bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between molecular connectivity and partition coefficients
Authors: BOYD J C , MILLERSHIP J S , WOOLFSON A D
Published: April 2011

Kier & Hall (1976) demonstrated that a relationship existed between molecular connectivity and Log P (the Log of the octanol/water partition coefficient) for several classes of compounds and also for the combined classes. This work utilized a number of Log P values calculated using π values. We have reinvestigated this relationship using experimentally determined Log P values. The results confirm Kier & Hall's findings although different connectivity indices are brought into the equations.
Fluidized bed granulation of an ordered powder mixture
Authors: Thiel W J , Nguyen L T
Published: April 2011

The phenomenon of ordered unit segregation is of paramount importance in determining the homogeneity of an ordered mixture. This problem can be avoided by using a monodisperse carrier, but it is uneconomic. The fluidized bed granulation of a 0.1% ordered mixture has been studied as a method of reducing the effects of segregation. The ordered units were stable when fluidized and no significant loss of the microfine adsorbed material occurred during processing. The distribution of the minor component in the granules was significantly more uniform than in the original ordered mixtures. The demixing potential

(where p = proportion of cohesive minor component and w is the weight % of carrier material in a particular size range) was used to quantify the distribution of the minor component as a function of particle size. DP is a coefficient of variation and can be directly compared with the specification standard deviation σA. Batches of granules were compressed into 100 or 350 mg tablets, containing approximately 100 and 350 μg of model drug substance. The weight and content coefficients of variation (c.v.) were determined for 20 tablets. All batches had a weight c.v. ≤1.5% and a content c.v. ≤4.6%. Granulation of an ordered mixture greatly reduces the potential for segregation to decrease the mixture homogeneity. It also provides a solution to the problems which may be encountered when the mixing of small quantities of cohesive materials during conventional fluidized bed granulation is attempted.
Inhibition of prostaglandin E2 release by salicylates, benzoates and phenols: a quantitative structure-activity study
Authors: Habicht J , Brune K
Published: April 2011

Concentrations inhibiting 50% of the prostaglandin E2 release from phorbol ester-stimulated mouse peritoneal macrophages in-vitro were determined for 59 monosubstituted congeners of salicylic acid, benzoic acid and phenol. Twenty-seven further compounds, mainly benzoic acids, were found to be inactive. An attempt was made to establish a quantitative structure-activity relationship (QSAR) from our experimental data using literature or calculated values for the logarithmic n-octanol/water partition coefficients of the compounds, molar refractivity and sigma values of substituents as well as structural indicator variables. The equations found have moderate predictive power and must be considered as a first step in the investigation of factors determining the biological activity of salicylates, benzoates and phenols.
Elimination from the circulation of cats of 6-keto-prostaglandin E1 compared with prostaglandins E2 and I2
Authors: Förstermann Ulrich , Neufang Brigitte
Published: April 2011

6-keto-PGE1, when injected intravenously (i.v.) or into the aortic arch of cats, produced similar dose-dependent decreases in mean arterial blood pressure. The hypotensive effect of PGI2 was slightly less pronounced compared with that of 6-keto-PGE1, but was equally potent after i.v. and intra-arterial administration. PGE2 had a more potent depressor effect than the two other compounds when injected into the aortic arch, but was much less effective after i.v. injection. Plasma concentrations of 6-keto-PGE1, 6-keto-PGF1α and PGE2 were measured by radioimmunoassay after bolus injections of 6-keto-PGE1, PGI2 and PGE2. The half-life (t 1/2) of the initial rapid decrease in immunoreactivity, indicating the rate of elimination, was found to be 1˙04-2˙19 min for 6-keto-PGE1, 1˙16-2˙01 min for PGI2 and 0˙29-1˙08 min for PGE2. We have confirmed in the cat that 6-keto-PGE1, like PGI2 but unlike PGE2, is not substantially inactivated by the lungs and thus could act as a circulating hormone. However, despite its higher chemical stability, the t 1/2 of 6-keto-PGE1 in the circulation is similar to that of PGI2. PGE2 has a shorter t 1/2, probably due to its extensive pulmonary inactivation. Thus 6-keto-PGE1 seems to be removed from circulation as quickly as PGI2 by organs other than the lung and is unlikely to mediate prolonged effects of PGI2 in the systemic circulation.
The involvement of 5-hydroxytryptamine in the release of dendritic dopamine from slices of rat substantia nigra
Authors: Williams John , Davies John A
Published: April 2011

[3H]dopamine (DA) accumulated by slices of rat substantia nigra was released following superfusion with Krebs solution containing 5-hydroxytryptamine (5-HT) in a dose-dependent fashion with maximal release being produced by 1 × 104  m. This 5-HT-induced release of [3H]DA was calcium-dependent and was inhibited by pretreatment with the 5-HT antagonist cinanserin. These results are interpreted as supporting the possibility that 5-HT has a role in regulating dopaminergic activity in the nigro-striatal pathway.
Models of hepatic drug clearance: discrimination between the ‘well stirred’ and ‘parallel-tube’ models
Authors: Ahmad Anis B , Bennett Peter N , Rowland Malcolm
Published: April 2011

The predictive ability of two models of hepatic drug clearance are compared. The ‘parallel-tube’ model predicts that the steady-state drug concentration following constant rate oral administration increases with increase in hepatic blood flow. The ‘well-stirred’ model predicts that this parameter is not sensitive to changes in hepatic blood flow. Using the steady-state reservoir drug concentration as the discriminatory index, the predictions of the models were tested in a recirculating isolated perfused rat liver system with lignocaine and pethidine, both of which are highly extracted, as test drugs. The steady-state reservoir concentration of both drugs was found to be constant when flow through the liver was increased from 10 ml min−1 to 15 ml min−1. The experimental findings indicate that the ‘well-stirred’ model more accurately describes the elimination of highly cleared drugs with perturbations of flow than does the ‘parallel-tube’ model.
Aminoalkylindoles: atypical dopamine antagonists
Authors: Costall B , Dannenburg W N , Johnson D N , Naylor R J
Published: April 2011

The neuropharmacological profile of a series of aminoalkylindole compounds (AHR-1229-(3-[2-(3-indolyl)-ethyl]-butylamino-1-phenyl-pyrrolidine), AHR1771-(1-[2-(2-methyl-3-indolyl)ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1806-(1-[2-(5-chloro-3-indolyl)-ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1858-(1-[2-(3-indolyl)ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine), AHR1859-(1-[2-(1-methyl-3-indolyl)ethyl]-4-phenyl-1,2,3,6-tetrahydropyridine), AHR1709-(1-[2-(3-indolyl)ethyl]-4-phenyl-1,2,3,6-tetrahydropyridine) was determined in comparison with the classical neuroleptic agents haloperidol and oxypertine, the latter being of similar indole structure. The indole analogues were shown to antagonize amphetamine-induced toxicity in aggregated mice, to indicate a ‘tranquillizing’ action but, in contrast to haloperidol and oxypertine, showed weak or no activity in other classical behavioural tests for neuroleptic action, catalepsy induction and stereotypy antagonism. In further contrast to haloperidol or oxypertine, the indole derivatives failed to displace [3H]spiperone in radioligand binding assays and failed to increase prolactin levels. However, similarly to both typical and atypical neuroleptic agents, the indole derivatives were shown to inhibit the behavioural hyperactivity resulting from the intracerebral administration of dopamine into the mesolimbic nucleus accumbens of rat. The dissociation of an ability to antagonize a dopamine action in the mesolimbic system from classical neuroleptic actions involving other cerebral dopamine systems is the most important finding of the present study.
The effect of dosator nozzle wall texture on capsule filling with the mG2 simulator
Authors: Jolliffe I G , Newton J M
Published: April 2011

The effect on capsule filling, using an mG2 simulator, of the surface texture of the bore of the dosator nozzle has been investigated for size fractions of lactose. Since the angle of powder-wall friction between the powder and the nozzle cannot be readily measured insitu, this was determined using flat plates with similar surface textures fitted into a Jenike shear cell apparatus. The problems of reproducing surface textures on both types of surface are discussed and a lapping process employed as the most suitable method. Angles of wall friction for the nozzle surfaces were extrapolated from the values obtained from flat plates of similar roughness. Capsule filling experiments, using the mG2 simulator, showed the three resurfaced nozzles produced more uniform fill weights with smaller measured compression and ejection stresses than an untreated nozzle surface. One lapped nozzle surface produced a slightly greater improvement than the others. This supports the concept of an optimum angle of wall friction for powder retention (and hence uniformity of fill) with a minimum of applied compression stress.
Tensile strength requirements for sutures
Authors: Lee S , Hailey D M , Lea A R
Published: April 2011

The official requirements for sutures in Australia are those of British Pharmacopoeia (B.P.). The results of a survey conducted by this Laboratory indicate that the B.P. test and specifications for knot pull strength are no longer appropriate for sutures currently available in this country. It is suggested that tensile strength measurements on sutures should be carried out, without prior soaking, using the load cell type of constant rate of extension apparatus rather than the pendulum type tester specified in the B.P. Use of a simple knot is suitable for testing synthetic sutures, but the surgeon’s knot is preferred for catgut. All products tested easily met both the B.P. and the United States Pharmacopeia (U.S.P.) requirements for tensile strength.
Effect of enamine derivatives on the rectal absorption of insulin in dogs and rabbits
Authors: Kim Suni , Kamada Akira , Higuchi Takeru , Nishihata Toshiaki
Published: April 2011

Enamine derivatives resulting from the reaction between ethyl acetoacetate and amino acids were found to promote rectal absorption of insulin in normal rabbits, with the enamine of sodium DL-phenylalanate being the most effective adjuvant tested. Results of glucose tolerance tests in fasted alloxan diabetic rabbits showed that after oral administration of glucose, insulin suppositories containing enamines derived from either sodium phenylalanine or leucine were able to lower the serum glucose level to within the normal range for more than 2.5 h. The absorption-promoting effect of the sodium DL-phenylalanate enamine on rectal absorption of insulin in dogs was studied in two different formulations, gelatin microenema and suppository. The gelatin microenema containing the insulin solution caused a greater increase in the plasma insulin level than that obtained after administration of an insulin suppository.
Influence of prostacyclin and indomethacin on castor oil-induced gastrointestinal effects in rats
Authors: Vischer P , Casals-Stenzel J
Published: April 2011

The effects of castor oil, alone, as well as in combination with PGI2 and indomethacin on gastrointestinal functions have been examined in rats. Oral administration of the oil to fasted rats induced severe diarrhoea, with increased intestinal motility and fluid volume. Pretreatment with PGI2 (s.c.) inhibited the effect of the oil on intestinal fluid accumulation and decreased intestinal motility below control values, but only delayed the occurrence of mucoid diarrhoea. Indomethacin (i.p.) reduced the accumulation in intestinal fluid after castor oil administration to a much smaller extent (47%) than PGI2 and depressed the increased intestinal motility to control values. In contrast to PGI2, indomethacin inhibited the occurrence of diarrhoea after administration of castor oil. The present results do not definitely confirm the general opinion that the diarrhoeal action of laxative agents is due only to an altered intestinal electrolyte and water transport or an increase of intestinal motility.
Absorption of moisture by sodium cromoglycate and mixtures of sodium cromoglycate and lactose
Authors: Chan S Y , Pilpel N
Published: April 2011

The presence of up to about 15% w/w moisture has little effect on the tensile and shear properties of sodium cromoglycate and of 1:1 mixtures of sodium cromoglycate and lactose. Analysis of their adsorption and desorption isotherms using equations developed by Young and Nelson shows that this is because most of the moisture is absorbed into the interior of the sodium cromoglycate leaving little adsorbed moisture on the surfaces of the particles concerned.
Effect of anti-inflammatory drugs on partitioning characteristics of propranolol and oxprenolol
Authors: Parkin John E
Published: April 2011

The influence of a range of nine anti-inflammatory drugs on the octan-1-ol aqueous phosphate buffer pH 7·4 apparent partition coefficients of propranolol and oxprenolol has been examined. All produced a change in the apparent partition coefficient which can be explained in terms of partitioning of hydrophobic ion-pairs formed between the ionic anti-inflammatory compound and the protonated cationic drug.
Inhibition of cholinergic response by taurine in frog isolated skeletal muscle
Authors: Lehmann Anders , Hamberger Anders
Published: April 2011

Carbamylcholine-stimulated contractions of isolated frog gastrocnemius muscle were inhibited in a non-competitive fashion by 5–25 mm taurine. Taurine had no effect on the resting length of the muscle. Caffeine-induced contractures were unaffected by taurine which indicates that the sarcoplasmic reticulum is not an important site of action for taurine. A possible functional role for taurine in skeletal muscle is discussed.
The opioid κ-selective compound U−50,488H does not inhibit intestinal propulsion in rats
Authors: Tavani Alessandra , Gambino Maria Concetta , Petrillo Paola
Published: April 2011

The selective κ-compound U−50,488H, at doses producing strong central pharmacological effects (0·5–32 mg kg−1 i.p.) did not delay the intestinal transit of a charcoal meal and had little or no antagonist action against morphine-induced constipation. It appears that κ-opioid receptors are probably not involved in the mechanisms responsible for opioid-induced constipation.
Neuronal deamination of endogenous and exogenous noradrenaline in the mesenteric artery of the spontaneously hypertensive rat
Authors: Head R J , Cassis L A , Barone S , Stitzel R E , De La Lande I S
Published: April 2011

The noradrenaline (NA) content of the mesenteric arteries from spontaneously-hypertensive rats (SHR) are greater than those in arteries from normotensive Kyoto Wistar rats (WKY). The possibility that impaired neuronal monoamine oxidase (MAO) activity in mesenteric arteries from SHR rats was responsible for the differences in NA content was explored. The in-vitro formation of dihydroxyphenylethylene glycol (DOPEG) by intact segments of mesenteric arteries was used as an index of neuronal MAO activity. There were no differences in the production of DOPEG from endogenous NA by arteries from normotensive and hypertensive rats. Moreover, the formation of DOPEG from exogenous NA was similar in arteries from SHR and WKY rats. The neuronal uptake of NA was indistinguishable between mesenteric arteries from SHR and WKY rats. The results argue against an impairment of neuronal MAO in contributing to the enhanced content of NA in the mesenteric artery of the SHR rat.
Effect of dehydration on the binding capacity of particulate hydrates
Authors: Lerk C F , Zuurman K , Kussendrager K
Published: April 2011

The binding capacities of α-d-glucose dehydrated at temperatures from 60–135 °C increased with increasing temperature of dehydration.
The effects of binder film characteristics on granule and tablet properties
Authors: Reading Susan J , Spring M S
Published: April 2011

The physical properties of cast films of four polymers, which are used as binders in tableting, have been determined. Films were equilibrated at different relative humidities and tested both in tension, at three rates of strain, and by the use of indentation to determine creep compliance and hardness of the film under load. Granules and compacts have also been made using the four polymers as binders and the properties of these have been measured. One of the polymers, starch, formed a paste that was difficult to mix adequately. With the other three polymers a positive correlation was found between compact crushing strength and the creep compliance, the ultimate tensile strength and the elongation at fracture of the cast films. A negative correlation was found between the compact crushing strength and the Brinell Hardness of the films.
Effect of omeprazole and polyethylene glycol−400 on antipyrine elimination by the isolated perfused rat liver
Authors: Webster Lorraine K , Jones D Brian , Mihaly George W , Smallwood Richard A
Published: April 2011

The effect of the substituted benzimidazole, omeprazole, a potent inhibitor of gastric acid secretion, on the hepatic elimination of antipyrine was studied in the rat isolated perfused liver. Bolus dosage (10 mg in 100 ml perfusate) and infusions (1 μg ml−1 perfusate concentrations) of omeprazole in its solvent, polyethylene glycol−400 (PEG−400), reduced antipyrine clearance by approximately one third (P < 0·05). PEG−400 alone caused a 15% decrease in antipyrine clearance (P > 0·10), indicating that the effect seen with omeprazole was at least partly due to the vehicle of dissolution. A significant but mild choleresis was noted in all preparations (P < 0·01) exposed to PEG−400. We conclude that the effect of omeprazole on hepatic drug elimination in patients warrants further study.
‘Superactivation’ of alkaline phosphatase activity by cycloheximide in rat hepatoma cell cultures
Authors: Sorimachi Kenji , Mizuno Hideaki , Yasumura Yosihiro
Published: April 2011

We have found that rat hepatoma cells (R-Y121B) retain alkaline phosphatase activity, and that this enzyme activity is increased by cycloheximide. Actinomycin D also increased the enzyme activity. This increase due to actinomycin D was partially inhibited by cycloheximide. The characteristics of alkaline phosphatase of the cells treated or untreated with cycloheximide or actinomycin D were similar to each other; they were heat labile and the enzyme reaction was strongly inhibited by l−homoarginine, but weakly by l−phenylalanine. The increase in alkaline phosphatase activity with cycloheximide has been termed a ‘superactivation’ of alkaline phosphatase.
Physiological disposition of oral piracetam in Sprague-Dawley rats
Authors: Tacconi Maria T , Wurtman Richard J
Published: April 2011

The distribution and fate of piracetam (2-oxo-1-pyrrolidine acetamide, Nootropil), the prototype ‘nootropic drug’, was examined in rats given 100–1000 mg kg−1 by gavage, with or without [3H]piracetam as a tracer. Peak serum concentrations were attained after 60 min. Its half-life of disappearance from serum was about 2 h during the initial 8 h after administration and then about 6·4 h for the next 16 h. Brain piracetam concentrations equilibrated with those of serum at about 4 h, after which they fell exponentially but remained about twice those of serum; piracetam concentrations in the brainstem were lower (by 30–40%) than those in the cortex, olfactory bulb, and colliculi. No evidence could be obtained for significant piracetam metabolism, either in-vivo or when incubated with liver homogenates. No specific binding of [3H]piracetam to any of various subcellular fractions was observed after its administration along with unlabelled carrier. Repeated daily doses of piracetam (7 days, 100 mg kg−1) failed to elevate serum or brain concentrations beyond those observed after a single dose.
Inhibition by diethylcarbamazine of acetylcholine-induced endothelium-dependent relaxation of rabbit aorta: are leukotrienes involved?
Authors: Förstermann Ulrich , Neufang Brigitte
Published: April 2011

Acetylcholine caused relaxations of preconstricted rabbit aortic strips if the endothelium was intact. These relaxations were reversed in a concentration-dependent manner by diethylcarbamazine, an inhibitor of slow-reacting substance and leukotriene formation. However, when exogenous leukotrienes (LTA4, LTB4, LTC4 and LTD4) were added to the precontracted arterial strips none of them caused relaxation, showing that they are unlikely to be involved as mediators in the acetylcholine-induced relaxation of rabbit aorta.
Correlation between gastric irritancy and anti-inflammatory activity of non-steroidal anti-inflammatory drugs
Authors: Dearden J C , Nicholson R M
Published: April 2011

Gastric irritancies and anti-inflammatory potencies of 25 commercially available non-steroidal anti-inflammatory drugs (NSAIDs) have been measured in the rat. When irritancy is measured as the dose required to produce a specified level of gastric mucosal damage, it is found that irritancy increases with anti-inflammatory potency. However, when irritancy is measured as the level of gastric mucosal damage at the anti-inflammatory ED50 (which is a clinically realistic measure) then irritancy decreases as anti-inflammatory potency increases. Hence it should be possible to design high-potency, low-irritancy NSAIDs.
The effect of protein on the dissolution of phenytoin
Authors: Rosen A , Macheras P
Published: April 2011

Ultrafiltration of a continuous flow system was used to follow the dissolution of phenytoin powder in buffered solutions of pH 1, 4 and 7·4. The presence of either human serum albumin (HSA) or casein caused changes in both the absolute solubility and the dissolution rate. Normal protein binding cannot be responsible for the effects noted. It would seem likely that within the diffusion layer a higher degree of protein binding occurs than is possible in the bulk aqueous solution. The drug solubilized in this way is then released in solution in a form that is at least metastable with respect to phenytoin in normal solution. The effect of protein on phenytoin dissolution may well affect the bioavailability of the drug.
The in-vivo evaluation of an osmotic device (Osmet) using gamma scintigraphy
Authors: Davis S S , Hardy J G , Taylor M J , Stockwell A , Whalley D R , Wilson C G
Published: April 2011

The release of a radiolabelled marker from an orally administered osmotic pump device (Osmet) has been evaluated in-vivo in a group of 6 subjects, using the technique of gamma scintigraphy. The duration of residence of the pump in the stomach was greatly influenced by food intake. However, the release of the marker from the device was independent of food and position within the gastrointestinal tract. Furthermore, the material released from the osmotic pump was well distributed in the gastrointestinal tract. Good agreement between in-vitro and in-vivo release rates was obtained.
Biotransformation of the topical glucocorticoids budesonide and beclomethasone 17α,21-dipropionate in human liver and lung homogenate
Authors: Andersson P , Ryrfeldt Å , Draco AB
Published: April 2011

Tritiated budesonide and beclomethasone 17α,21-dipropionate (BDP) were incubated with the 9000g supernatant of human liver homogenate. BDP was immediately hydrolysed to beclomethasone 17α-propionate (BMP). BMP was then further biotransformed to polar metabolites. Budesonide was rapidly biotransformed (2–4 times more rapidly than BMP) to metabolites of low glucocorticoid potency. The compounds were also incubated with the 1000g supernatant of human lung homogenate. BDP was rapidly hydrolysed to BMP and then more slowly to beclomethasone. Budesonide was not biotransformed in the lung.
Influence of mecamylamine and atropine on tolerance development to nicotine hypothermia in rats
Authors: Horstmann Michael
Published: April 2011

Nicotine hypothermia is known as a central effect of nicotine waning after repeated administration due to the development of tolerance. In the present experiments using female rats, this tolerance was attenuated by the concomitant administration of mecamylamine. Atropine was without effect. It is concluded that tolerance to this effect of nicotine implies its contact with specific sites within the cns.
α-Adrenoceptor blocking action of aaptamine, a novel marine natural product, in vascular smooth muscle
Authors: Ohizumi Yasushi , Kajiwara Akiko , Nakamura Hideshi , Kobayashi Jun’ichi
Published: April 2011

In the rabbit isolated aorta and renal artery, aaptamine (3 times 10−5  m), a novel heteroaromatic substance isolated from a sea sponge Aaptos aaptos produced a parallel, rightward shift of the dose-response curve for noradrenaline, whereas that for histamine or KCl was not affected. But, the derivatives of aaptamine, demethylaaptamine, demethyloxyaaptamine, dihydroaaptamine and dihy-drodemethylaaptamine at concentrations of 10−5 to 10−4  m had no effect on the dose-response curve for noradrenaline. These results suggest that aaptamine is a competitive antagonist of α-adrenoceptors in vascular smooth muscles.
Is vasoactive intestinal peptide an inhibitory transmitter in the circular but not the longitudinal muscle of guinea-pig colon?
Authors: Bennett A , Bloom S R , Ch’ng J , Christofides N D , Peacock L E , Rennie J A
Published: April 2011

Circular muscle strips of guinea-pig isolated colon relaxed with vasoactive intestinal peptide or peptide histidine methionine, whereas the longitudinal muscle contracted. The non-adrenergic-non-cholinergic inhibitory nerves may therefore be different in these two muscle layers.
Pro- and anti-convulsant drug effects in combination with the convulsant benzodiazepine Ro 5–4864
Authors: Pellow Sharon , File Sandra E
Published: April 2011

The effects of several compounds believed to act at the GABA-benzodiazepine receptor complex and which have anticonvulsant or proconvulsant properties when administered in combination with picrotoxin and pentetrazol (leptazol, pentylenetetrazole) were investigated in combination with the convulsant benzodiazepine Ro 5–4864. Tracazolate (25–100 mg kg−1) failed to affect convulsions induced by Ro 5–4864; however, they were prevented by treatment with CL 218, 872 (20 mg kg−1). Compounds having proconvulsant activity in combination with a subthreshold dose of Ro 5–4864 were: CL 218,872 (5 mg kg−1), and CGS 8216 (20 mg kg−1) and FG 7142 (40 mg kg−1), two compounds characterized as ‘inverse agonists’; at benzodiazepine receptors. The phenylquinolines PK 8165 and PK 9084, originally believed to have anxiolytic properties, had no significant effect in combination with Ro 5–4864 (25–100 mg kg−1). The convulsant profile of Ro 5–4864 is compared with that of picrotoxin and pentetrazol.
Muscarinic receptor agonist-antagonist interaction in the rat rectum: are there ways of activating the same receptors?
Authors: Akah P A , Oriowo M A
Published: April 2011

The interaction between the muscarinic receptor agonists, carbachol, acetylcholine (ACh) and methacholine, and antagonists, atropine, gallamine, 4-DAMP and pirenzepine, was studied on the rat isolated rectum preparation. ACh (1.93 times 10−8-1.95 times 10−6M), methacholine (8.7 times 10−8-1.1 times 10−6 M) and carbachol (1.1 times 10−7-3.5 times 10−6 M) induced contractions that were reversibly antagonized by atropine (1.9 times 10−9-4.8 times 10−8 M), 4-DAMP (1.5 times 10−8-2.86 times 10−7 M) gallamine (1.12 times 10−6-1.12 times 10−4 M) and pirenzepine (2.8 times 10−7-7.0 times 10−6 M). The pA2 values were atropine: 8.99 ± 0.28, 9.29 ± 0.14 and 8.86 ± 0.05; 4-DAMP: 8.39 ± 0.10, 8.66 ± 0.15 and 8.26 ± 0.30, gallamine: 5.85 ± 0.23, 5.73 ± 0.25 and 5.96 ± 0.10 and pirenzepine: 6.85 ± 0.44, 7.17 ± 0.13 and 7.21 ± 0.03 against ACh, methacholine and carbachol, respectively. The experimental dose-ratio (atropine + gallamine) was greater than the expected dose-ratio (as predicted by the Paton & Rang rule) for ACh and methacholine while the experimental dose-ratio closely approximates the expected dose-ratio for carbachol. It is suggested that atropine, 4-DAMP pirenzepine and gallamine act on the same receptors but gallamine allosterically altered the binding of the agonists and antagonists to varying extents.
Characterization of α2-adrenoceptor binding properties of imidazoline-like drugs, azoloazepine derivatives and β-phenethylamine-like drugs in human platelet membranes
Authors: Vago Tarcisio , Meroni Rachele , Dagani Regina , Baldi Gabriella , Pagani Marco , Bevilacqua Maurizio , Norbiato Guido
Published: April 2011

To characterize the agonist profile of α2-adrenoceptor agonists (imidazoline-like drugs, azoloazepine derivatives, β-phenethylamines-like drugs) on human platelets, the characteristics of α2-adrenoceptors (KD, Bmax) have been evaluated and the affinity constants measured by displacement technique and computer-assisted analysis of the curves. Furthermore, since α2-adrenoceptor agonists interact with the post-synaptic receptors in a calcium-operated channel, whether the effect of calcium-entry inhibitors (verapamil, nifedipine, diltiazem) is related to a competition with α2-receptors has also been examined. By Scatchard analysis, it was calculated that in human platelets α2-adrenoceptors have KD = 3.45 nM and Bmax = 247 fmol (mg protein)−1. As far as the potency is concerned, imidazoline-like drugs were the most potent agonists in human platelet α2-adrenoceptors (guanabenz IC50 = 8.6 ± 0.8 times 10−8, B-HT 920 IC50 = 2.9 ± 0.3 times 10−7, (-)-adrenaline IC50 = 3.4 ± 0.5 times 10−7). Among the calcium-entry inhibitors only verapamil antagonized [3H]rauwolscine binding: the effect was stereospecific, (-)-D 600 being more potent than (+)-D 600. Nifedipine and diltiazem did not affect α2-receptor binding. It is concluded that human platelets α2-receptors share the agonist potency profile of other tissues containing α2-receptors (brain, pre-synaptic junction), and that among calcium-entry blockers only verapamil can antagonize α2-agonists. Nifedipine and diltiazem do not appear to interact stereospecifically with α2-adrenoceptors.
Influence of the granulation technique and starting material properties on the lubricating effect of granular magnesium stearate
Authors: Johansson Mats E
Published: April 2011

Magnesium stearate has been granulated in four ways to produce lubricant granulations with different properties. The lubricating properties, as well as the tablet properties with the granulated lubricant, were evaluated on tablets prepared from a mixture of dicalcium phosphate, corn starch and microcrystalline cellulose. The lubricating effect of the magnesium stearate granulations showed a similar pattern regardless of the granulation technique used except for a granulation with providone. Increasing the particle size of the magnesium stearate granulation increased the amount of lubricant required to obtain lubrication similar to powdered magnesium stearate. Variations in the specific surface area of the starting materials could be masked by using them in granular form.
The characterization of wet powder masses suitable for extrusion/spheronization
Authors: Harrison P J , Newton J M , Rowe R C
Published: April 2011

The characterization of the flow of wet powder masses has been achieved using a ram extruder. Force/displacement curves obtained when material is forced through dies of varying length were found to exhibit three stages: (1) compression (2) steady state flow and (3) forced flow. To provide high quality extrudate it was found preferable to ensure that the compression stage was as short as possible and that steady state flow predominated. To produce these conditions, an optimum composition, die length and ram speed were required. The implications of these findings in relation to the provision of suitable formulations and production conditions for the preparation of spherical granules are discussed.
Isolation of a new aloe-emodin dianthrone diglucoside from senna and its potentiating effect on the purgative activity of sennoside A in mice
Authors: Nakajima Née Sasakl Kazuko , Yamauchi Kazuko , Kuwano Shigeaki
Published: April 2011

Two aloe-emodin dianthrone diglucosides (I and II) were isolated from the leaves of Cassia angustifolia Vahl by successive column chromatography with Amberlite XAD-2, silica gel, Polyamide C-200 and Sephadex LH-20. The stereostructures of I and II were elucidated as trans and meso isomers at 10-10′, respectively, from the patterns of the ultraviolet absorption spectra and circular dichroism curves. This is the first report of isolation of diglucoside I from senna. Despite the lack of purgative activity, diglucoside I exerts a potentiating effect of about 1. 3 times on the purgative activity of sennoside A in mice when even 15% is included in the mixture. The difference between I and a third active glycoside based on aloe-emodin is also discussed.
Facilitated transport of sodium salicylate across an artificial lipid membrane by Azone
Authors: Hadgraft Jonathan , Walters Kenneth A , Wotton Paul K
Published: April 2011

The ability of Azone (1-dodecylazacylcoheptan-2-one), a recently developed penetration enhancer, to facilitate the transport of sodium salicylate across an artificial lipid membrane has been investigated using the rotating diffusion cell, a well defined model for percutaneous absorption. Azone was found to be capable of enhancing the transport of the salicylate anion across an isopropyl myristate membrane, by using a pH gradient as the chemical driving force. The results indicate that Azone may be capable of forming ion pairs with anionic drugs.
Kinetics of D-α-tocopherol in a water soluble base in man
Authors: Bateman N E , Uccellini D A
Published: April 2011

The kinetics of D-α-tocopherol (vitamin E) were investigated in 10 healthy, adult volunteers following a single dose of 500 iu D-α-tocopherol. Plasma concentration/time curves fitted using a one compartment open model, showed a rise to 12 ± 1.9 μmol litre−1 above endogenous values over 8-9 h and then a tailing away to 7 ± 1.1 μmol litre−1 after 24 h.
The effect of bezafibrate on hyperlipidaemia in experimental nephrotic syndrome in rats
Authors: Williams A J , Baker F E , Walls J
Published: April 2011

The effects of bezafibrate on hyperlipidaemia in experimental nephrotic syndrome in rats has been investigated. The treated group received bezafibrate l0 mg kg−1 p.o. daily. No significant differences in total serum cholesterol occurred, but a significant reduction in serum triglyceride (P < 0.005) and elevation in HDL cholesterol (P < 0.005) occurred. These findings may have implications for therapeutic intervention in severe hyperlipidaemia of the nephrotic syndrome in man.
Further investigation on aldehyde reductase activity in ageing rat tissues
Authors: Danh H Cao , Pasquier-Béchet P , Benedetti M Strolin , Dostert P
Published: April 2011

Aldehyde reductase (AR) activity was measured in whole brain, different brain areas, kidney and duodenum of 23-26 months old rats and then compared to matched animals of 3 months. No significant changes in AR activity were found in whole brain of old rats with D-glucose as substrate. A significant increase in AR activity in old rats was found in striatum (12%), cerebellum (26%), midbrain (6%), brainstem (19%) and hypothalamus (13%) with p-nitrobenzaldehyde, in striatum (14%), midbrain (10%), brainstem (52%), hypothalamus (9%) and hippocampus (20%) with D-glucuronate, in cerebellum (21%) with D-xylose, in striatum (43%), cerebellum (19%) and brainstem (22%) with DL-glyceraldehyde, and in brainstem (15%) with pyridine 3-aldehyde. A significant decrease in AR activity in old rats was found in midbrain (16%), brainstem (19%) and hypothalamus (19%) with D-xylose, and in midbrain (13%) with DL-glyceraldehyde. A significant decrease in AR activity in old rats was found in kidney with p-nitrobenzaldehyde (30%), D-xylose (31%), DL-glyceraldehyde (33%), pyridine 3-aldehyde (27%) and in duodenum with p-nitrobenzaldehyde (21%), but a significant increase was found in duodenum with pyridine 3-aldehyde (29%). Preliminary experiments show an increase (42%) of sorbitol dehydrogenase activity in whole brain of old rats. The present results clearly indicate that the AR activity increase in the brain of old rats is the high-Km form of aldehyde reductase. However, as the activity of the enzyme responsible for the catabolism of sorbitol increases, its accumulation in the brain with age seems to be improbable; this is different from what happens in the eye where enzymatic changes with age appear to favour sorbitol accumulation, which is responsible for cataractogenesis.
Cyclic nucleotides fail to affect mucus glycoconjugate secretion from canine tracheal explants
Authors: Barbieri Edward J , Barsigian Carl
Published: April 2011

Canine tracheal explants, incubated overnight with [3 H]glucosamine, elicited an enhanced secretion of ethanol-precipitated [3 H]labelled glycoconjugate when challenged with methacholine, 10 μM. Neither the β-adrenoceptor agonist isoprenaline, 10 μM, nor the phosphodiesterase inhibitor theophylline, 10 mM, had any significant effect on glycoconjugate secretion. Dibutyryl cyclic AMP, 1 mM, and dibutyryl cyclic GMP, 1 mM, alone or in combination with theophylline, 10 mM, were devoid of activity on unstimulated or methacholine-stimulated tracheal explants. The calcium ionophore A23187, 10 μM, stimulated [3 H]glycoconjugate secretion from each of the tissues tested; however, the cyclic nucleotides failed to modify this response. These data indicate that the cyclic nucleotides play little, if any, role in mucus glycoconjugate secretion by the canine trachea.
Biochemical and ultrastructural study of the effects of proline analogues on collagen synthesis in 3T6 fibroblasts
Authors: Carrington M J , Fornieri C , Bartlet C P , Heale G , Levene C I
Published: April 2011

The effects of two proline analogues, l-3,4-dehydroproline and l-azetidine-2-carboxylic acid, on collagen synthesis by cultured 3T6 fibroblasts have been studied. Prolyl hydroxylase activity was partially inhibited in cells cultured with dehydroproline for 24 h, resulting in the synthesis of collagen in which the proline was underhydroxylated. Azetidine had no effect on prolyl hydroxylase and less effect on the degree of hydroxylation of proline. Fibroblasts grown in the presence of either analogue and fixed in-situ contained greatly distended cisternae of the rough endoplasmic reticulum. Proline analogues otherwise caused few ultrastructural changes in the cells. Treated cells which had been handled more roughly during preparation for electron microscopy contained many large cytoplasmic vacuoles in addition to dilated cisternae. Our results indicate that the major effect of the proline analogues was the inhibition of prolyl hydroxylation. However, electron microscopy of the treated cells revealed hitherto unreported cytoplasmic damage.
A study on the aetiology of reserpine ulceration and the antiulcer action of solcoseryl in rat stomach
Authors: Cho C H , Ogle C W , Dai S
Published: April 2011

The aetiology of reserpine-induced gastric ulcer formation and the antiulcer effects of solcoseryl were studied in rats. Intraperitoneal injection of reserpine produced severe ulceration, as well as mast cell and histamine depletion, in the gastric glandular mucosa. Mepyramine and Cimetidine markedly antagonized the gastric lesions, but did not influence the reduced mast cell count; atropine pretreatment significantly inhibited both parameters. Intramuscular injection of solcoseryl lessened ulcer severity and prevented the decreased mast cell counts and histamine levels in reserpine-treated rats. However, the same dose of solcoseryl injected intraperitoneally was ineffective. Solcoseryl, irrespective of the route of administration, did not influence the gastric secretory activities of reserpine. It is concluded that resperine ulceration is both cholinergic- and histamine-mediated, and that the antiulcer effects of solcoseryl appear to be due to prevention of histamine depletion in the gastric mucosa.
Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone
Authors: Kwon Kwang-Il , Bourne David W A , Ho Paul C
Published: April 2011

The effects of caffeine on the in-vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated. Caffeine failed to decrease in-vitro protein binding of ceftriaxone. Rabbit plasma concentrations of ceftriaxone (30 mg kg−1 i. v.) were elevated significantly (P <005 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg−1 i.v. was co-administered compared with ceftriaxone given alone. Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 ± 38 ml kg−1 (mean ± s.d., n = 6) to 97 ± 33 ml kg−1 (caffeine 5 mg kg−1, P <0.05), and 94 ± 8 ml kg−1 (caffeine 10 mg kg−1, P <0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 ± 106 ml kg−1 (mean ± s.d., n = 6) to 31 ± 18 ml kg−1 (caffeine 5 mg kg−1, P <0.05) and 36 ± 31 ml kg−1 (caffeine 10 mg kg−1, P < 0.1). The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P <0.05) after caffeine. The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.
Lack of effect of BW755c on glucose-induced insulin secretion in the rat in-vivo
Authors: Byford A J , Furman B L
Published: April 2011

Glucose-induced elevations in plasma immunoreactive insulin (IRI) were examined in anaesthetized rats pretreated with BW755c, sodium meclofenamate or vehicle. Neither drug influenced the glucose-induced hyperinsulinaemia or the glucose disappearance rate. The results do not support a physiological role for arachidonic acid metabolites in the regulation of glucose-induced insulin secretion.
The effect of some excipients on the physical properties of a paracetamol tablet formulation
Authors: Esezobo S
Published: April 2011

The effects of the addition of the excipients sorbitol, sodium lauryl sulphate and Aerosil on the physical properties of a paracetamol tablet formulation have been evaluated. Increase in the concentration of sorbitol and sodium lauryl sulphate caused a decrease in the hardness with a corresponding increase in the friability, disintegration and dissolution rates of the tablets.

The mode of incorporation of the excipient, Aerosil, greatly influenced the physical properties of the paracetamol tablets. When added internally, the tablets' strength decreased while the friability, disintegration and dissolution rates increased. However, when Aerosil was added externally, the strength of the tablets increased while their friability, disintegration and dissolution rates decreased.
Vapour and liquid diffusion of model penetrants through human skin; correlation with thermodynamic activity
Authors: Barry B W , Harrison S M , Dugard P H
Published: April 2011

This work investigates vapour and liquid permeation through human skin of model penetrants benzyl alcohol, benzaldehyde, aniline, anisole and 2−phenylethanol applied in model vehicles butanol, butyl acetate, isophorone, isopropyl myristate, propylene carbonate, toluene, n-heptane and water. Vapour permeation was a linear function of thermodynamic activity as measured by headspace gas chromatography, except when the vehicle was n-heptane. Liquid permeation did not always follow simple thermodynamic predictions, e.g. for the penetrant, benzyl alcohol, when the vehicle damaged the skin (toluene, n-heptane) or when propylene carbonate produced low fluxes and isopropyl myristate, high values. At comparable thermodynamic activities, liquid fluxes were often ten-fold higher than vapour fluxes, and these differences were reflected by the partition coefficients and the amount of penetrant entering the stratum corneum membrane. The conclusion was that liquid fluxes were membrane controlled, whereas an interfacial effect probably contributed to low vapour permeation.
Stimulation of PGE2 synthesis and water and electrolyte secretion by senna anthraquinones is inhibited by indomethacin
Authors: Beubler E , Kollar G
Published: April 2011

The effect of dried senna pod extract, containing 10% sennoside B, on colonic electrolyte and fluid transport was examined in the anaesthetized rat in-situ. Oral administration of senna pod extract dose-dependently (17.5−30 mg kg−1, calculated as sennoside B) reversed net absorption of water, sodium and chloride to net secretion and increased potassium secretion. Senna pod extract stimulated the output of prostaglandin E2 into the colonic lumen. Inhibition of prostaglandin biosynthesis by pretreatment of the rats with indomethacin (10 mg kg−1) significantly inhibited the effects of senna pod extract (17.5–30 mg kg−1) both on net fluid transport and on prostaglandin E2 synthesis. The inhibitory effect of indomethacin on net fluid transport induced by senna pod extract (30 mg kg−1) was dose-dependent. It is concluded that anthraquinones exert their laxative action at least partially via stimulation of colonic fluid and electrolyte secretion, and that this secretion is mediated by stimulation of endogenous prostaglandin E2 formation.
Disposition of radiolabelled suppositories in humans
Authors: Jay Michael , Beihn Robert M , Digenis George A , Deland Frank H , Caldwell Larry , Mlodozeniec Arthur R
Published: April 2011

The disposition of Witepsol H 15 suppositories radiolabelled with [99m Tc] technetium hydroxymethyldiphosphonate was studied after rectal administration in volunteers. The migration of the radiolabel was monitored continuously by external scintigraphy. The resulting scintiphotos were superimposed on lower GI radiographs to determine the extent of spreading of the dosage form in the rectum. The dosage form migrated approximately 5−7 cm into the rectum in nearly all of the studies and was, in general, confined to the lower and middle regions of the rectum. Since the venous supply to the lower rectum leads primarily to the inferior vena cava, the data presented here indicate that the metabolism of drugs sensitive to the ‘first-pass’ effect may be partially avoided by their rectal administration.
Age-related changes in the activities of the amine metabolizing enzymes of rat eye
Authors: Cao Danh H , Strolin Benedetti M , Mousset A , Pasquier-Béchet P
Published: April 2011

Age-related changes in the activities of the amine metabolizing enzymes of rat eye

Eye MAO-A, MAO-B, semicarbazide-sensitive amine oxidase (SSAO) and aldehyde reductase (AR) activities were measured in young and old rats. When enzyme activity is expressed as nmol (mg protein)−1 min−1, a significant decrease (18–23%) of SSAO activity in the eye of old rats was found, whereas there was no significant difference in MAO-A and MAO-B activities. A significant increase of AR activity with D-xylose (67%), DL-glyceraldehyde (64%), D-glucuronate (43%) and D-glucose (21%) was found in the eye of old rats. These results suggest that changes in the activities of the amine metabolizing enzymes of rat eye with age might have consequences for their function in senescence; particularly, the increase of AR activity might be involved in cataract formation.