bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of moderate haemodilution with Fluosol-DA or normal saline on ampicillin kinetics in the rat
Authors: Shrewsbury Robert P
Published: April 2011

The effects of haemodilution with either Fluosol-DA or normal saline on renal excretion and glomerular filtration have been studied in the rat. Ampicillin clearance and renal creatinine clearance were used as in-vivo measures of renal excretion and glomerular filtration, respectively. Rats were moderately exchanged with either fluid and evaluated after 0.5, 24, 48, or 72 h. After exchange, ampicillin clearance was higher, but not significantly different, and the apparent volume of distribution was increased significantly in some groups. These changes are consistent with the effects expected when plasma protein binding is reduced by haemodilution. The percent of ampicillin recovered in urine and the renal creatinine clearance were not statistically different in any group. Thus, moderate haemodilution with either fluid did not change renal function compared with unexchanged animals.
Pharmacological evaluation of an injectable prolonged release emulsion of physostigmine in rabbits
Authors: Benita Simon , Friedman Doron , Weinstock Marta
Published: April 2011

Physostigmine was incorporated in an injectable emulsion in an attempt to prolong its pharmacological activity. Emulsions which remained stable over 6 month storage were prepared using optimal experimental conditions. The in-vitro kinetic examination revealed that the rate-determining step in the release process of physostigmine from the emulsion was its partitioning from the oily phase to the external aqueous phase. The in-vivo results indicated that the physostigmine emulsion was able to inhibit the cholinesterase activity for at least 4 h, while the conventional injection inhibited the cholinesterase activity for only 1 to 2 h. The preliminary pharmacokinetic analysis showed that the physostigmine emulsion apparently increased the bioavailability compared with the conventional injectable solution. This could be attributed either to the protection of the sensitive drug from the enzymatic degradation or to improved absorption. The presence of poloxamer micelles in the aqueous phase was shown to enhance the bioavailability of physostigmine without having any effect on its pharmacological activity or duration.
Characterization of mitomycin C-induced gastrointestinal damage: changes in the gastric absorption of drugs in rats
Authors: Mizuno Masayuki , Kawabata Shigeki , Hashida Mitsuru , Sezaki Hitoshi
Published: April 2011

The effect of mitomycin C (MMC) pre-administration intravenously on the absorption of drugs from rat stomach has been examined by means of the in-situ loop technique. 48 h after the MMC-treatment, the absorption of salicylic acid, aspirin and sulphanilic acid was not influenced but that of sulphanilamide was significantly increased compared with the control. At 96 h, a differential effect of MMC on the absorption of each drug was seen: the absorption of weakly acidic drugs was significantly decreased while that of bases and strong sulphonic acid increased. The decreased absorption of salicylic acid and aspirin correlated with the reduced gastric mucosal blood flow. At 96 h there were severe haemorrhagic lesions in the gastric mucosae. The increase in absorption of poorly absorbed drugs could be ascribed to the increased permeability of the blood-gastric epithelium barrier as was evidenced by leakage of Evans Blue.
[3H]Noradrenaline-releasing action of vinpocetine in the isolated main pulmonary artery of the rabbit
Authors: Pauló Tünde , Tóth Péter T , Nguyen Tinh Thi , Forgács Lilla , TÖRÖK TamáS L , Magyar Kálmán
Published: April 2011

Vinpocetine (10−6 − 3 × 10−5 M) increased both the resting and the nerve stimulation-evoked release of [3H]noradrenaline from the isolated main pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3 × 10−5 M; corticosterone, 5 × 10−5 M), and inhibited the nerve stimulation-evoked postsynaptic response. The resting transmitter releasing action of vinpocetine increased in the absence of cocaine. Exogenously applied (−)noradrenaline [(−)NA] (10−6 M) or clonidine (10−6 M) inhibited the vinpocetine (3 × 10−5 M)-potentiated [3H]NA release and contracted the circular muscle. The clonidine-induced contraction was abolished by 10−7 M prazosin. The inhibitory action of (−)-NA on vinpocetine-potentiated [3H]NA release was partly antagonized by 3 × 10−7 M yohimbine, a preferential α2-adrenoceptor blocker. In Ca-free Krebs solution containing 1 mM EGTA the neurotransmitter releasing action of vinpocetine was abolished, however, its stimulating action on the resting [3H]NA outflow was not changed. In Na-pump-inhibited arteries (K-free solution), where both the resting and the nerve stimulation-evoked release of neurotransmitter had already been increased, vinpocetine further enhanced the nerve stimulation-evoked release of [3H]NA. It is concluded that vinpocetine may have α2- and α1-adrenoceptor blocking action, as well as a tyramine-like effect. The presynaptic neurotransmitter releasing action of vinpocetine is presumably the consequence of its inhibitory action on the Ca-pump which is suggested by the finding that in K-free solution vinpocetine was able to enhance further the release of neurotransmitter.
Effect of acute renal failure on the disposition and elimination of [3H]N-acetyl procainamide ethobromide in the rat
Authors: Silberstein D J , Bowmer C J , Yates M S , Dean H G
Published: April 2011

The effect of glycerol-induced acute renal failure (ARF) on the disposition and elimination of the organic cation [3H]N-acetyl procainamide ethobromide (APAEB) was investigated in the rat. In rats with ARF the plasma clearance, rate constant for the terminal portion of the plasma concentration-time curve and apparent volume of distribution were all decreased (P < 0.01). Furthermore, the renal clearance of APAEB and the percentage dose excreted in urine were reduced by 85 and 74%, respectively. Decreased renal excretion probably accounted for the altered kinetics of APAEB in ARF because ligation of the renal pedicles of control rats produced changes in the kinetics of APAEB that were similar to those seen in animals with ARF. No change in either the hepatic content of APAEB or its biliary excretion were detected in rats with ARF. Similarly, the hepatic handling of ouabain and taurocholic acid was previously found to be unaltered in ARF; but by contrast, the hepatic uptake and initial biliary excretion of bromosulphophthalein and indocyanine green were decreased (Bowmer & Yates 1984, Br. J. Pharmacol. 83: 773–782). Together these studies indicate that there is a selective impairment of hepato-biliary transport in ARF.
Dopaminergic metabolism in various rat brain areas after L-dopa loading
Authors: Gemayel G El , Trouvin J H , Prioux-Guyonneau M , Jacquot C , Cohen Y
Published: April 2011

The time course of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT) and 3-methoxytyrosine (3-O-Medopa) concentrations in rat brain after treatment with L-dopa + benserazide has been investigated in the striatum, hypothalamus, hippocampus and cerebellum. These areas were selected for their different dopaminergic activities. After L-dopa loading, DA, DOPAC and HVA were increased in all the structures, but the largest increases were in those tissues with the less dopaminergic activity, while 3-MT increased in the hypothalmus, hippocampus and cerebellum but was lowered in striatum. 3-O-Medopa, which is the direct product of the O-methylation of L-dopa, did not show any specific distribution. The data provide evidence that the striatum, by feed-back mechanisms and specific enzymatic activity, is able to ensure a better regulation of dopaminergic activity than the other structures, thereby overcoming excess L-dopa.
The Nature of the Oil Phase and the Release of Solutes from Multiple (w/o/w) Emulsions
Authors: Omotosho James A , Whateley Tony L , Law Tak K , Florence Alexander T
Published: April 2011

The effect of the nature of the oil phase of w/o/w emulsions stabilized by interfacial complexation between span 80 (sorbitan mono-oleate) and albumin has been studied. The long-term stability of the systems has been assessed by photomicrography and by measuring the quantity of an internal marker (NaCl) remaining entrapped with time. The number of multiple oil drops and the diameters of the internal aqueous droplets were determined over 6 weeks, and the amounts of NaCl entrapped over the same period were followed. There were no significant changes in w/o/w emulsions prepared with a range of hydrocarbons (octane, dodecane, hexadecane, toluene and cyclohexane), indicating stable multiple emulsions. The release of NaCl and 5-fluorouracil (5-FU) separately entrapped in the internal aqueous phase of w/o/w emulsions was measured. Diffusion of the un-ionized species of 5-FU across the oil phase or through localized thin oil lamellae is the primary transport mechanism. In the presence of surface active agents, water is solubilized in inverse micelles which would possess the ability to solubilize other water-soluble components, such as NaCl and 5-FU. The mixed inverse micellar units of Span 80 and polysorbate (Tween) 80 therefore act as solute carriers across the liquid hydrocarbon membrane separating the two aqueous phases of the emulsions. The main factor in determining the differences in rates of release from the hydrocarbon emulsions appears to be the droplet size of the internal aqueous phase.
A platelet-aggregating and hypotensive phospholipid isolated from bovine brain
Authors: Yoshida Jun-Ichi , Tokumura Akira , Fukuzawa Kenzi , Terao Motonori , Takauchi Kenkichi , Tsukatani Hiroaki
Published: April 2011

A phospholipid that differs from known active lipids and causes potent platelet aggregation and weak hypotension has been isolated from bovine brain. Its platelet aggregating effect on heparinized platelet-rich plasma from rabbits, was at a threshold concentration of about 0.2 nmol ml−1 as phosphorus. The effect was inhibited by CV-3988. The phospholipid was converted by diazomethane treatment to another active lipid that caused short-term hypotension, but not platelet aggregation, rather it inhibited the aggregation of rabbit heparinized platelets induced by platelet-activating factor.
Investigation of the antimuscarinic and other actions of proadifen in-vitro
Authors: Choo L K , Malta E , Mitchelson F
Published: April 2011

The possibility that proadifen (SKF 525A) antagonizes endothelium-dependent relaxations to acetylcholine (ACh) in isolated blood vessel preparations via a muscarinic receptor blocking action has been investigated. In phenylephrine-contracted rat isolated aortic ring preparations (with endothelium), proadifen (10–100 μm) shifts ACh relaxant curves to the right without affecting the maximal response, yet endothelium-dependent relaxations to ATP are unaffected. At lower concentrations, proadifen (1–10 μm) (i) antagonizes negative inotropic responses to ACh and ATP in guinea-pig left atria, (ii) antagonizes contractile responses to ACh and elevated [K+] in guinea-pig ileal preparations, (iii) displaces (−)-[3H]quinuclidinyl benzilate from muscarinic binding sites in membrane homogenates of guinea-pig ileal longitudinal muscle and (iv) reduces contractile responses to elevated K+] in rat aortic ring preparations. It is concluded that proadifen may possess (i) complex interactions with muscarinic receptors and (ii) Ca2+ entry blocking properties in concentrations 10–100 times lower than those reported to inhibit cytochrome P450-catalysed reactions.
[3H]SCH 23390 identifies D-1 binding sites in rat striatum and other brain areas
Authors: Kilpatrick Gavin J , Jenner Peter , Marsden C David
Published: April 2011

The specific in-vitro binding of [3H]SCH 23390 has been characterized and its use in the identification of D-1 sites in various brain regions examined. At a single ligand concentration (0.4 nM) the specific binding of [3H]SCH 23390 to striatal membranes was routinely 98% of total binding as defined using 10−5 M cis-flupenthixol. Specific binding at 37 °C reached equilibrium at 15 min and was reversible with a t½ for dissociation of 14 min. Specific binding of [3H]SCH 23390 over a range of concentrations (0.01–3.5 nm) was saturable (Bmax 73 pmol g tissue−1) of high affinity (Kd 0.36 nM) and to a single population of binding sites. Specifically bound [3H]SCH 23390 (0.4 m) was stereo selectively displaced by the isomers of butaclamol and flupenthixol but not by the D-2 selective antagonist, sulpiride. 5-HT, noradrenaline and cinanserin caused little or no displacement. Specific binding of [3H]SCH 22390 (0.4 nM; as defined using 10−5 M cis-flupenthixol) showed marked regional variation. Specific binding was highest in the striatum; high levels were also observed in the mesolimbic area and substantia nigra. Lower specific binding was found in the frontal cortex and superior colliculus with the lowest levels in cerebellar preparations. The inclusion of 3 × 10−7 M cinanserin did not alter the extent of specific binding observed in any brain region. The properties of [3H]SCH 23390 suggest it to be an excellent ligand for identification of D-1 sites in a variety of brain regions.
N-Formylpenicillamine and penicillamine as degradation products of penicillins in solution
Authors: Bird A E , Jennings K R , Marshall A C
Published: April 2011

The degradation of several penicillins in unbuffered aqueous solution produces N-formylpenicillamine, in some cases in high yield. Very little or no penicillamine is formed under these conditions. N-Formylpenicillamine was produced from benzylpenicillin at pH values between 2.5 and 7, with a maximum yield of 30% at pH 5, whereas penicillamine was produced only at pH 5 or below in a yield of less than 1%. Benzylpenicillenic acid at pH 5 gave a 20% yield of N-formylpenicillamine and no penicillamine whereas benzylpenicilloic, penilloic and penillic acids gave no N-formylpenicillamine and a small amount of penicillamine.
The effect of sodium deoxycholate given by gavage with heparin on the histology of the intestinal mucosa of the rat
Authors: Guarini S , Adriana Fano Rita , Rompianesi Elena , Maria Martinelli Anna , Ferrari W
Published: April 2011

To gain direct insight into the mechanism of sodium deoxycholate (DOC)-induced enhancement of gastroenteral heparin absorption in rats, we performed light and electron microscopic examination of the mucosa of the small intestine of animals treated orally with DOC, heparin or DOC plus heparin. The sole morphological change observed after DOC and DOC plus heparin administration was a marked reduction in the length and distribution of glycocalyx filaments on the microvilli of epithelial cells. The morphological picture had reverted to normal after 24 h, when the promotion of enteral heparin absorption by DOC is greatly reduced. Thus, we suggest that DOC may promote the enteral absorption of heparin in rats by affecting some as yet unidentified barrier mechanism requiring glycocalyx integrity.
Early inflammatory response to carrageenan in the pleural cavity and paw of rats with altered body temperature
Authors: Thomas George , Socorro Sousa P
Published: April 2011

Polymorphonuclear leucocyte (PMNL) migration and oedema induced by carrageenan in the pleural cavity and paw, respectively, of rats made hyper- or hypothermic by physical and chemical means have been investigated. In rats placed in a warm environment to produce a rise in body temperature, carrageenan caused a moderate but significant increase in PMNL migration compared with the control animals. Opposite effects were obtained with hypothermic animals kept in a cold environment. While hyperthermia produced by amphetamine did not alter the PMNL migration, chlorpromazine-induced hypothermia caused a fall in the number of these cells present in the pleural cavity following carrageenan. Both hyper- and hypothermias, whether induced by physical or chemical means, inhibited the carrageenan paw oedema. The observed changes in the PMNL numbers in the pleural cavity did not reflect their numbers in the peripheral circulation. Results indicate that while a rise or a fall in body temperature may have opposite effects on PMNL migration, in carrageenan inflammation both conditions inhibit oedema formation.
The influence of degradable starch microspheres on liver uptake of 5-fluorouracil after hepatic artery injection in the rat
Authors: Teder H , Aronsen K F , Björkman S , Lindell B , Ljungberg J
Published: April 2011

The effect of degradable starch microspheres (DSM) on the distribution of 5-fluorouracil (5-FU) after hepatic artery injection was studied in normal rats. Carbon-14-labelled 5-FU was injected separately or together with DSM into the hepatic artery. Radioactivity was measured in liver tissue, bile, peripheral blood, and urine. When microspheres were added, the liver uptake of 5-FU was increased; its peak concentration in peripheral blood decreased, as did the early urinary excretion of radioactivity. The addition of degradable starch microspheres to hepatic artery injections of cytostatic drugs might be of value in increasing the drug concentration in tumour tissue and reducing systemic toxicity.
Particulate contamination of Australian ampoules
Authors: Gillies I R , Thiel W J , Oppenheim R C
Published: April 2011

Theoretical predictions and computer simulations indicate that it may be impossible to achieve values of the coefficient of variation usually found in large volume parenterals (LVP) when the intrinsic particulate contamination in small volume parenterals (SVP) is investigated. Snap-opened ampoules from Australian manufacturers containing 5, 10or 20 ml Water for Injections or Sodium Chloride Injection had a high level of particulate contamination, although within the USP XXI SVP limits. Heat-opened ampoules had much lower levels of contamination which were generally below the official LVP limits. Counts ml−1 were typically <10 and <1 for 5 and 20 μm particles, respectively. Coefficients of variation of the 5μm data from an ampoule in any batch examined, typically ranged over 30–70%. Statistical analysis of the 5μm data indicates significant differences between batches. Occasional ampoules had higher 5μm counts than others in the same batch. At no time were the particulate contamination levels considered to be clinically important.
An iterative curve stripping technique for pharmacokinetic parameter estimation
Authors: Dunne Adrian
Published: April 2011

Non-linear least-squares regression is commonly used for pharmacokinetic parameter estimation. Initial parameter estimates are required as a prelude to non-linear least-squares and the quality of the final parameter estimates may depend on these initial values. Polyexponential curve stripping is frequently used for the provision of initial estimates. It is demonstrated that under certain conditions conventional curve stripping yields biased estimates. A new iterative curve stripping technique is developed and is shown to be free of such bias. The two methods are compared using both simulated and real pharmacokinetic data.
The effect of varying carbachol concentration on the slope of Schild plots of selective β-adrenoceptor antagonists in the carbachol-contracted guinea-pig trachea
Authors: Keith R A , Donahue J Y , Salama A I
Published: April 2011

The effect of varying the level of smooth muscle tone induced by carbachol on the Schild analysis of atenolol (β1-selective) and ICI 118,551 (β2-selective) with salbutamol as agonist, on the guinea-pig tracheal preparation has been examined. When 10−6 M carbachol was used to induce near-maximal smooth muscle tone, Schild plot slopes for atenolol and ICI 118,551 were less than 1. Slopes of Schild plots for both drugs were equivalent to 1 when 10−7 M carbachol was used to produce approximately half-maximal smooth muscle tone. Depletion of neuronal noradrenaline by prior treatment with reserpine had no effect on the Schild analysis. Salbutamol produced maximal relaxation and was more potent when tone was induced with 10−7 M carbachol, but was less effective at 10−6 M carbachol. Pretreatment with reserpine increased the potency of salbutamol at each concentration of carbachol. The results suggest that either the level of smooth muscle tone or an unknown effect associated with a high level of smooth muscle tone induced by carbachol may contribute to low slope values of Schild plots of selective β-adrenoceptor antagonists in the carbachol-contracted guinea-pig trachea. The carbachol-contracted guinea-pig trachea can be used to determine theoretically valid pA2 values for selective β-adrenoceptor antagonists as long as substantially less than a maximal level of smooth muscle tone is induced by carbachol.
Enhancement of anti-inflammatory effects of biphenylylacetic acid by its incorporation into lipid microspheres
Authors: Shoji Y , Mizushima Y , Yanagawa A , Shiba T , Takei H , Fujii M , Amino M
Published: April 2011

Using lipid microspheres (LM), average diameter 0.2 μm, and containing methyl and ethyl esters of biphenylylacetic acid (BPAA) in the carrageenan paw oedema tests in rats, it was found that their anti-inflammatory activities were enhanced 3 to 8 times over that of free BPAA. By electron microscopy, LM were seen to be taken up into the endothelial cells of the blood vessels and macrophages at the inflamed sites. In a study using dogs, after an intravenous injection of BPAA-methyl ester incorporated into LM (lipo-BPAA-Me), lipo-BPAA-Me rapidly disappeared from the blood and the BPAA serum level was gradually elevated. These results, together with previous findings, suggest that part of lipo-BPAA-Me was immediately transferred to the inflamed site and taken up by prostaglandin (PG)-producing cells as macrophages. It is considered that the antiinflammatory effects of BPAA are enhanced by incorporating it into LM.
The effect of the molecular weight of polyethylene glycol on the bioavailability of paracetamol-polyethylene glycol solid dispersions
Authors: Vila-Jato José L , Blanco José , Alonso M José
Published: April 2011

A controlled study of the bioavailability of paracetamol in solid dispersion with PEG 6000, 10000 and 20000 has been made. The total amount of paracetamol excreted in urine increased with molecular weight of the PEG, but the rate of absorption of the drug was unaffected.
Effect of quinidine on the tissue binding of digoxin in guinea-pigs
Authors: Okudaira Kazuho , Sawada Yasufumi , Sugiyama Yuichi , Iga Tatsuji , Hanano Managu
Published: April 2011

The mechanism of quinidine-induced decrease in the tissue distribution of digoxin to heart, liver and skeletal muscle has been examined in guinea-pigs. Quinidine, in the presence of adenosine-5′-triphosphate (ATP), inhibited the specific binding of digoxin in homogenates of heart, liver and muscle, while in the absence of ATP the inhibition was observed only in heart. The decrease in the tissue-to-plasma unbound concentration ratios (Kpu) of heart and muscle determined from in-vitro binding studies was comparable to that in the Kpu values observed in-vivo, while in liver it was not sufficient to account for the fall in Kpuin-vivo values. It is concluded that quinidine-induced decrease in the tissue distribution of digoxin in heart and muscle is due to inhibition of tissue binding of this drug, while that in liver could be partially attributed to the decrease in the tissue binding.
Mechanisms of the relaxations induced by 5-hydroxytryptamine on the rat isolated caecum
Authors: Uguru Mary O , Bamgbose S O A
Published: April 2011

The mechanism by which 5-HT produces relaxations of the rat caecum has been examined. Propranolol and cocaine markedly attenuated the relaxations whereas tetrodotoxin had no effect. Higher doses of propranolol and cocaine (>10−6 M), as well as reserpinization, converted the relaxations into contractions. There was a residual relaxation resistant to propranolol, cocaine and reserpine treatment. High doses of 5-HT (>10−5 M) were thus thought to relax the rat caecum indirectly, through the release of noradrenaline from the tissue by a tyramine-like action. The relaxations do not seem to be due only to the release of noradrenaline.
Antagonism of non-depolarising neuromuscular blockade by aminopyridines in cats
Authors: Riesz Miklos , Kápáti Egon , Szporny László
Published: April 2011

The antagonism of pipecuronium- and vecuronium-induced neuromuscular blockade by 4-aminopyridine (4AP), 3,4-diaminopyridine (3,4AP) and 3-[(dimethylamino)-carbonyl] amino-4-aminopyridine (LF14) were studied in anaesthetized cats during constant infusion of the relaxants. Aminopyridines were administered cumulatively at steady state 90% block level. The ED50 values of 4AP, 3,4AP and LF14 were 243, 106 and 254 μg kg−1 in pipecuronium, and 232, 195 and 235 μg kg−1 in vercuronium blockade. It has been assumed that in cats the anticurare effect of aminopyridines is mainly a result of K+ channel blockade on motor nerve terminals which enhances the evoked release of acetylcholine.
Relative bioavailability of trimeprazine tablets investigated in man using HPLC with electrochemical detection
Authors: Hu Oliver Y-P , Gfeller Edward , Perrin John H , Curry Stephen H
Published: April 2011

The stability, partition coefficient, plasma protein binding, red blood cell distribution, and whole blood concentrations of trimeprazine were investigated. Trimeprazine solution was stable for 6 months at −20 °C and 3.5 months at 40 °C. In whole blood trimeprazine was stable for 5 weeks at −20 °C., 24 h at 4 °C., 4h at 25 °C and 1 h at 37 °C. The apparent hexane-water partition coefficient varied from 1.50 (at pH 4.83) to over 100 (at pH 10.54). The fraction bound to plasmaprotein exceeded 0.9 as estimated by equilibrium dialysis with correction for volume shift. The mean plasma/red blood cell concentration ratio was 1.17 and the mean red blood cell/plasma distribution coefficient was 8.65. Six healthy adult males received single 5 mg doses of trimeprazine in a syrup (5 mg in 10 ml) and tablets with at least two weeks between doses. Blood was collected for 48 h. The mean (±s.e.m.) times for peak blood concentrations were 3.5 ± 0.22 h for the syrup and 4.5 ± 0.43 h for the tablets. There were no significant differences in Cmax values. The overall mean (±s.e.m.) terminal phase half-life was 4.78 ± 0.59 h. Mean (±s.e.m.) areas under the concentration time curves from 0 to infinity (AUC∞) were 11.0 ± 1.99 ng h−1 ml−1 and 7.67 ± 1.05 ng h−1 ml−1 for syrup and tablets, respectively. The mean relative bioavailability for the tablets was approximately 70% with respect to the syrup.
Evidence that 5-hydroxytryptamine may exert both facilitatory and inhibitory control of electrical field stimulation-evoked contractions in longitudinal muscle taken from the body of guinea-pig stomach
Authors: Gunning S J , Bradbury A J , Costall B , Naylor R J
Published: April 2011

Electrical field stimulation (FS) of guinea-pig stomach body longitudinal muscle strips caused frequency-related contractions mediated via cholinergic mechanisms. Metoclopramide (10−8–10−5 M), MDL 72222 (10−9–10−7 M) and 5-hydroxytryptophan (5-HTP) (3 × 10−7–2.4 × 10−4 M) enhanced these contractions in all tissues, whereas 5-hydroxytryptamine (5-HT) (3 × 10−8–3 × 10−5 M) enhanced the contractions, but only in approximately 15% of the tissues tested. FS-induced contractions were also enhanced in tissues treated in-vitro with p-chlorophenylalanine (2.5 × 10−7–2.5 × 10−5 M) or monofluoromethyldopa (6 × 10−7–10−4 M) or in tissues taken from animals having received p-chlorophenylalanine or monofluoromethyldopa. It is concluded that cholinergic-mediated contractions of stomach strips are subject to 5-HT modulation in two ways. The predominant action of endogenous 5-HT is to exert an inhibitory tone mediated via a metoclopramide and MDL 72222-sensitive 5-HT neuronal receptor. Exogenously applied 5-HT has little overt action to increase the essentially maximal inhibitory action of endogenous 5-HT, but acts on a 5-HT facilitatory receptor system to enhance contractions. Therefore, the actions of 5-HT agonists and antagonists to modify contractions in stomach strips will reflect the balance between 5-HT inhibitory and facilitatory influences, and the specificity of action of the compounds for the two 5-HT receptor systems.
The influence of oxygen tension on theophylline clearance in the rat isolated perfused liver
Authors: Miller Raymond , Oliver Isabel F
Published: April 2011

The effect of changes in the rate of perfusion and oxygen tension (Po2) on theophylline clearance was determined in the rat isolated perfused liver. Changes in rate of perfusion had no effect on the extraction ratio of theophylline while a decrease in the Po2 significantly increased the half life of theophylline. These results suggest that changes in Po2 whether due to disease states or oxygen administration may necessitate theophylline dosage adjustment.
Soluble asparaginase-dextran conjugates show increased circulatory persistence and lowered antigen reactivity
Authors: Wileman Thomas E , Foster Ronald L , Elliott Peter N C
Published: April 2011

Oxidized dextrans of increasing molecular weight were bound covalently to Erwinia carotovora asparaginase. The resulting conjugates retained 50% of their enzyme activity and showed marked resistance to proteolysis by trypsin and chymotrypsin and inactivation by asparaginase-specific antibody. When tested in-vivo, the larger molecular weight conjugates showed prolonged circulatory survival in both immune and non-immune animals and failed to elicit full type III hypersensitivity or anaphylactic reactions when injected into sensitized guinea-pigs. Rabbits could tolerate multiple doses of the asparaginase conjugate without developing an immunity to the enzyme. A conjugate showing increased circulatory half-life and lowered antigen reactivity should have therapeutic potential.
QSAR of binding of dihydropyridine-type calcium antagonists to their receptor on ileal smooth muscle preparations
Authors: Mahmoudian Massoud , Richards W Graham
Published: April 2011

Quantitative structure-activity analysis (Hansch analysis) is applied to elucidate the structural requirement for the binding of dihydropyridine-type calcium antagonists (DHPs) to their receptor in the guinea-pig ileal muscle preparations. It is found that various steric (B1, L), electronic (σ) and hydrophobic (π) parameters or their combinations correlate well with the potency of various DHPs to inhibit the binding of [3H]nitrendipine to the microsomal preparations of the guinea-pig ileal muscle. The potency of DHPs increases with the minimum width (B1) of substituent at ortho- or meta-positions, but decreases with the increase in the length of substituent at the meta-position. The potency of DHPs decreases with the increase in both minimum width or length of substituent at the para-position and the optimal values were found to be those for hydrogen. The hydrophobicity (π) of substituents at different positions in the 4-phenyl ring affects the potency differently, indicating that a different environment exists around each position at the binding site. From the slopes of the π variable in the regression equations, it is concluded that the receptive environment of the ortho-position of the 4-phenyl ring of DHPs is lipophilic, and for that of the para-position hydrophilic. A good correlation is also observed between the Hammett electronic parameter (σ) and biological activity of meta-substituted DHPs. It is suggested that in the binding of the substituted 4-phenyl DHPs to their receptor, both electronic and hydrophobic interactions should be considered.
Solubility of diazepam and prazepam in aqueous non-ionic surfactants
Authors: Moro Manuel E , Velazquez M Mercedes , Cachaza Juan M , Rodriguez Licesio J
Published: April 2011

The solubility of diazepam and prazepam in aqueous polyoxyethylen-10-dodecanol, polyoxyethylen-23-dodecanol and polyoxyethylen-20-hexadecanol, has been determined at 25.0°C. Diazepam seems to achieve a higher micellar penetration than prazepam, in spite of an expected smaller hydrophobic character. Thermodynamic interpretation of the micellar solutions is carried out using the regular solutions approach. A surfactant-independent relation between solubilities of both drugs has been derived.
Preparation of single bilayer liposomes by an electrocapillary emulsification method
Authors: Ishii F , Noro S
Published: April 2011

The single bilayer liposomes have been prepared by an electrocapillary emulsification technique based on interfacial fluctuation in the absence of surfactant. Electron microscopy showed the liposome to be a unilamellar vesicle with a size generally in the range 60–120 nm.
Assessment of acetylcholine release from myenteric plexus of guinea-pig colon
Authors: Trout S J
Published: April 2011

Due to a complex mechanical tissue response to electrical stimulation, a colonic smooth muscle-myenteric plexus (SMMP) preparation, combined with radiolabelling techniques for assessing the acetylcholine release, has been developed to investigate intrinsic cholinergic nerve activity in the guinea-pig colon. Electrical field stimulation of the preparation gave reproducible release of label which was inhibited by tetrodotoxin. Release increased proportionally with the strength of stimulus (130, 150, 195 and 250 mA), but was inversely proportional to frequency of stimulation for a fixed number of pulses, 1 Hz releasing more than 10 Hz. Electrical stimulation of the tissue during incubation with [3H]choline enhanced the release by subsequent field stimulation. Release of label increased progressively towards the distal end of the colon.
Chronic treatment with iprindole reduces immobility of rats in the behavioural ‘despair’ test by activating dopaminergic mechanisms in the brain
Authors: Berettera C , Invernizzi R , Pulvirenti L , Samanin R
Published: April 2011

Iprindole, 10 mg kg−1 i.p., once daily for 21 days, enhanced the metabolism of dopamine in the frontal cortex and striatum of rats with no effect in the nucleus accumbens 1 h after the last injection. Noradrenaline metabolism in the brainstem and telecephalon was also increased in these conditions. No effect on dopamine or noradrenaline metabolism was seen 24 h after the last injection. The same repeated treatment schedule with iprindole markedly reduced the immobility of rats in the behavioural ‘despair’ test 1 h after the last injection and the effect was prevented by 0.5 mg kg−1 i.p. haloperidol and 100 mg kg−1 i.p. sulpiride but not by 3 mg kg−1 s.c. prazosin or 5 mg kg−1 i.p. (±)-propranolol. The data show that enhanced metabolism of brain dopamine and noradrenaline is associated with the presence of iprindole during repeated treatment and the effect on dopamine mechanism is important in iprindole's ability to reduce rats' immobility in the behavioural ‘despair’ test.
Investigations of the solubilization kinetics of binary mixtures of non-polar oils by non-ionic surfactants
Authors: O'Rourke Brian G C , Ward Anthony J I , Carroll Brendan J
Published: April 2011

An investigation of the solubilization kinetics of binary mixtures of non-polar oils by a non-ionic surfactant has been made using the drop-on-fibre technique. Variables studied were the oil composition, surfactant concentration and the temperature. Rates vary linearly with the surfactant concentration for all oil compositions. The observed rate during nearly total solubilization of each oil drop was constant, implying that in these systems solubilization is non-selective. The rates increase as the lower consolute (cloud) temperature of the surfactant is approached. Activation energies of the solubilization process are shown to be independent of the oil composition for the system studied. This suggests that the important stage of the process involves dissociation of the surfactant micelles.
The activity of 25 paroxetine/femoxetine structure variants in various reactions, assumed to be important for the effect of antidepressants
Authors: Plenge Per , Mellerup Erling T , Honoré Tage , Honoré Pierre Le Fèvre
Published: April 2011

Structure-activity relationships for 25 structural variants around the 5-hydroxytryptamine (5-HT) uptake inhibitors paroxetine and femoxetine have been investigated. Three parameters related to the 5-HT system were investigated: (i) The inhibition of [3H]5-HT uptake into rat brain synaptosomes, (ii) the inhibition of [3H]paroxetine binding to rat neuronal membranes and (iii) the effect of the compounds on the affinity of [3H]imipramine for the human platelet membrane binding site, measured as the dissociation rate of the [3H]imipramine human platelet membrane binding site complex. A highly significant correlation was found for 5-HT uptake inhibition and inhibition of [3H]paroxetine binding for the different substances, indicating that the two parameters are closely connected. However the slope of the regression line was only 0ṁ6 and not 1ṁ0; this may indicate that [3H]paroxetine binding is necessary, but not sufficient for 5-HT uptake inhibition. No correlation was found between the inhibition of [3H]paroxetine binding and the affinity of the compounds for the [3H]imipramine binding site complex. The two binding sites are therefore probably situated on different parts of the 5-HT transport system, the [3H]paroxetine binding site being part of the 5-HT transport mechanism whereas the [3H]imipramine binding site may represent a site modulating the activity of, and affinity for, 5-HT in the 5-HT transport mechanism. Structure-activity relationships among the substances showed that stereochemical changes from (-)- to (+)-trans changed the activity towards both 5-HT uptake inhibition and [3H]paroxetine displacement for most of the (-)-/(+)-pairs. The substitution of —H with —F or —CH3 also affected the activity. The results showed that in this series of compounds, (-)-trans-4-(p-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine (paroxetine) is an optimal structure for influencing the chosen parameters.
Effect of triglyceride on small intestinal absorption of cefoxitin in rats
Authors: Yoshitomi Hironori , Nishihata Toshiaki , Frederick Gregory , Dillsaver Margaret , Higuchi Late Takeru
Published: April 2011

Coadministration of trilaurin or monolaurin with sodium cefoxitin increased its absorption from the small intestine of the rat. Its absorption from the rectum was effected to a lesser extent except when lipase was present. Lipase, a natural constituent of the small intestine fluid, may therefore be essential for the adjuvant action of trilaurin on cefoxitin absorption across the intestinal membrane. Among the triglycerides used, trilaurin and tricaprin were the most effective enhancers of cefoxitin absorption. Both the rate of degradation of triglyceride to its fatty acid component and subsequently the rate of fatty acid absorption were factors influencing the enhancing action. Maintenance of fatty acid concentration at the small intestinal absorption site was shown to be necessary to obtain a cefoxitin bioavailability of up to 70%.
The neuromuscular blocking effect of trimetaphan alone and in combination with different non-depolarizing muscle relaxants in the rat
Authors: Pollard B J , Van Der Spek A F L
Published: April 2011

The effect of trimetaphan alone and in combination with pancuronium, tubocurarine or metocurine (dimethyl tubocurarine) has been examined on the rat phrenic nerve diaphragm preparation. Trimetaphan alone produced neuromuscular blockade in an all-or-none fashion once a concentration of between 2ṁ39 times 10−4 and 3ṁ00 times 10−4  M had been exceeded. Concentrations of trimetaphan below this threshold produced a dose-dependent potentiation of all three non-depolarizing relaxants studied. This potentiation was equal for tubocurarine and metocurine, but less for pancuronium.
Mandibular and parotid salivary excretion of procainamide and N-acetylprocainamide after intravenous administration of procainamide to rats
Authors: Watanabe Jun , Koyama Ineko , Iwamoto Kikuo , Ozeki Shoji
Published: April 2011

Flow rate, protein level and pH of mandibular and parotid saliva samples in rats were almost stabilized 2h after induction of salivation with pilocarpine (9ṁ0 mg h−1 kg−1). Salivary excretion profiles of procainamide, 50 mg kg−1 i.v., and its metabolite N-acetylprocainamide (NAPA) were then investigated. Plasma and salivary procainamide levels declined bi-exponentially with time almost in parallel. Salivary procainamide levels (Y) from both types of gland were correlated with the plasma level (X) over a wide concentration range [Y = 0ṁ108X + 1ṁ96 (r = 0ṁ795) for mandibular and Y = 0ṁ917X (r = 0ṁ974) for parotid glands]. The mean saliva to plasma concentration ratio (S/P ratio) was significantly higher in parotid (0ṁ974 ± 0ṁ243) than in mandibular (0ṁ284 05119) saliva samples. Similar correlations and S/P ratios were observed for NAPA. Procainamide and NAPA mean S/P ratios for saliva from both glands were fairly consistent with the calculated value according to the pH-partition hypothesis.
Pharmacokinetics of lisinopril (MK521) in healthy young and elderly subjects and in elderly patients with cardiac failure
Authors: Gautam P C , Vargas E , Lye M
Published: April 2011

The pharmacokinetics of lisinopril were determined in 6 healthy young, 6 healthy elderly and 6 elderly patients with cardiac failure. Lisinopril (5 mg day−1) was administered for 7 days. Plasma lisinopril concentration was measured at 1, 2, 4, 6, 8 and 24 h on days 1 and 7 of the study. The two elderly groups had higher serum lisinopril concentrations than the healthy young subjects (P < 0ṁ05). There were no significant differences in any of the areas under the curve (AUC) for lisinopril plasma concentration (over time) between the healthy young and healthy elderly groups. The healthy young patients had AUC values on day 7 lower than elderly patients with cardiac failure (P < 0ṁ01). Creatinine clearance was correlated wth lisinopril clearance (r = 0ṁ63; P = 0ṁ006) and with AUC on day 7 (r = −0ṁ67; P = 0ṁ004). Lisinopril clearance was different in the three groups (P < 0ṁ05): healthy young patients had the highest and elderly patients with cardiac failure the lowest values. Thus, in the elderly a reduced renal clearance of lisinopril leads to higher and more sustained blood levels. In elderly patients with cardiac failure, renal function should be estimated before lisinopril is prescribed as a reduction in dose may be appropriate.
Influence of pH on the buccal absorption of morphine sulphate and its major metabolite, morphine-3-glucuronide
Authors: Al-Sayed-Omar O , Johnston A , Turner P
Published: April 2011

Buccal absorption of morphine sulphate and morphine-3-glucuronide at various buffer pH values (4 to 10) over 5 min has been investigated in seven and four normal healthy volunteers, respectively. Increasing pH caused an increase in buccal absorption of both. The maximum mean absorption was 37% at pH 10 for morphine and 19% at pH 8 for morphine-3-glucuronide.
The separation of unbound prednisolone in plasma by centrifugal ultrafiltration
Authors: Miller P F W , Wheeldon J , Brocklebank J T
Published: April 2011

To study variable plasma protein binding of prednisolone in children with nephrotic syndrome we have devised a simple rapid method for measuring unbound prednisolone. The plasma was initially ultrafiltered at 37°C in a 35° fixed angle head at 1500 g for 30 min then the filtrate was analysed by high pressure liquid chromatography. The effects of variable ultrafiltration conditions were studied. The method was used to compare the AUC unbound prednisolone in a nephrotic child (plasma albumin concentration 18 g L−1) with a control (plasma albumin concentration 43 g L−1); their respective AUC unbound prednisolone values were 4.02 mg h L−1 and 1.07 mg h L−1.
Effect of trimethoprim, paracetamol and cimetidine on trimetrexate metabolism by rat perfused isolated livers
Authors: Webster Lorraine K , Tong William P , McCormack John J
Published: April 2011

Trimetrexate (TMTX), a non-classical antifolate, is currently in clinical trial as an antineoplastic drug. In the rat perfused isolated liver, it undergoes extensive metabolism to two metabolites, M1 and M2, which are excreted primarily in the bile. The metabolites result from demethylation, and M1 is also glucuronidated. We examined the effects of three commonly used drugs on the elimination of 1 mg of TMTX by the rat perfused isolated liver (perfusate volume was 100 mL). Co-administration of either 1 or 5 mg cimetidine, a well-known inhibitor of microsomal oxidation, caused an increase in TMTX terminal elimination half-life (69 and 100% at 1 and 5 mg, respectively) and a decrease in clearance (40 and 46% at 1 and 5 mg, respectively). Paracetamol (acetaminophen) was chosen for a possible interaction with TMTX because its major metabolic pathway is glucuronidation. Five mg paracetamol resulted in no change in TMTX pharmacokinetics, but M1 concentrations were increased by 72% in bile, and M2 was not present in perfusate. The third drug tested was trimethoprim, which has some structural similarities to TMTX; however, no effects were noted on the levels of TMTX, M1 or M2 after 1 mg trimethoprim. These results indicate that TMTX elimination can be inhibited by cimetidine, probably due to competition for microsomal enzymes, and that paracetamol may alter the metabolite profiles; trimethoprim had no effect on TMTX disposition under the conditions employed.
The effects of 17β-oestradiol or testosterone on the response to S-warfarin in castrated male rats
Authors: Winn M J , Park B K
Published: April 2011

The effects of castration alone, or followed by administration of 17β-oestradiol or testosterone, on the action of S-warfarin have been investigated in male Wistar rats castrated at 4 weeks of age. Six to 10 weeks later, blood samples were taken before, and at 24 h and 7 days after onset of administration of either 17β-oestradiol (50 to 500 μg kg−1 day−1 i.p.), testosterone (500 μg kg−1 day−1 i.p.), or vehicle (polyethylene glycol 200 i.p.). On the seventh day of these interventions, S-warfarin (6.3 mg kg−1 i.p.) was given; prothrombin complex activity (PCA) was then measured over the next 72 h. In addition, a group of sham-operated rats were given S-warfarin, alone. The control prothrombin times were lower in castrated rats (17ṁ9 ± 0ṁ4 s) than in sham-operated rats (19sham-operatedl ± 0ṁ6 s). Warfarin, over the first 24 h of its administration, caused a significant (P < 0ṁ01) fall in PCA in each group of rats, the fall PCA in castrated rats pretreated with vehicle being significantly (P < 0ṁ05) less than that seen in the sham-operated rats. The fall was the same in castrated rats given vehicle or those given 17β-oestradiol. In contrast, warfarin caused a greater fall in PCA in the presence of testosterone than in the other groups of castrated rats.
The twin impinger: a simple device for assessing the delivery of drugs from metered dose pressurized aerosol inhalers
Authors: Hallworth G W , Westmoreland D G
Published: April 2011

The development is described of the twin impinger, a two-stage separation device for assessing the drug delivery from metered dose inhalers and other oral inhalation delivery devices. The discharged aerosol is fractionated by firing through a simulated oropharynx and then through an impinger stage of defined aerodynamic particle size cut-off characteristics. The fine (pulmonary) fraction which penetrates is collected by a lower impinger. It is demonstrated that this device is able to assess individually the fine particle delivery of both components of two-drug aerosols. Formulations showing undue agglomeration or serious crystal growth of drug are readily detected. The twin impinger is shown to be a valuable device for routine quality assessment of aerosols during product development, stability testing and for quality assurance and comparison of commercial products.