)-triggered contraction has been tested on ring segments of the thoracic aorta removed from obese Zucker rats (plasma cholesterol 3·63 mM; n = 8) and from age matched lean rats (plasma cholesterol 2·38 mM; n = 8). In normal medium, PE (1 μM) elicited similar contractions in endothelium-denuded arteries of both strains. However, the presence of endothelium reduced these contractile events and the endothelium-dependent relaxation induced by carbachol (10 μM) was higher in obese rats. In rings incubated in Ca2+ free medium containing EGTA (1 mM), PE (1 μM) induced a phasic contraction and a sustained contraction following addition of Ca2+ (2·5 mM) to the medium. The phasic contraction was due to intracellular Ca + release, whereas the sustained response was dependent on extracellular Ca2+ influx. In endothelium-free preparations, the size of both the phasic and sustained contraction was similar for the two strains. The Ca2+ antagonist gallopamil (1 μM) reduced the sustained contraction of lean (24%) and obese (34%) rats without affecting the phasic contraction. In preparations possessing endothelium, the sustained, but not the phasic contraction, of both strains was inhibited. This inhibitory effect of endothelium on the sustained contraction was significantly higher in obese than in lean rats. Thus, it can be concluded that phenylephrine elicited quantitatively and qualitatively similar contractions in obese and lean rats. In both strains, the endothelium diminished the contraction induced by PE, however, this effect was more pronounced in obese rats than in lean ones. These results may explain, in part, the described absence of atherosclerotic lesions in the obese strain.
Supersensitivity of atherosclerotic rabbit aorta to ergometrine is mediated by 5-HT2 receptors
Authors: Kalkman H O , Neumann V , Brauner V
Published: April 2011

The concentration response curve of ergometrine in aortae from rabbits fed a high cholesterol diet for 12 weeks is biphasic. The first phase of the biphasic curve is antagonized by ketanserin, spiperone and cyproheptadine, but not by prazosin. pKB values are compatible with a 5-HT2 receptor mediated effect. The second phase is shifted to the right by prazosin, ketanserin and spiperone but not by cyproheptadine. In this case the pKB values are compatible with an α1-adrenoceptor mediated effect. The concentration response curves for ergometrine and phenylephrine in aortae from control rabbits are monophasic and pKB values again indicate an α1-adrenoceptor mediated response. Thus, ergometrine contracts the aortae of normal and cholesterol-fed rabbits via activation of α1-adrenoceptors. The supersensitivity observed in atherosclerotic strips seems to reflect the appearance of a high affinity component mediated by 5-HT2 receptors.
A simple intravenous infusion method in rodents for determining the potency of anticonvulsants acting through GABAergic mechanisms
Authors: Green A R , Murray T K
Published: April 2011

A simple method of intravenous infusion of convulsant drugs (pentetrazol and bicuculline) into the tail vein of rats has been used to determine seizure threshold and construct log-dose seizure threshold response curves for several anticonvulsant drugs (diazepam, phenobarbitone, pentobarbitone, chlormethiazole and valproate). It has been shown that an index of the dose required to increase seizure threshold by 50% (TI50) can be obtained using small numbers of animals. The advantages of this method over that of the subcutaneous pentetrazol method are several: small numbers of animals required, speed and reproducibility. The data also demonstrate the concordance between TI50 values obtained using pentetrazol and bicuculline as the convulsant agent. It is suggested that this method can be used routinely in screens of anticonvulsant drugs thought to work through GABAergic mechanisms.
Enhancement of Phosphatidylinositol Turnover and Cyclic Nucleotide Accumulation by Chronic Anethole Trithione Treatment in Rat Submaxillary Glands
Authors: Ukai Y , Taniguchi N , Yamazaki A , Kimura K
Published: April 2011

The effect of chronic treatment with anethole trithione (ANTT) on the phosphatidylinositol (PI) turnover and cyclic (c)AMP and cGMP accumulation in rat submaxillary glands (SMG) has been compared with the effect of chronic treatment with atropine and a Cholinesterase inhibitor, diisopropyl-fluorophosphate (dyflos, DFP). Experiments were performed 24, 48 and 24 h after the last dose of ANTT, atropine and dyflos, respectively. ANTT and atropine enhanced carbachol-stimulated [32P] incorporation into phosphatidic acid in the SMG slices, while dyflos showed no effect. Pilocarpine-stimulated in-vivo incorporation of [3H]myoinositol into inositol phosphates was significantly enhanced by ANTT, but not by atropine or by dyflos. Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by ANTT and atropine, but not by dyflos. Pilocarpine-stimulated in-vivo accumulation of cAMP and cGMP was enhanced by ANTT and atropine, but dyflos reduced cAMP accumulation without affecting cGMP accumulation. The enhancement of PI turnover and cyclic nucleotide accumulation seems to contribute to the development of supersensitivity of the salivary gland caused by chronic treatment with ANTT and atropine, while reduction of cAMP accumulation may be responsible for the subsensitivity caused by dyflos.
In-vivo (+)-[3H]Fenfluramine Binding to Rat Brain: Biochemical and Autoradiographic Studies
Authors: Gobbi Marco , Taddei Carlo , Mennlnl Tiziana
Published: April 2011

The in-vivo binding of (+)−[3H]fenfluramine to rat brain regions is saturable, as shown by the inhibition curves obtained by co-injecting increasing concentrations of unlabelled (+)−fenfluramine: at 2· 5 mg kg−1 the inhibition of total bound radioactivity was maximal in all regions. The regional distribution of (+)−[3H]fenfluramine specific binding sites (hypothalamus > striatum = cortex > brainstem > hippocampus > cerebellum) closely parallels the regional distribution of 5-hydroxytryptamine uptake. Computer-assisted quantitative autoradiography confirms these findings. The IC50 of (+)−fenfluramine for inhibition of its binding in-vivo is below 0·25 mg kg−1, compatible with the presence of high affinity sites. While the physiological role of (+)−[3H]fenfluramine binding sites in the brain, particularly in hypothalamic nuclei, is being investigated, it has been found that in-vivo labelling could also be obtained in the periphery, in lung and renal cortex. The possibility that this peripheral binding is due to the presence of blood platelets cannot be ruled out.
Effect of Histamine H2-Receptor Antagonists on Acute Inflammatory of the Rat Paw Oedema
Authors: Ezeamuzie Charles I , Umezurike Cyprain C
Published: April 2011

The effect of three histamine H2-antagonists, cimetidine, ranitidine, and loxtidine, on acute rat paw oedema induced by histamine, carrageenan or complete Freund’s adjuvant, have been examined. Administered intraperitoneally, all three antagonists inhibited histamine-induced paw oedema dose-dependently in the range 0·5–15 μmol kg−1. The highest dose of cimetidine produced an inhibition of 92% as against 38% with the same dose of mepyramine. Analysis of the concentration-effect curves produced IC50 values of 1·66, 5·12 and 12·30 μmol kg−1 for cimetidine, loxtidine, and ranitidine, respectively, on histamine-induced oedema. In carrageenan-induced inflammation 12·3 μmol kg−1 of each of the three drugs produced significant inhibition, whereas in adjuvant-induced inflammation, (acute phase), cimetidine was very active, loxtidine less so and ranitidine inactive. Thus the relative effectiveness of the antagonists (cimetidine > loxitidine > ranitidine) appears to differ from their known potency relationship (loxtidine > ranitidine > cimetidine) on H2-mediated effects. We conclude that H2-receptors are involved in the induction of rat paw oedema, especially those induced by histamine and carrageenan, but that their relative effectiveness appears atypical.
Effects of bovine serum albumin and recirculation rate on the uptake of propranolol by rat perfused lung
Authors: Iwamoto Kikuo , Watanabe Jun , Yonekawa Hina
Published: April 2011

Lungs isolated from 7-week-old rats were perfused with pH 7·4, oxygenated Krebs-Ringer bicarbonate buffer solution containing 2·5 μg mL−1 of propranolol and 3 to 5% BSA at the recirculation rate of 4 to 16 mL min−1, at 37°C for 60 min. The extent of propranolol metabolism after 60 min was less than 2·3% of the initial load under any in-vitro perfusion condition. Therefore, the amount disappearing from the perfusion medium was considered as being predominantly that taken up by tissue. Under all experimental conditions, perfusate drug level declined bi-exponentially with time. Apparent in-vitro pulmonary clearance of propranolol was not affected by the increase of BSA level from 3 to 5%. When the perfusate BSA level was fixed at 3%, the lowest recirculation rate (4 mL min−1) yielded the smallest clearance (about 0·15 mL min−1 g−1) but almost constant clearance value (about 0·40 mL min−1 g−1) was obtained at the rate ranging from 8 to 16 mL min−1. The tissue to medium concentration ratio of propranolol, after the perfusion with 3 to 5% BSA at the rate of 8 to 16 mL min−1, was approximately 35, whereas that with 3% BSA at 4 mL min−1 was reduced to about 20. The findings suggest evidence for flow-dependent in-vitro pulmonary clearance of propranolol.
Analgesic effects of 3-methoxybenzamide in rats
Authors: Sanders Robert , Dill Russell E , Dorris Roy L , Miller Edward G
Published: April 2011

The i.p. injection of 3-methoxybenzamide (3-MBA) in rats produces a dose-related elevation of the threshold for response to a painful stimulus. Metoclopramide, also a substituted benza-mide, has analgesic activity that is attenuated by bromocriptine, a dopamine receptor agonist, and by the narcotic antagonist, naloxone, suggesting involvement of dopamine and opiate receptors in the action of this drug. The involvement of these receptors in the analgesic action of 3-MBA has been examined using L -dopa and naloxone. Neither significantly altered the analgesic action. Although the results are preliminary, the analgesic action of 3-MBA would not seem to occur via opiate or dopamine receptors.
Marked increases in plasma catecholamine concentrations precede hypotension and bradycardia caused by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in conscious rats
Authors: Bagdy Gyoroy , Szemeredi Katalin , Murphy Dennis L
Published: April 2011

Plasma noradrenaline and adrenaline responses to 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, have been studied in conscious, freely moving rats. Intravenously administered 8-OH-DPAT caused dose-related and sustained increases in plasma noradrenaline (2-fold) and adrenaline (11-fold) concentrations. Neither metergoline pretreatment (0·5 mg kg−1 i.v.) nor splanchnicectomy had any effect on the noradrenaline and adrenaline elevation caused by 8-OH-DPAT (250 μg kg−1 i.v.). The catecholamine responses peaked early but were still present during nadirs in blood pressure and heart rate. The discrepancy between plasma catecholamine and cardiovascular changes raises further questions about the mechanism of action of 8-OH-DPAT and supports other evidence suggesting a role for vagus stimulation in the cardiovascular effects caused by this drug.
The availability of diltiazem: A study on the sorption by intravenous delivery systems and on the stability of the drug
Authors: de Vroe C , de Muynck C , Remon J P , Scheldewaert R , Colardyn F
Published: April 2011

The stability and the sorption by intravenous delivery systems of the calcium antagonist diltiazem dissolved into either 5% dextrose or 0·9% sodium chloride solutions have been investigated, under conditions simulating current clinical practice. Static experiments showed an excellent stability and no sorption after 48 h. Dynamic experiments, at a perfusion rate of 20 mg h−1, showed no sorption of the drug by infusion fluid containers, burettes or administration sets. For end-line filters a temporary decrease of the recovered amount of diltiazem was observed but only with the 0·9% NaCl solution. It is concluded that the stability and the sorption of diltiazem offers no problem with regard to clinical efficacy.
Diamorphine stability in aqueous solution for subcutaneous infusion
Authors: Omar O A , Hoskin P J , Johnston A , Hanks G W , Turner P
Published: April 2011

The influence of temperature and concentration on diamorphine stability during storage over 8 weeks has been investigated. Ampoules containing diamorphine hydrochloride in concentrations from 0·98–250 mg mL−1 have been stored at −20, 4, 21 and 37°C for 8 weeks. Their content of diamorphine, 6-monoacetylmorphine and morphine, on measurement by high performance liquid chromatography after 1, 2, 4, 6 and 8 weeks storage changed to slow degradation of diamorphine at all concentrations at temperatures of 4°C and above. This was accompanied by a corresponding increase in 6-monoacetylmorphine and morphine. There was an associated fall in pH and development of a strong odour characteristic of acetic acid. Precipitation and a white turbidity seen in solutions of 15·6 mg mL and above, appeared after 2 weeks incubation.
Evidence for α1-adrenoceptor subtype predominance in the rat seminal vesicle
Authors: Adenekan O O
Published: April 2011

Noradrenaline (0·6–19 μM and phenylephrine (2–130 μM induced contractions in the rat seminal vesicle that were competitively antagonized by the α1-adrenoceptor-selective antagonist corynanthine (120–920 nM). Yohimbine (60–450 nM), an α2 adrenoceptor-selective antagonist, produced a non-competitive antagonism of noradrenaline responses, suggesting that the responses were not α2-adrenoceptor mediated. It is concluded that the rat seminal vesicle has a predominance of α1-adrenoceptors.
Contribution of the tissue angiotensin converting enzyme to the antihypertensive effect of altiopril calcium (MC-838) in spontaneously hypertensive rats
Authors: Kamei Kenshi , Shiraki Yasuyuki , Koga Takaki , Sakai Kazushige
Published: April 2011

The effect of a new orally active angiotensin converting enzyme (ACE) inhibitor, calcium (—)-N-[(S)-3–[(N-cyclohexylcarbonyl-D -alanyl)thio]-2-methylpropionyl]-L -prolinate (MC-838, altiopril calcium), on systemic blood pressure (SBP) and tissue ACE activity has been examined in conscious spontaneously hypertensive rats (SHRs). MC-838 (3 mg kg−1) given orally to SHRs elicited a long-lasting hypotension lasting over 24 h. With the development of the hypotension, MC-838 significantly reduced ACE activity in the lung, kidney and aorta, but not in the brain and heart. Suppression of plasma ACE and rise of plasma renin activity occurred only transiently at an earlier stage.
Effects of indeloxazine hydrochloride on cognitive disturbance in cycloheximide-treated mice
Authors: Yamamoto M , Shimizu M
Published: April 2011

The effects of indeloxazine hydrochloride [(±)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride] on cognitive disturbance in mice subjected to cycloheximide have been examined. Indeloxazine ameliorated cycloheximide-induced amnesia in mice, indicating a facilitatory effect of this drug on cerebral functions. Piracetam, Ca-hopantenate, dihydroergotoxine and viloxazine did not show significant effect on the amnesia. These results suggest that indeloxazine possesses a wider pharmacological profile than Piracetam, Ca-hopantenate, dihydroergotoxine and viloxazine in anti-amnesic activities.
Quantitative Design for Photostabilization of Nifedipine by using Titanium Dioxide and/or Tartrazine as Colourants in Model Film Coating Systems
Authors: Teraoka Reiko , Matsuda Yoshihisa , Sugimoto Isao
Published: April 2011

The photostabilization of nifedipine by using film coating has been investigated in model systems in which a drug sample, dispersed on a glass plate, was covered with a free film and exposed to intensive light of mercury vapour lamp. The light transmission properties of films containing titanium dioxide or tartrazine alone as colourant were not always satisfactory. The tartrazine system exhibited superior light transmission properties to the titanium dioxide system at all additive concentrations. However, in combination both colourants gave much better light protection than did the colourants separately.

The film-coated drug degraded following apparent first-order kinetics. The degradation rate constant decreased as both colourant concentration and film thickness increased; thus photostabilization was almost completely achieved by applying a film (thickness: 60 μm) of the binary mixture system containing only 0·7% of each of these colourants. The protective effectiveness of a film could be quantitatively evaluated by plotting the degradation rate constant against CL value of film formulation (C: concentration of colourant; L: film thickness). The degradation rate constant showed a good linear correlation with the average percent transmittance of a film in the wavelength range relating to the photolytic degradation of the drug. The average percent transmittance was thus proved to be an important and useful parameter for estimating the photostability of film-coated drugs.
Non-specific Hyperreactivity to Pharmacological Stimuli in Tracheal and Lung Parenchymal Strips of Actively Sensitized Guinea-pigs
Authors: Ortiz J L , Cortijo J , Sanz C , Perpiñá M , Iriarte C F , Sarría B , Esplugues J , Morcillo E J
Published: April 2011

The responsiveness of tracheal and lung parenchymal strips isolated from actively sensitized guinea-pigs to CaCl2 (in K+-depolarized tissue), KCl, acetylcholine and histamine was compared with that of strips from unsensitized animals. The concentration-response curves to the mentioned agonists exhibited, in the sensitized group, a left upward displacement (greater maximal effect, lesser effective concentration 50% and a steeper slope) compared with those obtained in the unsensitized group. These results indicate the existence of a non-specific increase in responsiveness in the airway smooth muscle from sensitized animals.
Isolation and Characterization of Pelamis platurus (Yellow-bellied Sea Snake) Postsynaptic Isoneurotoxin
Authors: Mori Nobuhiro , Ishizaki Hiroyuki , Tu Anthony T
Published: April 2011

Pelamis platurus (yellow-bellied sea snake) venom contains several neurotoxins, the major toxin, which is most toxic, and two other isotoxins. The second most toxic neurotoxin (Pelamis toxin b) was isolated and characterized. It contains 60 amino acid residues with only one residue difference from the major toxin, Pelamis toxin a. The difference is at the tenth amino acid residue from the acid terminal. The isoelectric point of toxin b is 8·7. Raman spectroscopic examination of toxin b indicates that the toxin contains a considerable amount of antiparallel β-structure, β-turn, and random coil without α-helix as the amide I band appears at 1673 cm−1 and the amide III band at 1246 cm−1. Circular dichroic studies also indicate a typical β-sheet structure. The Pelamis toxin b is a typical postsynaptic neurotoxin as it binds to the acetylcholine receptor competitively with a well known toxin, α-bungarotoxin. The LD50 of toxin b is 0·185 μg g−1 in mice by intravenous injection, indicating high toxicity of a postsynaptic neurotoxin.
Effects of K+-Canrenoate on the Development of DOCA-salt Hypertension
Authors: Vargas F , Haro J M , Jodar E , Soler A , Del Rio C Garcia
Published: April 2011

The effects of K+-canrenoate, a digoxin antagonist, on the role of digoxin-like factor in the development of DOCA-salt hypertension has been examined. DOCA-salt rats treated with 66 mg kg−1 day−1 of K+-canrenoate (s.c.) presented a lower increase in blood pressure (P<0·01), less cardiac hypertrophy (p<0·05) and hypokalaemia (P<0·05) than non-treated DOCA-salt rats. K+-canrenoate treatment did not lead to significant changes in urinary volume, Na+ and K+ urinary excretion or suppression of plasma renin activity in DOCA-salt rats. None of the parameters were significantly different between uninephrectomized-salt rats treated or non-treated with K+-canrenoate. These data suggest a role for digoxin-like factor in DOCA-salt hypertension. However, the non-normalization of blood pressure observed in K+-canrenoate DOCA-salt treated rats indicates that other factors contribute to the initiating mechanisms in this type of hypertension. Moreover, these data suggest that digoxin-like factor plays no role in the suppression of plasma renin activity induced by DOCA and salt treatment.