bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscarinic receptors on rat ileal villus and crypt cells
Authors: Wahawisan Ruchaneekorn , Wallace Lane J , Gaginella Timothy S
Published: April 2011

Ileal villus and crypt cells exhibit morphological and biochemical differences which may be responsible for functional differences in relation to ion transport. Cholinergic agonists act directly on epithelial cell muscarinic receptors, but it is not known if these receptors exist on both villus and crypt cells. Using the potent muscarinic antagonist [3H](−)-quinuclidinyl benzilate (QNB) we have determined the distribution of muscarinic receptors in rat ileal villus and crypt cells. Plasma membrane preparations from ileal villus and crypt cells possessed a specific, saturable, and high affinity QNB binding site with apparent dissociation constants of 0.23 ± 0.05 and 0.21 ± 0.04 nM (mean ± s.e., n = 6) and densities of 92.2 ± 2.8 and 90.1 ± 16.2 fmol (mg protein)−1, respectively. Both types of cells showed similar potencies for agonist and antagonist competition of QNB binding. The muscarinic receptors in membrane fractions from villus cells were found primarily on the basolateral membrane rather than on the brush border membrane. Secretion induced by cholinergic stimulation of the small intestine might, therefore, be due to an effect on both villus and crypt cells as both types contain muscarinic receptors. Furthermore, such stimulation also may result in mucin secretion, as goblet cells were present in the preparation we studied, and receptors on these cells may have contributed to the amount of binding of [3H]QNB.
A comparison of the antagonisms by neostigmine and diaminopyridine against the neuromuscular block caused by cobrotoxin and (+)-tubocurarine
Authors: Chang C C , Su M J , Hong S J , Shieh B H , Chiou L C
Published: April 2011

Cobrotoxin was about 11-fold more potent than (+)-tubocurarine on a weight basis in blocking neuromuscular transmission in mouse isolated phrenic nerve-diaphragm preparations. Neostigmine and diaminopyridine increased the concentrations of cobrotoxin for 70% inhibition of indirect contraction by 290 and 320%, and increased those of (+)-tubocurarine by 180 and 230%, respectively. More than additive increases were obtained when neostigmine and diaminopyridine were used simultaneously. Cobrotoxin, however, was only 6-fold more toxic than (+)-tubocurarine after intraperitoneal injection in mice. The lethal dose of (+)-tubocurarine was increased by 80% when both antidotes were used together, but only by 15–20% when used alone. In contrast, the lethality of cobrotoxin was not decreased by these drugs. Unexpectedly, the time to death after treatment with cobrotoxin was shortened when mice were pretreated with these antidotes.
Fluidized bed film coating of an interactive powder mixture to produce microencapsulated 2–5 μm particles
Authors: Thiel W J , Sberna F J
Published: April 2011

Previous work has shown an interactive (ordered) powder mixture, formed from 2–5 μm salicylic acid and a coarse spray-dried sugar, is stable when fluidized. The micronized material adheres to the carrier during fluid bed air suspension and may be film coated with a polymer. This process offers a novel method of microencapsulating very fine particulates, providing a way of manufacturing enteric-coated and sustained release microdose drug delivery systems. Different processing conditions were used in an attempt to optimize the retention of micronized model drug beneath the film. The effect of altering the following variables was investigated; polymer spray rate, addition of a third component which adhered to the binary adhesion units, and different materials of construction for the mixer used to form the interactive mixture. The microencapsulated adhesion units retained 90–95% of the micronized model drug. A statistical evaluation of the content uniformity showed that a very uniform dispersion was formed (CV <5%, 99% confidence). Multilayer film-coated adhesion units were also produced using a sequence of mixing and coating operations. This process offers a method of film coating microdose quantities of a drug, to produce a free flowing product, possessing excellent content uniformity.
The kinetics of 4-nitrophenol conjugation by perfused livers and hepatic microsomes from streptozocin-induced diabetic rats
Authors: Morrison M H , Barber H E , Foschi P G , Hawksworth G M
Published: April 2011

The formation of both glucuronide and sulphate conjugates of 4-nitrophenol is deficient in perfused livers from male diabetic rats. Experiments with ‘native’ hepatic microsomes demonstrated that the defect in glucuronidation is due to a decrease in the maximal velocity of the reaction. There is no alteration in the affinity of the glucuronyltransferase for 4-nitrophenol. Non-linear regression analysis of the 4-nitrophenol liver perfusate concentrations snowed that the elimination follows saturable Michaelis-Menten kinetics. Clearance values in ‘native’ microsomal preparations and in perfused livers were calculated and found to be similar in both systems. This provides evidence that glucuronyltransferase is ‘native’ in the intact liver.
Yohimbine affects the evoked overflow of neurotransmitters from rat brain slices by more than one mechanism
Authors: Hagan R M , Hughes I E
Published: April 2011

Both yohimbine (0.1–10 μm) and phentolamine (10 μm) increased the tritium overflow evoked by electrical stimulation (3Hz, 2 ms, 18 mA for 120s every 20 min) of rat brain cortex slices previously incubated with [3H](−)-noradrenaline. At their maximally effective concentrations, neither of these compounds produced an effect which was fully maintained over the 1 h of the experiment, but the decline in effect of yohimbine (1.25 μM) was more marked, falling sharply to reach, after 1 h, 25% of the effect observed after 20 min, whereas phentolamine only declined to 60% of the effect after 20 min. In rat brain cortex slices previously incubated with [3H]5-hydroxytryptamine ([3H]5-HT), the tritium overflow evoked by electrical stimulation (3 Hz, 2 ms, 40 mA for 120 s) was increased by yohimbine (0.1–1 μM) and phentolamine (0.1–10 μM), but a higher concentration of yohimbine (10 μM) decreased evoked overflow below the levels seen in the absence of either drug. It is concluded that, at concentrations effective in inhibiting the presynaptic α-adrenoceptor-mediated mechanisms controlling transmitter release in rat brain slices, a non-a-adrenoceptor-mediated, possible local anaesthetic, action of yohimbine contributes to the overall effect of this drug on transmitter overflow.
Stimulation by noradrenaline of inositol phospholipid breakdown in the rat hippocampus: effect of the ambient potassium concentration
Authors: Fowler Christopher J , O'Carroll Anne-Marie , Court Jennifer A , Candy John M
Published: April 2011

The stimulation by noradrenaline (NA) of inositol phospholipid (PI) breakdown has been studied using rat hippocampal miniprisms. Pretreatment with the monoamine oxidase inhibitor, pargyline, potentiated the stimulation produced by NA. On the other hand, pargyline pretreatment did not affect the stimulation of PI breakdown by the α1-adrenoceptor agonist phenylephrine. NA- and phenylephrine-stimulated PI breakdown were enhanced by increasing the ambient potassium concentration in the assay from 5,88 to 18.2 mM. This enhancement did not, in the case of NA, change either the EC50 value for this agonist (2–3 μM) or the pA2 value for the competitive antagonism of the stimulation by the α1-antagonist prazosin (pA2 value 9.2). Time-courses of the NA-stimulated PI turnover in different brain regions indicated that the rate of stimulation was in the order frontal cortex > hypothalamus ≥ hippocampus ≫ cerebellum.
A sensitive high performance liquid chromatographic assay of a new metabolite of ampicillin in man
Authors: Haginaka Jun , Wakai Junko
Published: April 2011

A sensitive, high-performance liquid chromatographic method has been developed for the determination of piperazine-2,5-dione, a new metabolite of ampicillin, in human urine. Piperazine-2,5-dione was separated from human urine on a C18-column using phosphate buffer-methanol (pH 3.5) as eluent. Subsequently, the effluent underwent a postcolumn reaction with mercurous chloride and was then detected at 305 nm. It was found that piperazine-2,5-dione was also excreted in the urine of a volunteer dosed with ampicillin.
Uridine-induced hyperthermia in the rabbit
Authors: Cradock J C , Vishnuvajjala B R , Chin T F , Hochstein H D , Ackerman S K
Published: April 2011

Uridine injection in 0.6% saline elevated rabbit temperatures (mean = 0.9 °C) in the USP XX pyrogen test. Hyperthermia was delayed in onset and peaking 3–4 h post injection, but the injection was negative in the limulus amoebocyte lysate (LAL) assay. Uridine from five lots of different sources exceeded USP XX limits in the rabbit pyrogen test and proved negative in the LAL assay. Because the dose of uridine was high, several procedures were used to determine if an impurity was the cause of temperature elevation. Uridine remained pyrogenic in spite of ultrafiltration (10 000 nominal mol. wt), recrystallization and preparative scale HPLC. Sterile filtration and autoclaving also did not affect the response. Hyperthermia, therefore, appears to be an inherent property of uridine. Uridine was also found to release endogenous pyrogen in-vitro from human mononuclear cells. Uridine has been reported to induce fever in man, thus the USP rabbit pyrogen test predicted for the clinical response.
The effect of ascorbate on the acetylcholine release from guinea-pig ileal myenteric plexus
Authors: Hayashi Eiichi , Haga Yuko , Shinozuka Kazumasa , Takeda Mitsuhiro
Published: April 2011

The effect of ascorbate on the release of acetylcholine from the longitudinal muscle-myenteric plexus preparation of the guinea-pig isolated ileum has been investigated using a bioassay and an isotopic technique. Ascorbate at 5 mM increased the spontaneous output of acetylcholine and enhanced DMPP-induced output of acetylcholine, while iso-ascorbate, 5 mM, did not. Ascorbate did not influence either the spontaneous or the DMPP-induced release of acetylcholine from synaptosomes of the ileal myenteric plexus. These results suggest that ascorbate promotes acetylcholine release from intramural cholinergic nerves.
The effect of α-(3,5-di-t-butyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), a new anti-inflammatory drug, on leucocyte migration in rat carrageenan pleurisy
Authors: Hidaka Takayoshi , Hosoe Kazunori , Katsumi Ikuo , Yamashita Toshiaki , Watanabe Kiyoshi
Published: April 2011

KME-4, α-(3,5-di-t-butyl-4-hydroxybenzylidene)-γ-butyrolactone was found to reduce the accumulation of leucocytes and exudate volume in the rat carrageenan pleurisy model. When administered orally 1 h before carrageenan, KME-4 (3–10 mg kg−1) induced a degree of inhibition of leucocyte migration almost equal to that of indomethacin (3–10 mg kg−1) in both 5 n and 24 h pleurisies. Furthermore, KME-4, when administered orally 5 h after the carrageenan, inhibited both monocyte numbers and exudate volume in a 24 h pleurisy and was more effective than indomethacin and BW755c which inhibited only monocyte migration. These results suggest that KME-4 has a differential anti-inflammatory activity. Dexamethasone (0.25 mg kg−1) showed strong inhibition of total cell numbers and exudate volume.
Measurement of hardness and strength of tablets and their relation to compaction performance of powders
Authors: Jetzer W E
Published: April 2011

Materials with different deformation properties were compressed into tablets at a range of pressures. The compacts were characterized in terms of indentation hardness which quantifies resistance to deformation and tensile strength quantifying resistance to fracture. A unifying description of these two competing mechanical responses is made using the evaluated single compaction parameters obtained with the equation proposed by Leuenberger. The compaction performance parameter and the bonding index make it possible to characterize the deformation and bonding behaviour of a substance under pressure. Furthermore, useful information is obtained for predicting when capping problems occur. It is evident that more than one index or parameter is necessary to describe the variety and complexity of the tableting properties.
Factors influencing cryoprotective activity and drug leakage from liposomes after freezing
Authors: Higgins J , Hodges N A , Olliff C J , Phillips A J
Published: April 2011

The effects of freezing and thawing conditions and cryoprotective additives on release of streptomycin from lecithin liposomes following freeze-thaw cycles have been investigated. Drug retention was maximized by slow cooling (approx. 1°C min−1). At temperatures between 0° and −20°C, the extent of drug loss was time-dependent indicating incomplete freezing; below −45°C this effect was abolished and the system was stable. Osmotic gradients across the liposome membrane during freezing were found to have little effect on drug loss. Marked cryoprotective activity was shown by dimethylsulphoxide, glycerol, alanine and glycinebetaine at concentrations of 3% w/v or less. At this concentration sucrose and mannitol had little activity.
The effects of peripherally administered monoaminergic drugs on ethanol diuresis in rats
Authors: Pohorecky L A
Published: April 2011

The effect of peripherally administered drugs that modify monoaminergic function, on ethanol (2.0 g kg−1, intragastrically)-induced changes in urine output has been examined in rats. The α-noradrenoceptor agonist, clonidine (0.05–0.15 mg kg−1) produced marked urine output and potentiated slightly the diuretic effect of ethanol. The α-noradrenoceptor antagonist, phentolamine (1–5 mg kg−1) dose-dependently decreased ethanol-induced diuresis. p-Chloroamphetamine (0.8–2.0 mg kg−1) produced significant diuresis and potentiated the diuresis produced by ethanol. Methysergide (1.25, 2.5 mg kg−1), a 5-hydroxytryptamine receptor antagonist, had no effect on urine output while it depressed the ethanol-induced increase in urine output. Apomorphine (0.8, 1.5 mg kg−1), a dopamine receptor agonist, did not modify urine output in either control or ethanol-treated animals, while the dopamine receptor antagonist, pimozide (0.75–3.0 mg kg−1), dose-dependently decreased ethanol-induced diuresis, but had no effect on urine output in control animals. Since our previous research indicates that the intraventricular administration of drugs that alter dopaminergic and 5-HT function does not alter ethanol-induced diuresis, the interaction of these types of agents with ethanol-induced diuresis in the present study suggests that the interaction was mediated peripherally.
Metabolism of cathinone to (−)-norephedrine and (−)-norpseudoephedrine
Authors: Brenneisen R , Geisshüsler S , Schorno X
Published: April 2011

S-(−)-Cathinone (S-(−)-α-aminopropiophenone) is the major active principle of khat leaves (Catha edulis), which are widely used in East Africa and the Arab peninsula as an amphetamine-like stimulant. After oral administration of synthesized cathinone (isomers, racemate), 22–52% was recovered in 24 h urine samples mainly as aminoalcohol metabolites. With GC/MS, HPLC and CD, the main metabolite of S-(−)-cathinone was identified as R/S-(−)-norephedrine and the main metabolite of R-(+)-cathinone as RR-(−)-norpseudoephedrine. Both aminoalcohols are formed by a stereospecific keto reduction.
Amineptine: its effect on the dopaminergic system of rats
Authors: Ponzio F , Achilli G , Garattini S , Perego C , Sacchetti G , Algeri S
Published: April 2011

3-Methoxytyramine formation was enhanced by amineptine (40 mg kg−1 i.p.) in the striatum and limbic area, indicating an increase in the concentration of dopamine in the extraneuronal space. Since dopamine turnover, determined as the rate of L-dopa accumulation, is reduced by the drug at short (10 min) times, the enhanced extraneuronal dopamine concentration seems mainly related to amineptine-induced inhibition of its uptake.
ATP causes postjunctional potentiation of noradrenergic contractions in the portal vein of guinea-pig and rat
Authors: Kennedy Charles , Burnstock Geoffrey
Published: April 2011

Superfusion of the portal vein of rat and guinea-pig with Krebs' solution maintained at 25°C greatly inhibits spontaneous contractions of the preparations and allows contractile responses to ATP and noradrenaline to be measured accurately. Under these conditions, continuous superfusion with ATP (10−5 M), a concentration which had no effect on either basal tension or spontaneous activity, caused a significant shift to the left of the concentration-response curve to exogeneous noradrenaline in both tissues. The mechanism of this potentiation induced by ATP may differ in the two tissues since in the rat portal vein potentiation appeared to be rapidly reversed by superfusing with ATP-free solution, whereas in the guinea-pig portal vein a further concentration-response curve to noradrenaline, in the absence of ATP, was still significantly shifted to the left compared with the control curve. However, potentiation in the rat portal vein may have had a longer duration than is suggested by the results since control concentration-response curves to noradrenaline in this tissue showed a progressive shift to the right which, although not significant, is likely to have affected the apparent time course of potentiation. It is concluded that ATP can potentiate contractions to exogeneous noradrenaline in the portal vein of rat and guinea-pig via an, as yet, unidentified postjunctional mechanism.
Eating caused by neuropeptide-Y injection in the paraventricular hypothalamus: response to (+)-fenfluramine and (+)-amphetamine in rats
Authors: Bendotti C , Garattini S , Samanin R
Published: April 2011

(+)-Fenfluramine and (+)-amphetamine have been compared for their ability to reduce food intake in food-deprived rats or eating caused by injecting neuropeptide-Y in the paraventricular hypothalamus of free feeding rats. (+)-Fenfluramine at doses ranging from 0ṁ625 to 5 mg kg−1 reduced eating caused by neuropeptide-Y more effectively than it did the food intake of food-deprived rats, whereas (+)-amphetamine (dose range 0ṁ625-2ṁ5 mg kg−1) reduced both types of eating to a similar extent. The results confirm that (+)-fenfluramine, although less potent than (+)-amphetamine in reducing eating by food-deprived rats, markedly reduces overeating caused by various endogenous substances or stress in free feeding rats. The physiological significance of the neuropeptide-Y-induced eating and its control by (+)-fenfluramine remains to be elucidated.
Influence of the new antihypertensive drug, SM-2470 (a quinazoline derivative), on cholesterol metabolism in rats
Authors: Seki Kunio , Watanabe Takafumi , Suga Tetsuya
Published: April 2011

The influence of SM-2470. (4-amino-2-{4-[bicyclo(2,2,2)oct-2-ene-5-carbonyl]-1-piperazinyl}-6,7 -dimethoxyquinazoline), a new antihypertensive agent, on cholesterol metabolism was investigated in hypercholesterolaemic rats, using the dual isotope method (cholesterol absorption) and the intestinal ligated loop method (cholesterol uptake). In the hypercholesterolaemic model, 1-30 mg kg−1 doses of SM-2470 significantly inhibited the elevation of the total serum cholesterol and very low and low density lipoproteins (VLDL + LDL)-cholesterol, without causing any change in the hepatic cholesterol level. In a dual isotope model experiment, SM-2470 (10, 30 mg kg−1) inhibited the intestinal absorption of cholesterol, but did not affect biliary excretion of sterol and/or bile acids, nor did it affect cholesterol movement from the liver to blood. In the intestinal ligated loop method, SM-2470 remarkably inhibited the mucosal uptake of cholesterol in a dose-dependent manner in 0dependent manner in5-2dependent manner in0 mg mL−1 of micellar solution. In addition, SM-2470 inhibited micellar formation in-vitro, which increased the distribution of large sized micelles as well as cholesterol absorption inhibitors. From these results, it can be assumed that a possible mechanism behind the hypocholesterolaemic effect of SM-2470 is the inhibition of cholesterol absorption related to the reduction of cholesterol solubilization, occurring in the gut micelles, similar to the action of plant sterol.
Selective agonists and antagonists for 5-hydroxytryptamine receptor subtypes, and interactions with yohimbine and FG 7142 using the elevated plus-maze test in the rat
Authors: Pellow Sharon , Johnston Amanda L , File Sandra E
Published: April 2011

The effects of some 5-HT receptor ligands were investigated on measures of anxiety in an elevated plus-maze test in the rat. Quipazine (2 and 4 mg kg−1), a non-specific 5-HT agonist and ritanserin (0ṁ25-10 mg kg−1), a 5-HT2 receptor antagonist displayed anxiogenic profiles by reducing both of the measures of anxiety used in this test. Two 5-HT1A receptor ligands, buspirone (4 and 8 mg kg−1) and ipsapirone (2.5-10 mg kg−1) and the 5-HT1 agonist, RU 24969 (0ṁ1875-1ṁ5 mg kg−1) significantly reduced only the percentage of time spent on the open arms. (-)-Propranolol (5 and 10 mg kg−1), a 5-HT1 receptor antagonist significantly reduced only the percentage of entries made onto the open arms. Metergoline (4 mg kg−1), a non-specific 5-HT antagonist displayed anxiolytic effects in this test by increasing both measures of anxiety. The 5-HT1A receptor agonist, 8-OH-DPAT (0ṁ0625-0dependent manner in25 mg kg−1) had no effect on either of the measures of anxiety. The results from the non-specific ligands (quipazine and metergoline) are consistent with the theory that a reduction in 5-HT function reduces anxiety. However, in spite of their more selective effects on 5-HT receptors the results in this test from the more specific ligands are not consistent with a strong involvement of any single receptor subtype. The interaction studies with yohimbine and FG 7142 (β-carboline-3-carboxylate methylamide) provided no clear evidence for a major role of 5-HT pathways in the mediation of their anxiogenic effects.
Effects of three new anthracyclines and doxorubicin on the rat isolated heart
Authors: Chen Zheng Min , Colombo Tina , Conforti Laura , Donelli Maria Grazia , Fiedorowicz Roza J , Marchi Stefano , Paolini Angela , Riva Emma , Zuanetti Giulio , Latini Roberto
Published: April 2011

The acute cardiac toxicity of three second-generation anthracycline analogues and doxorubicin was compared in a model of the rat isolated Langendorff perfused heart. The drugs, doxorubicin (DX), 4-epi-doxorubicin (4′EDX), 4-demethoxy-daunorubicin (4DMDR) and 4′-deoxy-doxorubicin (4′dxDX) were infused for 40 min at a concentration of 26 μM into the isolated hearts. All four compounds significantly reduced cardiac work and its first derivative. The time to 50% decrease in work (TW50) was respectively 36, 23, 9 and 7 min for DX, 4′EDX, 4′dxDx and 4DMDR. The three anthracycline derivatives, but not DX, significantly increased coronary resistance. Heart rate was reduced by all compounds compared with baseline, but not compared with controls. Rhythm disturbances were seen with all five hearts perfused with 4DMDR, which stopped beating before 40 min; 2/5 hearts in the 4′EDX group and 1/5 hearts in the 4′dxDX group also stopped before the end of perfusion. All the compounds reached concentrations in the myocardium 8 to 50 times higher than in the perfusing medium. The more cardiotoxic the compound, the higher was its myocardial concentration; a significant correlation was found for all four agents. Noradrenaline was never measurable in the perfusate of control and DX hearts; perfusion with the three anthracycline derivatives caused some release, but the pattern was not clearcut and the maximum concentrations attained in the perfusate were relatively low (< 1ṁ6 times 10−9 M). In conclusion, in the rat isolated perfused heart, the early cardiotoxicity induced by equimolar concentrations of the three anthracycline compounds was greater than that induced by DX and was directly related to drug accumulation in the myocardium. Catecholamines do not seem to have a major role in the development of toxicity in this model.
The effects of the calcium channel agonist, Bay K-8644, on guinea-pig ileum and rat uterine horn
Authors: Conte-Camerino Diana , Lograno Marcello D , de Luca Annamaria , Persichella Michele , Franconi Flavia
Published: April 2011

Bay K-8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate) concentration-dependently caused contractions of the partly depolarized ileum, but at higher concentrations (10−6 to 10−5 M) produced relaxation. 10−8 to 4 times 10−7M nifedipine antagonized while 10−9 and 4 times 10−9 M potentiated Bay K-8644. On the partly depolarized uterus, Bay K-8644 (10−9 to 10−6 M) had only a spasmogenic effect whereas nifedipine (4 times 10−9 to 10−7 M) was spasmolytic. Verapamil and diltiazem (each at 10−4 M) both reduced the maximal response to Bay K-8644, while other spasmolytics were ineffective. Thus, Bay K-8644 activates ileum and uterus by opening voltage-operated Ca2+ channels, but its relaxant action at high concentration and its potentiation by nifedipine is not seen in both organs. Such differences probably depend on the concentration of the compounds used and the polarization state of the cell membranes.
Monolayer studies on poly(isobutylcyanoacrylate)-ampicillin association
Authors: Baszkin A , Couvreur P , Deyme M , Henry-Michelland S , Albrecht G
Published: April 2011

Surface pressure-area isotherms (π-A) of poly(isobutylcyanoacrylate) monolayers with or without glucose and dextran as polymerization adjuvants used in the preparation of nanoparticles have been derived from measurements made at the air-water interface with the subphase pH at 2ṁ7, 5ṁ5 or 8ṁ8. The isotherms were characteristic of the expanded type of polymer monolayer curves, yielding unusually low limiting area values compared with those of other known poly(acrylate) derivatives. This behaviour may be explained by the folding of polar moieties of the polymer groups in the water subphase. Ampicillin incorporated during preparation of nanoparticles had a negligible effect on the general behaviour of adjuvant-free monolayers, but a significant one on the adjuvant-loaded polymer monolayer system which showed an increase in surface area throughout the compression cycle, as compared with the surface area of the adjuvant-free polymer system although the collapse pressure was practically the same at 67 mN m−1.
Comparison of albumin and casein microspheres as a carrier for doxorubicin
Authors: Chen Yan , Willmott N , Anderson J , Florence A T
Published: April 2011

Doxorubicin (Adriamycin)-loaded casein and albumin microspheres, with diameters between 14 and 38 μm (50% weight average) were prepared by glutaraldehyde stabilization of the aqueous phase (containing protein and drug) of a water in oil emulsion. Physical properties, drug loading characteristics and release rates from microspheres in-vitro have been compared and correlated with effects on tumour growth when injected intratumourally in rats. Compared with albumin, the surface charge of the casein system was more negative and the microspheres exhibited a slower release of drug in-vitro. Both observations could be explained by the lower drug content of the casein system. There was evidence for the formation of a doxorubicin complex in the microspheres, the significance of which is not yet known. Casein microspheres containing 11 μg of doxorubicin had a similar inhibitory effect on tumour growth (growth delay = 20ṁ7 days) to 85 μg of drug incorporated into albumin microspheres (growth delay = 18ṁ6 days). The absence of a simple dose-response relationship shows that carrier matrix can influence potency of incorporated drug. The results are consistent with release rate of the drug from microspheres (obversely, rate of drug delivery to the tumour), being a determinant of potency in these systems.
The stereoselectivity of the ‘single drug binding site’ of human α1-acid glycoprotein (orosomucoid)
Authors: Brunner F , Müller W E
Published: April 2011

The stereoselective binding of six pairs of basic, one pair of acidic drug enantiomers, and one pair of diastereomers to human α1-acid glycoprotein was investigated by means of competition experiments against [3H]propranolol- or [14C]nicardipine-labelled binding sites using equilibrium dialysis to separate free from bound marker ligand. The affinity constants (Ka) for association of [3H]propranolol and [14C]nicardipine with α1-AGP were 1ṁ 2 ± 0ṁ6 times 105M−1 and 3ṁ4 ± 1ṁ4 times 105M−1, respectively, and control binding amounted to 57 ± 7 and 91 ± 2%, respectively. The following selectivity factors, calculated as the ratio of the higher over the lower enantiomer concentrations displacing 15% of control radiomarker binding (IC15***-value), were obtained against propranolol and nicardipine: (-)-/(+) propranolol: 1ṁ9 and 1ṁ7.; (+)-/(-)-disopyramide: ***2ṁ8 and 1ṁ4; (+)-/(-)-verapamil: 1ṁ6 and 1ṁ9; (+)-(S)-/(-)-(R)-202-791, a dihydropyridine derivative: 2ṁ6 and 2ṁ0; (-)-/(+)-asocainol: 1ṁ7 and 3ṁ0; (+)-/(-)-tilidine: 1ṁ1 and ã2; (-)-(S)-/(+)-(R)- warfarin: 1ṁ6 and 2ṁ4; (±)-cis/(±)-trans-trans-tilidine: 1ṁ7 and 1ṁ8. When the calculation of radioligand-free fractions is also taken into account, it is apparent that only the tilidine isomers show no selectivity at propranolol-marked, and the disopyramide isomers at nicardipine-marked α1-AGP-binding sites, in all other cases, a weak selectivity is detectable, which is, however, far below the values obtained for most neurotransmitter receptors. It is concluded that the single drug binding site of α1-AGP is only slightly stereoselective and that the stereoselective binding of the drugs investigated is probably of no clinical consequence.
Investigation into the effects in-vitro of the 5-hydroxytryptamine reuptake inhibitor, alaproclate, on carbachol-stimulated inositol phospholipid breakdown in the rat cerebral cortex
Authors: Fowler Christopher J , Thorell Gun , Ögren Sven-Ove
Published: April 2011

The effect of alaproclate in carbachol-stimulated inositol phospholipid (PI) breakdown in rat cerebral cortical miniprisms has been investigated. Carbachol-stimulated PI breakdown was greatly enhanced by increasing the assay potassium concentration from 5ṁ88 to 18ṁ2 mM. Alaproclate, on the other hand, did not influence carbachol-stimulated PI breakdown over the concentration range tested (0-100 μM) at either assay [K+]. The elution pattern of the inositol phosphates from the Dowex-1 columns was also unaffected by alaproclate both in the absence and presence of carbachol. Thus, the potentiation by alaproclate of tremor and salivation induced by the muscarinic agonist oxotremorine in-vivo reported previously is not seen when muscarinic function is measured in-vitro using carbachol-stimulated PI breakdown.
Effect of vanadate on cooling-induced tension changes in K-depolarized smooth muscles from guinea-pigs
Authors: Sunano Satoru , Shimada Tomoko , Kato Satoru , Shimamura Keiichi
Published: April 2011

Sodium vanadate reversed cooling-induced relaxation of K-depolarized taenia coli of guinea-pigs but failed to reverse it in the portal vein and uterus. It potentiated cooling-induced contraction of K-depolarized vas deferens and ureter. These effects were not mediated by the inhibition of Na,K-ATPase, but by the inhibition of the Ca-pump.
Diazepam facilitates reflex bradycardia in conscious rats
Authors: Yang C P , Chou L S , Liu H J , Lin M T
Published: April 2011

The effects of diazepam on cardiovascular function were assessed in conscious rats. Intravenous administration of diazepam (1-30 mg kg−1) produced a dose-dependent decrease in both the mean arterial pressure and the heart rate. Also, reflex bradycardia was produced in rats by intravenous infusion of adrenaline (1ṁ25-2ṁ5 μg kg−1). Intravenous pretreatment of the rats with diazepam, although causing no change in the adrenaline-induced pressor effect, did enhance the adrenaline-induced reflex bradycardia. However, the diazepam enhancement of adrenaline-induced reflex bradycardia was antagonized by pretreatment of rats with an intravenous dose of picrotoxin (an agent blocks chloride channels by binding to sites associated with the benzodiazepine-GABA-chloride channel macromolecular complex). The data indicate that diazepam acts through the benzodiazepine-GABA-chloride channel macromolecular complex within the central nervous system to facilitate reflex bradycardia mediated through baroreceptor reflexes in response to an acute increase in arterial pressure.
The calcium channel antagonist, verapamil, potentiates the inhibitory action of morphine on intestinal and biliary motility
Authors: Shah M H , Dikshit R K , Mansuri S M
Published: April 2011

The effects of morphine and verapamil have been assessed on the gastrointestinal propulsion of charcoal meal and egg yolk-induced gall bladder emptying in mice. Each drug significantly inhibited these functions. In combination, an additive effect was seen on the inhibition of gastrointestinal transit, whilst verapamil potentiated the morphine-induced inhibition of gall bladder emptying. It is concluded that calcium ion channel antagonists may potentiate the activity of opiate drugs.
High capacity for pulmonary first-pass elimination of propranolol in rats
Authors: Iwamoto Kikuo , Watanabe Jun , Aoyama Yoko
Published: April 2011

Plasma propranolol concentrations after i.v. and i.a. 1, 2ṁ5, 5 and 10 mg kg−1 doses of the drug given intravenously or intra-arterially have been compared in 7-week-old male Wistar rats. The areas under the curves after i.a. dosing were almost twice those after i.v. dosing at any dose, despite the elimination half-lives being the same. The difference in total body clearance after i.a. dosing from that after i.v. dosing indicated a significant contribution by pulmonary clearance, which ranged from about 20 to 30 mL min−1 kg−1, to the overall first-pass elimination after the i.v. administration. The pulmonary extraction ratio was approximately 0ṁ4 to 0ṁ5 at the i.v. doses used. Mean pulmonary transit time was estimated to be about 1 to 2 min. There was no dose-dependence in the pulmonary first-pass elimination kinetics of propranolol.
Punch velocities during the compaction process
Authors: Armstrong N Anthony , Palfrey Lynn P
Published: April 2011

Velocities achieved by the upper punch of an eccentric tablet press during compaction have been compared with those predicted by equations describing the movement of the punch in an empty die. Up to the point of maximum punch penetration, actual speeds are invariably less than the predicted speed, the magnitude of the deceleration being determined by the machine speed and applied force. As the punch withdraws from the die, its speed can exceed that predicted on theoretical grounds, due to the elastic expansion of the tablet assisting punch ejection.
Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation
Authors: Villar A , Gascó M A , Alcaraz M J
Published: April 2011

Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and β-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.
Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin
Authors: Barry B W , Bennett S L
Published: April 2011

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in-vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: (1) solvents which enhanced permeation of polar and non-polar compounds e.g. 2-pyrrolidone, N-methylpyrrolidone, N-methylformamide and propylene glycol plus Azone; (2) enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and (3) accelerants which mainly modified the non-polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.
Casting solvent effects on the permeability of polymer films of differing quaternary ammonium (cation) content
Authors: Okor R S , Anderson W
Published: April 2011

Films of certain acrylate-methacrylate copolymers of varying cation (quaternary ammonium) content were cast from three different solvents: acetone, chloroform, and ethanol; their permeability to urea was determined at 30 °C. In films containing 66 mole cation mol−1 polymer chain, and cast from acetone, chloroform or ethanol, the permeation rates were 480, 900 and 2807 mg h−1, respectively. Differences in permeation rates were however less significant when polymers of cation content lower than 46 mole cation mol−1 polymer chain were used to form films. This observation may relate to differences in the degree of dissociation of the polymer in the different solvents.
Fenfluramine antagonizes the stimulation of food intake induced by the putative 5-hydroxytryptamine1A agonist, isapirone, in non-fasted rats
Authors: Wong David T , Reid Leroy R
Published: April 2011

Isapirone, a 5-hydroxytryptamine1A receptor agonist, stimulated food intake in non-fasted rats in a dose-dependent manner (1, 3 and 10 mg kg−1 s.c). Fenfluramine, an antiobesity agent and a 5-HT releaser, at 3 and 10 mg kg−1 s.c. antagonized the isapirone-induced (3 mg kg−1 s.c.) feeding. These results are consistent with the known inhibitory role of 5-HT in the control of food intake in rats.
Direct vasomotor effects of theophylline and enprofylline on human coronary artery in-vitro: comparison with feline coronary and cerebral arteries
Authors: Sjögren Anders , Edvinsson Lars
Published: April 2011

The vasomotor effects of theophylline and enprofylline were investigated on circular segments of human coronary artery taken 6 h after death. Isolated arterial segments were examined using a sensitive myograph and isometric contractions were recorded with Grass transducers. The results were compared with those obtained in feline coronary and cerebral arteries. Theophylline and enprofylline induced pronounced relaxation of all types of precontracted arteries. In feline cerebral arteries the potency for eliciting relaxation was slightly higher for theophylline compared with enprofylline, while there was no difference in potency for the methylxanthines in coronary arteries. Prostaglandin F2α frequently induced rhythmic contractions in human, but not in feline coronary arteries. Theophylline increased the amplitude of the rhythmic contractions while this was not seen following administration of enprofylline. Whether this mode of activity by theophylline contributes to its arrhythmogenic properties in-situ requires clarification.
Mechanically strong films produced from cellulose acetate latexes
Authors: Bindschaedler C , Gurny R , Doelker E
Published: April 2011

Mechanically strong films, comparable with those obtained from organic solutions, can be produced from cellulose acetate latexes, a new type of dispersion, both by casting and spraying. The prerequisite conditions for high strength, which include choice of water-soluble plasticizers possessing some degree of volatility, are discussed.
The inhibition of monoamine oxidase by tricyclic antidepressants: the influence of the nature of the substrate and the source of the enzyme
Authors: Green A L , McGachy H Adrienne
Published: April 2011

Five tricyclic antidepressants, amitriptyline, clomipramine, desipramine, imipramine and iprindole, have comparable potencies as inhibitors of monoamine oxidase in rodent brain and liver. With rodent brain, potency was always greater with phenethylamine as substrate than with benzyl-amine, and was generally least with 5-HT. With mouse liver, in which monoamine oxidase is mainly B type, potency with tyramine and dopamine as substrates was close to that found with phenethylamine. The kinetics of inhibition varied with both the substrate and the tissue, and were inconsistent with a simple ping-pong model for substrate oxidation. The relevance of these observations to clinical effectiveness is discussed.
Pharmacokinetics and biliary excretion of rose bengal in rats with acute and chronic renal failure
Authors: Silberstein D J , Bowmer C J , Yates M S
Published: April 2011

The effects of glycerol-induced acute renal failure (ARF) and surgically induced chronic renal failure (CRF) on the pharmacokinetics and biliary excretion of rose bengal have been examined in the rat. Both the pharmacokinetics and biliary excretion of rose bengal were unaltered in either ARF or CRF. The latter results in CRF contrast with those of Tse et al (1976, Int. J. Nucl. Med. Biol. 3: 134–137) who reported decreased removal of the dye from blood and reduced biliary excretion. In addition, rose bengal behaves differently from bromosulphophthalein and indocyanine green whose hepatic uptake and initial biliary excretion are known to be decreased in ARF. The results suggest that rose bengal may have a hepato-biliary transport route which differs from that of bromosulphophthalein and indocyanine green, and the findings also emphasize the selective nature of altered organic anion uptake by the liver in ARF.
Effect of egg yolk lecithin on transdermal delivery of bunazosin hydrochloride
Authors: Kato Akira , Ishibashi Yasuo , Miyake Yasuo
Published: April 2011

Transdermal delivery of bunazosin HCl and the enhancing effect of egg yolk lecithin were examined using an in-vitro hairless mouse skin preparation and rabbits for in-vivo systemic absorption. The delivery of bunazosin in-vitro was small, but it was significantly enhanced when lecithin was incorporated into the same vehicle. This enhancing effect was confirmed with other drugs in-vitro. The enhancing ability was also seen in-vivo. Very little bunazosin was delivered from a propylene glycol suspension, but levels of 100–200 ng mL−1 were achieved by the incorporation of the lecithin.
Re-evaluation of the metabolism and excretion of diethylpropion in non-sustained and sustained release formulations
Authors: Beckett A H , Stanojčić Milena
Published: April 2011

A direct gas chromatographic method for unstable amino ketones, using a neutral column and moderately alkaline conditions during extraction has been developed. Its application has given a new perspective to the relative importance of the metabolic routes in the complex metabolism of diethylpropion which after oral administration in man is rapid and extensive (only 3–4% of the drug remains unchanged). Mono-N-de-ethylation is the main pathway (about 35% of the dose). N-De-ethylation is more important than carbonyl-reduction, occurring mainly with the unchanged drug (about 20% of the dose). Norephedrine, thought previously to be one of the main metabolites, has been shown to be present only in negligible amounts. About 30% of the dose, which cannot be accounted for as the sum of the amines recovered in urine, is probably metabolized by deamination, followed by oxidation and conjugation to give hippuric acid.
A comparative study of the interaction of warfarin with human α1-acid glycoprotein and human albumin
Authors: Otagiri M , Maruyama T , Imai T , Suenaga A , Imamura Y
Published: April 2011

The interaction of warfarin with human α1-acid glycoprotein (α1-AGP) and human albumin (HA) has been investigated using fluorescence and circular dichroism techniques. The fluorescence of warfarin is greatly enhanced following binding to α1-AGP or HA, the binding constant for a single site being estimated by the Scatchard method. The binding constants for the two serum proteins are similar, but the thermodynamic parameters differ. The binding constants increase as the pH is raised to 9ṁ0. Various basic drugs, such as chlorpromazine, propranolol and imipramine, markedly inhibited the binding of warfarin to α1-AGP. But, some acidic drugs, including phenylbutazone, effectively displaced warfarin bound to HA. The difference in CD spectra observed for α1-AGP and HA indicated that the drug-binding sites of the two proteins might have different asymmetries. It thus appears that the mode of interaction of warfarin with the two proteins differs.
Amiodarone and desethylamiodarone tissue uptake in rats chronically treated with amiodarone is non-linear with the dose
Authors: Latini R , Bizzi A , Cini M , Veneroni E , Marchi S , Riva E
Published: April 2011

Four groups of rats were given amiodarone chronically at 25, 37ṁ5, 50, 75 mg kg−1/12 h for 3 weeks; on day 21 the animals were killed and blood, plasma, heart, lung, liver and fat were collected and assayed for amiodarone and desethylamiodarone. Amiodarone plasma concentrations ranged from 0ṁ74 to 4ṁ68 μg mL−1 and desethylamiodarone from 0ṁ08 to 2ṁ05 μg mL−1. Plasma, blood and tissue concentrations of amiodarone and desethylamiodarone increased significantly with the dose. Blood/plasma and tissue/plasma partition ratios of amiodarone and desethylamiodarone increased significantly at the higher doses. Blood/plasma ratio was a good predictor of tissue/plasma ratios of amiodarone and its metabolite, except in fat. Total phospholipid concentrations in lung were correlated with amiodarone and desethylamiodarone concentrations in plasma, blood and lung.
The relation between effects of adenosine, theophylline and enprofylline on the contractility of sensitized guinea-pig lung strips
Authors: Napier Fiona E , Temple Diana M
Published: April 2011

Contractile responses of lung parenchymal strips from ovalbumin-sensitized guinea-pigs to cumulative addition of antigen were significantly potentiated by 10 min pretreatment with adenosine 10 μM. This potentiation was unaffected by the adenosine uptake inhibitor, dipyridamole, 2 μM. Cumulative addition of adenosine 0ṁ1–100 μM to parenchymal strips without antigen produced variable responses, unrelated to sensitization, some contracting, some relaxing. Theophylline 100 μM caused relaxation of parenchymal strips and significantly inhibited the antigen-induced contraction with a parallel shift of the log concentration-response line. It also inhibited the adenosine-induced potentiation of contraction. Enprofylline 100 μM caused a greater relaxation of the tissue than theophylline. While it inhibited the adenosine-induced potentiation of the response, enprofylline, in contrast to theophylline, failed to inhibit the antigen-induced contraction of guinea-pig parenchyma. At these concentrations, theophylline and enprofylline each inhibited the antigen-induced release of SRSA (leukotrienes C4, D4 and E4), and of histamine, from sensitized guinea-pig lung fragments.