bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrogel Patches for Transdermal Drug Delivery; In-vivo Water Exchange and Skin Compatibility
Authors: Boddé H E , van Aalten E A C , Junginger H E
Published: April 2011

Hydrogel patches based on water swellable polyacrylates have been developed for long-term transdermal drug delivery. Two properties, relevant to the performance of hydrogel patches in-vivo have been investigated in humans over five days. These were: (i) the kinetics of water exchange between the skin and the patches; (ii) the skin compatibility of the patches. It was found that initially there was a gradually increasing uptake of water from the skin by the patches, but after about 20 h the water exchange followed a regular fluctuating pattern, peaking once a day and once a night. The skin compatibility of the patches was satisfactory, in that no redness or pustulation was noticed throughout the five days. This was most likely due to the capability of the patches to exchange water with the skin.
Naloxone-insensitive Inhibitory and Excitatory Effects of Opioid Agonists in the Rat Isolated Uterus
Authors: Ohia S E , Laniyonu A A
Published: April 2011

Morphine (3 × 10−6−10−3 M) produced a concentration-dependent inhibition of both spontaneous rhythmic contractions and tonic contraction induced by potassium chloride (KCl) (50 mM) in rat isolated uterus. Uteri at the metoestrus phase were the most sensitive to the inhibitory effect of morphine. Morphine-induced relaxation was characterized by a post-wash tonic contraction. The μ-specific opioid agonist, D-alaglymepheglycol (DAGO) (4 × 10−8−1·2 × 10−5 M) did not affect spontaneous rhythmic contraction but produced a partial inhibition of the KCl depolarized uterus. There was no post-wash contraction following DAGO. In contrast to the inhibition produced by both morphine and DAGO, methionine enkephalin (8 × 10−7−2·4 × 10−5 M) produced a concentration-dependent contraction of the KCl depolarized uterus. Naloxone up to 100 μM, propranolol (10 μM), flurbiprofen (50 μM) and metiamide (10 μM) did not affect either the relaxation produced by morphine and DAGO or the contraction produced by methionine enkephalin. The results showed that the opioid agonists may have non-receptor mediated direct effects on the rat uterus.
Influence of streptozocin-induced diabetes on reductive metabolism of acetohexamide in rat liver
Authors: Imamura Yorishige , Kojima Yuichiro , Otagiri Masaki
Published: April 2011

Streptozocin-induced diabetes significantly decreased acetohexamide reductase activity of 10 000 g supernatant of liver homogenates from both male and female rats. However, the decrease in activity from female rats was smaller than that from male rats, thereby eliminating the sex difference in the activity of the 10 000 g supernatant. In male rats, the diabetes markedly decreased acetohexamide reductase activity only in the microsomal fraction of liver homogenate, whereas in female rats, it decreased the activity only in the cytosolic fraction. These results indicate that the mechanism for the decreasing effect of the diabetes on reductive metabolism of acetohexamide in 10 000 g supernatant differs between male and female rats.
Deamination of aliphatic amines of different chain lengths by rat liver monoamine oxidase A and B
Authors: Yu Peter H
Published: April 2011

Monoamines with from 1 to 18 straight chain carbon atoms have been analysed as rat liver monoamine oxidase substrates. Methylamine and ethylamine are clearly not substrates of monoamine oxidase (MAO). n-Propylamine, n-butylamine, n-dodecylamine and n-octadecylamine are relatively poor substrates, i.e. with high Km and low Vmax values for the enzyme. n-Pentylamine, n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine and n-decylamine are all very good MAO substrates. All these aliphatic amines are found to be typical type B substrates according to the sensitivities of the enzyme towards the selective MAO-B inhibitor selegiline and the MAO-A inhibitor, clorgyline. The sensitivity towards selegiline with respect to these amines is even higher, i.e Ki = 1 × 10−9 M for butylamine, than that of the typical type B substrate β-phenylethylamine (Ki = 1 × 10−8 M). The sensitivity towards selegiline decreases slightly with increasing chain length of these aliphatic amines.
Controlled Release of LHRH Agonist, Leuprolide Acetate, from Microcapsules: Serum Drug Level Profiles and Pharmacological Effects in Animals
Authors: Ogawa Yasuaki , Okada Hiroaki , Heya Toshiro , Shimamoto Tsugio
Published: April 2011

The pharmacokinetic behaviour of leuprolide acetate from a controlled release parenteral dosage form has been studied in rats and dogs. The release of the drug in rats after a single subcutaneous injection exhibited pseudo-zero-order kinetics for one month in doses ranging from 0·0135 to 1·35 mg/rat; the release rate at a dose of 1·35 mg/rat was 2·8% of dose/day; after intramuscular injection the response was similar. In rats, the serum leuprolide acetate levels increased sharply immediately after injection by either route as a consequence of the initial release of the drug; subsequently, the levels attained a plateau for two weeks. The serum level profiles in dogs showed essentially the same pattern as those in rats. When the dosage form was injected into rats, the serum testosterone level (a pharmacological index) sharply peaked, abruptly decreased to below the normal level, and then was sustained at a suppressed level for over six weeks at a dose of 1·35 mg/rat (equivalent to 3 mg kg−1) and higher, while the serum testosterone level after an injection of 0·0135 and 0·135 mg/rat was not sufficiently suppressed. The profiles in dogs showed essentially the same pattern as those in rats. With multiple administrations (once every 4 weeks), serum testosterone levels in dogs did not show any sharp rise after the second and third injections. Changes in rat reproductive organ weights agreed well with the serum testosterone profile in the suppression. The results demonstrate that this dosage form releases the drug at a constant rate for one month and has a long-acting potency.
A high dose of MPTP overcomes the protective effect of selegiline against dopaminergic neurotoxicity
Authors: Fuller Ray W , Hemrick-Luecke Susan K
Published: April 2011

1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) at 90 mg kg−1 s.c., a dose lethal in non-pretreated mice, was well tolerated in selegiline ((—)-deprenyl)-pretreated mice and produced persistent depletion of striatal dopamine and its metabolites one week after the last of four daily injections. The protective effect of selegiline against dopaminergic neurotoxicity of MPTP can thus be overridden by a high dose of MPTP that would be lethal without selegiline pretreatment.
Effect of [D-Ala2,MePhe4,Gly-ol5]enkephalin and [D-Ala2,D-Leu5]enkephalin on ion and amino acid transport in rabbit ileum
Authors: Meyer G , Botta G , Tavani A , Algeri S , Cremaschi D
Published: April 2011

The selective μ-opioid agonist [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAGO) (10 μM) reduced the short circuit (Isc) and the L-valine induced increase of the transepithelial potential difference and Isc(δVms and δsc) measured in-vitro in rabbit ileum, with a mechanism antagonized by naloxone (1 μM). [D-Ala2, D-Leu5]enkephalin (DADLE) (10 μM) had no significant effect on the transepithelial potential difference (Vms), Isc, δVms and δIsc. In the ileum deprived of the serosa and muscolaris, DAGO reduced the δVms and δIsc, but not the Vms and Ics, suggesting localization of the receptors responsible for this latter effect in the myenteric plexus and/or the muscularis mucosae. These preliminary results suggest that in the rabbit ileum opioids influence electrolyte and amino acid transport and these effects may be at least partly mediated by μ-receptors.
α-Blockade on Blood Pressure and on Cardiac Noradrenaline Content in SHR and DOCA-salt Rats
Authors: Sanchez Adela , Torres Andres , Saiz Jesus
Published: April 2011

The current study was designed to explore the effects of peripherally administered α-adrenoceptor inhibiting drugs (either prazosin or yohimbine) in spontaneously hypertensive (SHR) and DOCA-salt hypertensive rats before the development of established hypertension, as well as to characterize changes induced by prazosin and/or yohimbine in the cardiac noradrenaline (NA) content that might be responsible for the development of hypertension in these strains. The α-adrenoceptor blockade can prevent hypertension in DOCA and salt-treated animals in such a way that their blood pressure stabilizes at levels significantly lower than those observed in similarly treated normotensive controls. Significantly lower cardiac NA content was observed in DOCA-salt rats under basal and experimental conditions. The blood pressure of the treated rats and the heart NA content of the SHR were unaltered by treatment. Thus, administration of the α-adrenoceptor blocking agents, prazosin and/or yohimbine, throughout the developmental stage of SHR hypertension failed to alter either the progressive rise in blood pressure or in NA content. There may be differences between the cardiac adrenergic mechanisms responsible for the development of hypertension in each of these two models of hypertension.
The role of vagal adrenergic activity in the mechanism of gastric acid secretion after pylorus-ligation in the rat
Authors: Salim Aws S
Published: April 2011

The role of the vagus nerve and adrenoceptor stimulation in acid secretion after pylorus-ligation in the rat has been examined. All drugs were administered intraperitoneally. Atropine (5 mg kg−1) depressed the H+ output (111 μmol ± 33·8 vs 412·5 μmol ± 62·2, mean ± s.e.m., n = 10, P<0·001); Cimetidine (40 mg kg−1) did not enhance this action, while vagotomy was more effective than atropine (32·7 μmol ± 4·9, mean ± s.e.m., n = 10, P<0·05). Atropine (10 mg kg−1) produced a similar depression to the 5 mg kg−1 dose. Cimetidine (100 mg kg−1) depressed the H+ output (248·5 μmol ± 46·8, mean ± s.e.m., n = 10, P<0·05). Propranolol (5–20 mg kg−1) had no significant effect on the H + output but dose-dependent inhibition was produced by phenoxybenzamine or phentolamine; an inhibition similar to that achieved by vagotomy was seen with the 20 mg kg−1 dose. Both these drugs (5 or 10 mg kg−1) had no significant effect on the H+ output when given with atropine (5 mg kg−1) but the H+ output was significantly lower than that produced by either drug at the same dose given alone. Atropine (5 mg kg−1) with phenoxybenzamine or phentolamine (20 mg kg−1) produced H + output not significantly different from that with vagotomy or either α-adrenoceptor given alone at 20 mg kg−1, but the result was significantly (P<0·05) lower than the H+ output with atropine (5 mg kg−1) alone. The results suggest that pylorus-ligation in the rat produces vagal α-adrenoceptor delivery to the stomach causing cholinergic and non-cholinergic stimulation to acid secretion.
Comparison of Transport Characteristics of Amino β-Lactam Antibiotics and Dipeptides Across Rat Intestinal Brush Border Membrane
Authors: Iseki Ken , Sugawara Mitsuru , Saitoh Hiroshi , Miyazaki Katsumi , Arita Takaichi
Published: April 2011

The transport characteristics of amino β-lactam antibiotics, ampicillin and cephradine, have been examined and compared with that of glycylglycine using brush border membrane vesicles isolated from rat small intestine. The initial rate of glycylglycine uptake was markedly stimulated in the presence of an inward H + gradient compared with the uptake rates in the absence of an H + gradient. With the same H + gradient the stimulation of cephradine uptake was lower and ampicillin uptake was not altered. Cephradine uptake, however, was greater than that of glycylglycine in both vesicular conditions ((pH)i > (pH)0 and (pH)i = (pH)0). Inhibitory effects of dipeptides, ampicillin and cephradine on the initial uptake of glycylglycine were also examined. Glycylglycine uptake was significantly decreased in the presence of L-phenylalanylglycine or carnosine. Ampicillin and cephradine did not alter the uptake of glycylglycine. These results suggest that the contribution of the inward H+ gradient to the permeation of ampicillin, cephradine and glycylglycine across the rat small intestinal brush border membranes is different for each of the substances examined.
The Effect of Some Preservatives Used in Nasal Preparations on the Mucus and Ciliary Components of Mucociliary Clearance
Authors: Batts A H , Marriott C , Martin G P , Wood C F , Bond S W
Published: April 2011

Efficient mucociliary clearance is a function of the physical properties of the mucus coupled to appropriately functioning cilia and may be altered by substances affecting ciliary beat frequency (CBF). Therefore the effect of preservatives on CBF was investigated using a photoelectronic technique. Methyl-p-hydroxybenzoate, propyl-p-hydroxybenzoate, chlorbutol and chlorocresol inhibited beat frequency, an effect which was reversible upon rinsing out the first three compounds but not chlorocresol. The effect of chlorhexidine and phenylmercuric borate on CBF was complicated by an interaction with chloride ions in the media used. EDTA did not appear to be ciliotoxic, while the effect of benzalkonium chloride was variable. Thiomersal halted ciliary beating after 40–100 min. Mucociliary clearance may also be affected by an alteration of the physical properties of the mucus layer, therefore the effect of each compound on the rheological properties of purified pig gastric mucus glycoprotein was investigated. None of the preservatives significantly altered the viscoelastic properties of the gel, measured using dynamic techniques.
Cyclosporin Treatment Alters Prostanoid and Thromboxane Production by Rat Isolated Kidney Mitochondria
Authors: Erman Arie , Chen-Gal Batia , Rosenfeld Joseph
Published: April 2011

This study was designed to investigate the effects of chronic treatment with cyclosporin A (CSA) on the endogenous synthesis of prostanoids (PGs) and thromboxane (Tx) by renal isolated medullary and cortical mitochondria. The administration of CSA, dissolved in 10% ethanol in olive oil, to male Wistar rats (20 mg kg−1 day−1 i.p.) for 14 days resulted in alterations in mitochondrial biosynthesis of immunoreactive PGs. The endogenous synthesis of thromboxane by medullary and cortical mitochondria isolated from CSA-treated rats was significantly enhanced by 120 and 55%, respectively, whereas the synthesis of prostaglandin E2 by medullary mitochondria was reduced by 35%. The synthesis of prostaglandin F2, and prostacyclin was not affected by CSA treatment. The conversion of exogenous arachidonic acid to PGs and Tx by cortical mitochondria isolated from CSA-treated rats was significantly increased. In addition, CSA treatment resulted in i) a reduced acylation of arachidonic acid into medullary phospholipids by 25% and into medullary and cortical triglycerides by 33 and 27%, respectively, and ii) an increase in cortical and medullary triglycerides. We suggest that the alterations in the endogenous mitochondrial production of PGs and Tx caused by CSA, may play a role in the impairment of membrane mediated functions.
Pharmacological modulation of 2-methyl-carbamate-PAF induced rat paw oedema
Authors: Castro-Faria-Neto H C , Silva P M R , Martins M A , Silva P S , Henriques M G O M , Cordeiro R S B , Vargaftig B B
Published: April 2011

Intraplantar injections of 2-methyl-carbamate-PAF (2-MC) (0.125-16.0 μg/paw) into the rat paw were followed by a bell-shaped dose response curve for inflammatory oedema, with an ascending phase at 0.125-2.0 μg/paw, and a descending phase at 4.0–16.0 μg/paw. The inflammatory response to 2-MC was partially inhibited by pre-treatment with aspirin (200 mg kg−1), NDGA (100 mg kg−1), dexamethasone (0.1 mg kg−1), verapamil (50 mg kg−1) and by a specific PAF antagonist BN 52021 (5–10 mg kg−1). The cyclo-oxygenase inhibitors indomethacin (2 mg kg−1) and piroxicam (1.8 mg kg−1) as well as antihistamine meclizine (40 mg kg−1) and ranitidine (50 mg kg−1) failed to block the oedematogenic response to 2-MC. Our data suggest that 2-MC induced rat paw oedema is mediated by PAF-acether receptors and is partially dependent on arachidonate lipoxygenase pathway and extracellular Ca2+.
Presence of non-cholinergic motor transmission in human isolated bladder
Authors: Luheshi G N , Zar M A
Published: April 2011

Atropine-sensitivity of the motor transmission in the isolated detrusor preparation from human bladder has been examined. The preparations were contracted by electrical field stimulation consisting either of short trains of pulses or of long trains of pulses. Part of the stable response to short-train stimuli (28%) was resistant to atropine, was not potentiated by physostigmine and was blocked by tetrodotoxin. The stable responses to long-train stimuli were fully blocked by atropine. It is concluded that the detrusor of the bladder in man, in common with other mammalian species, contains a non-cholinergic component in its motor transmission, and that prolonged stimulation with long-train stimuli causes an extinction of the non-cholinergic motor transmission, probably through depletion of transmitter stores in the nerve-terminals.
Electrophoretic Study of Nitrofurantoin in Aqueous Suspensions. Effect of the Addition of a Polymeric Thickener
Authors: Gallardo V , Delgado A , Parera A , Salcedo J
Published: April 2011

The electrophoretic mobility of nitrofurantoin (based on the microelectrophoresis method) has been studied in dilute dispersions of the drug. Specifically, the effect of NaCl, CaCl2 and AlCl3, pH, and a thickener, Carbopol 934, was determined. The electrophoretic mobility (μ) increases in absolute terms when the pH is raised between 3 and 9, although μ remains negative in this pH range. The variation of absolute mobility (|μ|) with NaCl concentration shows a pronounced maximum for a concentration of about 10−4 M. However, when the concentration of CaCl2 in the medium is increased, |μ| decreases steadily. The effect of AlCl3 concentration on the mobility is markedly influenced by the pH of the dispersing medium although a general trend is observed for μ to become more positive with increasing concentration of the salt. Finally, Carbopol 934 appears to impart an extra negative charge to the nitrofurantoin surface, since higher negative mobilities were measured in the presence of the polymer.
Pharmacokinetics, Bioavailability, Metabolism, Tissue Distribution and Urinary Excretion of γ-L-Glutamyl-L-dopa in the Rat
Authors: Cummings J , Matheson L M , Maurice L , Smyth J F
Published: April 2011

γ-L-Glutamyl-L-dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg−1 intravenously (i.v.) and 60 mg kg−1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2α of 7 min and terminal half-life of 67 min. After i.p. administration absorption was rapid (t 1/2ab 6 min), elimination was monophasic with a terminal half-life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L-dopa, dopamine, DOPAC and γ-L-glutamyl-dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L-dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man.
Zinc Acexamate Inhibits Gastric Acid and Pepsinogen Secretion in the Rat
Authors: Bulbena Oriol , Esplugues Juan V , Escolar Ginés , Gil Luz , Navarro Carmen , Esplugues Juan
Published: April 2011

Pretreatment with zinc acexamate (25–100 mg kg−1 i.p.) inhibited acid and pepsinogen secretion in the pylorus-ligated rat. Zinc acexamate (5–50 mg kg−1 p.o.) also inhibited the increases in acid secretion induced by carbachol (10 μg kg−1) and 2-deoxy-D-glucose (200 mg kg−1) in the perfused stomach of the anaesthetized rat. A delayed antisecretory effect was observed with this drug on histamine induced responses. High concentrations of zinc acexamate (10−5-10−2 M) did not modify the in-vitro activity of pepsin. Administration of zinc acexamate resulted in an increase in the presence of pepsinogen at the mucosal level. A morphological examination of the gastric mucosa confirmed an accumulation of zymogencontaining granules in the gastric chief cells of zinc acexamate-treated rats (50 mg kg−1 p.o.). These results indicate that zinc acexamate decreases acid and pepsinogen secretion in-vivo, and this may explain its antiulcer activity.
A Comparison of the Effects of Nicotine and (+)-Amphetamine on Rat Behaviour in an Unsignalled Sidman Avoidance Schedule
Authors: Balfour D J K
Published: April 2011

In agreement with the results of previous studies, the withdrawal of nicotine from rats trained on an unsignalled Sidman avoidance schedule under the influence of the drug (0.4 mg kg−1 given subcutaneously 3 min before each training session) was associated with a reduction in lever-pressing responses (P < 0.05) and an increase in the number of shocks received (P < 0.01). The number of shocks received by the withdrawn rats was also greater (P < 0.05) than the number of shocks received by rats trained and tested with saline, whereas the number of lever-pressing responses recorded for saline-treated rats was not influenced significantly by the drug used during training. The subcutaneous administration of (+)-amphetamine (0.5 mg kg−1 30 min before the test session) stimulated lever-pressing in rats trained with saline or nicotine and abolished the increase in the number of shocks received by the nicotine-withdrawn rats, but had no significant effect on the number of shocks received by rats trained with saline. The number of shocks received by the rats trained on the schedule with (+)-amphetamine but tested after an injection of saline was also greater (P < 0.05) than the number of shocks received by rats trained and tested with saline. It is concluded that the disruption in shock avoidance performance observed for the nicotine- and (+)-amphetamine-withdrawn rats may reflect the development of dependence upon the stimulant properties of these drugs.
Inhibition of Metoprolol Metabolism by Chloroquine and other Antimalarial Drugs
Authors: Lancaster D L , Adio R A , Tai K K , Simooya O O , Broadhead G D , Tucker G T , Lennard M S
Published: April 2011

The ability of a series of antimalarial drugs to impair the metabolism of metoprolol in rat and man has been examined. Chloroquine was a potent inhibitor in rat liver microsomes (Kj value for metoprolol α-hydroxylation = 0.18 μM and for O-demethylation = 0.36 μM). The other antimalarial drugs also inhibited metoprolol oxidation. Quinine was similar to chloroquine in potency, while quinidine, primaquine and mefloquine were slightly less potent. Chloroquine also inhibited metoprolol oxidation in human liver microsomes, although it was about two orders of magnitude less potent than in the rat and the extent of impairment varied greatly between individual livers. Intraperitoneal administration of chloroquine to anaesthetized rats decreased the clearance of metoprolol (40 mg tartrate salt kg−1 i.p.) to 54, 34, 20 and 26% of the control value at doses of 2.5, 4.0, 25 and 40 mg kg−1, respectively. We conclude that antimalarial treatment might have contributed to a previously reported difference in the metabolic pattern of metoprolol between Caucasians and Nigerians.
Smoking, eicosanoids and ulcerative colitis
Authors: Motley R J , Rhodes J , Williams G , Tavares I A , Bennett A
Published: April 2011

In this study, which is the first of its kind using normal tissue samples that are very difficult to obtain, we have investigated the hypothesis that smoking protects against ulcerative colitis by altering the colonic mucosal formation of prostaglandins and related substances. Colonic mucosa biopsied from healthy young men produced prostaglandin E, 6-keto-PGF1α (formed from PGI2), leukotriene B4 and leukotriene C4/D4/E4 as determined by radioimmunoassay. With each substance, the median yield was lower in the group of smokers who smoked 3 cigarettes in the 2 h before biopsy, than in the non-smokers. However, with each eicosanoid the statistical probability approached only the 10% level, but the fact that the trend was the same for all eicosanoids somewhat strengthens the possibility of a real difference between the groups.
The Retention of Entrapped Molecules within Erythrocyte Ghosts During Cryopreservation
Authors: Brearley C A , Hodges N A , Olliff C J
Published: April 2011

In view of the interest in erythrocyte ghosts and carrier erythrocytes as potential drug delivery systems, this work was undertaken to determine conditions facilitating the retention of entrapped molecules during cryopreservation. Upon freeze-thaw treatment intact erythrocytes and erythrocyte ghosts displayed different damage profiles with respect to cryoprotectant concentration. Non-penetrating cryoprotectants showed optimum protection of intact cells at 0.4-0.5 M; this optimum was not observed with ghosts, in which damage decreased with concentration up to 1 0 M. The concentration optimum for intact cells was not abolished by oxidative or reductive treatments suggesting that its absence in ghosts is not due to altered protein-protein or protein-lipid interactions. The extent of freeze-thaw damage to ghosts was influenced by the qualitative ionic composition of a cryoprotectant-free suspending medium, with 10–12% haemolysis observed in the presence of Li+ and Mg2+ but > 60% for Na+, Cs+, K+ and NH4+ with increasing loss following that order. The release on freezing of entrapped haemoglobin, inulin and sucrose was found to be inversely proportional to their molecular weights.
Inhibition of Dapsone-induced Methaemoglobinaemia in the Rat Isolated Perfused Liver
Authors: Coleman M D , Hoaksey P E , Breckenridge A M , Park B K
Published: April 2011

We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 ± 3.0%, mean ± s.d.) which reached a maximum (22.6 ± 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30–45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 ± 267.8 μg min mL−1) was almost three-fold higher than control (345.0 ± 68.1 μg min mL−1, P < 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 ± 48.2 min vs 51.2 ± 22.9, P < 0.05). The clearance of DDS (3.0 ± 0.55 mL min−1) was greatly reduced in the presence of cimetidine (1.03 ± 0.26 mL min−1  P < 0.01). The AUC0.3 h for DDS-NOH (28.3 ± 21.2 μg min mL−1) was significantly reduced by cimetidine (8.1 ± 3.40 μg min mL−1, P < 0.01). In contrast, there was a marked increase in the AUC0.3 h for MADDS (32.7 ± 25.8 μg min mL−1) in the presence of cimetidine (166.0 ± 26.5 μg min mL−1  P < 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.
Comparison of Propranolol and Sotalol Pharmacokinetics in Obese Subjects
Authors: Poirier J M , le Jeunne C , Cheymol G , Cohen A , Barré J , Hugues F C
Published: April 2011

Six obese subjects (mean ± s.d.: 145.1 ± 16.7% of ideal body weight) were randomly assigned to a single i.v. dose either of (±)-propranolol base (0.108 mg kg−1 of ideal body weight) or of (±)-sotalol base (1.06 mg kg−1 of ideal body weight). Each subject received the other drug 7 days later. Pharmacokinetic parameters were compared with those obtained previously in non-obese control subjects. In obese subjects, the pharmacokinetic data calculated for sotalol were comparable with those measured in controls (total body clearance = 9.4 ± 2.9 L h−1; volume of distribution during the terminal phase = 79.8 ± 19.8 L or 0.9 ± 0.2 L kg−1; terminal half-life = 6.2 ± 1.6 h). For propranolol, total clearance (44.3 ± 15.9 L h−1) and volume of distribution (230.5 ± 48.2 L or 2.7 ± 0.7 L kg−1) were significantly less than control values. The terminal half-life (3.9 ± 1.1 h), was not significantly increased. These results could be explained by altered tissue blood flow and a decreased metabolic capacity of the liver in obese subjects.
Stereoselective hydrolysis of O-acetyl propranolol as prodrug in human serum
Authors: Takahashi Koichi , Haginaka Jun , Tamagawa Satoko , Nishihata Toshiaki , Yasuda Hiroyuki , Katagi Toyoshi
Published: April 2011

A direct high-performance liquid chromatographic method was developed for the assays of the enantiomers of O-acetyl propranolol. Using this procedure, the stereochemical characteristics on hydrolysis of racemic O-acetyl propranolol as a prodrug have been studied in phosphate buffer (pH 7.4) and in 90% human serum. In the phosphate buffer, no difference in the hydrolysis rate between the esters of (R)- and (S)-propranolol was observed. In 90% human serum, the hydrolysis of the esters was accelerated, and the hydrolysis rate of the ester of (R)-isomer was about three times faster than that of the ester of (S)-isomer. The interconversion between (R)- and (S)-isomer was not observed during the hydrolysis of prodrug in buffer and in human serum. These results indicated that hydrolysis of O-acetyl propranolol occurs stereoselectively in human serum.
In-vivo and in-vitro hepatoprotective effect of 4-thia-prostaglandin E1 and 7-fluoroprostacyclin in rats
Authors: Koyama Tamotsu , Uno Hiroshi , Ishii Shigeyuki , Bannai Kiyoshi , Hasato Atsuo , Makita Tokutaro
Published: April 2011

4-Thia-prostaglandin E1 and to a lesser extent 7-fluoroprostacyclin showed a potent protective effect against carbon tetrachloride-induced liver injury in-vivo and in-vitro in rat.
Comparison of Calculated and Experimentally Determined Punch Displacement on a Rotary Tablet Press Using both Manesty and IPT Punches
Authors: Oates R J , Mitchell A G
Published: April 2011

An indirect method of calculating punch displacement on a rotary tablet press from measurements of the change in punch force with the turret position was in good agreement with direct measurements of punch displacement made using a linear variable displacement transducer (LVDT)-slip ring system. The direct measurements were made during the compaction of three direct compression agents using Manesty punches. However, the agreement between calculated and experimentally determined punch displacements was unsatisfactory when IPT punches were used. The IPT punches have a much flatter punch head profile than the Manesty punches. Due to this difference, the analytic equation does not accurately describe the dynamics of the press under normal operating conditions. Terms in the analytic equation, determined originally under static conditions, were re-evaluated under dynamic conditions for both sets of tooling using the LVDT-slip ring system. Excellent agreement for both IPT and Manesty punches was found between punch displacement calculated using the revised analytic equation and direct experimental measurements. Punch displacements determined from punch head profile and machine geometry only, without taking machine deformations into account, were shown to differ widely from the calculated and experimental values.
The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations
Authors: Rosland Jan Henrik , Hole Kjell
Published: April 2011

The effect of (±),(+) and (—)-nefopam on the uptake of 5-hydroxytryptamine (5-HT), noradrenaline and dopamine in synaptosomal preparations from rat forebrain, hippocampus and striatum has been investigated. All three forms of nefopam inhibited the amine uptake in the investigated structures, the order of potency being(+) > (±) > (—). (+)-Nefopam was 7–30 times more potent than (—)-nefopam. The same order of potency has also been found for the antinociceptive effect of these three forms, however, the differences were smaller. Inhibition of 5-HT and noradrenaline uptake may not be the sole mechanism underlying the analgesic effect of nefopam.
Relaxant and β2-adrenoceptor blocking activities of (±)-, (+)-and (—)-pindolol on the rat isolated aorta
Authors: Doggrell Sheila A
Published: April 2011

The KCl contracted rat aorta is relaxed by procaterol, (±)-,(+)-and (—)-pindolol. The relaxations to procaterol, but not to (±)-pindolol, were prevented by ICI 118,551 at 10−6 M. The relaxations to (±)-pindolol are, therefore, not due to β-adrenoceptor agonism. At 10−7 M ICI 118,551, (±)-, (+)-and (-)-pindolol were β2-adrenoceptor antagonists as they inhibited the relaxant responses of the aorta to procaterol.
Evaluation of Methodology for Assessing Release Characteristics of Thermosoftening Vehicles
Authors: Kopcha Michael , Tojo Kakuji J , Lordi Nicholas G
Published: April 2011

Methodology has been devised for the testing and evaluation of the mechanistic release of drug or markers from thermosoftening materials, as represented by the Gelucire class of excipients, which could be predictive. Release of a drug (anhydrous theophylline) and a marker (D&C yellow No. 10) was determined using a calibrated stationary disc/rotating fluid system. Of the fourteen commercially available Gelucire excipients, six were investigated in detail (G46/07, G48/09, G50/02, G50/13, G53/10, G62/05) and found to have biphasic release profiles. Lipid soluble materials demonstrated predominantly diffusion-controlled release, while water-dispersible materials absorbed water and showed signs of swelling which led to erosion as an additional component of the release characteristics.
The Possible Mechanism of Interaction between Xanthines and Quinolone
Authors: Hasegawa Takaaki , Nadai Masayuki , Kuzuya Takafumi , Muraoka Isao , Apichartpichean Ruttikorn , Takagi Kenzo , Miyamoto Kenichi
Published: April 2011

To clarify the mechanism of interaction between theophylline and enoxacin, the effects of enoxacin and its metabolite, 4-oxo-enoxacin, on the disposition of new xanthine derivatives, 1-methyl-3-propylxanthine (MPX) and 3-propylxanthine (enprofylline), as models of theophylline have been investigated in rats. Pretreatment with enoxacin significantly delayed the elimination of MPX from plasma. No significant change in the volume of distribution of MPX was observed in the presence of enoxacin, but the total body clearance of MPX was significantly decreased by approximately 60 and 80% after pretreatment with 25 and 100 mg kg−1 of enoxacin, respectively. The amount of the decrease in total body clearance depended on the dose of enoxacin. 4-Oxo-enoxacin had little or no effect on MPX disposition. A newly developed quinolone, NY-198, which does not affect the disposition of theophylline, also did not affect the disposition of MPX. Enoxacin also had no effect on the disposition of enprofylline. These results indicate that the mechanism for decrease in theophylline clearance induced by enoxacin may not be due to its metabolite, 4-oxo-enoxacin, but to enoxacin itself, and that enoxacin does not inhibit solely the elimination process depending on cytochrome P450 isoenzyme for N-demethylation. It is likely that enoxacin has no influence on the renal excretion of xanthines.
Prevention by a Ginkgo biloba Extract (GBE 761) of the Dopaminergic Neurotoxicity of MPTP
Authors: Ramassamy Charles , Clostre François , Christen Yves , Costentin J
Published: April 2011

In mice implanted subcutaneously with osmotic minipumps releasing the neurotoxic agent N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days (105 μg h−1/mouse) (∼ 100 mg kg−1 day−1) a significant reduction (∼ 25%) in the striatal dopaminergic nerve endings was observed. This neurotoxic effect was prevented by the semi-chronic ingestion of a Ginkgo biloba extract for 17 days (GBE 761, ∼ 100 mg kg−1 day−1). The high concentrations (∼ 1 g L−1) at which GBE 761 in-vitro either prevented the uptake of [3H]dopamine by synaptosomes prepared from striatum, or prevented the specific binding of the pure dopamine uptake inhibitor [3H]GBR 12783 to membranes prepared from striatum suggests that the prevention of the MPTP neurotoxicity does not depend on an inhibition of the MPTP uptake by dopamine neurons. This is also suggested by the lack of prevention of the in-vitro striatal binding of [3H]GBR 12783 administered i.v. at a tracer dose, in mice pretreated for 8 days with GBE 761 (100 mg kg−1 p.o.) and receiving a supplementary gastric administration of GBE 761 (100 mg kg−1) 1 h before testing. Similar treatment with GBE 761 did not modify the toxicity for dopamine neurons of 6-hydroxydopamine (20 μg) directly injected into the striatum of rats.
The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers
Authors: Titulaer H A C , Zuidema J , Kager P A , Wetsteyn J C F M , Lugt Ch B , Merkus F W H M
Published: April 2011

The pharmacokinetics after oral, intramuscular and rectal administration of artemisinin, a new potent antimalarial drug, to healthy volunteers has been examined. The study was set-up as a four-way cross-over design with a wash-out period of one week between the test days. In ten volunteers artemisinin concentrations in serum were monitored using a reversed phase HPLC assay with UV detection after derivatization. After oral administration, artemisinin was rapidly but incompletely absorbed, the mean absorption time was 0.78 h and the bioavailability relative to the intramuscularly injected suspension in oil 32%. The mean residence time of the latter (10.6 h) was 3 times that of the oral formulation (3.4 h). This seems to enable a twice daily dosage regimen for the intramuscular oil injection, while the oral formulation necessitates a more frequent dosing interval. After intramuscular injection and rectal administration of an aqueous suspension, very low and variable artemisinin concentrations in serum were observed, probably indicating a poor and erratic absorption.
Rat Paw Oedema and Mast Cell Degranulation Caused by Two Phospholipase A2 Enzymes Isolated From Trimeresurus mucrosquamatus Venom
Authors: Wang Jih-Pyang , Teng Che-Ming
Published: April 2011

Two phospholipase A2 (PLA2) enzymes, TMVPLA2 I and TMVPLA2 II, isolated from Trimeresurus mucrosquamatus venom (TMV) induce rat hind-paw oedema in a dose-dependent manner. This response is suppressed by pretreatment with diphenhydramine, methysergide or compound 48/80, which reduces tissue histamine content. In isolated mast cells, TMVPLA2 I and TMVPLA2 II cause concentration-, time-and calcium-dependent release of histamine and β-glucuronidase. This effect is inhibited by disodium cromoglycate, mepacrine, nordihydroguaiaretic acid, piriprost and BW 755C, but not by aspirin or indomethacin. These observations indicate that the mast cell plays a predominant role in TMVPLA2 I-and TMVPLA2 II-induced paw oedema, and that venom PLA2 enzyme needs an intact lipoxygenase pathway to induce mast cell degranulation.
A Survey of the Antibacterial Activity of Some New Zealand Honeys
Authors: Allen K L , Molan P C , Reid G M
Published: April 2011

To assess the variation in antibacterial activity of honey a survey was carried out on 345 samples of unpasteurized honey obtained from commercial apiarists throughout New Zealand. Most of the honeys were considered to be monofloral, from 26 different floral sources. The honeys were tested against Staphylococcus aureus in an agar well diffusion assay, with reference to phenol as a standard. Antibacterial activity was found to range from the equivalent of < 2% (w/v) phenol to 58% (w/v) phenol, with a median of 13·6 and a standard deviation of 12·5. Neither the age of the honey samples nor whether they had been processed by the apiarist was associated with lower activity. However, the difference between floral sources in the antibacterial activity was very highly significant. Kanuka (Kunzea ericoides (A. Rich.) J. Thompson. Family: Myrtaceae), manuka (Leptospermum scoparium J. R. et G. Forst. Family: Myrtaceae), ling heather (Calluna vulgaris (L.) Hull. Family: Ericaceae) and kamahi (Weinmannia racemosa Linn. f. Family: Cunoniaceae) were shown to be sources likely to give honey with high antibacterial activity. When antibacterial activity was assayed with catalase added to remove hydrogen peroxide, most of the honeys showed no detectable antibacterial activity. Only manuka and vipers bugloss (Echium vulgare L. Family: Boraginaceae) honeys showed this type of activity in a significant proportion of the samples. The high antibacterial activity of manuka honey was in many cases due entirely to this non-peroxide component.
Pharmacokinetics of Anti-HIV Nucleosides in Microswine
Authors: Swagler Anne R , Qian Mingxin , Gallo James M
Published: April 2011

The objective of the study was to determine if the micropig (Sus scrofa) would serve as an animal model for the anti-HIV nucleosides 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), and 2′,3′-dideoxycytidine (ddC). Four adult male micropigs were administered i.v. 20 mg kg−1 AZT, 20 mg kg−1 ddI, both as 10 min infusions, and 5 mg kg−1 ddC, as an i.v. bolus. At least 12 days separated each drug administration. Following each drug administration, blood samples were collected by venipuncture and urine was collected by placement of the animals in metabolism cages. Concentrations of parent drug and AZT's glucuronide metabolite were quantitated in plasma and urine by HPLC. Data were analysed by non-compartmental methods to obtain pharmacokinetic parameters for each drug. Total and renal clearances for AZT, 0·482 ± 0 058 and 0·326±0·075 L h−1 kg−1, respectively, and for ddI, 0·500±0057 and 0·337 ± 0·100 L h−1 kg−1, showed that these drugs were eliminated primarily by renal excretion rather than by liver metabolism as in man. ddC's clearances were similar to rates in man. Volume of distribution at steady state values were 0·784 ± 0·071, 1·192±0·288 and 0·886±0·199 L kg−1 for AZT, ddI and ddC, respectively. Half-life values for AZT, ddI and ddC were 1·39±0·127, 2·585 ± 0·243 and 1·832 ± 0·380 h, respectively. Based on these findings, the micropig could be an appropriate model for the study of ddC in man, but not for AZT of ddI.
β-Adrenoceptor Profile of Ractopamine HCl in Isolated Smooth and Cardiac Muscle Tissues of Rat and Guinea-pig
Authors: Colbert Walter E , Williams Patricia D , Williams Gail D
Published: April 2011

The investigational sympathomimetic amine, ractopamine hydrochloride, has been profiled for adrenergic activity in selected smooth and cardiac muscle preparations. There was no significant interaction of ractopamine with α-adrenergic receptors in the rat vas deferens at concentrations up to 10−5  m. However, ractopamine produced a concentration-dependent increase in the force and rate of contractions of atria isolated from normal and reserpinized guinea-pigs (EC50= 1 × 10−7  m). These increases were submaximal compared with isoprenaline (70–85%), suggesting partial agonist activity at the β1-receptor site. Ractopamine completely relaxed the KCl-contracted guinea-pig trachea and rat costo-uterine smooth muscle to their resting tensions (EC50 = 3 × 10−7 and 5·5 × 10−8m, respectively), indicative of full β2-agonist properties. Propranolol blocked the response of ractopamine in isolated tracheal and atrial tissues (pA2 = 7·70), demonstrating a β-adrenergic mechanism of activity. Ractopamine also exhibited antagonism of the response of the guinea-pig trachea to the β-agonist, isoprenaline. Relative to other β-agonists, ractopamine was 100-fold more potent than the phenethanolamines, salbutamol and ritodrine, at the β1-adrenoceptor, and approximately 7- to 11-fold more potent than ritodrine, but only one-sixth to one-tenth as potent as salbutamol at the β-adrenoceptor. Thus, ractopamine possesses significant β1- and β2-agonist properties. The submaximal stimulation of the force and rate of atrial contractions is indicative of a partial β1-agonist, while the maximal relaxation of tracheal and costo-uterine smooth muscle is characteristic of a full β2-agonist.
Pirarubicin-induced Endothelium-dependent Relaxation in Rat Isolated Aorta
Authors: Hirano Shin-Ichi , Agata Naoki , Hara Yutaka , Iguchi Hiroshi , Shirai Masataka , Tone Hiroshi , Urakawa Norimoto
Published: April 2011

The mechanism of relaxation produced by pirarubicin [(2″R)-4′-O-tetrahydropyranyladriamycin, THP] has been studied in rat isolated aorta. THP (1·5 × 10−6–4·5 × 10−5  m) markedly relaxed contractions induced by noradrenaline (10−7  m) in the aorta with endothelium, but not in that without endothelium. The relaxation induced by 1·5 × 10−5  m THP was inhibited by methylene blue (5 × 10−6  m), hydroquinone (10−4  m), phenidone (5 × 10−5  m), haemoglobin (10−6  m) and p-bromophenacyl bromide (5×10−5  m), but not by indomethacin (2·5 ×10−5  m). The relaxation induced by THP (1·5 × 10−7 − 4·5 × 10−5  m) was inhibited by NG-nitro-l-arginine (10−5  m), but enhanced by superoxide dismutase (10 units mL−1) or by L-arginine (10−2  m). However, the THP-induced relaxation was not inhibited by various receptor antagonists such as atropine (10−6  m), cimetidine (10−5  m), diphenhydramine (3 × 10−6  m) and [D-Pro4, D-Trp7,9,10]-substance P(4–11) (1·5 × 10−6  m). In fifteen anthracycline analogues, THP and 13-dihydropirarubicin (both with a tetrahydropyranyl group) produced endothelium-dependent relaxations. These results suggest that the THP-induced relaxation which is probably mediated by endothelium-derived relaxing factor (EDRF) was not produced by an activation of muscarine, histamine H1 or H2, or substance P receptor, and further that the tetrahydropyranyl group must play an important role in the THP-induced relaxation.
Receptor binding at two different temperatures to discriminate agonist and antagonist behaviour of adenosine A1 receptor ligands in rat brain
Authors: Borea Pier Andrea , Varani Katia , Malaguti Valeria , Gilli Gastone
Published: April 2011

The inhibitory binding constants, Ki, at the adenosine A1 receptor in rat brain have been measured at 0 and 25°C for 25 typical ligands. The Ki ratios at the two temperatures are greater and smaller than unity for adenosine agonists and xanthine antagonists, respectively. These results suggest that two-temperature measurements of in-vitro Ki constants represent a simple method of discriminating between in-vivo agonistic and antagonistic behaviour of A1 adenosine receptor ligands.
Inhibition of lipid peroxidation by methylated analogues of uric acid
Authors: Nishida Y
Published: April 2011

The effects of purines and methylated purine analogues on hydrogen peroxide- and ozone-induced lipid peroxidation in human erythrocyte membranes were studied in-vitro. Many purines and purine analogues showed a suppressive effect on the formation of thiobarbituric acid reactive materials. 1,3-Dimethyluric acid and 1,3,7-trimethyluric acid showed high potency in prevention of lipid peroxidation. These effects were shown to be concentration dependent and were more potent at low concentrations of hydrogen peroxide and ozone. 1,3-Dimethyluric acid and 1,3,7-trimethyluric acid may be useful as antioxidants.