bluuebunny/crossref_metadata_2025 huggingface dataset:
Postreceptor effect of metformin on insulin action in mice
Authors: Lord J M , Puah J A , Atkins T W , Bailey C J
Published: April 2011

To investigate the possibility that metformin (dimethylbiguanide) modifies insulin-mediated glucose metabolism by an effect that is independent of insulin receptor binding, glycogenesis and insulin binding were measured in soleus muscles isolated from streptozocin diabetic mice after treatment with 60 mg kg−1 metformin daily for 10 weeks. This dose of metformin increased insulin-stimulated glycogenesis but did not affect insulin binding in the soleus muscles of streptozocin diabetic mice. The results suggest that metformin can influence postreceptor sites of insulin action independently of insulin receptor binding.
Dose-dependent presystemic elimination of propranolol due to hepatic first-pass metabolism in rats
Authors: Iwamoto Kikuo , Watanabe Jun
Published: April 2011

Gastrointestinal first-pass elimination of propranolol and the effect of dose (1.0, 2.5, 5.0 and 10.0 mg kg−1) on its systemic availability were studied in male Wistar rats which received the drug intravenously, orally or intraportally. The plasma elimination half-life was not altered either by the route of administration or the dose. There was no gastrointestinal first-pass metabolism of propranolol, since the same systemic availability was obtained after oral and intraportal administration. Hepatic clearance was estimated to be constant at any dose. In contrast, the hepatic intrinsic clearance was found to be largely dependent on the portal dose.
Pharmacological actions of ifenprodil in the rat isolated anococcygeus muscle
Authors: Adeagbo A S O , Magbagbeola A O
Published: April 2011

The effect of ifenprodil on the contractile responses of the rat anococcygeus muscle to noradrenaline, methoxamine, carbachol, potassium chloride and calcium chloride has been examined. Ifenprodil (10−8-10−7M) non-competitively antagonized noradrenaline and methoxamine-induced contractions while carbachol-induced responses were unaffected. Similarly, contractile responses to KCl (in tissues from reserpinized animals, or tissues bathed in Tyrode containing 10−6M phentolamine) and CaCl2 in tissues bathed with Ca2+-free depolarizing solution were blocked non-competitively by ifenprodil (10−7-10−6M). These findings suggest that ifenprodil possesses α-adrenoceptor antagonist activity, with intrinsic Ca2+ blocking properties.
Flow defects in wet powder mass extrusion
Authors: Harrison P J , Newton J M , Rowe R C
Published: April 2011

Surface impairment, in the form of the flow defects roughness and sharkskinning, has been shown to occur with microcrystalline cellulose/lactose/water mixes on extrusion under varying process conditions. These defects result from the imbalance of stresses at the outer wall of the extrudate on leaving the die and can be avoided by changing the process conditions that are known to affect these stresses, e.g. the length of the die, the velocity of throughput and the moisture content of the formulation.
The use of gamma scintigraphy to follow the gastrointestinal transit of pharmaceutical formulations
Authors: Christensen F N , Davis S S , Hardy J G , Taylor M J , Whalley D R , Wilson C G
Published: April 2011

The technique of gamma scintigraphy has been used to follow the transit of a solution and a pellet formulation in the gastrointestinal tract of healthy volunteers. The emptying of the formulations from the stomach and their arrival at the caecum could be quantified, thereby allowing calculation of transit times for the small intestine. Gastric emptying was affected by the nature of the formulation, i.e. liquid or solid. However, transit through the small intestine was independent of the nature of the administered material.
The effect of formulation on oesophageal transit
Authors: Channer K S , Virjee J P
Published: April 2011

The oesophageal transit of barium sulphate in small or large, heavy or light capsules or film coated and plain oval tablets was measured during fluoroscopy in five separate studies involving 175 subjects. Transit of large, but not small capsules was significantly faster than plain oval tablets in both erect and supine subjects (P < 0 05). Heavy large capsules entered the stomach in all subjects within 20 s, whereas in all other studies some subjects retained dosage forms in the oesophagus for over 5 min. The transit of heavy capsules was significantly faster than light capsules in erect subjects (P < 0.0005). Light capsules tended to have faster transit times than heavy capsules in the supine position. Film coating significantly enhanced oval tablet transit in erect (P < 0.00003) and supine subjects (P < 0.05). When large capsules of equal weight but less dense than film coated oval tablets were directly compared, the tablet transit was significantly superior in the erect subjects (P < 0.0001). In supine subjects the transit of the light capsule was significantly faster (P < 0.005). It is concluded that different drug formulations can have significant effects on oesophageal transit, and hence on the development of drug induced oesophageal ulceration.
Effect of sodium azide and sodium selenite on prostaglandin synthesis in rabbit kidney medulla slices
Authors: Fujimoto Yohko , Yamamoto Taku , Niwase Nobuyuki , Fujita Tadashi
Published: April 2011

Sodium azide, a catalase inhibitor, stimulated the generation of medullary prostaglandin E2, while the glutathione peroxidase activator sodium selenite inhibited it. These results suggest that hydroperoxides play an important role in the control of prostaglandin synthesis.
Influence of chronic bisacodyl treatment on the effect of acute bisacodyl on water and electrolyte transport in the rat colon
Authors: Beubler E
Published: April 2011

Excessive or unnecessary taking of laxatives leads to a vicious circle with perpetuation of laxative abuse and increase of laxative dosage, accompanied by severe clinically evident disturbances. It was investigated in rats whether chronic administration of bisacodyl reduces the effects of acute bisacodyl administration on net water and electrolyte flux in the rat colon transport in-vivo. After chronic pretreatment with bisacodyl had been given for 21 days (3 mg and 10 mg kg−1 day−1), net water and sodium absorption was found to be decreased whereas potassium secretion was increased. After 21 days of pretreatment, the effect of acute bisacodyl (10 μg ml−1 intraluminal) on net water and sodium transport was reduced whereas the effect on potassium secretion remained unchanged. Serum and erythrocyte levels of sodium and potassium remained unchanged in chronically pretreated rats. Serum aldosterone levels were enhanced two fold. It is concluded that under the experimental conditions described, chronically administered bisacodyl leads to elevated serum aldosterone which counteracts the effect of bisacodyl on net water and sodium transport but acts synergistically with bisacodyl on the effect on potassium loss.
Cocaine-like action of diphenhydramine in cat cerebral arteries
Authors: Balfagón Gloria , Marco Emilio J
Published: April 2011

Diphenhydramine (5.3 times 10−7 M) significantly reduced the tritium efflux evoked by 10 −7 M tyramine from cat cerebral arteries preloaded with [3 H]noradrenaline but not that brought about by 50 mM KCl. These results indicate the ability of diphenhydramine to block the amine neuronal uptake.
Cardiac reactivity in rats with acute renal failure
Authors: Yates M S , Critchley M A , Askey Elizabeth A , Bowmer C J
Published: April 2011

Cardiac reactivity has been determined in rats with acute renal failure (ARF) induced by either bilateral nephrectomy or intramuscular glycerol injection. Rats with bilateral nephrectomy showed reduced chronotropic responses to cervical sympathetic stimulation but no appreciable alteration in the chronotropic responses to vagal stimulation. By contrast, we have previously noted that rats with glycerol-induced ARF show diminished chronotropic responses to stimulation of both nerves. The negative chronotropic and inotropic responses to carbachol in isolated atria from both nephrectomized and glycerol-injected rats were not significantly different from their respective controls. In both models of ARF the atrial positive chronotropic responses to isoprenaline were significantly decreased whilst positive inotropic responses were not significantly different from controls. The results indicate that the cause of the reduced chronotropic response to vagal stimulation observed in glycerol-injected rats is of presynaptic origin whilst the reduced chronotropic response to cervical sympathetic stimulation noted in both models of ARF may be due to an impaired postsynaptic response.
Characterization of [3 H]zetidoline binding to rat striatal membranes
Authors: Barone Domenico , Assandri Alessandro , Galliani Giulio , GläSser Alfredo , Tarzia Giorgio
Published: April 2011

The binding of [3 H]zetidoline, a novel neuroleptic agent, to rat brain striatal membranes was investigated in-vitro. The optimal binding conditions for [3 H]zetidoline differed from those for [3 H]spiperone in pH, temperature and time. [3 H]Zetidoline has high affinity for striatal dopamine receptors. Its binding is saturable, stereo-specific, has a low non-specific component and is reversible and tissue specific. The Scatchard analysis gave a biphasic curve, indicating that [3 H]zetidoline interacts with more than one population of receptor sites (B'max = 67 fmol mg−1 protein, K'd = 0.11 nM; B”max = 500 fmol mg−1 protein, K'd = 2.49 nM). Kinetic analysis of rates of association and dissociation yielded a Kd value in agreement with that measured at equilibrium. Inhibition studies indicated that only dopamine and dopaminergic agents are able to displace [3 H]zetidoline from its binding sites, and in a different rank order from that for displacement of [3 H]spiperone. (-)-Sulpiride was especially effective in inhibiting [3 H]zetidoline specific binding. Furthermore, like that of [3 H]benzamides, [3 H]zetidoline binding appears to be highly Na+ -dependent and Li+ only partially substitutes Na+.
Evidence for the involvement of endogenous substance P in the motor effects of capsaicin on the rat urinary bladder
Authors: Maggi Carlo Alberto , Santicioli Paolo , Meli Alberto
Published: April 2011

[pro4, trp7,9, Leu11]SP-(4−11), a substance P(SP) antagonist, selectively antagonized contractions produced by either capsaicin or SP on the rat isolated urinary bladder. These experiments provide direct evidence indicating that the motor effects of capsaicin on rat urinary bladder are attributable, at least in part, to the release of endogenous SP.
Effect of verapamil and diltiazem on isolated gastro-oesophageal sphincter of the rat
Authors: Morales-Olivas Francisco J , Cortijo Julio , Esplugues Juan Vicente , Rubio Elena , Esplugues Juan
Published: April 2011

The effect of verapamil and diltiazem on the contraction induced by agonists on the rat lower oesophageal sphincter in-vitro has been studied. Both calcium entry blockers inhibited the contractile response to acetylcholine, carbachol and KCl. The potency of the inhibitory action was diltiazem > verapamil. The results give substance to the use of calcium entry blockers in the treatment of oesophageal spasm.
Influence of surfactant-treated starch on the disintegration and dissolution of sulphadiazine tablets
Authors: Nasipuri R N , Omotosho J A
Published: April 2011

The effects of treating cassava starch with sodium lauryl sulphate and Polysorbate 80 and the method of incorporating the treated and plain starch as disintegrant on the physical properties of sulphadiazine tablets were investigated. Disintegration and dissolution rates were faster with starch in which surfactant was incorporated in dry state than with starch treated with solution of surfactant. A direct correlation was observed between the Hardness-Friability Index and T90 values. Polysorbate 80-treated starch exhibited a better dissolution profile than SLS-treated starch.
Metronidazole-induced myocardial depression: chemical and pharmacological studies on the role of calcium in-vitro
Authors: Essien E E , Femi-Onadeko B , Ojewole J A O
Published: April 2011

The interaction of metronidazole with calcium to form a water-soluble complex has been studied by titration with ethylenediaminetetraacetate (EDTA), direct current and pulse polarographic reduction steps of the nitro-group at pH 5 and 7, and by ultraviolet absorption. Stoichiometric calculations, X-ray powder diffraction pattern of the synthesized metronidazole-calcium complex, and molecular ion peak at m/z 381 in the mass spectrum of this product, showed that a 2: 1 complex is formed. The interaction of metronidazole with calcium on myocardial contractile performance of guinea-pig electrically-driven isolated left atria in physiological solution was also examined. Metronidazole induced a sustained, concentration-dependent depression of the tension that was reversed by changing the bathing fluid to physiological solution, and/or by adding excess calcium ion. The drug-induced negative inotropic response was antagonized competitively by increasing calcium ion in the bath, whereas noradrenaline antagonized metronidazole-induced negative inotropic responses non-competitively. Addition of the metronidazole-calcium complex to the bath did not affect normal myocardial contractile performance. The results show that metronidazole produces a direct negative inotropic effect on isolated atrial muscles by interfering with Ca2+, and by preventing Ca2+ function in the events leading to contractile activity of atrial muscles.
Reflectance measurements on gels and emulsions containing cetrimide and cetostearyl alcohol–-a preliminary investigation
Authors: Rowe R C , Patel H K
Published: April 2011

Various light scattering properties–-the reflectivity, contrast ratio and scattering index of a series of gels and emulsions containing cetrimide, cetostearyl alcohol, water and liquid paraffin have been examined using reflectance measurements made at 560 nm using a four-filter, tristimulus colorimeter. The scattering properties of both systems were dependent on the total interfacial surface area of either the dispersed unreacted cetostearyl alcohol and/or the dispersed droplets of liquid paraffin, and hence increased with increasing concentration of both ingredients. For the emulsion containing liquid paraffin, the scattering properties increased linearly with the concentration of liquid paraffin but with the ternary gel system the scattering properties were not directly related to cetostearyl alcohol concentration. This was confirmed by microscopy as due to the changes in the size of the dispersed unreacted cetostearyl alcohol. The results illustrate the potential of this simple, reproducible non-destructive technique in the study of the structure of such systems.
Changes in the disposition of promethazine during multiple dosing in the rabbit
Authors: Taylor G , Houston J B
Published: April 2011

During a multiple dosing regimen, the area under the promethazine blood concentration-time profile progressively decreased indicating auto-induction of metabolism. The increase in promethazine clearance (mean 35%) was not reflected in changes in either elimination half-life or minimum blood concentrations during the dosing interval. This was attributed to a deep compartment in the disposition of promethazine in the rabbit. The changes in promethazine clearance were accompanied by proportionally larger changes in the clearance of the monodesmethylpromethazine metabolite. The effect of promethazine pretreatment on the clearance of antipyrine was also studied and was found to be significantly increased by a mean of 17% following pretreatment with promethazine. However, the changes in the clearance of antipyrine did not highly correlate with those of promethazine and monodesmethylpromethazine. This may indicate that promethazine induces metabolic systems in the rabbit for which antipyrine is not a good substrate.
Effects of acute and chronic treatment on the pro-and anti-convulsant actions of CL 218, 872, PK 8165 and PK 9084, putative ligands for the benzodiazepine receptor
Authors: File Sandra E , Wilks Lucy
Published: April 2011

CL 218, 872 is a triazolopyridazine that acts at the benzodiazepine binding site. At low doses (0.5−7.5 mg kg−1) it is proconvulsant when combined with subconvulsant doses of picrotoxin but not when combined with pentetrazol (leptazol, pentylenetetrazol). At high doses (20−60 mg kg−1) CL 218, 872 counteracted seizures caused by pentetrazol but not those caused by picrotoxin. There was tolerance to the proconvulsant effects after five days of treatment and to the anticonvulsant effects after 15–20 days. Two phenylquinolines, PK 8165 and PK 9084, that also act at the GABA-benzodiazepine receptor complex have proconvulsant actions in combination with picrotoxin. Significant tolerance to these effects had not developed even after 20 days of treatment. It is concluded that three different sites on the GABA-benzodiazepine complex mediate the pro- and anti-convulsant actions of CL 218,872 and the proconvulsant actions of PK 8165 and PK 9084.
Comparison of (β-adrenoceptor populations in cat and guinea-pig left atria
Authors: Molenaar Peter , Mcpherson Grant A , Malta Errol , Raper Colin
Published: April 2011

The subtypes of β-adrenoceptor present in left atrial preparations from the guinea-pig and cat have been assessed using both responses obtained in organ bath experiments and radioligand binding studies. From the positive inotropic responses to procaterol, the pKB values for practolol using a variety of agonists, and from displacement of [125 I]cyanopindolol from left atrial membrane homogenates by the selective β1 and β2-adrenoceptor antagonists L643, 717-01J10 and ICI 118, 551, it was concluded that guinea-pig left atria possess only β1-adrenoceptors, whilst cat left atria possess both β1- and β2-adrenoceptor subtypes.
Cardiovascular effects in the Sprague-Dawley rat of 8−hydroxy−2(di- N-propylamino) tetralin, a selective 5−hydroxytryptamine receptor agonist
Authors: Gradin K , Pettersson A , Hjorth S , Hedner T , Arvidsson L E , Persson B
Published: April 2011

The intravenous administration of 8−hydroxy−2(di-N-propylamino) tetralin, a selective 5−HT receptor agonist, caused a biphasic blood pressure response and bradycardia in Sprague-Dawley rats. The initial pressor response involved peripheral α1-adrenoceptors since it was present in pithed rats and was antagonized by prazosin. Though the intracerebroventricular route of administration was not more effective the hypotension and bradycardia were probably of central origin. The bradycardia was prevented by pretreatment with atropine and propranolol suggesting an involvement of vagal as well as sympathetic activity. These results support the view that central 5−HT receptor activation reduces the blood pressure and heart rate.
The absorption of β-adrenoceptor antagonists in rat in-situ small intestine; the effect of lipophilicity
Authors: Taylor David C , Pownall Rowena , Burke Wendy
Published: April 2011

The absorption of β-adrenoceptor antagonists in rat in-situ small intestine; the effect of lipophilicity

Intestinal absorption characteristics of eleven β-adrenoceptor antagonists were measured by monitoring their disappearance from in-situ intestinal loops in the anaesthetized rat. All have basic pKa values of around 9.5 (with the exception of sotalol) but show a wide range of lipophilic character (octanol-water log P values from −0.79 to 3.65). The results show two types of absorption behaviour, indicating different mechanisms for ‘hydrophilic’ and ‘lipophilic’ β-adrenoceptor antagonists. The four most hydrophilic molecules (sotalol, atenolol, nadolol and practolol) show virtually identical absorption rate constants. Absorption is slow and relative rates in jejunum (mean pH 6.5) and ileum (mean pH 7.3) are not consistent with pH-partition (jejunum > ileum). The more lipophilic members of the series (pindolol, timolol, metoprolol, oxprenolol, alprenolol and propranolol) are all absorbed much more rapidly. Absorption rate constant rises rapidly with log P and the expected pH effects are seen (ileum > jejunum). Acebutolol shows anomalously slow absorption for its log P value.
Fat contents of meals and bioavailability of griseofulvin in man
Authors: Ogunbona F A , Smith I F , Olawoye O S
Published: April 2011

The bioavailability of griseofulvin was followed in twelve healthy volunteers by measuring the urinary excretion of the major metabolite 6-demethylgriseolfulvin, after each volunteer had ingested one 500 mg griseofulvin tablet under (1) fasting conditions, (2) immediately after a typical low-fat and (3) high-fat Nigerian meals. An increase of about 70 and 120% absorption occurred with the ingestion of the low-fat and high-fat meals respectively compared to the fasting state (P < 0.01). The maximum excretion rates of the free metabolite (Vmax.) were also significantly increased (P < 0.01) following consumption of low and high fat meals. Our results thus suggest that the higher the fat content of the meals the higher the enhancement of the bioavailability of griseofulvin in man.
Protein binding of disopyramide–-displacement by mono -N-dealkyldisopyramide and variation with source of α-1-acid glycoprotein
Authors: Haughey David B , Steinberg Irving , Lee Min Hwa
Published: April 2011

The binding of disopyramide to human serum proteins and human α-l-acid glycoprotein (AAG) was determined over a wide drug concentration range. Addition of 3.7 times 10−5 mol litre−1 mono- N-dealkyldisopyramide caused a 20–100% increase in disopyramide free fraction. The disopyramide free fraction in AAG solutions prepared from various commercially available sources of α-l-acid glycoprotein varied up to 2.5 fold at corresponding disopyramide concentrations. Pronounced differences in the calculated binding constants (affinity and capacity) were observed among the commercially available AAG preparations. These findings suggest that binding studies should be performed in appropriately harvested human serum or plasma to avoid possible artifacts associated with the use of commercial preparations of α-l-acid glycoprotein for binding studies.
An allylamine derivative (MDL 72145) with potent irreversible inhibitory actions on rat aorta semicarbazide-sensitive amine oxidase
Authors: Lyles Geoffrey A , Susan Fitzpatrick C M
Published: April 2011

(E)-2-(3, 4-dimethoxyphenyl)-3-fluoroallylamine (MDL 72145) was found to be an extremely potent inhibitor of the semicarbazide-sensitive amine oxidase (SSAO) in rat aorta homogenates. Considerable inhibition, which was not reversed by dialysis, could be produced under appropriate in-vitro conditions at drug concentrations around 10 nM. The pseudo first order kinetics for time-dependent inhibition by MDL 72145 (10–100 nM) were found to be consistent with a bimolecular reaction between enzyme and inhibitor with a rate constant for this step of 2 times 106 min−1 M−1. A similar rate of inhibition under an oxygen atmosphere to that obtained under nitrogen was produced upon incubation of enzyme with inhibitor, suggesting that oxidation of the inhibitor to an active metabolite was not required for its activity. Incubation of homogenates for very short periods (1 min) with inhibitor (0.05-0.5 μM) and benzylamine (1–10 μM) as substrate indicated non-competitive kinetics for the early interaction of enzyme with the drug. Benzylamine (50 μM), but not pyridoxal phosphate (100 μM), was able to protect SSAO from inhibition by 10 nM MDL 72145. However, pyridoxal phosphate alone appeared to produce some irreversible inhibition of the enzyme. Dialysis against buffer containing 50 μM or 1 mM benzylamine was unable to reactivate SSAO inhibited by 10 nM MDL 72145. It is concluded that MDL 72145 irreversibly inhibits SSAO by acting at, or near, the substrate binding site, but the exact nature of the complex formed remains to be identified.
Modulation of substance P-induced bronchoconstriction by lipoxygenase metabolites
Authors: Stewart A G , Thompson D C , Fennessy M R
Published: April 2011

In anaesthetized, mechanically ventilated guinea-pigs, substance P induces a bronchoconstrictor response comprising increases in airway resistance and decreases in dynamic compliance. Eicosatetraynoic acid (ETYA, 20 mg kg−1 i.v.) or BW755c (20 mg kg−1 i.v.) potentiated the substance P-induced bronchoconstriction. Neither indomethacin (1 or Smgkg-' i.v.) nor aspirin (20 mg kg−1 i.v.) significantly altered the potency of substance P on bronchomotor responses. These observations are consistent with the existence of a bronchodilator lipoxygenase metabolite(s).
The mouse anococcygeus muscle as a preparation for the bioassay of oxytocin
Authors: Botting J H , Gibson A
Published: April 2011

Oxytocin (0.1–10 nM) caused reproducible, dose-related contractions of the male mouse anococcygeus. Desensitization was not a major problem. The muscle was shown to be a useful oxytocin bioassay preparation, having a good index of precision (0.04).
Monoamine oxidase-A selective inhibition in human hypothalamus and liver in-vitro by amiflamine and its metabolites
Authors: Tipton Keith F , O'Carroll Anne-Marie , Mccrodden John M , Fowler Christopher J
Published: April 2011

Amiflamine (FLA 336(+)) and its two metabolites, FLA 788(+) and FLA 668(+) were found to be competitive inhibitors of the activity of monoamine oxidase-A in homogenates of human hypothalamus and liver obtained at autopsy. KI values, determined at pH 7.2, were 1.3,0.3 and 22 μM (liver) and 0.8, 0.2 and 14 μM (hypothalamus) for amiflamine, FLA 788(+) and FLA 668(+), respectively. Monoamine oxidase-B activity was only weakly inhibited by the compounds.
Dopamine receptor agonistic activities of R- and S-enantiomers of 4-hydroxy-2-di-n-propylaminoindan in cat hearts
Authors: Ilhan Mustafa , Flynn Jan R , Long John P , Bhatnagar R K , Cannon Joseph G
Published: April 2011

In-vitro and in-vivo studies were used to evaluate the presynaptic dopamine receptor stimulating activities of R-and S-enantiomers of 4-hydroxy-2-di-n-propylaminoindan in cat hearts. Bioassay results show that the R-enantiomer is 100 times more potent than the S-enantiomer in both in-vitro and in-vivo preparations.
Disposition of HI-6 oxime in rats after intravenous and intramuscular administration
Authors: Simons K J , Briggs C J
Published: April 2011

The pharmacokinetics of HI-6, a cholinesterase-reactivating oxime, were studied in rats, following intravenous or intramuscular administration. A two-compartment model was used to analyse the intravenous data and a one-compartment open model with first-order absorption was used for intramuscular data. Drug concentration had no influence on rate and extent of absorption of intramuscular injections, and bioavailability was 100%. Peak plasma concentrations of HI-6 occurred 15 min after intramuscular injection. No significant differences were found between mean values for half-life, plasma clearance, volume of distribution and area under the plasma concentration versus time curve for the two intramuscular doses and the intravenous dose used. Mean HI-6 plasma concentrations were 140.5 ± 4.2 μg ml−1 3 min after 20 mg ml−1 i.v., with a mean elimination half-life of 65.2 ± 21 min. Plasma clearance rate was 3.95 ± 0.93 ml min−1 kg and the apparent volume of distribution was 0.38 ± 0.17 litre kg−1. The oxime is rapidly distributed in and eliminated by rats when administered intravenously or intramuscularly.
Cocaine potentiates the responses to methacholine and noradrenaline in the rat vas deferens
Authors: Bradley Lynn , Doggrell Sheila A , Edmonds Sarah C
Published: April 2011

The ability of cocaine (10 μM) to potentiate the contractile responses of the epididymal half of the rat vas deferens to methacholine was reversed by prazosin. Prazosin also partially reversed the ability of cocaine to increase the spontaneous overflow of 3 H following loading of the tissue with [3 H]noradrenaline. We suggest that cocaine potentiated the responses to methacholine by stimulating, directly or indirectly, α1-adrenoceptors.
The interaction of Cimetidine with various antihypertensive agents in the spontaneously hypertensive rat
Authors: Dadkar N K , Aroskar V A , Gupte R D , Dohadwalla A N
Published: April 2011

The H2-receptor antagonist Cimetidine (250 μg) administered intracerebroventricularly (i.e.v.) 15 and 30 min before Clonidine (25 μg kg−1 i.v.), significantly antagonized clonidine-induced hypotension in anaesthetized spontaneously hypertensive rats. The hypertensive response of Cimetidine was correlated with the inhibition of clonidine-induced hypotension. In addition, Cimetidine (250 μg i.e.v.) counteracted the hypotensive effects of pentolinium (5.0 mg kg−1 i.v.), guanethidine (5.0 mg kg−1 i.v.) and minoxidil (1.0 mg kg−1 i.v.) These data do not support previous suggestions that the hypotensive action of Clonidine is caused by stimulation of the H2-receptor, but suggest that central administration of Cimetidine causes peripheral vasoconstriction and this may offer resistance to the hypotensive action of different antihypertensive agents.
Bile-acid content of a commercial secretin
Authors: Kyffin D , Mclean I , Rutishauser S C B
Published: April 2011

Secretin, produced by the Boots Co., is an adsorbate on ox and pig bile acids of secretin from pig duodenum prepared after the method of Crick et al (1950). It is to be expected that this product will not only stimulate the secretion of fluid and electrolytes by the pancreas and the liver but that it will also increase the secretion of bile acids in bile. A recent study in rats showed that the infusion of secretin (Boots) did indeed increase biliary bile acid secretion but implied that this might be due to unidentified contaminants other than bile acids, in that the bile acid content of the batch of secretin used was found to be negligible (Romanski & Bochenek 1983).
Assessment of the wettability and surface energy of a pharmaceutical powder by liquid penetration
Authors: Buckton G , Newton J M
Published: April 2011

The use of a technique involving the assessment of the rate of penetration of a liquid into powder beds has been critically evaluated as a method for characterizing the wetting and surface energy of a hydrophobic powder (amylobarbitone). The choice of the perfect wetting liquid has been assessed, and the possible use and value of extrapolation techniques to indicate the theoretical result for water have been explored. Values of 99.5 and 102.8 obtained for the contact angle, and 25.7 and 26.9 mNm−1 for the critical surface energy, were the best estimates obtainable by this technique. Previously reported limitations of the Washburn equation have been considered.
In-vitro enhancement of cholesterol dissolution by commonly used drugs
Authors: King R O , Bell G D , Short A H , Heathcote B V , Hawkey C J
Published: April 2011

A rotating disc apparatus was used to study the dissolution of cholesterol in sodium cholate solutions and ox bile. Drugs with structures that render them capable of lowering interfacial resistance were tested and shown to increase cholesterol dissolution rates in both systems. In sodium cholate solutions, loperamide (3 times 10−4 M) increased the rate of dissolution by over six times, and a similar effect was observed with amitriptyline (3 times 10−3 M), diphenhydramine (3 times 10−3 M), dicyclomine (3 times 10−3 M) and propantheline (3 times 10−3 M). These drugs are as effective as benzalkonium chloride at these concentrations. Amitriptyline, propantheline, dicyclomine and diphenhydramine also increased cholesterol dissolution rates into ox bile. If these drugs are excreted into human bile in sufficient quantities and in an active form they may be able to enhance the speed of cholesterol gallstone dissolution therapy.
Influence of ophthalmic formulations on sodium cromoglycate disposition in the albino rabbit eye
Authors: Shrewsbury Robert P , Swarbrick James , Newton Kimberly S , Riggs Linda C
Published: April 2011

The effect of different ophthalmic vehicles on the disposition of sodium cromoglycate in tears and ocular tissues of the rabbit eye has been studied over 6 h. The vehicles contained sodium cromoglycate, 2% in an aqueous solution, 2 and 4% in an oleaginous formulation of polyethylene and mineral oil (Plastibase 5W), and 4% in an absorption ointment base of 10% hypoallergenic acetylated lanolin (Modulan) in paraffins. The last formulation was superior to all others studied over 6 h in prolonging the retention of sodium cromoglycate in the precorneal area and the conjunctiva. The concentration of sodium cromoglycate in the tears, conjunctiva and cornea 6 h after administration of the acetylated lanolin base equalled or exceeded the concentrations obtained with the aqueous solution 1 h post-instillation.
Cardiodepressant effects of ethanol on guinea-pig atria: presynaptic and postsynaptic components
Authors: Mantelli Laura , Corti Vittorio , Ledda Fabrizio
Published: April 2011

Ethanol, at concentrations ranging from 0.5 to 1.5%, depressed myocardial contractility of electrically-stimulated guinea-pig atria. This effect was evident in preparations bathed with a low calcium concentration, but was progressively reduced by increasing the extracellular calcium. The same concentrations of ethanol produced a dose-dependent inhibition of the cardiac response to field stimulation of the adrenergic nerve terminals. This effect was again calcium-dependent. These results support the hypothesis that the pre- and postsynaptic components of the cardiodepressant effects of ethanol are due to a reduction in calcium availability both at the nerve endings and in the contractile cells.
Amiodarone does not affect digoxin kinetics in the rabbit
Authors: Buss D C , Routledge P A
Published: April 2011

It has been reported that amiodarone may interact with digoxin in man. We investigated the effects of amiodarone pretreatment (35 mg kg−1 day−1) on the pharmacokinetics Of a single dose of digoxin (50 μg kg−1) in 6 rabbits. Total body clearance of digoxin was 138.84 ± 44.67 and 147.99 ± 29.17 ml min−1, serum half life 187.9 ± 60.9 and 181.34 ± 25.57 min and volume of distribution 35.4 ± 8.54 and 37.8 ± 3.9 litres before and after amiodarone treatment, respectively. None of these changes were statistically significant. We conclude that the presence of an amiodarone-induced change in digoxin pharmacokinetics in the rabbit was not evident and that other animal models will be necessary for studying this interaction.
A strain dependent sex difference in ouabain-induced cardiotoxicity in rats
Authors: Wilson S A , Hewick D S
Published: April 2011

Male rats of the BDIX strain were about twice as sensitive to the lethal effects of intravenously infused ouabain than were their female counterparts. This sex difference in ouabain sensitivity was not exhibited by rats of the Wistar strain. In bile duct-cannulated animals, ouabain biliary excretion was much faster in female BDIX rats. This finding could partly explain the greater ouabain resistance, although certain aspects of the cardiac/plasma ouabain concentration data aid suggest that there may have been a component of the sex-related resistance that was not explicable on a pharmacokinetic basis. The faster ouabain biliary excretion in female rats could also partly explain the fact that for similar rates of infusion, the plasma ouabain concentration during infusion was similar in both sexes, despite the body size of the female rats being about one-third smaller.
The influence of conformational factors on the metabolic conjugation of aryloxyacetates
Authors: Van De Waterbeemd Han , Testa Bernard , Caldwell John
Published: April 2011

Among p-chlorophenoxyalkanoic acids, the acetate and 2-propionate are essentially inert towards metabolic conjugation, whereas the isobutyrate (clofibric acid) undergoes extensive glucuronidation, as well as amino acid conjugation in carnivores. To try to explain these differences, the conformational behaviour of three model compounds was studied by quantum mechanical calculations (PCILO method). All three compounds prefer syn (folded) conformers, but the isobutyrate, in contrast to its two lower homologues, also has anti (extended) conformers of relatively low energy. Based on these results, a hypothetical topographical model is proposed for the binding site of glucuronyltransferase.
Can the effects of meptazinol on the guinea-pig isolated ileum be explained by inhibition of acetylcholinesterase?
Authors: Ennis Christine , Haroun Faizal , Lattimer Norman
Published: April 2011

It has previously been shown that there is a cholinergic component in the antinociceptive action of the opioid analgesic drug meptazinol. In the present study meptazinol was shown to be an inhibitor of acetylcholinesterase in-vitro with a potency one hundredth that of physostigmine. This activity was found to reside only in the (−)-enantiomer of meptazinol. The anticholinesterase activity of meptazinol may explain the increase in the size of the electrically-evoked contraction of the guinea-pig isolated ileum preparation since by using a long pulse width (5 ms) it was found that the (−)-enantiomer of meptazinol modified only the component of the response due to neuronally released acetylcholine and had no direct effect on the smooth muscle. This property of meptazinol may also be responsible for the cholinergic effects of the drug in-vivo.
Dose-related effects of ethylketazocine on nociception, behaviour and autonomic responses in the horse
Authors: Kamerling Steven G , Dequick David J , Weckman Timothy J , Tobin Thomas
Published: April 2011

Sensitive methods for measuring the analgesic, physiological and behavioural effects of opioids in the horse have recently been developed. Fentanyl, a prototypic μ-opiate receptor agonist, has been previously shown to produce a syndrome characterized by marked analgesia and locomotor stimulation as well as tachycardia, tachypnoea and behavioural arousal. To determine whether other opiate receptors mediate some of the actions of the narcotic analgesics in the horse, an agent with activity at κ and to a lesser extent μ-receptors was studied using a vigorous experimental protocol. Like fentanyl, ethylketazocine (EKC) (1.0025–1.012 mg kg−1 i.v.) produced marked dose-related analgesia to noxious thermal stimuli. Modest dose-related increases in locomotor activity, pupil diameter and rectal temperature were also observed. However, in contrast to fentanyl, EKC failed to produce any change in cardiac or respiratory rates and produced behavioural sedation rather than arousal. These data suggest that μ- and possibly κ-receptors can mediate the actions of narcotics in the horse.
Evidence that 6-hydroxydopamine is an inhibitor of catechol-O-methyltransferase in intact tissue
Authors: Reid Julianne J , Stitzel Robert E , Head Richard J
Published: April 2011

The effect of in-vitro sympathetic denervation on the O-methylation of 2-hydroxyoestradiol was examined using the rabbit thoracic aorta. Aortic segments were exposed to 6-hydroxydopamine (400 mg litre−1, 10 min), incubated in 2-hydroxyoestradiol (5 μm, 60 min), and the 2-methoxyoestradiol formed was quantified using HPLC with electrochemical detection. Pre-exposure to 6-hydroxydopamine reduced O-methylation by 90% in intact aortic strips. However, O-methylation was also reduced (81%) in rabbit aorta that had been surgically denervated before exposure to 6-hydroxydopamine. Furthermore, the O-methylation of 2-hydroxyoestradiol (20 μm, 15 min) by partially purified soluble catechol-O-methyltransferase was inhibited by 6-hydroxydopamine (400 μg litre−1) by 95% and 51% in the absence and presence of antioxidant, respectively. These results suggest that the inhibition of catechol-O-methyltransferase by 6-hydroxydopamine reported for the purified enzyme, applies to the intact tissue and that the inhibition is dependent on oxidation of the 6-hydroxydopamine. Subsequent experiments using dialysis techniques demonstrated that the inhibition of soluble catechol-O-methyltransferase by 6-hydroxydopamine was irreversible in part, but the degree of irreversibility was influenced by pH and by the extent of in-vitro oxidation of 6-hydroxydopamine.
Dose versus survival time curves in the evaluation of ‘prompt’ and ‘delayed’ acute toxicities
Authors: Molinengo L , Orsetti M
Published: April 2011

The acute toxicity of arecoline, diisopropylfluorophosphate, nicotine and pilocarpine alone or in association with atropine has been evaluated from percentage lethality and from the linear correlation of (doses/(survival time)) vs doses. The experimental points obtained with arecoline and diisopropylfluorophosphate, alone or in association with atropine 50 mg kg−1, are apparently ordered according to two straight lines. That at lower doses gave the LD50 values of the compounds studied. The values found are comparable to those found with percentage lethality. The straight line found at high doses may indicate that over certain doses the drugs kill by a different mechanism. It is concluded that the evaluation of the survival time may be a reliable method in identifying and in evaluating quantitatively the two forms of toxicity.
Similarity in the aldehyde oxidases from guinea-pig liver and polymorphonuclear leucocytes
Authors: Beedham C
Published: April 2011

Partially purified enzyme from guinea-pig leucocytes has been shown to have properties similar to both guinea-pig and rabbit liver aldehyde oxidase. The presence of molybdenum in the leucocyte enzyme has been demonstrated and substrate oxidation by either guinea-pig enzyme was found to be completely inhibited by menadione, a potent inhibitor of rabbit liver aldehyde oxidase. The leucocyte enzyme resembles the guinea-pig liver enzyme in terms of substrate specificity but there is considerable variation in substrate oxidation rates between the two species.
A vacuum microbalance technique for studies on the wettability of powders
Authors: Buckton G , Beezer A E , Newton J M
Published: April 2011

A vacuum microbalance technique has been used to evaluate the wettability of powders. The rate of uptake, and equilibrium weight of uptake, of water vapour onto outgassed powder samples, of differing wettabilities, were determined at different known temperatures. Standard techniques of data analysis were used to establish the enthalpy, entropy and Gibb's free energy of the activation and adsorption processes. The values obtained appeared to be in the correct order of magnitude and those for activation clearly reflected the relative wettability of the powders. Tests for compensation demonstrated that with the exception of phenobarbitone, there was probably a common mechanism producing the adsorption.
Antihistamine-sensitive active vasodilatation in the perfused hindquarters of the rat
Authors: Holcslaw Terry L , Randall Robert D
Published: April 2011

The innervated, constant flow perfused hindquarters of the rat have been used to evaluate post-stimulation vasodilatation, which is a model of active reflex vasodilatation in this species. The vasodilatation resulting from lumbar sympathetic stimulation was dependent on stimulation frequency and duration. Maximal vasodilatation (16 ± 2%) was at 8 Hz for 15 s, while markedly reduced vasodilatation was seen after stimulation for longer than 30 s at all frequencies tested. The vasodilatation was transient. Atropine (2.0 mg kg−1 i.v.) failed to attenuate post-stimulation vasodilatation at a time when hindquarter vasodilatation to i.a. acetylcholine had been abolished. The H1 antihistamine, tripelennamine (2.5 mg kg−1 i.v.) significantly reduced (77%) post-stimulation vasodilatation relative to controls at a time when hindquarter vasodilatation due to i.a. histamine was essentially abolished. Reactive hyperaemia is an unlikely cause of vasodilatation since it is not blocked by H1 antihistamines; 60 s post-occlusion hyperaemia also, was not demonstrable. These data suggest that there is an active component of baroreceptor-mediated vasodilatation in the rat and that histamine, rather than acetylcholine, could be a mediator of this vasodilatation.
The pH-dependence of chloroquine uptake by phosphatidylcholine vesicles
Authors: Ferrari V , Cutler D J
Published: April 2011

The pH-dependence of chloroquine uptake by phosphatidylcholine bilayered vesicles was investigated to examine the relative affinity of ionized and un-ionized chloroquine species to membrane bilayers. The results suggest that the neutral species and monocation are taken up by the bilayers but only the un-ionized species interacts significantly with the hydrocarbon interior.
Direct measurements on individual microcapsule dissolution as a tool for determination of release mechanism
Authors: Hoffman A , Donbrow M , Benita S
Published: April 2011

A method is described for simultaneous microscopic observation of individual microcapsule core material dissolution together with quantitative measurement of the individual kinetics of release of the contents. These may be conductimetric in the case of ionized materials or spectro-photometric otherwise. This enables correlation of changes in core surface area during dissolution with kinetics. Surprisingly, both ethyl cellulose- and polymethacrylatecoated cores of potassium dichromate crystals, used as a model, showed localized internal dissolution universally, providing evidence of the exit of the salt via pores in the membrane, in spite of the kinetics being invariably zero order, as expected for individual microcapsules. The advantages of the method are presented.
Evidence against VIP-involvement in neurogenic relaxations of the mouse anococcygeus muscle
Authors: Carvajal A , Gibson A , Yu O
Published: April 2011

Vasoactive intestinal polypeptide (VIP) antiserum, α-chymotrypsin, and repeated exposure to VIP markedly reduced relaxations of the mouse anococcygeus muscle to VIP but not to field stimulation. This evidence suggests that VIP does not mediate non-adrenergic, non-cholinergic relaxations in the mouse anococcvpeus.
Effect of particle size and food on gastric residence time of non-disintegrating solids in beagle dogs
Authors: Itoh Tomoh , Higuchi Takeru , Gardner Colin R , Caldwell Larry
Published: April 2011

The gastric residence times of various sizes of radio-opaque particles and tablets were measured in beagle dogs by X-ray, both in the fasted state and after a single meal. During the course of the studies, changes in intragastric pH were also monitored with a radiotelemetric pH sensor, the Heidelberg capsule. The gastric residence time increased with increasing particle size and with particles ≥5 mm in diameter approached a plateau value both in the fasted state and after feeding. This value was about 7.5 h after feeding and about 1.5 h in the fasted state, and probably corresponded to the occurrence of the interdigestive migratory myoelectric complex (IMMC wave). The pH in the stomach was variable in the fasted state, but an abrupt pH increase (up to pH 6–7) was observed during the emptying of larger tablets. In some instances this high pH in the stomach was maintained until the next IMMC wave occurred. The gastric emptying of larger tablets administered with food was alo associated with an abrupt pH increase.
Detection of endotoxin in mice by measurement of endotoxin-induced changes in plasma concentrations of zinc and of the acute-phase protein serum amyloid P-component
Authors: Poole S , Das R E Gaines , Baltz M , Pepys M B
Published: April 2011

Preparations of six bacterial endotoxins reduced plasma concentrations of zinc and increased concentrations of the acute-phase protein serum amyloid P component (SAP) in mice. The changes were sufficiently sensitive to permit use of either response in tests for endotoxin and hence for pyrogenic contamination.