bluuebunny/crossref_metadata_2025 huggingface dataset:
The Vagus Nerve and its Non-cholinergic Mechanism in the Modulation of Ethanol-induced Gastric Mucosal Damage in Rats
Authors: Ko J K S , Cho C H , Ogle C W
Published: April 2011

The role of the cholinergic pathway in the vagus nerve in modulating gastric lesion formation by ethanol was examined, using an ex-vivo stomach chamber preparation. Subdiaphragmatic vagotomy significantly increased the lesion areas but lowered acid secretion and gastric mucosal blood flow (GMBF). Atropine had no effect, whereas pirenzepine antagonized ethanol-induced mucosal damage. All three procedures showed similar potencies in depressing acid secretion, but only pirenzepine reversed the fall in the GMBF produced by ethanol. These differential effects of vagotomy, atropine and pirenzepine on gastric function suggest that the cholinergic component in the vagus nerve may not be important in the formation of ethanol-induced gastric damage. The persistent protective action as well as the restoration of ethanolinduced GMBF drop by pirenzepine in vagotomized animals further support this hypothesis. The worsening effect of vagotomy is probably modulated by a non-cholinergic mechanism, the abolition of which makes the gastric mucosa more susceptible to damage by ethanol. The acid-independent protective action of pirenzepine and its influence on the GMBF, which were not exhibited by atropine, are indeed unique and perhaps may be attributed to this non-cholinergic pathway.
Plasma Protein Binding of the Experimental Antitumour Agent Acridine-4-carboxamide in Man, Dog, Rat and Rabbit
Authors: Evans Sean M H , Robertson Iain G C , Paxton James W
Published: April 2011

The plasma binding of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) was investigated in-vitro by equilibrium dialysis for 3 h at 37°C against isotonic phosphate buffer (pH 7·35) using [3H]AC. There were significant species differences with the smallest % free fraction (mean ± s.d.) occurring in human plasma (3·4 ± 0·2), followed by dog (8·1 ±0·4), mouse (14·8 ± 0·8), rat (16·3 ± 0·9) and rabbit (20·2 ± 0·7). In plasma from healthy individuals (n = 5), the % free fraction ranged from 2·7 to 3·8. In physiological solutions of human proteins, the greatest binding was observed for α-acid glycoprotein (AAG) (0·75 g L−1) with a mean free fraction of 24·1 ± 2·2%, followed by albumin (40 g L−1) with 31·6 ± 0·7 and 39·8 ± 2·5% for fatty-acid-free and globulin-free, respectively. There was also some binding to globulins (5 g L−1) with a mean % free fraction of 70·3 ± 1·6 and 84·8 ± 2·2 for Conn’s fraction I and IV, respectively. Binding data from the displacement of [3H]AC by increasing concentrations of AC in human AAG (0·75 g L−1) or albumin solution (40 g L−1) indicated that AAG had 10-fold greater binding affinity for AC (Ka, 7·8 × 104 m−1) compared with albumin (Ka, 6·8 × 103 m−1). In human plasma enriched with AAG there was a significant negative linear correlation (r = 0·932; P < 0·001) between % AC free fraction and increasing AAG concentration over the range 0·6–4·5 g L−1. Small but significant (P < 0·05) increases in AC free fraction occurred in the presence of various metabolites (50 and 100 μm) but, of those tested, only N-monomethyl-acridine carboxamide increased the free fraction to the same extent as parent AC.
Development and Characterization of a Liposome Preparation by a pH-Gradient Method
Authors: Vemuri Sriram , Rhodes C T
Published: April 2011

A pH gradient across liposome bilayers was established in order to load a model drug (orciprenaline sulphate) into liposome vesicles. This method of liposome loading resulted in yields as high as 80–85% encapsulation. An eight-step process was designed to scale-up the process and was evaluated. In this process a diafiltration technique was successfully used to remove the excess orciprenaline sulphate present in the external medium. Finally, drug-loaded liposomes were lyophilized using lactose as an internal and external liposomal cryoprotectant. Five-month stability data for the liposomes is reported. An HPLC technique was used to determine the drug concentration and a laser light-scattering technique was employed to determine the liposome vesicle size and polydispersity factor. Liposomes prepared by the pH-gradient method showed high encapsulation efficiency. Upon storage at 2–8°C the vesicle size increased and encapsulation efficiency decreased with time. These phenomena are attributed to gradual fusion of liposomes and loss of drug to the extra-liposomal media.
Evaluation of a Liposome System for the Delivery of Desferrioxamine to Lungs in Rats
Authors: Tabak A , Hoffer E , Taitelman U
Published: April 2011

Liposomes with various lipid composition and sizes, prepared by two different techniques were evaluated for their potential to deliver desferrioxamine to lungs as a treatment against oxidative lung damage. Multilamellar vesicles (MLV) and reverse evaporation vesicles were prepared out of a lipid mixture containing dipalmitoyl phosphatidylcholine, stearyl amine, cholesterol and vitamin E. The administration of desferrioxamine-encapsulated liposomes to rats by the intravenous route at a dose of 100 mg kg−1, significantly prolonged the presence of desferrioxamine in all the tested organs when compared with the administration of free desferrioxamine. The injection of reverse evaporation vesicles extruded through a 2 μm polycarbonate membrane exhibited a longer residence time of the desferrioxamine and of liposomal vitamin E in lungs compared with the other types of liposomes tested. The examination of liposome components in the bronchoalveolar lavage fluid (BALF) and the alveolar macrophages recovered from BALF revealed that about 7 × 10−3% of the administered desferrioxamine dose was recovered by this technique at 3 and 17 h after liposome administration. This high residual concentration in the alveolar space confirms the hypothesis that liposomes can be delivered to the lung tissue when encapsulated in alveolar macrophages.
Effect of Perfusion Flow Rate on the Tissue Uptake of Solutes After Dermal Application Using the Rat Isolated Perfused Hindlimb Preparation
Authors: Cross Sheree E , Wu Zhenyu , Roberts Michael S
Published: April 2011

The rat perfused hindlimb preparation was investigated as a model to study the dermal clearance and tissue distribution of three solutes with differing physicochemical properties ([3H]water, [3H]diazepam, and [14C]lignocaine). The dermal clearance of each solute increased and the depth of tissue preparation decreased with increasing perfusion flow rate. The half-life for solute efflux from tissues into perfusate, and the peak times for amount of solute in tissue were in the order water > lignocaine > diazepam. Topical iontophoresis, which has previously been shown to achieve similar clearances from topical sites to those seen following passive dermal application, resulted in a clearance of lignocaine in the perfused hindlimb comparable with that obtained in the preparation following passive absorption through exposed dermis. The distribution of capillary blood flow in the perfused hindlimb was quantified using 51Cr-labelled 15-μm microspheres, with greater increases in flow found in deeper muscle tissues with increasing perfusion flow rate compared with superficial layers. Microsphere studies in anaesthetized rats also demonstrate slight differences in the distribution of flow within the hindlimb compared with the perfused preparation. We conclude that the rat perfused hindlimb preparation successfully combines many of the advantages of in-vitro and in-vivo methods and has potential for routine use in the study of solute dermal absorption kinetics.
A Stable and Highly Potent Hexamethonium Derivative Which Modulates Muscarinic Receptors Allosterically in Guinea-pig Hearts
Authors: Bejeuhr G , Blaschke G , Holzgrabe U , Mohr K , Sürig U , Terfloth G
Published: April 2011

W84 (N, N,N′,N′-tetramethyl-N,N′-bis-(3-phthalimidopropyl)-N,N′-hexane-1,6-diyl-bis-ammomum dibromide) is a potent stabilizer of antagonist binding to muscarinic receptors; however, W84 hydrolyses in aqueous buffered medium. The synthesis of the stable derivative CHIN3/6 is presented containing a 2-phenyl-quinazolinone instead of the labile phthalimide substituent. This compound retarded [3H]N-methylscopolamine-dissociation in guinea-pig cardiac membranes with slightly higher potency than W84, the EC50 values amounting to 7·5 × 10−7and 13× 10−7  m, respectively. Molecular modelling revealed differences in the electron density of the substituents and in their molecular shape. It is suggested that the derivatives use partially different sites of attachment when occupying the allosteric binding site of the receptor protein.
Intestinal bacterial hydrolysis is indispensable to absorption of 18β-glycyrrhetic acid after oral administration of glycyrrhizin in rats
Authors: Akao Teruaki , Hayashi Tomoko , Kobashi Kyoichi , Kanaoka Matao , Kato Hiromi , Kobayashi Masashi , Takeda Shuichi , Oyama Tsutomu
Published: April 2011

Gnotobiote rats were prepared by infecting germ-free rats with Eubaclerium sp. strain GLH, a human intestinal bacterium capable of hydrolysing glycyrrhizin to 18β-glycyrrhetic acid. Their faeces and caecal contents showed glycyrrhizin-hydrolysing activities (31·7 and 31·3 pmol min−1 (mg protein)−1, respectively) similar to those (81·0 and 39·9 pmol min−1 (mg protein)−1, respectively) of conventional rats, although there was no detectable activity in germ-free rats. When glycyrrhizin (100 mg kg−1) was orally administered to conventional, germ-free and gnotobiote rats, no glycyrrhizin could be detected in plasma 4 or 17 h after the administration, using EIA and HPLC assays. Plasma 18β-glycyrrhetic acid was not detected 4 or 17 h after the administration of glycyrrhizin to germ-free rats nor could this compound be detected in caecal contents or in the faeces. However, 18β-glycyrrhetic acid (0·6–2·6 nmol mL−1) was detected in plasma of the conventional and the gnotobiote rats 4 and 17 h after the administration, and the caecal contents after 4 h and the cumulative faeces up to 17 h of the conventional and the gnotobiote rats contained considerable amounts of 18β-glycyrrhetic acid. These findings indicate that orally administered glycyrrhizin is poorly absorbed from the gut, but is hydrolysed to 18β-glycyrrhetic acid by intestinal bacteria such as E. sp. strain GLH, and the resulting 18β-glycyrrhetic acid is absorbed.
Interactions of opioids with caffeine: evaluation by ambulatory activity in mice
Authors: Kuribara Hisashi , Uchihashi Yoshitaka
Published: April 2011

Morphine (up to 10 mg kg−1), buprenorphine (up to 0·1 mg kg−1), pentazocine (30 mg kg−1) and caffeine (up to 10 mg kg−1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D1- and D2-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0·1–3 mg kg−1) itself did not change mouse ambulation, at 3 mg kg−1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg−1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg−1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg−1) with buprenorphine (0·3 mg kg−1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg−1) by the repeated treatment with buprenorphine (0·3 mg kg−1) was inhibited by caffeine (10 mg kg−1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on μ- or σ-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.
Effects of hypolipidaemics cetaben and clofibrate on mitochondrial and peroxisomal enzymes of rat liver
Authors: Schön Hans J , Grgurin Mario , Klune Gerhard , Prager Christiane , Marz Richard , Legenstein Elisabeth , Böck Peter , Kramar Robert
Published: April 2011

Clofibrate or cetaben was administered to male rats for 10 days. Peroxisomal and mitochondrial enzymes were assayed in liver subcellular fractions. Clofibrate affected the specific activities of both mitochondrial enzymes (glycerol-3-phosphate dehydrogenase and nicotinamide-linked isocitrate dehydrogenase) and peroxisomal enzymes (fatty acyl-CoA oxidase, glycerone phosphate acyltransferase, urate oxidase, and D-amino-acid oxidase). In contrast, cetaben raised only the peroxisomal enzymes, acyl-CoA oxidase, glyceronephosphate acyltransferase, D-amino-acid oxidase, catalase, and urate oxidase. Thus, the hypolipidaemic activity of these drugs may be. exclusively related to stimulated peroxisomal functioning, while mitochondria play only a minor role.
Aluminium β-Cyclodextrin Sulphate as a Stabilizer and Sustained-release Carrier for Basic Fibroblast Growth Factor
Authors: Fukunaga Kazuhiro , Hijikata Shigeki , Ishimura Kimihiro , Sonoda Ryouichi , Irie Tetsumi , Uekama Kaneto
Published: April 2011

The water-insoluble aluminium salt of β-cyclodextrin sulphate (Al · β-CyD-Sul) was used as a stabilizer and sustained-release carrier for recombinant human basic fibroblast growth factor (bFGF). An adsorbate of bFGF with Al · β-CyD-Sul was prepared by incubating the protein with a suspension of Al · β-CyD-Sul in water. The mitogenic activity of bFGF released from the adsorbate, as indicated by the proliferation of kidney cells of baby hamster (BHK-21), was almost comparable with that of the intact bFGF. Al-β-CyD-Sul significantly protected bFGF from proteolytic degradation by pepsin and α-chymotrypsin, compared with the water-soluble sodium salt. The in-vitro release of bFGF from the adsorbate was sustained in proportion to a rise in the ratio of Al · β-CyD-Sul to the protein in the adsorbate. Of the bFGF preparations evaluated, the adsorbate of bFGF with Al ·β-CyD-Sul, when given subcutaneously to the rat, showed the most prominent increase in the formation of granulation tissues, due to the stabilization and slow-release of the mitogen. The limited data presented here suggest that the adsorbate of bFGF with Al · β-CyD-Sul has a potent therapeutic efficacy for wound healing, and may be applicable to oral protein formulations for the treatment of intestinal mucosal erosions.
The Aggregation of Bovine Serum Albumin in Solution and in the Solid State
Authors: Jordan Geraldine M , Yoshioka Sumie , Terao Tadao
Published: April 2011

The aggregation of bovine serum albumin (BSA) in the solid state and in solution was studied to elucidate the effect of water mobility on the aggregation rate and mechanism. The results suggest that the freeze-dried BSA forms covalently-bonded aggregates via disulphide bonding during storage in the moistened solid state and in solution. The aggregation rate largely depended on the water content. The freeze-dried BSA to which a small amount of water was added (in the moistened state) was found to be more liable to aggregation than that in solution. The aggregation rate in the moistened solid state exhibited a maximum at a very low level of moisture. In contrast, the aggregation rate in solution increased with increasing ratio of water to protein (with decreasing protein concentration). The results suggest that the increased rate is related to the increase in water mobility, as measured by the spin-lattice relaxation time, T1, of water using 17O NMR, with increasing ratio of water to protein.
In-vitro Interaction between H2 Antagonists and Vecuronium
Authors: Mishra Y , Torda T , Ramzan I , Graham G
Published: April 2011

The interaction between histamine H2 antagonists and the neuromuscular blocking drug vecuronium was investigated in the rat phrenic nerve-hemidiaphragm preparation. Cimetidine alone, in the concentration range 800–4000 μm produced between 14 and 74% neuromuscular paralysis with an EC50 (mean ± s.e.) of 2900 ± 100 μm. Ranitidine augmented the indirectly-evoked muscle response at concentrations between 30 and 160 μm but at higher concentrations, between 300 and 1800 μm, produced neuromuscular paralysis. Famotidine produced negligible and statistically insignificant (0–5%) neuromuscular paralysis at concentrations between 0·3 and 300 μm. Cimetidine (800 μm) shifted the neuromuscular concentration-effect curve of vecuronium to the left in a parallel manner, while ranitidine (160 μm) shifted it to the right. The potentiation ratio was 1·90 ± 0·14 for cimetidine and 0·62 ± 005 for ranitidine. Famotidine (30 μm) did not alter the response to vecuronium. These data indicate that higher than clinically relevant concentrations of cimetidine and ranitidine produce neuromuscular paralysis and may potentiate the action of vecuronium. Low concentrations of ranitidine may antagonize the action of vecuronium. Famotidine, in contrast, lacks significant neuromuscular effects.
The Disposition of Thioperamide, a Histamine H3-Receptor Antagonist, in Rats
Authors: Sakurai Eiichi , Gunji Eri , Iizuka Yukisumi , Hikichi Noboru , Maeyama Kazutaka , Watanabe Takehiko
Published: April 2011

An HPLC method using an ovomucoid-conjugated column has been developed for measurement of thioperamide, a histamine H3 antagonist, with a minimum quantitation limit of 0·05 μg mL−1 The assay was used to study the disposition of thioperamide in rats. After bolus intravenous administration of thioperamide (10 mg kg−1), the plasma concentration decreased monoexponentially with a half-life of 26·9 min. The apparent total body clearance of thioperamide from rat plasma was 74·6 mL min−1 kg−1. Although thioperamide was quickly transferred to various tissues, its concentrations in peripheral tissues were higher than that in the brain. However, the brain regional tissue/plasma ratios of thioperamide increased continuously after its injection.
Adaptogenic and Cardioprotective Action of Galleria mellonella Extract in Rats and Frogs
Authors: Rachkov A K , Spiridonov N A , Kondrashova M N
Published: April 2011

Pharmacological and metabolic effects of Galleria mellonella larvae extract used in Russian folk medicine to treat cardiovascular and senile diseases were studied. It was shown that the extract possesses adaptogenic, cardiotropic, cardioprotective, and hypocoagulant properties. The extract possesses low toxicity and does not cause significant changes in biochemical parameters in the blood serum of laboratory animals. Increase in catecholamine content in the heart and aortic tissues and their decrease in adrenal glands are unfavourable effects of high doses of the extract.
Enzymatic Hydrolysis of Zenarestat 1-O-Acylglucuronide
Authors: Tanaka Yoshio , Suzuki Akira
Published: April 2011

Zenarestat, (3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-y1) acetic acid, an aldose reductase inhibitor is metabolized mainly to the glucuronide in rat and man. The glucuronide was purified from urine of volunteers after ingestion of zenarestat. The structure of the glucuronide was confirmed by LC-MS and NMR as 1-O-acyl-β-glucuronide. This compound was unstable at physiological pH, being converted to its structural isomers and the aglycone with half-life of 25 min at pH 7·4 and 37°C in aqueous solution. Enzymatic hydrolysis of the glucuronide was studied in urine, blood and tissues. β-Glucuronidase in human urine contributed little to the hydrolysis of the glucuronide, while in rat urine at pH 6, it was degraded by β-glucuronidase and the formation of zenarestat was clearly faster than its formation in buffer at pH 6. In both rat and human blood, these reactions were accelerated by albumin, although rat red blood cells may also contribute. The rate of degradation was not affected by red blood cell membrane, haemoglobin, globulin, esterases or β-glucuronidase. Arylesterase in rat liver, arylesterase and acetylcholinesterase in the kidney, and β-glucuronidase in both tissues may contribute. Thus, enzymatic degradation of zenarestat 1-O-acyl-β-glucuronide is dependent not only on pH and temperature but also on species and the type of tissue or body fluid.
Purine- and Nucleotide-mediated Relaxation of Rabbit Thoracic Aorta: Common and Different Sites of Action
Authors: Chinellato A , Ragazzi E , Pandolfo L , Froldi G , Caparrotta L , Fassina G
Published: April 2011

The mechanisms of the relaxant effect of purines and pyrimidines in New Zealand rabbit isolated aorta were investigated at endothelial and smooth muscle cell levels. Endothelium-mediated relaxation by ATP was only partially inhibited by the P2-purinoceptor antagonist suramin (0·1 Mm). The pyrimidine UTP produced vasodilation by acting at the endothelial level and relaxation was not antagonized by suramin (0·1 Mm). This effect was not mediated by P2 purinoceptors, indicating that UTP, like ATP to a certain extent, produces relaxation via an endothelium nucleotide (N) pyrimidinoceptor. ATP, ADP, AMP, adenosine, 5′-N-ethylcarboxamidoadenosine (NECA) and inosine were all active as relaxants on smooth muscle. The NECA relaxant effect was not antagonized by P1-purinoceptor antagonists 3,7-dimethyl-1-propargylxanthine (50 μm) or 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (5 μm), excluding a P1-mediated effect. P2-related activity was excluded because adenosine-mediated relaxation was not antagonized by suramin (0·1 Mm). UTP was ineffective as a relaxant at smooth muscle level, thus excluding the presence of muscular nucleotide (N) pyrimidinoceptor and suggesting a P3 purinoceptor. The rank order of potency of this muscle purinoceptor was NECA > adenosine > ATP ≅ ADP ≅ AMP ≅ inosine.
Disposition of Nifurtimox and Metabolite Activity Against Trypanosoma cruzi using Rat Isolated Perfused Liver
Authors: González-Martin Guillermo , Paulos Claudío , Guevara Alfredo , Ponce Graciela
Published: April 2011

Nifurtimox disposition was investigated using the rat isolated perfused-liver method after administration of 25 μg mL−1 nifurtimox, and its disappearance was monitored by analysing the perfusate sample at various times. Biliary excretion was also measured. The drug concentration profile underwent a biexponential decline over the 2-h study period, with a terminal half-life of 62·76 ± 17·56 min. Nifurtimox is a high clearance compound (15·23±5·53 mL min−1). The extraction ratio was 0·621 ±0·159. Biliary excretion accounted for 0·05% of the dose, the remainder consisting of highly polar metabolites. By 2 h, a minimal fraction of unchanged nifurtimox was recovered from the perfusate. Nifurtimox activity against Trypanosoma cruzi (clone CA-1) during the perfusion was also determined. Epimastigotes isolated from continuous culture were exposed to the samples of perfusate at different perfusion times in a microtitre plate. After an incubation time of 72 h at 27°C, the parasite number in each well was counted under a microscope. From 0 to 75 min after the perfusion, the anti-trypanosomal activity decreased, but an increase in activity was observed at the later times. These findings show that active metabolites are formed during the perfusion.
Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the dissociation of the drug
Authors: Sakane Toshiyasu , Akizuki Motohiro , Yamashita Shinji , Sezaki Hitoshi , Nadai Tanekazu
Published: April 2011

We aimed to clarify the relationship between drug dissociation (sulphisomidine) and its direct transport from the nasal cavity to the cerebrospinal fluid (CSF). Rat nasal cavities were perfused in a single pass system with buffers (pH 5·5, 6·5, 7·4, 8·7 and 9·4). Plasma and CSF were collected and the concentration of sulphisomidine was measured. Nasal clearance increased with the increase in the un-ionized fraction of the drug. The ratio of the drug concentration in CSF to that in the nasal perfusion fluid (the index of the degree of the drug transport from the nasal cavity to CSF), was changed in accordance with the un-ionized fraction of drug. These results show that both the nasal absorption and the drug transport conform to the pH partition theory.
Vasorelaxing effect in rat thoracic aorta caused by laurotetanine isolated from Litsea cubeba Persoon
Authors: Chen Wen-Ying , Ko Feng-Nien , Wu Yang-Chang , Lu Sheng-Teh , Teng Che-Ming
Published: April 2011

The pharmacological effects of laurotetanine on rat isolated thoracic aorta were examined. The contraction of aortic rings caused by high potassium (60 Mm) and cumulative concentrations of calcium (0†03–3 Mm) was inhibited by 3–50 μm laurotetanine in a dose-dependent manner with an IC50 value of 19·8 ± 3·6 μm (n = 6) in a 1 Mm Ca2+ medium. The phenylephrine (3 μm)-induced contraction was also inhibited by laurotetanine. Its effect was more marked on the tonic contraction than on the phasic contraction and was not easily washed-out. On addition of laurotetanine during the tonic contraction, relaxation could also be observed. This relaxing effect was not antagonized by indomethacin (20 μm) and was still seen in denuded aorta or in the presence of nifedipine (1 μm). The caffeine (20 Mm)-induced contraction was not affected by laurotetanine. cAMP and cGMP levels of aorta were not changed by laurotetanine. It is concluded that laurotetanine relaxed the rat thoracic aorta mainly by suppressing the Ca2+ influx through both voltage- and receptor-operated calcium channels.
Effects of epidermal growth factor dosage forms on dermal wound strength in mice
Authors: Çelebi N , Erden N , Gönül B , Koz M
Published: April 2011

The effect of topically administered epidermal growth factor (EGF) dosage forms was investigated on skin wound healing in mice. Two EGF dosage forms were prepared containing 100 ng mL−1 EGF. The solution dosage form was prepared in 0·9% w/v NaCl. A bioadhesive gel form was prepared in 0·2% Carbopol 940 polymer. The two dosage forms were applied on the skin incision wounds of mice at the rate of 5 μL twice a day for 7 and 15 days. The wound tear strength was tested for skin wound healing at the 7th and 15th days of treatment and compared with controls. The results indicate that the wound tear strength of mice were significantly higher at the 15th day of treatment in the gel-treated group compared with the solution-treated mice and controls (P < 0·001).
Modification of the Dissolution Behaviour of a Water-insoluble Drug, Naftazone, for Zero-order Release Matrix Preparation
Authors: Giunchedi Paolo , Maggi Lauretta , La Manna Aldo , Conte Ubaldo
Published: April 2011

The preparation of hydrophilic matrix tablets able to release naftazone, a water-insoluble drug, into an aqueous medium at a constant rate (zero-order dissolution) is described. Enhancement of dissolution rate of the drug was achieved using cross-linked carmellose sodium, β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Hypromellose was used as a water-gelling polymer. Tablets could be prepared that released naftazone at a constant rate over 16 h.
Plasma Levels of Peptide YY Correlate with Cisplatin-induced Emesis in Dogs
Authors: Perry Marc R , Rhee John , Smith William L
Published: April 2011

The effect of cisplatin on plasma peptide YY (PYY) and 5-hydroxytryptamine (5-HT) concentrations was determined in conscious dogs (n = 6 per group) pretreated with either saline, or the 5-HT3-receptor antagonists ondansetron or granisetron. Cisplatin (30 mg kg−1, i.v.) caused emesis (18·8 ± 2·9 episodes; 75–284 min) and significantly increased the mean area under the curve (AUC) over a 6-h period of plasma PYY concentrations (7·4 ± 1·8 to 11·5 ± 3·7 ng) in all saline-pretreated dogs, whereas the mean AUC of plasma 5-HT concentrations did not significantly increase (34·7 ± 7·4 vs 35·6 ± 12·3 pM h). The concentrations of PYY correlated closely with the incidence of emesis (r = 0·99). In animals pretreated (36 min) with ondansetron (0·316 mg kg−1, i.v.) or granisetron (0·316 mg kg−1, i.v.), the number of cisplatin-induced emetic episodes was significantly (P < 0·005) decreased compared with control. In animals receiving cisplatin and pretreated with ondansetron, PYY concentrations were not significantly altered, whereas the mean AUC of plasma concentrations of 5-HT over 6 h increased (35·6 ± 12·3 to 82·3 ± 34·6 Pm h; P < 0·05). In animals receiving cisplatin and pretreated with granisetron, plasma concentrations of 5-HT were not significantly altered, whereas the mean AUC of plasma PYY concentrations were significantly reduced compared with control (6·2 ± 1·7 vs 11·5 ± 3·7 ng h). Furthermore, in animals receiving ondansetron without cisplatin treatment, there was no change in the mean AUC of 5-HT or PYY concentrations, whereas the mean AUC of plasma 5-HT concentrations increased significantly (34·7 ± 7·4 to 68·6 ± 37·2 Pm h; P < 0·05) in animals treated with granisetron alone. These studies indicate that plasma concentrations of PYY, and not 5-HT, correlate with cisplatin-induced emesis in dogs. Peptide YY may be an important mediator in cancer chemotherapy-induced emesis and other types of emesis.
U-46619-induced Ischaemic Electrocardiographic Changes in Rats: Preventive Effects of Prostacyclin and Nitroglycerin
Authors: Yamamoto Taku , Kikuta Chie , Hosoki Kanoo
Published: April 2011

The anti-anginal effect of nitroglycerin and prostacyclin was examined using, as an index, the ischaemic electrocardiogram (ECG) change (ST elevation) induced by intracoronary arterial injection of 9,11-dideoxy-11α,9α-epoxymethano-PGF2α (U-46619), a stable thromboxane A2 agonist, in anaesthetized rats. The ST elevation induced by U-46619 (5–20 μg kg−1, i.c.a.) was dose-dependent and reproducible. U-46619-induced ST elevation was markedly prevented by the pretreatment of intravenous administration of prostacyclin (0·01 μg kg−1), and to a lesser extent by nitroglycerin (0·3 mg kg−1). Simultaneously, platelet count decreased significantly in the coronary arterial blood which indicated that platelet aggregation was enhanced by U-46619. The decrease of platelet count in coronary arterial blood at the time of ST elevation was significantly suppressed by prostacyclin (0·1 μg kg−1, i.v.), but not by nitroglycerin (0·3 mg kg−1, i.v.). These results suggest that the ST elevation induced by intracoronary arterial injection of U-46619 may be derived from spasm of coronary artery and platelet aggregation in the intracoronary artery in rats.
Metabolic Cage Isolation Reduces Antipyrine Clearance in Rats
Authors: Brunner Lane J , Dipiro Joseph T , Feldman Stuart
Published: April 2011

Rats are commonly isolated individually in cages during pharmacokinetic studies. However, isolation-induced changes in drug disposition are not commonly examined. Antipyrine is a marker of hepatic oxidative function and total body water. The purpose of the study was to investigate the effect of individual housing on antipyrine pharmacokinetics. Rats were individually housed in either standard polycarbonate boxes (n = 8) or metabolic cages (n = 10). On day 1 and day 9 rats were administered a single intravenous bolus injection of antipyrine 20 mg kg−1. Blood samples (100 μL) were obtained before and at 20, 40, 60, 90, 120, 180, 240, 300 and 360 min following the administration of the dose. Rats remained in their respective cages between evaluations. Serum antipyrine concentrations were determined by capillary electrophoresis. Pharmacokinetic parameters were estimated by model-independent methods. Antipyrine clearance was reduced by 383·4% in rats isolated in metabolic cages for eight days (P = 0·013) while the volume of distribution remained unchanged in both rat groups. These data suggest that the isolation of rats in metabolic cage systems may markedly alter the pharmacokinetics of xenobiotics, thus possibly masking experimental outcome.
Enantioselective Pharmacokinetics of Homochlorcyclizine: Disposition of (+)- and (–)-Homochlorcyclizine after Intravenous and Oral Administration of Racemic Homochlorcyclizine to Rats
Authors: Nishikata Mayumi , Nakai Aki , Fushida Hitomi , Miyake Keishiro , Arita Takaichi , Iseki Ken , Miyazaki Katsumi
Published: April 2011

Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg−1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg−1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (–)-isomer. The AUC0-x values of the (+)- and (–)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (–)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.
Pharmacokinetics and brain distribution of zolpidem in the rat after acute and chronic administration
Authors: Trenque T , Bustany P , Lamiable D , Legros S , Choisy H
Published: April 2011

The pharmacokinetics of zolpidem were studied after single dose, administered for either 7 or 28 days to rats. Thirty minutes after the last dose, animals were killed and the brain removed. The highest concentrations in plasma, which were observed at the first sampling time (0·5 h) were 2341±540 (day 0), 1956 ± 325 (day 7) and 2908 ± 1369 ng mL−1 (day 28). Corresponding AUC values of 1742 ± 488, 1583 ± 422 and 2683 ± 1249 ng mL−1 h were found. MRT increased significantly from 0·46 ± 0·06 h on day 0 to 0·67 ± 0·02 h on day 28. The cerebral levels showed no significant change during the chronic administration (766 ± 285, 685 ± 171 and 887 ± 264 ng g−1, respectively). No modification of the principal kinetic parameters was detected up to the 28th day of treatment.
Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent, and indomethacin after oral administrations in rats
Authors: Yamada Ichimaro , Nagamatsu Yuko , Imayoshi Tomonori , Shibata Masahiro , Tsuji Akira
Published: April 2011

N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M1) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M1 and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean Cmax (1·13 μg mL−1) of M1 after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean Cmax (3·38 μg mL−1) after 3 h in plasma. The mean AUC of M1 and indomethacin in plasma were 5·45 μg h mL−1 and 22·49 μg h mL−1, respectively. The mean tmax, Cmax and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/108 cells and 58·6 ng (164 pmol) h/108 cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/108 cells and 95·2 ng (266 pmol) h/108 cells, respectively. The PMNs/plasma ratio of M1 was about 2·8 times that of indomethacin. These results indicate that the association of M1, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.
The Influence of Cosolvents on the In-vitro Percutaneous Penetration of Diclofenac Sodium From a Gel System
Authors: Ho Hsiu-O , Huang Feng-Chin , Sokoloski Theodore D , Sheu Ming-Thau
Published: April 2011

The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, alcohol and propylene glycol with Carbomer 940. The synthetic membrane Durapore and hairless mouse skin were employed as barriers in a Franz-type diffusion cell. It was found that the penetration through the synthetic membrane was well described by the Higuchi model. There existed a better inverse relationship between the penetration rate and the drug solubility in the respective vehicle. It appeared to be a membrane-controlled mechanism when using hairless mouse skin as the barrier. The penetration rates in steady-state for nine formulations were fitted to a polynomial equation based on this simplex lattice method. A three-dimensional plot was constructed in this simplex surface studied. The maximal penetration rate was found to be from the vehicle containing water and ethanol in an exact volume ratio of 3:1 and the minimal penetration rate was observed from the vehicle containing water only.
Nasal Absorption of Desmopressin in Rats and Sheep. Effect of a Bioadhesive Microsphere Delivery System
Authors: Critchley H , Davis S S , Farraj N F , Illum L
Published: April 2011

The nasal absorption of desmopressin was studied in two animal models, the rat and the sheep. The bioavailability after nasal administration was found to be 13 times higher in the rat model. This discrepancy is suggested to be due to the impaired mucociliary clearance mechanism in the rat model and possibly differences in enzymatic degradation and elimination rates of the drug. The effect of the addition of L-α-lysophosphatidylcholine (LPC) to the formulations as an absorption enhancer was most pronounced in the sheep model. The use of the bioadhesive starch microsphere delivery system, especially in combination with LPC, had a profound effect on the absorption of desmopressin in sheep, with bioavailabilities reaching nearly 10% compared with 1·2% for a simple nasal solution of desmopressin.
Constipation Evoked by 5-HT3-Receptor Antagonism: Evidence for Heterogeneous Efficacy among Different Antagonists in Guinea-pigs
Authors: Sanger G J , Wardle K A
Published: April 2011

The abilities of selective 5-HT3-receptor antagonists to evoke constipation were examined in conscious guinea-pigs and in preparations of guinea-pig isolated colon. Compared with vehicle-treated guinea-pigs, acute doses of granisetron (0·1, 1 and 10 mg kg−1, i.p.) and tropisetron (10 mg kg−1, i.p., but not 1 and 0.1 mg kg−1, i.p.) significantly (P < 0·05) reduced the total number of faecal pellets excreted during a 12-h observation period. By contrast, BRL 46470 (0·1–10 mg kg−1, i.p.) had no significant effect on the incidence of defecation. Mid-to-distal lengths of guinea-pig isolated colon spontaneously expelled faecal pellets. Granisetron (0·1 and 1 μm) and tropisetron (1 μm) reduced or prevented the rate at which they were spontaneously expelled. Morphine (0·1 μm) and clonidine (10 nm) also slowed faecal pellet transit time. Naloxone (0·1 μm) had no effects alone, but reversed the actions of granisetron, morphine and clonidine. BRL 46470 (1 μm) had no significant effect on the transit of faecal pellets in guinea-pig isolated colon. In segments of guinea-pig isolated colon which did not contain faecal pellets, granisetron, tropisetron and BRL 46470 antagonized the ability of 5-HT to evoke cholinergically-mediated contractions of the longitudinal muscle. The respective pA2 values and slopes of the Schild plots were 8·5 ± 0·05, slope 1·06 ± 0·03; 8·5 ± 0·1, slope 0·91 ± 0·04; and 7·9 ± 0·1, slope 0·93 ± 0·05. Our experiments suggest that not all 5-HT3-receptor antagonists are the same. In particular, BRL 46470 does not prevent defecation or faecal pellet expulsion in guinea-pig colon, even though this compound is an effective 5-HT3-receptor antagonist in the same tissue. For the 5-HT3-receptor antagonists which did cause constipation, the effects can be at least partly attributed to an indirect opioid-dependent action within the colonic enteric nervous system.
The Release of Macromolecules from Fatty Acid Matrices: Complete Factorial Study of Factors Affecting Release
Authors: Kaewvichit S , Tucker I G
Published: April 2011

A replicated complete factorial design to study the main effects and interactions of four factors: bovine serum albumin (BSA) particle size (Factor A); stearic acid particle size (Factor B); BSA loading (Factor C); and compression force (Factor D), on the release of BSA from compressed stearic acid pellets was performed in isotonic phosphate buffer pH 7·4 at 37°C. Samples were withdrawn over 64 h. Analysis of variance of the percentage released at 64 h showed that A, B, and C., but not D, affected the release and the interactions AB, BC, ABC were highly significant. At low loading (5%), the surface release depended on BSA particle size. The release increased when BSA particle size was large. At high loading (20%), more release was shown when stearic acid particle size was large. More release with increasing BSA particle size occurred only when stearic acid particle size was small. It is proposed that release is due to the interconnected pore networks created, not only by BSA particles, but also by the void space between stearic acid particles. These void spaces vary according to particle size-dependent arrangements of stearic acid and BSA particles. An increase in the pellet thickness was observed probably due to the relaxation of compacted stearic acid particles.
Biodegradable Controlled Antibiotic Release Devices for Osteomyelitis: Optimization of Release Properties
Authors: Zhang Xichen , Wyss Urs P , Pichora David , Goosen Mattheus F A
Published: April 2011

Controlled antibiotic release films, melt-extruded cylinders, and suspension-extruded/coated cylinders were manufactured from biodegradable poly(d, l-lactide) (PDLLA) and poly(d, l-lactide-co-∈-caprolactone). These devices have potential application in the treatment of osteomyelitis. The in-vitro release properties of the devices were examined with drug loadings varying from 16 to 50%. Gentamicin sulphate films and melt-extruded gentamicin/PDLLA cylinders demonstrated a large initial burst and incomplete release. The films and melt-extruded cylinders made from poly(d, l-lactide-co-∈-caprolactone), low mol. wt poly(d, l-lactide), and a mixture of d, l-lactic acid oligomer and high mol. wt poly(d, l-lactide), did not remain intact during the entire release period. While this is undesirable, these materials do have the advantage of not requiring a processing temperature of greater than 110°C. Antibiotic release from high mol. wt PDLLA-coated gentamicin/PDLLA cylinders, with 40 and 50% loading, was very rapid. The antibiotic could only diffuse out through the open ends of the cylinder. Coated gentamicin sulphate cylinders with 20 and 30% drug loading gave the most promising properties in terms of a small initial burst, and a gradual and sustained release. The release rate and duration from the coated cylinders could be adjusted by cutting the cylinder into different lengths; the time required for 90% of the entrapped gentamicin to be released into water from 30% loaded PDLLA-coated cylinders 0·2, 0·4, 0·7 and 1 cm in length was 1000, 1700, 2300, and 2800 h, respectively. This offers a convenient method to adjust the release to meet the specific antibiotic requirement of different patients. Cephazolin and benzylpenicillin were found to be unsuitable for sustained release longer than 300 h due to the hydrolytic instability of the drugs in water.
Effect of caffeine and nicotine on avoidance learning in mice: lack of interaction
Authors: Sansone Mario , Battaglia Mario , Castellano Claudio
Published: April 2011

Tested alone, nicotine (0·25 or 0·5 mg kg−1) improved shuttle-box avoidance learning in mice of the CD-1 strain. Caffeine had no effect at doses of 2·5 and 5 mg kg−1 and impaired performance at a dose of 10 mg kg−1. Combinations of the two drugs did not increase avoidance responses more than nicotine alone, nor was nicotine able to attenuate performance depression induced by the highest dose of caffeine. Lack of drug interaction in the avoidance test contrasts with the occurrence of interactive effects of the two drugs in a locomotor activity test. When given in combination, caffeine and nicotine increased locomotor activity at doses ineffective by themselves. The results seem to indicate no advantage in combining caffeine and nicotine to improve active avoidance learning.
Effect of Preservatives on Systemic Delivery of Insulin by Ocular Instillation in Rabbits
Authors: Sasaki Hitoshi , Tei Choyu , Yamamura Kenzo , Nishida Koyo , Nakamura Junzo
Published: April 2011

The effects of absorption promoters and ophthalmic preservatives on the systemic absorption of insulin through the ocular route were investigated in albino rabbits. Insulin absorption was evaluated by its hypoglycaemic response. Although ocular instillation of insulin alone did not decrease the serum glucose concentration, instillation of insulin with absorption promoters such as EDTA and saponin decreased it. The promoting effect depended on the concentration of the absorption promoters. Of ophthalmic preservatives investigated (benzalkonium chloride, paraben, 2-phenylethanol, benzyl alcohol and sorbic acid), benzal-konium, chloride and paraben showed promoting effects. The promoting effect for benzalkonium chloride was reversible and dependent on concentration of both benzalkonium chloride and insulin in the formulation.
Alterations of In-vitro 5-HT Receptor Pharmacology as a Function of Multiple Treatment with 5-Hydroxytryptamine or 8-Hydroxy-2-(di-N-propylamino) Tetralin in Rat Isolated Aorta, Uterus and Fundus, and Guinea-pig Isolated Trachea
Authors: Helton David R , Colbert Walter E
Published: April 2011

The effects of single and multiple (5, 10, or 15 days) administration of the 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) (3 mg kg−1, i.p.) or 5-HT (3 mg kg−1, i.p.) in-vivo on the response of selected isolated smooth muscles to 5-HT in-vitro were investigated. Single dosing with 8-OH-DPAT did not alter the responses of the isolated tissues (rat aorta, uterus or fundus, or guinea-pig trachea) to 5-HT, while multiple dosing with 8-OH-DPAT produced rightward shifts and a suppression of the maximum response of all these tissues to 5-HT, with the exception of the rat stomach fundus. Multiple administration of 5-HT had no effect on the in-vitro response of the tissues to 5-HT. These data indicate that multiple administration of 8-OH-DPAT desensitizes or down-regulates the peripheral 5-HT2 receptors found on the rat aorta and uterus, and guinea-pig trachea.
Aescin formation in calli and embryoids from cotyledon and stem explants of Aesculus hippocastanum L.
Authors: Profumo Paola , Caviglia Anna Maria , Gastaldo Paola
Published: April 2011

Aescin in calli and embryoids obtained from both cotyledon and stem explants of Aesculus hippocastanum were investigated by HPLC. Determinations were carried out on tissues cultured in agarized medium supplemented with growth substances (2,4-dichlorophenoxyacetic acid; kinetin; 1-naphthaleneacetic acid). The results indicate that aescin was produced in all the analysed samples. The amount of active principle present in some samples was higher than that found in horse-chestnut seeds.