bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting effect of the new chymotrypsin inhibitor FK-448 on the intestinal absorption of insulin in rats and dogs
Authors: Fujii Setsuro , Yokoyama Toru , Ikegaya Koji , Sato Fumiyasu , Yokoo Nobuo
Published: April 2011

FK-448 is a potent and specific inhibitor of chymotrypsin, which enhances the intestinal absorption of insulin in rats and dogs resulting in a decrease in blood glucose levels in these animals. In dogs, the immunoreactive insulin (IRI) level of plasma rose proportionally to the decrease in blood glucose level. From in-vitro data, insulin was inactivated by pancreatic enzymes or the supernatants of intestine or liver homogenates. FK-448 suppressed the digestion of insulin by pancreatic enzymes and its enhancement of the intestinal absorption of insulin was found to be related to its inhibition of digestive enzymes, especially chymotrypsin.
Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on dopamine metabolism in mouse and rat striatum
Authors: Pileblad E , Fornstedt B , Clark D , Carlsson A
Published: April 2011

Monoamines and metabolites in mouse striatum were measured at intervals (0-6 h) after injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 50 mg kg-1 subcutaneously). In addition, the accumulation of 3,4-dihydroxyphenylalanine (dopa), induced by inhibition of the aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazihe (NSD 1015), was assessed during every 15 min (0-135 min) after MPTP administration. The alterations induced by MPTP during the first hour after injection were a transient acceleration followed by a marked retardation of dopa synthesis, a decrease in 3,4-dihydroxyphenylacetic acid (DOPAC; −55%) and an increase in 3-methoxytyramine (3-MT; +400%). Between 60 and 75 min after administration, some dramatic changes took place: a 40% reduction of dopamine (DA), a marked additional increase in 3-MT (to 1300% of control) and an increase in homovanillic acid (HVA; +50%). The period after 75 min was characterized by a further depletion of DA, a decrease in 3-MT and a transient increase in HVA (max. 240% of control). Six hours after the administration, all concentrations of DA and its metabolites were subnormal, i.e. DA (30% of control), 3-MT (10%), DOPAC (10%) and HVA (65%). The MPTP-induced retardation of dopa synthesis was not antagonized by haloperidol or by reserpine pretreatment. MPTP (25 or 50 mg kg−1 s.c.) produced similar acute changes in the levels of DA and its metabolites in rat as in mouse striatum, though much less pronounced. Fourteen days after injection of MPTP (2 times 50 mg kg−1; 16 h interval) in mice, significant reductions in the striatal levels of NA, DA, 3-MT, DOPAC, HVA and 5-HT were observed. In rat striatum, no changes in the levels of monoamines and metabolites were noted 14 days after injection of MPTP (2 times 25 mg kg−1; 16 h interval). The possible mechanisms underlying the rather dramatic acute biochemical changes induced by MPTP as well as their relationship to the neurotoxic effect are discussed.
Assessment of the contribution of α1-acid glycoprotein to the serum binding of basic drugs using serum treated with sulphosalicylic acid and DEAE-cellulose
Authors: Suzuki Yasuyuki , Sugiyama Yuichi , Sawada Yasufumi , Iga Tatsuji , Hanano Manabu
Published: April 2011

Treatment of human serum with DEAE-cellulose in acid conditions almost completely removed α1-acid glycoprotein (α1-AG) with little change in the concentration of albumin and β-lipoprotein, while treatment with sulphosalicylic acid removed almost all the proteins except α1-AG. The binding of various drugs to serum treated as above was measured by equilibrium dialysis and the contribution of α1-AG to drug binding by human serum was assessed. Sulphosalicylic acid-treated serum exhibited a saturable binding for propranolol, which was considered to be due to the binding to α1-AG while DEAE-cellulose-treated serum mostly exhibited non-saturable binding, for which albumin and β-lipoprotein may be responsible. With this treated serum, α1-AG was estimated to contribute approximately 40% to the binding of therapeutic concentrations of propranolol, 15% to that of imipramine and 15-20% to that of desipramine, respectively, in serum samples pooled from healthy adults. However, no contribution of α1-AG was observed in the binding of salicylic acid to the serum. Dissociation constants of the propranolol binding to the high affinity site in control serum, sulphosalicylic acid-treated serum and purified α1-AG showed similar values (3.7-6.7 μM). These results suggest that treatment of serum with sulphosalicylic acid and DEAE cellulose is useful in assessing the contribution of α1-AG to the serum binding of basic drugs.
The pharmacokinetics and dynamics of Oxprenolol: a simulation study with six subjects
Authors: Saunders L , Ingram D , Warrington S J
Published: April 2011

Experimental results of plasma concentration determinations and lowering of exercise heart rate for six subjects taking a conventional tablet and a sustained release preparation of Oxprenolol have been analysed by a comprehensive computer simulation model. Individual plasma values were simulated using a least squares procedure and the results were applied to evaluate individual release patterns following dosage with the sustained release preparation. Application of the model to the lowering of exercise heart rate indicated that the response is in a steady state with the plasma values and that the response-concentration relation is of the saturable, Emax, type. The parameters for this were evaluated for each subject for the results after a dose of a conventional tablet. These parameters were applicable to the results after dosage with a sustained release preparation. The method should be applicable to other sustained release preparations.
Deviating central hypotensive activity of Urapidil in the cat
Authors: van Zwieten P A , Mathy M J , Thoolen M J M C
Published: April 2011

Urapidil, a novel antihypertensive drug, as well as possessing a peripheral α1-adrenoceptor antagonistic effect, also has a significant degree of central hypotensive activity. When injected into the left vertebral artery of ***chloralose-anaesthetized cats the dose-dependent hypotensive effect of the drug was much stronger than after its systemic administration. Prior treatment, also via the vertebral artery, with various receptor antagonists (yohimbine, prazosin, diphenhydramine, metiamide, sulpiride, pirenzepine, R 56413, naloxone) did not antagonize the central hypotensive effect of Urapidil administered subsequently. Accordingly, the central hypotensive action of Urapidil is not mediated by central receptors of the following types: α2- or α1-adrenoceptors; H1- and H2-histamine; dopaminergic; muscarinic; 5-hydroxytryptamine; opiate. As such the mechanism of the central hypotensive action remains unexplained. It obviously deviates from that of classical centrally acting antihypertensive drugs like Clonidine, guanfacine and α-methyldopa, which are agonists of central α2-adrenoceptors.
Effect of dantrolene sodium on [3H]nitrendipine binding to rat cardiac plasma membranes
Authors: Pong S F , Demuth S M , White R L
Published: April 2011

Dantrolene sodium (Dantrium) has antiarrhythmic activity in addition to its direct-acting skeletal muscle relaxant activity. Dantrolene sodium exerts its skeletal muscle relaxant action by reducing Ca2+ release for sarcoplasmic reticulum. The mechanism by which dantrolene sodium produces its antiarrhythmic effects is not well defined. The effects of dantrolene sodium on [3H]nitrendipine binding to rat cardiac plasma membranes were, therefore, investigated to determine whether the antiarrhythmic action involves an interaction with calcium channels. Whereas 1,4-dihydropyridines maximally inhibited [3H]nitrendipine binding with IC50 values less than 1 nM, verapamil and gallopamil (D 600) inhibited the binding not more than 70% with IC50 values at μM concentrations. Dantrolene sodium caused only minimal inhibition at concentrations up to 100 μM. Thus, the antiarrhythmic action of the drug probably involves a mechanism(s) other than an interaction with the nitrendipine binding site of the slow inward calcium channel.
Correlation of thermodynamic activity and vapour diffusion through human skin for the model compound, benzyl alcohol
Authors: Barry B W , Harrison S M , Dugard P H
Published: April 2011

This work tested the potential for predicting percutaneous absorption rates of a volatile penetrant from any vehicle by using thermodynamic activity measurements. Benzyl alcohol was chosen as a non-ideal, hydrogen bonding, volatile model penetrant. A manual headspace gas chromatography method measured benzyl alcohol vapour concentrations and thermodynamic activities above binary mixtures with vehicles: butanol, butyl acetate, isopropyl myristate, isophorone, toluene and propylene carbonate. Benzyl alcohol vapour diffusion through human, abdominal skin was also measured in-vitro for these mixtures. The benzyl alcohol vapour flux was linearly related to the activity, suggesting that percutaneous absorption is controlled by thermodynamic activity when the vehicle has no effect on the stratum corneum barrier.
Morphine inhibits the carrageenan-induced oedema and the chemoluminescence of leucocytes stimulated by zymosan
Authors: Gyires Klñra , Budavñri I , Fürst S , Molnñr I
Published: April 2011

Morphine inhibited the oedema formation induced by carrageenan. The anti-inflammatory activity developed 120 min after carrageenan injection, suggesting that inhibition of the kinin phase might be partly responsible. This assumption is supported by the findings that morphine inhibited bradykinin oedema but did not influence oedema formation induced by histamine, 5-HT or PGE2. The anti-inflammatory activity of morphine was partially inhibited by naloxone (0.5−1 mg kg−1) in the carrageenan oedema test. Zymosanstimulated chemoluminescence of neutrophils of the rat was inhibited both by morphine (0.1-10 μM) and naloxone (1-100 μM). When morphine and naloxone were administered simultaneously (10 μM) their inhibitory effects were additive. Naloxone also failed to antagonize the inhibitory action of morphine in lower dose (0.1 μM). These results suggest that the effect of morphine in inflammation might be mediated either by one of the opiate receptor subtypes insensitive to naloxone or a non-opiate mechanism might be involved.
Repeated treatment with amitriptyline reduces immobility in the behavioural ‘despair’ test in rats by activating dopaminergic and β-adrenergic mechanisms
Authors: Borsini F , Nowakowska E , Pulvirenti L , Samanin R
Published: April 2011

Seven days of treatment with amitriptyline 10 mg kg−1 day−1, reduced the immobility time in the behavioural ‘despair’ test in rats. 0.5, but not 0.25 mg kg−1 haloperidol significantly counteracted the reduction of immobility caused by amitriptyline. Its anti-immobility effect was reduced by 50 and 100 mg kg−1 sulpiride, another blocker of dopamine receptors, and 5 mg kg−1 (±)-propranolol, a β-adrenolytic drug. Prazosin, 3 mg kg−1, an antagonist of post-synaptic α-adrenoceptors, had no effect. It is suggested that dopaminergic and β-adrenoceptors mediate the anti-immobility effect of repeated amitriptyline treatment in rats.
Effects of phenobarbitone and 6-methylprednisolone pretreatment on pressure/flow relations in the superior mesenteric and iliac arterial beds of the rat
Authors: Hiley C R , Nichols A J , Wilson A C
Published: April 2011

The in-situ blood perfused rat superior mesenteric arterial and right iliac arterial preparations were used to investigate the effects of pretreatment for 5 days with either phenobarbitone (80 mg kg−1 daily) or 6−methylprednisolone (17 mg kg−1 daily) on regional vascular resistances. The elevation of the regression of perfusion pressure on perfusion rate in the superior mesenteric arterial bed was significantly decreased by both phenobarbitone and 6−methylprednisolone over the range of flow rates used. Neither phenobarbitone nor 6−methylprednisolone had a significant effect on hepatic portal venous pressure nor was there any significant effect on the regression of perfusion pressure on flow rate in the in-situ iliac arterial bed. It is concluded that pretreatment with either phenobarbitone or 6−methylprednisolone lowers vascular resistance in the superior mesenteric arterial by approximately 9 and 8% respectively but does not affect vascular resistance in the iliac arterial bed.
Pyrimethamine pharmacokinetics and its tissue localization in mice: effect of dose size
Authors: Coleman M D , Mihaly G W , Edwards G , Ward S A , Howells R E , Breckenridge A M
Published: April 2011

The plasma pharmacokinetics and mass fate of [14 C]pyrimethamine were investigated in the mouse, following dosage with 12.5, 25, 50, and 75 mg kg−1 (i.p.). Peak plasma concentrations of pyrimethamine were reached between 1 and 2 h and then declined monoexponentially. The mean values for AUC 0 → 30 h increased linearly in relation to the administered dose of pyrimethamine (r = 0.979, P < 0.001). The mean values for intraperitoneal clearance and half-life were not significantly different between dose groups, indicating that the plasma pharmacokinetics of pyrimethamine were independent of dose. The percentage of the administered dose excreted in urine as pyrimethamine (1.3−3.5%) and 14 C-radioactivity (21.7−29.1%) did not change with increasing dose. In contrast, the cumulative percentage of the dose excreted as 14 C-radioactivity in faeces (16.7−22.8%) after the three highest doses 25, 50 and 75 mg kg−1 was significantly less than that seen with the lowest dose of 12.5 mg (50.3%). This suggests extensive biliary excretion of radioactivity, and that the capacity of this process may have been exceeded with the highest doses. Seven days after the administration of each of the three highest doses, a significantly greater percentage of [14 C]pyrimethamine was localized in the soft tissues; i.e. heart, lung and kidney (7.8−13.8%), gut (5.4−9.4%) and particularly the liver (25.0−27.9%) when compared with the lowest dose of the drug (1.2, 1.0, 0.3% respectively). Following each dose, between 85 and 97% of the administered radioactivity was accounted for. These studies indicate, that with higher doses of pyrimethamine, the parent drug and/or metabolites may accumulate in soft tissue, particularly the liver, but without appreciable effects on the plasma disposition and urinary excretion of the drug.
Prostanoids and adrenaline release: a study of [3 H]adrenaline efflux from the rabbit isolated, perfused, adrenal gland
Authors: Collett A R , Dusting G J , Story D F , Purchase M
Published: April 2011

[3 H]Adrenaline was incorporated in an isolated perfused preparation of the rabbit adrenal gland and the effects of indomethacin, PGE2 and PGI2 on its release were investigated. Efflux of [3 H]adrenaline was elicited by electrical stimulation of the splanchnic nerve (60 s at 5 Hz). Indomethacin (3 and 30 μM) had no effect on stimulation-induced efflux. PGE2 (30, 90 and 300 nM) reduced the efflux; with 90 nM PGE2 the inhibition amounted to approximately 30%. PGI2, in concentrations from 90 to 600 nM, was without effect. These findings indicate that release of [3 H]adrenaline from the rabbit adrenal gland is not subject to modulation by endogenous adrenal prostaglandins; however, PGE2 may play a role in some pathological situations.
Effect of valproic acid on 5−hydroxytryptamine turnover in mouse brain
Authors: Whitton Peter S , Oreŝković Darko , Jernej Branko , Bulat Marin
Published: April 2011

The effect of the antiepileptic drug valproic acid (di-n-propylacetic acid, 200 mgkg−1) on brain 5−hydroxytryptamine (5−HT) synthesis during monoamine oxidase inhibition by pargyline hydrochloride (120 mg kg −1) was studied in mice. Valproic acid increased 5−HT synthesis and elevated 5−hydroxyindoleacetic acid level in brain indicating that turnover of 5−HT is increased. The possible significance of this effect in relation to anticonvulsant action of valproic acid is discussed.
Pharmacological characterization of postsynaptic α-adrenoceptor subtypes in five different dog arteries in-vitro
Authors: Polónia J J , Paiva M Q , Guimarāes S
Published: April 2011

The responses of helically cut strips of arteries isolated from five different sites in the body of dogs to relatively selective α1- and α2-adrenoceptor agonists and the antagonism exerted on these responses by relatively selective α1  - and α2-adrenoceptor blockers have been studied. On all arteries (renal, splenic, cranial mesenteric, jejunal and femoral) phenylephrine was a full agonist whereas UK−14, 304 was a partial agonist causing maximal contractions of 49, 30, 27, 27 and 10% of the maximum, respectively. Phenylephrine was more potent than UK−14, 304, being 9 times more potent in the renal artery and up to 42 times more potent in the cranial mesenteric artery. In the dog saphenous vein, where there are both α1- and α2-adrenoceptors, it has been previously shown that UK−14, 304 is 530 times more potent than phenylephrine. Prazosin in low concentrations displaced concentration-response curves for both phenylephrine and UK−14, 304 (pA2 values of 8.16−8.43 and 8.13−8.79, respectively) whereas yohimbine was much less potent (pA2 values of 6.53−6.88 and 6.50−7.20, respectively). The results suggest that the α-adrenoceptors of all arteries studied are predominantly, if not exclusively, of the α1-subtype.
The effect of non-ionic surfactant vesicle (niosome) entrapment on the absorption and distribution of methotrexate in mice
Authors: Azmin M N , Florence A T , Handjani-Vila R M , Stuart J F B , Vanlerberghe G , Whittaker J S
Published: April 2011

Non-ionic surfactant vesicles (niosomes) prepared from a non-ionic surfactant, cholesterol and dicetyl phosphate and containing methotrexate (MTX) have been administered to mice. Given intravenously the niosomes prolong the levels of MTX in the blood, large amounts of the drug being taken up by the liver. There was also an increased uptake of MTX into the brain, perhaps due to an effect of the niosome components on the permeability of the blood brain barrier. Absorption of the drug from the gastrointestinal tract following oral ingestion, appeared to be increased at some doses; most of the entrapped MTX was taken up by the liver, but uptake of MTX into the brain was also increased. The metabolic profile of the drug is altered by the niosomes which appear to prevent the rapid formation of 7-hydroxy methotrexate.
A new method for studying cell growth in suspension, and its use to show that indomethacin enhances cell killing by methotrexate
Authors: Gaffen John D , Bennett Alan , Barer Michael R
Published: April 2011

Microturbidimetry has been used to measure the growth of cells in suspension. Disaggregated mouse NC carcinoma cells in culture medium were added to the wells of a microtitre test plate and incubated. Absorbance of 600 nm light was measured daily for 4 days using a microplate reader. As the cells grew, light absorbance increased. Methotrexate 2–40 ng ml−1 reduced cell growth; this effect was increased by indomethacin 1 μg ml−1, possibly by displacing methotrexate from its binding by serum protein or by enhancing cell uptake of methotrexate. Similar results were obtained by conventional clonogenic assays. The new technique offers simplicity, better reproducibility, and substantial savings in time and cost.
Pergolide elevation of MHPG sulphate concentration in rat hypothalamus blocked by spiperone and mimicked by other dopamine agonists
Authors: Fuller Ray W , Hemrick-Luecke Susan K , Perry Kenneth W , Toomey Richard E
Published: April 2011

Pergolide increased the concentration of MHPG sulphate (3-methoxy-4-hydroxy-phenylethylene glycol sulphate) in rat hypothalamus, and the increase was prevented by pretreatment with spiperone, a dopamine antagonist. An increase in hypothalamic MHPG sulphate concentration similar to that caused by pergolide was found after injection of quinpirole, a ‘partial ergoline’ that is a selective D2 agonist not affecting α-adrenoceptors, and by (-)- N-propylnorapomorphine, a dopamine agonist not related to the ergolines. Although the increase in MHPG sulphate concentration produced by pergolide had earlier been assumed to result from blockage of α-adrenoceptors, the present data indicate that it is an effect produced by dopamine D2 receptor stimulation.
Ethanol diuresis in rats: Possible modifying factors
Authors: Pohorecky L A
Published: April 2011

Ethanol has been shown to produce a biphasic dose-dependent effect on urine output in rats. Experiments were carried out to examine factors which may influence ethanol diuresis. Immobilization stress (30 min) decreased and ethanol (2.5 g kg−1) increased urine output of intragastrically hydrated rats. In stressed rats, ethanol had a more pronounced diuretic effect compared with home cage control rats. This increased sensitivity to ethanol disappeared when rats were immobilized daily for four days, indicating development of tolerance. The diuretic action of ethanol was not influenced by adrenalectomy.
Effect of prostaglandin F2α on brain and stomach 5 -hydroxytryptamine
Authors: Sanyal A K , Chakrabarti A , Goel R K
Published: April 2011

PGF2α initially inhibits the rate of 5-HT synthesis in both rat brain and stomach and subsequently stimulates it. The results suggest that PGs of E and F series modulate tryptaminergic neuronal activity which in its turn variously affects 5-HT mediated responses.
Optimization of bioavailability of topical steroids: non-occluded penetration enhancers under thermodynamic control
Authors: Bennett Susan L , Barry Brian W , Woodford Roger
Published: April 2011

The non-occluded vasoconstrictor test under thermodynamic control assessed the effect of penetration enhancers on the topical bioavailability of a model steroid betamethasone 17-benzoate, using aqueous dimethylisosorbide (DMI) as a standard solvent. The aqueous potential penetration enhancers used were at 10% steroid saturation i.e. ideally at identical steroid thermodynamic activity. In the vasoconstrictor test, 2-pyrrolidone, N-methyl-2-pyrrolidone, propylene glycol with oleic acid, propylene glycol with azone and dimethylformamide (DMF) increased the steroid bioavailability compared with that from DMI, while propylene glycol alone produced borderline improvement. Azone and oleic acid in combination with DMI or Betnovate cream did not increase the steroid bioavailability indicating the importance of the correct cosolvent. The pyrrolidones established superior stratum corneum reservoirs compared with DMI, the other vehicles being similar to DMI. It was concluded that excepting DMI, the solvents tested were penetration enhancers for the model steroid betamethasone 17-benzoate and are worthy of further study. However, irritant effects may make some of them unacceptable for clinical use.
Properties of rat striatal D-2 dopamine receptors solubilized with the zwitterionic detergent CHAPS
Authors: Kilpatrick G J , Jenner P , Marsden C D
Published: April 2011

The specific binding of [3 H]spiperone was determined in membrane preparations of rat striatum and following solubilization treatment with the zwitterionic detergent CHAPS. Membrane protein solubilization was confirmed by ultrafiltration, gel filtration and increased heat sensitivity. Specific binding of [3 H]spiperone to the solubilized preparation was saturable and of high affinity, although solubilization led to an approximate 10 fold decrease in receptor affinity for [3 H]spiperone. The drug displacement profile of binding to the CHAPS solubilized preparation corresponded to that of the dopamine D-2 receptor; binding was stereoselectively displaced by the isomers of butaclamol. The sodium dependence of sulpiride displacement of specific [3 H]spiperone binding was retained in the CHAPS solubilized preparation. GTP (100 μM) only altered the ability of dopamine to displace [3 H]spiperone binding to the solubilized preparation in the presence of 120 mM sodium chloride. The GTP effect was small compared with that observed in the membranes. Specific [3 H]spiperone binding sites in the solubilized preparation were preferentially retained by a wheat germ agglutinin affinity column and subsequently eluted with N-acetyl-D-glucosamine. Gel filtration of the solubilized preparation using a Sepharose column resulted in two peaks of specific [3 H]spiperone binding, the larger component had a Stokes radius of 7.7 nm. CHAPS treatment of rat striatal membranes results in solubilization of the D-2 receptor in an active form. The D-2 site appears to be a glycoprotein of high molecular weight.
Intrinsic dissolution of lithium carbonate in aqueous solutions
Authors: Wall B P , Parkin J E , Sunderland V B
Published: April 2011

Intrinsic dissolution rate studies were carried out on lithium carbonate discs that were prepared with the disc in a component on the final support. This overcame the problem of further handling of the fragile discs. Dissolution media employed were similar to those used for the routine evaluation of lithium carbonate dosage forms. Linear dissolution rate profiles were found in simulated gastric fluid (SGF), Tris buffer and water. Data in SGF and water showed positive intercepts with the Levich model. The dissolution process of lithium carbonate was considered to be complex. Dissolution profiles in simulated intestinal fluid (SIF) containing phosphate showed a marked initial curvature and a subsequent reduced dissolution rate. This was due to the precipitation of trilithium phosphate onto the disc. Dissolution rate studies on lithium carbonate dosage forms could be invalidated where a phosphate buffer system has been used.
Age-related changes in monoamine oxidase and semicarbazide-sensitive amine oxidase activities of rat aorta
Authors: Danh H Cao , Benedetti M Strolin , Dostert P , Mousset A
Published: April 2011

Aorta MAO-A and SSAO activities were measured on young (3 months) and old (23–26 months) rats. A significant decrease (30–40%) in SSAO activity was found with benzylamine as substrate and the decrease was due to a reduction in Vmax. No significant changes in MAO-A activity were found in the aorta of old rats. β-PEA is oxidized mainly by SSAO in rat aorta. However, the significance of this is unclear since the physiological role of that enzyme remains unknown.
Evidence against putrescine and polyamines as endogenous mediators of fever
Authors: Dascombe M J , Haegele K D
Published: April 2011

Endogenous concentrations of putrescine, spermidine, spermine and related biosynthetic enzymes were not affected by the administration of bacterial endotoxin and the subsequent development of fever in rabbits. In addition, the febrile response to endotoxin was unaffected either by the ornithine decarboxylase inhibitor, DL-α-difluoromethylornithine or by putrescine. These data indicate polyamines are not involved in the development of fever.
Comparison of the affinity constant of some muscarinic receptor antagonists with their displacement of [3 H]quinuclidinyl benzilate binding in atrial and ileal longitudinal muscle of the guinea-pig
Authors: Choo L K , Mitchelson F J
Published: April 2011

The ability of the muscarinic receptor antagonists fenipramide, 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP) and secoverine to displace [3 H]QNB binding was correlated with the inhibition of responses of cholinomimetics at muscarinic receptors in the atria and ileal longitudinal muscle of the guinea-pig. Fenipramide and 4-DAMP exhibited a 2–4 fold higher affinity for muscarinic receptors in ileal longitudinal muscle in both types of experiments. Secoverine exhibited no difference in affinity in the two tissues.
A selective potentiation by naloxone of L-dopa but not atropine suppression of oxotremorine-induced tremor in mice
Authors: Quock Raymond M , Scott Lucas T
Published: April 2011

Oxotremorine-induced tremor activity in mice was suppressed by pretreatment with either L-dopa or atropine. Additional pretreatment with the opiate receptor blocker naloxone significantly potentiated the antitremor effect of L-dopa but not that of atropine. These findings indicate a selectivity of drug interaction between naloxone and L-dopa.
Relations between gastric irritancy/ulcerogenicity and anti-oedemic activity of non-steroidal anti-inflammatory drugs
Authors: Rainsford K D
Published: April 2011

Recently, Dearden & Nicholson (1984) reported a study of the relation between gastric irritancy and anti-inflammatory activity for some 25 non-steroidal anti-inflammatory (NSAI) drugs in which they made statements concerning work by Rainsford that require clarification because there appears to be some misinterpretation—viz:
In-vitro cytotoxic activity of cross-linked protein microcapsules
Authors: Desoize B , Jardillier J C , Kanoun K , Guerin D , Levy M C
Published: April 2011

Microcapsules (5-100 μm) were prepared through interfacial cross-linking of various proteins (human serum albumin, lysozyme, haemoglobin, casein, pepsin) with glutaraldehyde or terephthaloylchloride. Surprisingly they all snowed an inhibitory effect on cultured cells in a concentration range of 100 μg ml−1 to 10 mg ml−1. This effect seemed non-specific, reversible and to depend on contact with the cell plasma membrane. The electric charges of microcapsules could be involved in the inhibition phenomenon.
Concentration-response relations for apomorphine effects on heart rate in conscious rats
Authors: Paalzow Lennart K , Paalzow Gudrun H M
Published: April 2011

The pharmacokinetics of apomorphine in plasma and brain tissue have been studied in relation to the time courses of effects on heart rate in conscious rats. The kinetic behaviour was investigated after 2 mg kg−1 i.v. and 5 mg kg−1 s.c., respectively. Apomorphine showed a high total plasma clearance (165–207 ml min−1 kg−1) and, despite a relatively large volume of distribution (3.4–4.1 litre kg−1), a biological half-life of about 14 min was obtained irrespective of route of administration. The kinetics in whole brain were identical with those in plasma. Apomorphine produced biphasic effects on the heart rate during the time courses of subcutaneous single doses: a low dose (50 μg kg−1) induced pure bradycardia while the doses of 100 μg kg−1 and 5 mg kg−1 produced responses oscillating between bradycardia and tachycardia. When we evaluated the relation between apomorphine concentrations and effects on the heart frequency with a composed sigmoid Emax model, apomorphine exhibited a U-shaped steady-state plasma concentration-response curve. Bradycardia appeared after low concentrations, reached a maximum and then decreased with increasing concentrations. A further augmentation of apomorphine concentration resulted in the opposite effect, i.e. tachycardia. Separate concentration-response curves for bradycardia and tachycardia were calculated. The changes in biophase concentration that occur during the absorption and disposition may thus cause the fluctuations between contrasting effects seen during the time course of a single dose.
The effect of an aqueous extract of Tanacetum parthenium L. on arachidonic acid metabolism by rat peritoneal leucocytes
Authors: Capasso Francesco
Published: April 2011

The effect of feverfew (Tanacetum parthenium L., Schultz Bip.) as a whole plant on an aqueous extract equivalent to 20 mg dried plant per ml, has been examined on both cyclo-oxygenase and lipoxygenase activity in rat leucocytes in-vitro. At 1–25 μg ml−1 feverfew had no effect on the formation of arachidonate metabolites while at highest concentrations (51–200 μg ml−1) it inhibited both cyclo-oxygenase and lipoxygenase metabolic products.
The degradation of temocillin, a 6α-methoxypenicillin, and identification of the major degradation products
Authors: Burton George , Dobson Christopher R , Everett Jeremy R
Published: April 2011

Temocillin, 6β-(R,S-2′-carboxy-2′-thien-3-ylacetamido)-6α-methoxypenicillanic acid, shows good stability in mild aqueous acid or base; in stronger acid the methoxypenillic acid is formed whereas alkaline or enzyme hydrolysis results in the formation of the methoxypenicilloic acid and the C-5‡ epimer.
Antiarrhythmic effect of acute and chronic amiodarone treatment in conscious rats
Authors: Varró András , Rabloczky George
Published: April 2011

The effect of amiodarone after acute and chronic pretreatment was studied in the early phase of arrhythmias induced by coronary artery ligation in conscious rats. Both acute and chronic amiodarone pretreatments improved survival during the first 20 min after coronary ligation. Only chronic amiodarone pretreatment reduced significantly the incidence of ventricular fibrillation. It was concluded that chronic amiodarone pretreatment seemed to be more effective than the acute one.
Effects of sulphonylureas on spontaneous motility and induced contractions in rat isolated uterus
Authors: Villar A , Ivora M D , D'Ocon M P , Anselmi E
Published: April 2011

To clarify the action of sulphonylureas on calcium, the effect of tolbutamide and ghbenclamide has been investigated on a Ca-dependent process, the contractile activity of uterine smooth muscle. Both sulphonylureas antagonized the contractions evoked by CaCl2 in a non-competitive manner when the uterus was maintained in depolarizing solution and did not affect the spontaneous contractions of rat uterus. The capacity of tolbutamide and ghbenclamide to relax vanadate-induced contraction of rat uterus in Ca-free medium suggests that sulphonylureas may have an intracellular site of action related to cytosolic free Ca levels, or effect a reduction in Ca action.
The metabolism or atropine in man
Authors: van der Meer M J , Hundt H K L , Müller F O
Published: April 2011

A metabolic pattern of atropine in man, based on the detection of radiolabelled products in urine by high performance liquid chromatography after administration of [3H]atropine sulphate to a normal volunteer is proposed. Noratropine (24%), atropine-N-oxide (equatorial isomer) (15%), tropine (2%) and tropic acid (3%) appear to be the major metabolites, while 50% of the administered dose is excreted as apparently unchanged atropine. No conjugates were detectable. Evidence that atropine is present as (+)-hyoscyamine was found, suggesting that stereoselective metabolism of atropine probably occurs.
The pharmacokinetics of pyrimethamine in the rat: effect of mefloquine
Authors: Coleman M D , Thompson A J , Edwards G , Braithwaite I M , Breckenridge A M
Published: April 2011

The pharmacokinetics and tissue distribution of pyrimethamine have been determined in the rat. Following administration of pyrimethamine alone, drug concentrations declined biexponentially. By contrast, in the presence of mefloquine, the decline in pyrimethamine concentration more closely fitted a monoexponential pattern and the AUC0-6h, for pyrimethamine was significantly reduced. Significantly more pyrimethamine was recovered from the livers but less from the lungs of the mefloquine-dosed rats compared with control. This study outlines a potentially clinically relevant drug interaction.
The adenosine receptor antagonist, 8-phenyltheophylline, causes diuresis and saliuresis in the rat
Authors: Collis M G , Baxter G S , Keddie J R
Published: April 2011

The diuretic and adenosine antagonist actions of two alkylxanthines have been compared in the conscious rat. 8-Phenyltheophylline (10 mg kg−1) antagonized adenosine-induced bradycardia in the rat for at least 3 h whereas enprofylline (10 mg kg−1) had no effect on this response. 8-Phenyltheophylline (10 mg kg−1) evoked diuresis and saliuresis in the rat whereas enprofylline (10 mg kg−1) had no effect on excretory parameters. These results indicate that the diuretic action of some alkylxanthines may be related to adenosine antagonism.
Concentration and pH dependency of α-methyldopa absorption in rat intestine
Authors: Amidon G L , Merfeld A E , Dressman J B
Published: April 2011

The intestinal absorption of α-methyldopa from perfused segments of rat intestine was determined. Jejunal and ileal segments were studied at pH 4.5, 6.0 and 7.4 at an α-methyldopa concentration of 0.01 mM, and at pH 6.0 at concentrations of 0.01, 0.10 and 10 mM. Intestinal absorption was found to depend on both concentration and pH but not on segment. A weak positive correlation (r = 0.5) was observed between net water absorption and α-methyldopa absorption, similar to that observed for amino acids. The low intestinal wall permeability of α-methyldopa under normal intestinal pH conditions (pH 7.4) is consistent with the incomplete oral bioavailability of this drug.
Protein binding of nifedipine
Authors: Otto J , Lesko L J
Published: April 2011

The protein binding of nifedipine in concentrations up to 1200 ng ml−1 has been measured in serum, pure human albumin solution and pure human α1-acid glycoprotein (AAG) solutions by ultrafiltration. The drug was extensively bound in serum from four healthy volunteers with a mean (±s.d.) fraction bound of 0.992 ± 0.008. In albumin solution (40 g litre−1) the mean (±s.d.) fraction bound 0.970 ± 0.012, was not significantly different (P > 0.05) from that in serum, suggesting that albumin is the major, but not necessarily the only, binding protein for nifedipine in serum. The binding of nifedipine in solutions of A AG was proportional to the AAG concentration and ranged from 0.514 ± 0.059 to 0.755 ± 0.035 in solutions containing 50 and 150 mg% AAG, respectively. Binding of nifedipine in all protein solutions was linear.
A comparison of the effect of viscosity on the precorneal residence of solutions in rabbit and man
Authors: Zaki I , Fitzgerald P , Hardy J G , Wilson C G
Published: April 2011

The precorneal drainage of radiolabeled solutions containing polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC) have been measured in rabbit and man by gamma scintigraphy. Concentration of the polymers was varied to produce solutions with a viscosity range between 10.2 and 102 mPas. Solution drainage was faster in man than in the rabbit with a more pronounced effect of viscosity. Significant retardation of drainage in man was noted at the higher polymer concentrations (0.9% HPMC or 5.85% PVA).
Interactions of muscarinic drugs with their receptors in single cells of guinea-pig taenia caecum
Authors: Takayanagi Issei , Koike Katsuo , Hiruta Tsuyoshi
Published: April 2011

Single cells were prepared from the guinea-pig taenia caecum and used for the study of drug-receptor interactions. The cells showed a graded response to carbachol, the dose response curve being shifted in a parallel fashion by atropine, indicating a competitive antagonism. The pA2-value of atropine was in agreement with that estimated using the intact tissue. [3H]QNB (quinuclidinyl benzilate) combined with the single cells, the Scatchard plot yielding a straight line. The dissociation constant of QNB was similar to values estimated in other membrane preparations. The apparent dissociation constants of cholinergic drugs estimated from inhibition of the specific binding of [3H]QNB (0.20 nM) to the single cells by the cholinergic drugs were also in agreement with the values in other membrane preparations. The results indicate that the single smooth muscle cells are useful for the study of drug-receptor interactions.
Accumulation of nifedipine after multiple doses
Authors: Lesko L J , Hunter J R , Burgess R C , Rodgers G P
Published: April 2011

The single and multiple dose pharmacokinetics of oral nifedipine capsules, 10 mg, have been examined in five patients with peripheral vasospasm. After a single dose, nifedipine was rapidly absorbed in three and slowly absorbed in two patients. Mean bioavailability parameters included a tmax of 2.9 h, a Cmax of 33.3 ng ml−1 and a AUC0–8 h of 113.3 ngh ml−1. After multiple dosing with either 10 or 20 mg every 8 h for 10 days the mean tmax at steady state was 2.1 h while the mean dose-corrected (to 10 mg) Cmax and AUC0–8 h were 51.9 ng ml−1 and 146.9 ngh ml−1, respectively. The mean elimination rate constant was 0.173 h−1 after both single and multiple doses. The mean extent of accumulation of nifedipine, defined as the ratio of AUC0–8 h (steady state)/AUC0–8 h (single dose), was 1.3; we concluded that nifedipine accumulates in the body when it is administered every 8 h. This should be taken into account when predicting steady state serum concentrations and haemodynamic effects of nifedipine from single dose kinetic data.
Non-ionic surfactant vesicles, niosomes, as a delivery system for the anti-leishmanial drug, sodium stibogluconate
Authors: Baillie A J , Coombs G H , Dolan T F , Laurie J
Published: April 2011

Liver and serum concentrations of antimony in the mouse have been determined after administration of sodium stibogluconate in the free, liposomal and niosomal form. High liver and low serum values were attained by the use of both vesicular formulations. Niosomal sodium stibogluconate was shown to be more active than free drug against experimental murine visceral leishmaniasis, an effect apparently dependent on maintaining high drug levels in the infected reticuloendothelial system.
Diuertic effect of L-threo-3,4-dihydroxyphenylserin, a noradrenaline precursor, in rats and mice
Authors: Katsube Junki , Kato Terufumi , Katsuyama Michiko , Maeda Yukio , Nishikawa Sumiko , Nakamura Mitsutaka
Published: April 2011

L-Threo-DOPS, a noradrenaline (NA) precursor, produced a dose-dependent increase in the volume of urine in mice and rats. It also increased the total output of sodium and chloride ions, but not the excretion of potassium ion. Treatment with peripheral decarboxylase inhibitors antagonized not only the diuretic action, but also the increase in the concentration of kidney NA produced by L-threo-DOPS. These results suggest that the diuretic action of L-threo-DOPS might not be due to its direct action, but largely to NA formed by its decarboxylation in the kidney.
Saliva secretion of chloroquine in man
Authors: Ogubona F A , Lawal A A , Onyeji C O
Published: April 2011

The presence of chloroquine in saliva from seven healthy volunteers for 21 days after a single 600 mg oral dose of the drug was established by chromatographic and spectroscopic methods. The results showed the drug to be rapidly absorbed with a tmax in saliva of 3.9 ± 1.6 h. A long elimination half-life of 7–20 days, calculated from the saliva concentration-time profile, is in agreement with values previously reported for the drug using plasma level data. In three of the volunteers from whom simultaneous blood samples were obtained, the mean Cs/Cp value was 1.20 ± 0.27. It is suggested that saliva level determination may be used in evaluating patient compliance, therapeutic drug monitoring and pharmacokinetic parameters of chloroquine.
Evidence against leukotriene-mediation of propranolol-induced airway hyperreactivity to acetylcholine
Authors: Murlas Christopher
Published: April 2011

In unanaesthetized guinea-pigs, propranolol treatment (0.l mg kg−1 i.v.) substantially increased reactivity to intravenous acetylcholine infusion or aerosolized histamine to a comparable degree. Neither BW755c (5 mg kg−1 i.v.), FPL 55712 (1 mg kg−1 i.v.), nor piriprost (5 mg kg−1 i.v.) pretreatment influenced propranolol's effect on muscarinic reactivity although BW755c abolished histaminic hyperreactivity. This suggests that propranolol-induced muscarinic hyperreactivity in the guinea-pig is not mediated by leukotrienes whereas histaminic hyperreactivity may be.
Tetrodotoxin inhibits directly acting stimulants of intestinal fluid secretion
Authors: Coupar Ian M
Published: April 2011

Intravenous injection of tetrodotoxin (20 μg kg−1) to anaesthetized rats blocks PGE1- and inhibits VIP-induced fluid secretion from the mucosa of the jejunum without affecting the physiological rates of net water and glucose absorption. It is suggested that the toxin might release an endogenous inhibitor of secretion or that it might possess direct antisecretory activity on the epithelial cells of the jejunum. It is further suggested that results where tetrodotoxin has been used to investigate secretagogue action should be treated with caution.
Clonidine reduces plasma melatonin levels
Authors: Lewy A J , Siever L J , Uhde T W , Markey S P
Published: April 2011

Clonidine, an α-adrenoceptor agonist, reduces human plasma melatonin levels when administered intravenously at 2–3 (μg kg−1 to sleeping volunteers. Measurement of plasma melatonin levels after administration of clonidine could be the basis for a clinical in-vivo test of α-adrenoceptors.
Cytochrome P450 metabolic intermediate complex of nefopam
Authors: Leurs R , Donnell D , Timmerman H , Bast A
Published: April 2011

NADPH-catalysed biotransformation of nefopam in liver microsomes obtained from phenobarbitone-pretreated rats leads to the formation of an inactive cytochrome P450 metabolic intermediate (MI) complex. This complex can be detected spectrophotometrically by an absorbance maximum at 459 nm. The extent of the in-vitro MI complexation of 33 μm nefopam, a cyclic analogue of orphenadrine, was almost equal to the extent of the in-vitro MI complexation of 33 μm tofenacine, the mono-N-demethylated metabolite of orphenadrine. The time course of the MI complexation of nefopam and studies with two of its major metabolites suggest an initial biotransformation, which has to occur before MI complexation can take place. Maximal MI complexation of nefopam occurred at approximately 25 μm, whereas the MI complexation could not be detected at 100 μm nefopam.
Effect of pre-existing inflammation on carrageenan-induced paw oedema in rats
Authors: Bhattacharya S K , Das Neeta , Rao P J R Mohan
Published: April 2011

Twenty-four hours after injection of carrageenan into one hind paw, injection of the same amount into the contralateral paw produced a significantly attenuated inflammatory response. However, when the second injection was given 7 days later, the inflammation induced in the contralateral paw was comparable with the initial response to carrageenan. A time-course study of carrageenan-induced inflammation in rats showed that significant oedema persisted 24 h after carrageenan administration and complete recovery was achieved in 7 days. The attenuated inflammatory response in the contralateral paw after 24 h was antagonized by bilateral adrenalectomy and chemical sympathectomy induced by 6-hydroxydopamine. Carrageenan-induced paw oedema was also significantly less in rats with subacute inflammation induced by the croton oil granuloma pouch technique. This attenuated response was antagonized by pretreatment of the rats with metyrapone, an inhibitor of adrenocorticoid synthesis, and by 6-hydroxydopamine. It is likely that the pre-existing acute or subacute inflammation attenuates the inflammatory response of carrageenan, by acting as a stressor, inducing activation of the sympatho-adrenal system.
A study of PAF-induced ocular inflammation in the rat and its inhibition by the PAF antagonist, L-652, 731
Authors: Gautheron P D , Coulbault L , Sugrue M F
Published: April 2011

A significant inflammatory reaction in the rat conjunctiva followed the subconjunctival injection of synthetic platelet activating factor (PAF) in doses which ranged from 10 ng to 1 μg, an inflammatory response being evaluated as the increase in both tissue weight and extravasation of Evans blue dye in the conjunctival tissue. Inflammation was still present 6 h after the injection of 0ṁ1 μg of PAF. Orally administered indomethacin or BW 755C failed to alter the response to 0ṁ1 μg of PAF. In contrast, the PAF-induced inflammation was blocked by the oral administration of the PAF receptor antagonist, L-652, 731, a dose as low as 5 mg kg−1 eliciting a significant inhibition. The topical administration of L-652, 731, (two doses of 100 μg as a 1% suspension), elicited a slight, but significant blockade of 23%. Its antagonistic action was more striking when it was co-injected subconjunctivally with 0ṁ1 μg of PAF, a dose as low as 3 μg evoking a significant blockade. The topical administration of 0ṁ1 μg of PAF did not elicit a significant inflammatory reaction and this contrasts with the results obtained after its subconjunctival injection.