bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocrine dependence of prostatic cancer upon dihydrotestosterone and not upon testosterone
Authors: Petrow V , Padilla G M , Mukherji S , Marts S A
Published: April 2011

Growth of the Dunning R3327−H prostatic adenocarcinoma, implanted in the rat, is inhibited by 6−methylene progesterone. This compound is a potent inhibitor of rat prostatic 5-α-reductase and in-vivo produces marked involution of the prostate. Thus the tumor requires dihydrotestosterone and not testosterone for growth.
SCH 23390 can enhance field stimulation-induced contractions of longitudinal smooth muscle from guinea-pig stomach
Authors: Costall Brenda , Gunning Simon J , Naylor Robert J
Published: April 2011

Field stimulation-induced contractions of guinea-pig stomach longitudinal muscle strips were enhanced by metoclopramide (a D−2 receptor antagonist) and SCH 23390 (a D−1 receptor antagonist) but not by cis-flupenthixol (a D−1 and D−2 receptor antagonist) or sulpiride (a D−2 receptor antagonist). SCH 23390 is the first non-benzamide neuroleptic drug shown to enhance cholinergic mediated contraction responses of gastric smooth muscle, but the response does not appear to reflect a D−1 receptor antagonism.
Drug migration into soft gelatin capsule shells and its effect on in-vitro availability
Authors: Armstrong N A , James K C , Pugh W K L
Published: April 2011

Analysis of the shells and contents of soft gelatin capsules containing acetomenaphthone, ephedrine, 4−hydroxybenzoic acid or phenobarbitone, dissolved in isopropyl myristate, revealed that the percentage of solute taken up by the shells increased with increasing aqueous solubility of the substrate. Thus no acetomenaphthone, which has a negligible aqueous solubility, was found in the shells, in comparison with 92% of the 4-hydroxybenzoic acid, which has a significant solubility in water. Uptake was not influenced by the solubility in isopropyl myristate. The effect of the oily solvent was studied using blends of 1-octanol and isopropyl myristate in which either 4−hydroxybenzoic acid or phenobarbitone were dissolved. Solute release shows that both release and migration can be predicted from a knowledge of the aqueous solubility of the solute and its partition coefficient between water and the non-polar solvent. Samples of capsules containing 4-hydroxybenzoic acid in isopropyl myristate were withdrawn at various stages of the manufacturing process, and the distributions between shell and contents noted. Most of the transfer took place while the capsules were being dried in rotating basket driers, and at this point 67% of the acid had migrated. This increased to 92% during tray drying, and remained so for at least 6 months after manufacture.
GABAB receptor mediated inhibition of field stimulation-induced contractions of rabbit bladder muscle in-vitro
Authors: Santicioli Paolo , Maggi Carlo Alberto , Meli Alberto
Published: April 2011

The effects of GABA and selective GABAA and GABAB receptor agonists and antagonists have been investigated on field stimulation-induced contractions (0·1 Hz) of rabbit urinary bladder strips in-vitro. Atropine inhibits twitches of bladder strips obtained from the bladder dome more effectively than those obtained from the bladder base. Both GABA and the selective GABAB receptor agonist, (±)-baclofen inhibited field stimulation-induced contractions to about the same extent, while the selective GABAA receptor agonist, homotaurine had no effect. In the presence of atropine, GABA failed to inhibit further the amplitude of twitches. The effects of either GABA or (±)-baclofen were antagonized by the GABAB receptor antagonists homotaurine and 5−aminovaleric acid, while the GABAA receptor antagonist picrotoxin had no effect. Neither GABA nor (±)-baclofen had any significant effect on acetylcholine-induced contractions of unstimulated bladder strips, but they were abolished by atropine. These results suggest that GABAB receptors inhibit field stimulation-induced contractions of rabbit bladder muscle by reducing the amount of acetylcholine released per nerve impulse.
No correlation exists between antidepressant activity and the ability of 5−HT uptake inhibitors to interact with 5−HT receptors of the rat stomach fundus strip
Authors: Pawlowski Leszek , Kwiatek Halina
Published: April 2011

Several 5−HT uptake inhibitors, established and potential antidepressant drugs, were tested for their ability to counteract contractions of the rat isolated stomach fundus strip induced by 5−HT and BaCl2. Of 12 inhibitors tested, only doxepine, amitriptyline, clomipramine, imipramine, Ro 11–2465 (cyan-imipramine), citalopram and fluvoxamine antagonized the contraction induced by 10−6 m 5−HT with IC50 values below 10−4 m. Amitriptyline, doxepine and cyproheptadine, at concentrations inhibiting the effect of 5−HT, did not antagonize the strip contractions induced by 3 times 10−3 m BaCl2, while the remaining compounds that antagonized 5−HT-induced contractions, also antagonized–-with at least a similar potency–-the contractions induced by BaCl2. From among antidepressant compounds investigated, only doxepine and amitriptyline may be regarded as antagonists of the 5−HT receptor in the rat stomach strip.
Quantitation of norantipyrine sulphate and norantipyrine glucuronide as major metabolites of antipyrine in man and rat
Authors: Böttcher J , Bässmann H , Schüppel R
Published: April 2011

Two assay procedures are described for the quantitation of norantipyrine sulphate and norantipyrine glucuronide present in biological material. One, a selective acid hydrolytic assay procedure that affords the discriminative determination of both conjugates without prior separation, measures free norantipyrine by tlc-uv. The other is a tlc separation procedure for intact norantipyrine conjugates, which, in conjunction with radiolabelled material, derived from [3−14C]antipyrine, enables the direct quantitation of both conjugates independently. In man, about 25% of dose of antipyrine (1200 mg) was excreted as norantipyrine glucuronide within 48 h. The amount of norantipyrine sulphate was small. In the rat, norantipyrine sulphate represented about 15–20% of the dose of antipyrine (40–50 mg kg−1); no norantipyrine glucuronide was formed. Free norantipyrine has not been detected in urine of either species after antipyrine dosage. Pretreatment with 3-methylcholanthrene in the rat substantially enhanced excretion of norantipyrine sulphate, whereas induction with phenobarbitone was without effect on the microsomal N-demethylation of antipyrine. The lability of free norantipyrine was examined under different conditions and contrasted with the relative stability of norantipyrine conjugates. Two of the main degradation products of norantipyrine were identified as 4-phenylazo-norantipyrine and a 4,4−bipyrazole-derivative.
Liquid chromatographic retention of β-adrenoceptor antagonists: an index of lipid solubility
Authors: Arendt Rainer M , Greenblatt David J
Published: April 2011

The in-vitro lipophilicity of nine β-adrenoceptor antagonists was evaluated based on retention on a reverse-phase C−18 high-pressure liquid chromatographic (hplc) system at physiologic pH. Propranolol was by far the most lipophilic drug, while atenolol and sotolol were the least. Hplc retention was highly correlated (r = 0·92) with octanol: buffer partition coefficient. Thus hplc retention is a rapid and replicable approach to the determination of in-vitro lipophilicity that does not require radioactive drug.
The effect of week-long infusion of propranolol, via an osmotic minipump, on blood pressure, heart rate and vascular responses in spontaneously hypertensive rats
Authors: Sun Ching-Long J , Thompson Teresa J , Hanig Joseph P
Published: April 2011

Propranolol was infused in SHR subcutaneously for 7 days at two concentrations (either 3·75 or 7·5 mg kg−1 day) via a minipump. Mean blood pressure and heart rate measured under pentobarbitone anaesthesia on day 7 after implantation showed a significant dose-dependent decrease in both propranolol-treated groups. In the low-dose propranolol-treated rats, there was no change in contractile responses to phenylephrine over controls. In rats receiving the higher dose of propranolol there was a significant increase in the response to phenylephrine. There was no change in the relaxation response of any of the groups to isoprenaline. The results indicate that propranolol, while lowering blood pressure and heart rate, is also modifying the α-receptor response of the vascular wall in the spontaneously hypertensive rat.
5−Hydroxytryptamine desensitization fails to modify GABA-induced inhibitory responses in the guinea-pig colon
Authors: Onori L , Saltarelli P , Marcoli M , Lecchini S , Frigo G M , Tonini M
Published: April 2011

In segments of guinea-pig colon, treated with 1 μm hyoscine, a 5−HT desensitization procedure that decreased the potency of 5−HT 41−fold in relaxing the longitudinal musculature, failed to modify the non-adrenergic GABA-induced inhibitory responses, suggesting that the action of GABA in this preparation is not 5−HT-mediated. These results are at variance with those obtained in the guinea-pig ileum where 5−HT seems to play a role in GABA-induced cholinergic contractions.
Monoamine oxidase inhibition by the tremorogenic drug–-LON 954
Authors: Mitra C , Ganguly D K , Guha S R
Published: April 2011

N-Carbamovl−2−(2,6−dichlorophenyl)acetamidine HCl (LON 954), a tremorogenic drug, inhibited MAO activity in various tissue preparations in a reversible, competitive manner showing some degree of selectivity towards type-B MAO.
Effects of nomifensine and its metabolites on dihydropteridine reductase
Authors: Shen Rong-sen , Sheng Wen-Lu , Abell Creed W
Published: April 2011

Nomifensine and three of its metabolites were studied as potential inhibitors of dihydropteridine reductase. Purified enzyme preparations from human liver and the P2 fraction of rat striatal synaptosomes were used as enzyme sources. Nomifensine and its 3−hydroxyl derivative inhibit this enzyme from both sources at 1·3 to 3·5 times 10−4 m (150 values). 4−Hydroxylated nomifensines, however, non-competitively inhibited this enzyme with Ki values of 2·8 to 4·4 times 10−5 m. Dihydropteridine reductase regenerates tetrahydrobiopterin, the required cofactor for the hydroxylation of tyrosine and tryptophan, from quinonoid dihydrobiopterin. Inhibition of this enzyme could reduce the availability of the biopterin cofactor for the synthesis of dopamine and 5−hydroxytryptamine.
Nadolol binding to human serum proteins
Authors: Patel L , Johnston A , Turner P
Published: April 2011

Nadolol protein binding was measured in serum from 95 healthy subjects. Binding was found to range between 4 and 27%, with a mean of 14 ± 4% (s.d.). There was a small but significant correlation found between the degree of nadolol binding and the serum α-1−acid glycoprotein concentration. However it was concluded that changes in the serum protein binding of nadolol were unlikely to give rise to any untoward clinical effects.
The pharmacokinetic profile of carbidopa in dogs
Authors: Obach R , Menargues A , Vallès J M
Published: April 2011

A pharmacokinetic study of carbidopa in beagle dogs has been carried out after intravenous (4 mg kg−1) and oral (75 mg) administration. An open model of three compartments was the best approach for the pharmacokinetic profile of carbidopa administered intravenously. The estimated biological t1/2 was 5 h and the plasma clearance 0·0053 (litre kg−1) min−1. The oral absorption of carbidopa was almost complete and the absolute bioavailability (F) was 88%.
Preparation and evaluation of biodegradable polymeric systems for the intra-articular delivery of drugs
Authors: Ratcliffe J H , Hunneyball I M , Smith A , Wilson C G , Davis S S
Published: April 2011

Colloidal suspensions of four biodegradable polymers, polylactic acid (PLA), polybutylcyanoacrylate (PBCA), gelatin (PG) and albumin (PA) were prepared within the size range 1–10 μm. In-vivo biocompatibility tests with synovial tissues were carried out to assess the irritancy of the polymers following intra-articular injection into rabbit knee joints. PLA, PBCA and PG were found to cause joint inflammation whereas PA was well tolerated by the tissues. PA microspheres may provide a means of sustaining the release and reducing the rate of clearance of drugs from the knee joint.
Effects of diflunisal on fever in the rabbit and the rat
Authors: Dascombe M J
Published: April 2011

The antipyretic efficacy of diflunisal was assessed in rats made febrile by yeast and in rabbits made febrile by bacterial endotoxin. Diflunisal was a more potent antipyretic than aspirin in rats, reducing a maximum fever in doses not producing overt toxic effects. In contrast, submaximal fever in rabbits was not reduced by diflunisal. Fatal hyperthermia of rapid onset was observed in rats and rabbits receiving high doses of diflunisal after administration of microbial pyrogen but not in control animals. These data indicate the toxicity of diflunisal may be potentiated by the presence of pyrogens. It is concluded that the apparent antipyretic efficacy of a drug can depend on the species-pyrogen combination used to screen for antipyresis.
Triethylphosphine gold: Cellular uptake and disposition after single and repeated oral doses in rats
Authors: Sharma R P , Smillie J , Laverty R
Published: April 2011

The tissue and subcellular pharmacokinetics of gold following single and repeated oral doses of triethylphospine gold (auranofin) has been studied in rats. After a single dose, the tissue and subcellular gold levels were 5–10 times lower than those reached with injectable gold compounds. In the liver tissues, gold concentrations peaked within 24 h followed by a biphasic clearance, with an initial rapid phase (t1/2 32 h) and a slow terminal phase (t1/2 11 days). Renal gold concentrations continued to increase for 3 to 5 days and then decreased exponentially with a first order t1/2 of about 7 days. Intracellularly, between 60–80% of hepatic and 50–70% of renal gold was present in the cytosol. In rats given repeated doses of auranofin, the hepatic and renal gold concentrations were 3–5 times higher than those measured after a single dose. The proportion of cellular gold present in the cytosol was markedly lower, with 43% in the liver and 30% in kidney tissues. In both the liver and kidney, gold concentrations were dose-dependent, whereas in the gastrointestinal tissues the increases as a function of dose were minimal.
Effect of formulation on the bioavailability of retinol, d-α-tocopherol and riboflavine
Authors: Bateman N E , Uccellini D A
Published: April 2011

Formulation factors influencing vitamin bioavailability have been investigated, with vitamins A, E and B2, formulated in a new liquid vehicle (Aqua-Biosorb) and encapsulated into soft gelatin capsules, being compared with commercial formulations. There was an enhanced vitamin bioavailability from the new vehicle which appeared to be related to the surfactant system employed and the absence of vegetable oil in the formulation.
Covalent binding of antibodies to liposomes using a novel lipid derivative
Authors: Goundalkar Ashok , Ghose Tarun , Mezei Michael
Published: April 2011

N-[3−(2−Pyridyldithio) propionyl] stearylamine (PDP-SA) was synthesized from a reaction between stearylamine and the heterobifunctional reagent N-succinimidyl−3−(2−pyridyldithio) propionate. Use of this PDP-SA to covalently couple antibodies to liposomes was investigated. The binding efficiency was found to be 24–32%. The antibodies bound to liposomes were shown to retain the specific antibody activity. This new procedure of coupling antibodies to lipsosomes could be an efficient means to deliver drugs to selected target organs, especially in cancer chemotherapy.
Is the hypothermic effect of α-methyldopa mediated by opioid peptides?
Authors: Sitsen J M A , Nijkamp F P
Published: April 2011

At an ambient temperature of 21 °C α-methyldopa (25–200 mg kg−1) induces a dose-dependent decrease in body temperature in rats. A relationship between adrenergic and opioid neuronal systems has been reported. Therefore, in this study the hypothesis that α-methyldopa produces hypothermia through release of endogenous opioid peptides has been investigated using the opiate antagonist naltrexone. The hypothermic effect of α-methyldopa is potentiated by naltrexone pointing to antagonism of an hyperthermic acting opioid system. However, at an ambient temperature of 6 °C, pretreatment with naltrexone did not significantly alter the hypothermic effect of α-methyldopa. Although the hypothesis proved not to be correct, it is concluded that depending on ambient temperature opioid peptides are involved in the determination of the ultimate effect of α-methyldopa on body temperature in rats.
Dopamine receptor binding sites in the rat superior colliculus
Authors: Chivers J K , Hall M D , Kelly E , Jenner P , Marsden C D
Published: April 2011

Following intravenous administration of [3H]spiperone or [3H]N,n-propylnorapomorphine (NPA) to rats, radioactivity derived from the ligands accumulated in the striatum and superior colliculus when compared with cerebellar levels. The accumulation of [3H]spiperone in both areas was prevented by intraperitoneal administration of (+)-butaclamol, haloperidol and sulpiride but not by (-)-butaclamol, cinanserin, propranolol or prazosin. The accumulation of [3H]NPA was prevented by administration of (+)-butaclamol, haloperidol and apomorphine but not by (-)-butaclamol. In in-vitro experiments, membrane preparations from the superior colliculus showed a small number of specific binding sites for both [3H]spiperone and [3H]NPA. The dissociation constant (KD) for [3H]NPA was not different from that for striatal preparations but that for [3H]spiperone was 10−fold higher. We conclude that dopamine receptors may be present within the superior colliculus.
Effect of morphine on the tissue cyclic AMP and cyclic GMP content in two strains of mice
Authors: Muraki T , Uzumaki H , Kato R
Published: April 2011

The effect of morphine on the cyclic (c) AMP and cyclic (c) GMP concentrations in several organs, and its reversal by naloxone have been investigated in C57BL and DBA strains of mice. Morphine increased the cAMP contents in lungs and muscle, and the cGMP contents in lungs, intestine, heart, liver and muscle in a naloxone-reversible way in C57BL mice only. This is consistent with our previous observation that morphine increased plasma cyclic nucleotide levels in C57BL mice, whereas such an increase was marginal in the DBA strain. These results show that there is a strain difference in the effect of morphine on tissue cyclic nucleotide contents and the possible origin of the plasma cyclic nucleotides which are increased by morphine.
The action and interaction of β-phenethylamines and imidazolines on prejunctional α2-adrenoceptors of guinea-pig ileum in the presence of the non-competitive antagonist benextramine
Authors: Mottram D R , Thakar Y
Published: April 2011

The effects of benextramine, a selective non-competitive, irreversible antagonist of α-adrenoceptors, against α2-adrenoceptor agonists has been investigated in isolated field-stimualted guinea-pig ileum. Benextramine was equipotent against the imidazoline, clonidine and the thiazoloazepine B-HT920, however, higher concentrations of benextramine were required for an equivalent non-competitive antagonism of the β-phenethylamine, α-methylnoradrenaline. Using benextramine to differentially block the agonist effects of clonidine but not α-methylnoradrenaline it was shown that clonidine can competitively antagonize the effects of α-methylnoradrenaline. From these and previous results on the differential effects of imidazoline-like and β-phenethylamine-like drugs on α2-adrenoceptors, it is proposed that two distinct populations of these receptors exist.
Differential effects of 5-hydroxytryptaminergic antagonists upon apomorphine- and lergotrile-induced hypothermia and stereotyped behaviour in rats
Authors: Wade Rolin L , Quock Raymond M , Malone Marvin H
Published: April 2011

The dopaminergic stimulants apomorphine and lergotrile both evoked hypothermia and stereotyped behaviour in rats. These drug effects were sensitive to antagonism by haloperidol, a dopaminergic receptor blocker. In rats pretreated with 5-hydroxytryptaminergic receptor blockers, cinanserin reduced apomorphine-induced hypothermia but cyproheptadine did not. Both cinanserin and cyproheptadine significantly potentiated lergotrile-induced hypothermia. Similarly, the stereotypic effects of apomorphine were partly reduced by cyproheptadine, although higher doses of cyproheptadine did potentiate lergotrile-induced stereotyped behaviour. These findings of different influences of 5-HT antagonists upon the effects of apomorphine and lergotrile indicate that these two dopaminergic stimulants may not work in identical manner to produce outwardly similar drug effects.
An homogeneous population of β1-adrenoceptors subserves inhibitory responses in guinea-pig ileal preparations
Authors: Mian M Aqleem , Malta Errol , Raper Colin
Published: April 2011

In transmurally stimulated guinea-pig ileal preparations, the pA2 values obtained with the selective β1- and β2-adrenoceptor antagonists atenolol and ICI 118,551 were independent of the β-adrenoceptor agonist used ((-)-isoprenaline or fenoterol) and were similar to values reported in isolated cardiac tissue. On the basis of these results, the relaxant responses to β-adrenoceptor agonists in guinea-pig ileal preparations appear to be mediated by an homogeneous population of β1-adrenoceptors.
Central and peripheral inhibition of gastrointestinal transit in rats: narcotics differ substantially by acting at either or both levels
Authors: Peracchia Francesca , Bianchi Giancarlo , Fiocchi Roberto , Petrillo Paola , Tavani Alessandra , Manara Luciano
Published: April 2011

The roles of local intestinal and centrally mediated opiate-specific mechanisms underlying gastrointestinal transit inhibiton by five typical narcotic analgesics were assessed by the rat charcoal meal test. The doses (mg kg−1 s.c.) reducing the progression of charcoal to 50% of drug-free controls in 5 min (ID50) were approximately 1 for morphine and methadone, 0·5 and 40 for diamorphine and pethidine (all given 25 min before charcoal) and 0·001 for etorphine (10 min before charcoal). The delay in test meal travel caused by these ID50 doses was completely prevented by i.p. naloxone. Intracerebroventricular (i.c.v.) naloxone fully antagonized pethidine and etorphine but had no effect on morphine. Morphine, but either pethidine nor etorphine, was antagonized by i.p. N-methyl naloxone (a peripheral antagonist). Diamorphine and methadone were partially antagonized by i.c.v. naloxone or i.p. N-methyl naloxone.
Human angiotensin I competes with two non-thiol converting enzyme inhibitors (CGS 13934 & MK-422) to inhibit the angiotensin-converting enzyme activity of human plasma
Authors: Chen Dong-Sheng , Nussberger Jürg , Brunner Hans R , Waeber Bernard
Published: April 2011

A simple in-vitro enzyme system has been used to demonstrate that human angiotensin I interacts competitively with the two non-thiol converting enzyme inhibitors CGS 13934 and MK-422 to inhibit the hydrolysis of a synthetic substrate by human plasma ACE.
The effect of therapeutic agents on cartilage degradation in-vivo
Authors: Sedgwick A D , Moore A R , Sin Y M , Al-Duaij A Y , Landon B , Willoughby D A
Published: April 2011

Implantation of minced autologous cartilage into inflamed air pouches in mice allows the study of therapeutic agents on both the inflammatory process and cartilage degradation. Non-steroidal anti-inflammatory agents were found to reduce cell accumulation in response to carrageenan, but were unable to prevent proteoglycan loss from cartilage. In contrast. d-penicillamine had no effect on the inflammatory process but significantly reduced proteoglycan loss. Our findings suggest that the autologous cartilage transplantation model in the mouse may be useful for studying novel anti-arthritic agents.
A possible cytochrome P-450-mediated N-oxidation of diethylcarbamazine
Authors: Joseph C A , Dixon P A F
Published: April 2011

There was a marked sex difference in the N-oxidation of diethylcarbamazine (DEC) in the rat. In 72 h, 41 and 20% of the administered DEC was excreted in urine as the N-oxide in male and female rats respectively. Safrole, metyrapone and ethanol inhibited this N-oxide formation in male rats by 71, 37 and 44% whereas in female rats the values were 20, 25 and 0% respectively. Phenobarbitone and anthracene enhanced N-oxide formation in male rats by 17 and 20% and in female rats by 50 and 90% respectively, but the amount of the N-oxide formed was more in the males. The result suggests a possible involvement of a sub-population of cytochrome P-450 isozyme (which is more in male rats) in the N-oxidation of DEC.
The effect of in-vivo dispersion and gastric emptying on glibenclamide absorption from a novel, rapidly dissolving capsule formulation
Authors: Ganley J A , Mcewen J , Calvert R T , Barker M C J
Published: April 2011

The in-vivo dispersion and gastric emptying of a novel glibenclamide dose form have been investigated using γ-scintigraphy and related to the absorption of glibenclamide determined by measuring glibenclamide plasma concentrations. Its absorption is determined by the rate of emptying of the dose form from the stomach with the lag time between dosing and the start of gastric emptying (and hence absorption of the dose) largely dependent on the in-vivo disintegration time. The presence of food in the stomach has a marked effect on in-vivo disintegration/dispersion of the dose form and hence on the lag time between dosing and the start of absorption.
Anti-inflammatory action of drugs that raise adenosine-3′,5′-cyclic monophosphate and putrescine levels in-vivo
Authors: Hidir S Mohd , Lewis D A
Published: April 2011

Isoprenaline and salbutamol, two β-adrenoceptor agonist drugs, and 3-isobutyl-methyl xanthine and thioacetamide have been shown to be anti-inflammatory. Their mode of action is probably due to an increase in the levels of the three endogenous substances adenosine-3′,5′-cyclic monophosphate and putrescine and spermidine in-vivo.
Effect of central prostaglandins on carrageenan-induced pedal oedema in rats
Authors: Bhattacharya S K , Das Neeta
Published: April 2011

The possible modulatory effect of central prostaglandins (PGs) on carrageenan-induced pedal inflammation, was investigated in rats. Intracerebroventricularly (i.c.v.) administered arachidonic acid, the PG precursor, produced a statistically insignificant increase in the inflammatory response, though PG synthesis inhibitors, administered by the same route, markedly attenuated the oedema. Centrally administered PGE2 had a significant proinflammatory effect, whereas PGF2α exerted an antiinflammatory action. The results indicate that central PGs may modulate peripheral inflammation and that, at least partly, the anti-inflammatory activity of PG synthesis-inhibiting non-steroidal anti-inflammatory agents may involve central PGs, as has been proposed for their analgesic effect.
Scatchard plots with a positive slope: dependence upon ligand concentration
Authors: Clegg L Stephen , Lindup W Edward
Published: April 2011

The inverse dependence of binding constants (nK) upon albumin concentration for 2-(4′-hydroxybenzeneazo) benzoic acid (HABA) has been investigated with bovine and human albumin by equilibrium dialysis. Data obtained by the use of a range of concentrations of either bovine or human albumin, together with a single ligand concentration, gave positive Scatchard plots indicative of binding constants inversely dependent upon protein concentration. The slope of each plot was influenced by the particular ligand concentration used and an increase in the ligand concentration in the case of both bovine and human albumin resulted in a decrease in the slope of the positive Scatchard plot. Higher concentrations of ligand produced a transformation from a positive to a negative plot with both bovine and human albumin.
Evidence for a pharmacokinetic interaction between ibuprofen and meptazinol in the mouse
Authors: Stephens R J
Published: April 2011

Of a variety of non-steroidal anti-inflammatory drugs administered concurrently with meptazinol (p.o.), only ibuprofen potentiated the antinociceptive response (mouse, hot-plate test) to the opioid. In addition, the brain tritium concentration of mice given [3H]meptazinol (p.o. or i.v.) was significantly raised by the oral administration of ibuprofen. It is argued that the interaction between these drugs is pharmacokinetic in nature, due probably to an action of ibuprofen on the biotransformation of meptazinol.
Inhibition of semicarbazide-sensitive amine oxidase by monoamine oxidase B inhibitors from the oxazolidinone series
Authors: Dostert P , Guffroy C , Benedetti M Strolin , Boucher T
Published: April 2011

The purpose of the present work was to study the semicarbazide-sensitive amine oxidase (SSAO) inhibitory properties of MD 240931 and MD 240928 (the two enantiomers of MD 780236) as well as those of the corresponding primary amines, MD220662 and MD220661, in rat heart and aorta. MD 240928 and MD 240931 are rather weak SSAO inhibitors, MD 240931 being more potent than MD 240928. Of the four compounds studied, the most potent inhibitor of SSAO is MD 220662, its IC50 value ranging from 2·10−6 to 6·10−6m. The SSAO inhibitory potency of this compound does not change significantly with the time of preincubation in both the absence and presence of clorgyline (10−4m). MD 220661 is also an inhibitor of SSAO; however, its SSAO inhibitory potency, which without preincubation is comparable to that of MD 220662, does decrease with the time of preincubation to the same extent in both the absence and presence of clorgyline (10−4  m). These results suggest that MD 220661 is not only an inhibitor of SSAO, but is also a substrate of the enzyme.
Assessment of gelling in insulin solutions for infusion pumps
Authors: Hutchison K G
Published: April 2011

Prolonged, gentle agitation of U100 insulin solutions containing various ingredients has shown that gelling can take place. The extent of gelling was evaluated by low shear rheometry and quantified in terms of the effective molecular weight increase using the method of reduced variables. Maximal viscosities of gelled systems in excess of 100 Pas were achieved. From a knowledge of the hydrodynamics of infusion pump systems, the reduction in insulin delivery rate caused by an increase in viscosity can be calculated. In commercial, syringe-driven pumps, pressure differentials as high as 104 Nm−2 and shear rates in excess of 104 s−1 can occur, although the flow is invariably laminar.
The effects of K+-depolarization medium, chelating agents and thiol groups on cadmium uptake and efflux in the guinea-pig taenia coli
Authors: Nasu T , Koshiba H
Published: April 2011

Cadmium uptake by taenia coli was dose-dependent, achieving equilibrium after approximately 60 min of incubation. The SH-blocker, N-ethylmaleimide inhibited cadmium uptake. When muscles were washed with normal medium or that containing 0.5 mM EDTA following 0.5 mM Cd2+ treatment for 60 min, the tissue cadmium concentration reached equilibrium levels after 60 min and approximately 43 or 27% of the initial tissue cadmium concentration was retained, respectively. Both glutathione and dithiothreitol also increased cadmium efflux. However the contractions of glycerinated taenia coli caused by Ca2+ and Mg-ATP, completely returned to control values after washing with 0.5 mM EDTA medium following 0.5 mM Cd2+ treatment for 60 min, suggesting that EDTA seems to exert intracellular effects in glycerinated taenia coli. These results suggest that SH-dependent mechanisms in cadmium uptake play a role in intact taenia coli. In addition, in intact taenia coli, Cd2+ are accumulated in intracellular compartments which EDTA cannot reach and may exert an inhibitory action on internal sites in the cells.
Route- and dose-dependent pharmacokinetics of hexobarbitone in the rat: a re-evaluation of the use of sleeping times in metabolic studies
Authors: Van Der Graaff M , Vermeulen N P E , Breimer D D
Published: April 2011

The metabolic clearance (CL) and half-life of racemic hexobarbitone and sleeping time were studied in rats following intra-arterial (i.a.), intraperitoneal (i.p.) and oral (p.o.) administration, at dose levels of 25 and 100 mg kg−1 of its sodium salt. CLp.o. was higher than CLi.a. at both 25 and 100 mg kg−1. CLi.a. and CLi.p. values were much lower, but CLi.p. was higher than CLi.a. at 25 mg kg−1 and lower than CLi.a. at 100 mg kg−1. There was no distinct dependency of the half-lives on route of administration, but a slight increase upon increasing the dose was observed. Hexobarbitone blood concentrations at which the rats awoke were significantly higher after 100 mg kg−1 i.p. than after 100 mg kg−1 i.a., although there was only a small difference in sleeping time. It is postulated that the rate of uptake of the barbiturates into the portal system after i.p. administration is so high that transient saturation of hepatic first-pass metabolism occurs. Therefore neither CLi.p. nor sleeping times can be used as an accurate reflection of drug-metabolizing enzyme activity in the rat; instead CLp.o. should be used.
Ionization constants and partition coefficients of 1-arylpiperazine derivatives
Authors: Caccia S , Fong M H , Urso R
Published: April 2011

The ionization constant (pKa and liposolubilities (log P) of fourteen 1-arylpiperazines were determined by n-octanol/buffer partition. pKa varied little across the entire series. Log P values ranged from less than 1 to about 2 for the highly lipophilic derivatives of the preset series. The results are discussed in relation to the extent to which these derivatives, known to be centrally active, may enter the brain.
Gastrointestinal transit of an osmotic tablet drug delivery system
Authors: Wilson C G , Hardy J G
Published: April 2011

The gastrointestinal transit of a radiolabelled osmotic tablet drug delivery system has been monitored in groups of young and elderly healthy subjects, using gamma scintigraphy. The gastric emptying and small intestinal transit times were similar for both groups of subjects. The units were observed to move through the gastrointestinal tract at about the same rate as the released contents, arriving at the caecum on average 7 h after dosing. The data suggest that tablet adhesion to the mucosal surface is unlikely to be the mechanism responsible for the side effects reported for the indomethacin formulation Osmosin.
Effect of the absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin
Authors: Sugibayashi Kenji , Hosoya Ken-ichi , Morimoto Yasunori , Higuchi William I
Published: April 2011

The effect of the percutaneous absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin has been investigated by an in-vitro permeation technique using 2-chamber diffusion cells. Azone (3% w/v) emulsions were used. Azone enhanced the permeability of drug 10–100 times across the full-thickness skin although there was a lag time about 10 h. The long lag time, however, disappeared with Azone pretreatment. Azone also affected the transport across stripped skin. These results suggest that Azone mainly affects the stratum corneum. It seems to change the diffusivity of drug in that layer and is not so effective against diffusivities in the epidermis and dermis.
Three different ways in which 5-hydroxytryptamine can affect cholinergic activity in guinea-pig isolated ileum
Authors: Sanger G J
Published: April 2011

The effects of 5-hydroxytryptamine (5-HT) have been studied on electrically-evoked contractions mediated by cholinergic nerves in guinea-pig isolated ileum. Low concentrations of 5-HT (0.0001-0.01 μg ml−1) caused a sustained increase in submaximal, electrically-evoked contractions. Higher concentrations of 5-HT (0.1–10 μg ml−1) initially evoked a fast, rapidly-fading contraction of the muscle. Subsequently, 5-HT 0.1–10 μg ml−1 caused a sustained reduction in the height of the electrically-evoked contractions. The effects of 5-HT 0.01 and 0.1 μg ml−1 on the electrically-evoked contractions were not blocked by methysergide 0.1 μg ml−1 or by hexamethonium 10 μg ml−1, and may be due to changes in neuronal acetylcholine (ACh) release, since contractions evoked by exogenous ACh were unaffected by 5-HT. The results therefore imply that 5-HT can affect gut cholinergic activity in at least three different ways, two of which may modulate evoked ACh release by mechanisms which may be insensitive to tachyphylaxis.
The effect of sodium lauryl sulphate, cetrimide and polysorbate 20 surfactants on complex coacervate volume and droplet size
Authors: Duquemin Sarah Jane , Nixon J R
Published: April 2011

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the complex coacervation of varying concentrations of gelatin and acacia have been described. The overall effect of increasing concentration of SLS was to reduce the weight of coacervate formed. The addition of increasing concentrations of cetrimide produced an increase in the weight of coacervate. The two lowest concentrations of polysorbate 20 produced an increase in coacervate weight while the highest concentration, above the CMC, reduced the coacervate weight. These effects have been explained in terms of shielding of electrostatic attractions between gelatin and acacia polyions by adsorption of ionic and non-ionic surfactant molecules onto the polyions. The addition of surfactants influenced the size distribution of the coacervate droplets that were produced. It is believed that the reduction in interfacial tension by the aggregation of surfactant molecules at the coacervateequilibrium liquid interface permitted the formation of smaller coacervate droplets.
The use of strain gauges for radial stress measurement during tableting
Authors: Huckle P D , Summers M P
Published: April 2011

The influence of size, configuration and positioning of die wall strain gauges on the measurement of radially transmitted stress developed during tableting was investigated. Calibration of strain gauges attached to a cutaway die wall was achieved by compression of rubber-like materials in the die, Breon Polyblend 504 being more effective than red rubber for this purpose. Hysteresis of response observed when calibrating a thin-walled die was possibly due to excessive distortion of the weakened die wall although the extent of this hysteresis varied with calibration material. The use of full bridge arrangements produced an increase in response when the compression site was moved away from the gauges. The opposite effect was seen when half bridge arrangements, using two active gauges, were used. The paradoxical effect observed when full bridge arrangements were used was shown to be due to straining of the compensating gauges. The dependence of die wall response on compact position was substantially reduced by the use of multiple gauges mounted along the die length and connected together to form a single gauge on each side of the die.
Effect of phenobarbitone on the pharmacokinetics and tissue levels of amiodarone in the rat
Authors: Fruncillo Richard J , Bernhard Ronald , Swanson Brian N , Vlasses Peter H , Ferguson Roger K
Published: April 2011

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half-life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have Implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.
Effect of phenobarbitone on the distribution and elimination of imipramine in rats
Authors: Lin Tsu-Han , Sawada Yasufumi , Sugiyama Yuichi , Iga Tatsuji , Hanano Manabu
Published: April 2011

The effect of phenobarbitone on the steady state volume of distribution (Vdss) and the total body blood clearance (CLtot, b) of imipramine and the serum concentration of its metabolite, desipramine was examined. The serum disappearance of imipramine after an 8 mg kg−1 i.v. dose followed a biexponential decline in both control and phenobarbitone-treated rats while the concentration of its metabolite increased in the phenobarbitone-treated rats then rapidly declined compared with that in control rats. Since CLtot, b was nearly equal to the hepatic blood flow (QH), QH may be the rate-determining step of imipramine elimination. In the control rats the Vdss of imipramine was large at 19.9 litre kg-1. In the phenobarbitone-treated rats the pharmacokinetic parameters, biological half-life (t 1/2) and Vdss significantly decreased to approximately 23-40% while CLtot, b increased to 126% of those in the control rats, although the latter difference was not statistically significant. The blood-to-plasma concentration ratios (RB) of imipramine and desipramine decreased in the phenobarbitone-treated rats. The urinary excretion ratios of imipramine and desipramine, to the dose of imipramine over 8 h, were <1.5% in both groups. These ratios were not significantly changed in the phenobarbitone-treated rats. It was concluded that the significant decrease in t 1/2 of the phenobarbitone-treated rats may not be attributed to the changes in CLtot,b and/or in the urinary excretion, but mainly to the decrease in Vdss.
Induction of drug metabolizing enzymes in the liver of rats infested with Fasciola hepatica
Authors: Galtier P , Larrieu G , Lesca P
Published: April 2011

Adult, male rats were infected with 20 metacercariae of Fasciola hepatica given orally, other rats were left untreated. Five weeks after infestation, some animals received phenobarbitone, 3-methylcholanthrene, β-naphthoflavone or Arochlor 1254, to induce liver drug metabolizing enzymes. Fascioliasis provoked decreases in aminopyrine N-demethylase, aniline hydroxylase, the mutagenic activity of cyclophosphamide and cytochrome P-450 concentration in untreated or phenobarbitone or Arochlor pretreated rats. In contrast, cytochrome b5, NADPH cytochrome c reductase, ethyoxycoumarin O-deethylase and the enzymatic activation of ethidium bromide were not affected by fascioliasis whatever pretreatment was given. Fascioliasis decreased liver drug metabolizing enzymes which were specifically induced by both phenobarbitone and Arochlor, this could be due to either the specific action of toxic excretions of flukes or to the particular localization of tissue damage within the liver lobule.
Flumezapine and zotepine: 5-hydroxytryptamine antagonism not involved in the lack of synergism of these antipsychotic drugs with amfonelic acid in rats
Authors: Fuller Ray W , Snoddy Harold D
Published: April 2011

Two antipsychotic drugs, flumezapine and zotepine, resembled clozapine, not spiperone, in not acting synergistically with amfonelic acid to elevate striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in rats. Since flumezapine, zotepine and clozapine antagonize 5-hydroxytryptamine (5-HT) receptors with potency similar to their potency in antagonizing dopamine receptors, the possibility that 5-HT receptor blockade prevented their synergism with amfonelic acid was considered. Methiothepin, a potent 5-HT antagonist and dopamine antagonist, mimicked spiperone in causing a marked increase in striatal DOPAC in amfonelic acid-treated rats, indicating that 5-HT antagonism is not involved in the lack of synergism of flumezapine and zotepine with amfonelic acid.
Absorption of delayed-release prednisolone in ulcerative colitis and Crohn's disease
Authors: Thomas P , Richards D , Richards A , Rogers L , Evans B K , Dew M J , Rhodes J
Published: April 2011

The absorption and urinary excretion of [3 H]prednisolone after oral ingestion was examined using hard gelatin capsules with and without a coating of Eudragit-S which delayed release of the contents. In 6 patients with ulcerative colitis absorption was delayed until the preparation reached the colon but the total absorption was unchanged. In 6 patients with Crohn's disease and ileal strictures the preparation broke proximal to the stricture and absorption was delayed until this occurred (within 4-12 h). In 5 patients with Crohn's disease and intestinal resections the capsules broke unreliably.
Gloss measurement on film coated tablets
Authors: Rowe R C
Published: April 2011

The gloss of film coated tablets has been assessed using a commercially available specular glossmeter modified to measure the specular reflectance of individual flat-faced, film-coated tablets. For all the pigmented film formulations studied, there was a decrease in gloss with increasing pigment concentration, the magnitude of the decrease being dependent on the pigment used. Film coatings prepared using an aqueous coating system had a much lower gloss reading than those prepared using an organic solvent coating system. Increasing the mean particle size of an inert filler particle resulted in a minimum gloss reading at intermediate particle sizes, while increasing the polymer concentration resulted in a significant decrease in gloss. In the latter case a power law equation was found to fit the data relating the percentage decrease in gloss with the percentage increase in roughness. The results are consistent with the known theories of specular reflectance and illustrate the potential of this rapid and simple technique in the optimization of film formulation and process variables during product development.
Models for evaluating the anti-inflammatory effects of inhibitors of arachidonic acid metabolism
Authors: Blackham A , Norris A A , Woods F A M
Published: April 2011

Inhibitors of arachidonic acid metabolism were characterized by their ability to modulate slow reacting substance (SRS) and prostaglandin E2 (PGE2) release from stimulated mouse peritoneal macrophages in-vitro. Differential effects of cyclo-oxygenase (CO) and lipoxygenase (LO) enzyme inhibitors and compounds which inhibit both enzymes were demonstrated using several animal models of inflammation. Carrageenan-impregnated sponges implanted subcutaneously in rats and immune-complexes injected intraperitoneally in mice produced inflammatory responses characterized respectively by polymorphonuclear (PMN) cell infiltration and by increased vascular permeability. Dual CO/LO inhibitors (eg. BW 755c and timegadine) were capable of suppressing both parameters and reduced SRS and PGE2 formation in-vivo. In contrast, selective CO inhibitors (e.g. indomethacin, naproxen and R-830) were less active against permeability, and potentiated SRS release. Although selective CO inhibitors reduced PMN migration, this occurred at doses which exceeded those required for inhibition of PGE2. Compounds possessing LO inhibitory activity suppressed the cellular component of an Arthus type reaction in the rat pleural cavity, but were less active than selective CO inhibitors against carrageenan-induced paw oedema in rats.
The effect of phenothiazine and dibenzazepine pretreatment on the metabolism of methamphetamine in rats
Authors: Mori M , Fujita M , Kozuka H
Published: April 2011

There was marked variation between p-hydroxylation and N-demethylation of methamphetamine in rats. Within 24 h, 10.4,24.7 and 41% of the administered methamphetamine was excreted in urine unchanged, p-hydroxymethamphetamine (p-OH-MP, free plus conjugated) and also as amphetamine, respectively. Treatment by imipramine, desipramine, chlorpromazine, perphenazine and propericiazine 8 h before the administration with methamphetamine completely inhibited the urinary excretion of p-OH-MP whereas the excretion of amphetamine was enhanced by about 700 to 800%. This effect was also observed in rats treated with imipramine 16 and 24 h before methamphetamine. Phenothiazine and dibenzazepine derivatives reverse the degree of p-hydroxylation and N-demethylation of methamphetamine in-vivo in rats.