bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative inotropic effect of pinacidil on the rat left atria
Authors: Doggrell Sheila A
Published: April 2011

Cromakalim at 50 μm and pinacidil at 0·1–10 μm had no effect, but pinacidil at 0·1 Mm had a negative inotropic effect on the rat electrically-driven left atria without altering the positive inotropic responses to isoprenaline or phenylephrine alone. Glibenclamide had no effect but 4-aminopyridine, procaine (30 μm) and tetraethylammonium (3 Mm) augmented the cardiac stimulation response. The ability of pinacidil to attenuate the cardiac stimulation response was not altered by glibenclamide, 4-aminopyridine or procaine but was prevented by pretreatment with tetraethylammonium. Thus, on the rat left atria, pinacidil has a negative inotropic effect which is unrelated to the opening of ATP-sensitive potassium channels, but may be due to opening the inward rectifying potassium channels.
Spontaneous Formation of Small Sized Albumin/acacia Coacervate Particles
Authors: Burgess D J , Singh O N
Published: April 2011

Microgel coacervate particles form spontaneously on mixing aqueous solutions of oppositely charged albumin and acacia, under specific conditions of pH, ionic strength, and polyion concentration, close to but not at the optimum conditions for maximum coacervate yield. The mean particle diameter of these coacervate particles is approximately 6 μm when suspended in aqueous media, as determined by HIAC/Royco particle analysis. The geometric standard deviation of the particles falls in the range 1·2–1·9 μm. The particle size was not dependent on the method of emulsification of the coacervate in the equilibrium phase, or on the stirring speed applied during the manufacturing process. The microgel particles were stable on storage, for periods up to forty-six days, without the addition of a chemical cross-linking agent, or the application of heat. Stability was measured with respect to the change in particle size of samples stored at different temperatures. The non-cross-linked microcapsules were also shown to be stable on pH change, to pH values outside the coacervation pH range. At the optimum conditions for maximum coacervate yield the albumin/acacia system formed a very viscous coacervate phase, which was unsuitable for microcapsule preparation. The Theological properties of albumin/acacia and gelatin/acacia complex coacervates optimized for maximum coacervate yield were compared. The albumin/acacia coacervate was shown to be three orders of magnitude more viscous than the gelatin/acacia system.
The Redistribution of Bulk Aqueous Phase Phospholipids During Thermal Stressing of Phospholipid-stabilized Emulsions
Authors: Groves M J , Herman C J
Published: April 2011

The mechanism of the stabilization of triglyceride emulsions by phospholipids has been studied using an HPLC-FID method to determine phosphatidylcholine, lyso-phosphatidylcholine and phosphatidylethanolamine in the oil and aqueous phases of a model emulsion consisting of soybean oil 20 g, egg phospholipid 1·2 g, glycerol 2·25 g and water to 100 mL. It was shown that, on heat sterilization of the emulsions, the phospholipids rapidly relocate from the aqueous phase to the oil phase. It is suggested that the phospholipids concentrate in the oil/water meso phase, forming a cubic liquid crystalline phase, the bulk of which is converted to a lamellar phase on cooling, and that this organization of interfacial material accounts for the enhanced stability of phospholipid emulsions after heat sterilization.
Comparison of Depolarizing and Direct Current Systems on Iontophoretic Enhancement of Transport of Sodium Benzoate Through Human and Hairless Rat Skin
Authors: Numajiri Sachihiko , Sakurai Hidetomo , Sugibayashi Kenji , Morimoto Yasunori , Omiya Harumi , Takenaka Haruyuki , Akiyama Noriyoshi
Published: April 2011

A direct current (DC) system and a pulsed depolarization (PD) system were evaluated for their iontophoretic permeation of sodium benzoate, as a model drug, through hairless rat and human skin. Approximately the same initial permeation of sodium benzoate through the hairless rat skin was obtained at 0·1 mA for the DC device and at 3·0 mA for the PD device. Study of the drug’s permeation was performed using a two-chamber iontophoretic diffusion cell, over two cycles of three successive on-off experimental conditions [stage I (off) 0–4 h, II (on) 4–6 h, III (off) 6–10 h, saline washing 10–24 h, IV (off) 24–28 h, V (on) 28–30 h and VI (off) 30–34 h]. Skin permeation rate during stage IV of the iontophoresis as compared with the control group through hairless rat or human skin for the DC system was 2–4 times that in stage I, whereas in the same stage using the PD system it was almost the same as in stage I. Impedance of skin decreased during the application of either system (stage II); however, the value significantly recovered during stage III only in the case of the PD system use on human skin. Histological observation revealed no tissue alteration in the hairless rat skin after using either system. When the DC or PD system was applied to volunteers, the minimum current density producing pain was 0·016 or 2·7 mA cm−2, respectively. These results suggested that the PD system was more appropriate for iontophoresis application than the DC system from the point of view of skin permeability of the drug and effect on the skin.
Effects of Capsaicin on the Pharmacokinetics of Antipyrine, Theophylline and Quinine in Rats
Authors: Wanwimolruk S , Nyika S , Kepple M , Ferry D G , Clark C R
Published: April 2011

Capsaicin is the active principal of capsicum fruits, such as hot peppers. The influence of 1-week pretreatment of capsaicin (25 mg kg−1) on the pharmacokinetics of antipyrine, theophylline and quinine was investigated in rats. The drugs were given as an intravenous bolus dose. The control rats received the vehicle solvent (polyethylene glycol) only. Clearance of antipyrine in the capsaicin-pretreated rats was significantly lower than that observed in the control rats (0·241 ± 0·029 vs 0·344 ± 0·034 L h−1 kg−1, P < 0·05). This is consistent with a prolongation in the elimination half-life of antipyrine in animals pretreated with capsaicin (2·06 ± 0·30 vs 1·61 ± 0·27 h), as the volume of distribution was not significantly changed. In contrast, capsaicin pretreatment had no significant effect on the pharmacokinetics of theophylline and quinine.
The Effects of N-Benzoyl-β-alanine, a New Nephroprotective Drug, on the Distribution and Renal Excretion of Enprofylline in Rats
Authors: Wang Li , Hasegawa Takaaki , Nadai Masayuki , Nabeshima Toshitaka
Published: April 2011

The effects of the new nephroprotective drug N-benzoyl-β-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2·5 mg kg−1 under three different steady-state plasma BA concentrations (100,200 and 400 μg mL−1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 μg mL−1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 μg mL−1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.
Distribution of Free and Liposome-encapsulated Cefoxitin in Experimental Intra-abdominal Sepsis in Rats
Authors: Kresta A , Shek P N , Odumeru J , Bohnen J M A
Published: April 2011

The distributions of radiolabelled free cefoxitin (FC) and liposome-encapsulated cefoxitin (LC) were compared in an animal model of intra-abdominal sepsis. Intraperitoneally administered LC was initially retained in the peritoneal cavity with subsequent preferential drug targeting to the liver (14% injected LC) and spleen (6% injected LC) by 3 h post-injection. Differing patterns of liposomal drug and lipid retention indicated that drug release from the liposome complex occurred within the peritoneum, liver and spleen. Intraperitoneal FC was rapidly taken up into the systemic circulation, with peak recovery in the blood (9% injected FC) and liver (5% injected FC) at 1 h post-injection. FC was also rapidly eliminated; 7% of the injected drug was recovered in the kidney 1 h post-injection. A negligible amount of FC was recovered in the spleen and very little FC or LC was found in the lungs of treated animals. Unlike FC, LC was found to provide a sustained bactericidal drug level (> 40 μg mL−1) in the peritoneal fluid for up to 5 h post-injection. LC also achieved significantly higher drug levels, compared with FC, within the liver at 3 and 5 h post-injection. Since severe intra-abdominal sepsis is often characterized by the presence of intraphagocytic bacteria in hepatic and splenic reticuloendothelial systems, the enhanced delivery of liposome-encapsulated anti-microbial agents, such as cefoxitin, to the liver and spleen may provide a more effective treatment for the septic condition.
Genetic Control of Drug-induced Recovery from Murine Visceral Leishmaniasis
Authors: Carter K C , Baillie A J , Alexander J
Published: April 2011

The influence of host genetic background on the response of Leishmania donovani-infected mice to chemotherapy was studied using the H-2d and H-2b haplotypes on a BALB or a B10 genetic background. Animals were treated with free or liposomal sodium stibogluconate and parasite burdens in the liver, spleen and bone marrow were assessed. In all the mouse strains and their congenic derivatives examined, the liver responded best to therapy regardless of drug formulation, whilst the spleen and the bone marrow respectively were increasingly less responsive to chemotherapy. Treatment with free drug was more effective in congenic mice carrying the H-2b haplotype than in those carrying the H-2d haplotype and in mice carrying the same H-2 haplotype, animals from a BALB background were better responders than those from a B10 genetic background. Liposomal drug was more effective than free drug treatment in all four mouse strains and produced a similar significant suppression (> 99%, P < 0·001) in liver parasite burdens to that obtained using a six times greater free drug dose. This liposomal drug dose was more effective than free drug in reducing bone marrow parasite burdens in all four mouse strains and equally (BALB/c mice) or more effective (P < 0·01, BALB/B, B10 and B10.D2 strains) in reducing spleen parasite numbers. Liposomal drug, particularly in the B10 genetic background, effectively negated the H-2 dependent influences apparent using free sodium stibogluconate. These results are discussed in relation to the genetic factors which are known to control the course of L. donovani infection in mice.
Influence of Chinoin-170, a Novel Antitussive, on the Mucociliary Activity in Respiratory Airways of Rats, Rabbits, Guinea-pigs and Man
Authors: Saano Veijo , Minker Emil , Joki Susanna , Virta Pasi , Nuutinen Juhani , Korbonits Dezsö
Published: April 2011

Chinoin-170 (Ch-170; 3,7-dihydro-1,3-dimethyl-7-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]1H-purine-2,6-dione) is a new antitussive with bronchodilating activity. Its effects on the ciliary beating frequency (CBF) and mucociliary clearance were studied. In tracheal explants of rats, Ch-170 dose-dependently at concentrations 2 and 5 mg mL−1 depressed CBF by 24 and 33%, respectively. In human mucosal explants, however, no effects were seen at concentrations up to 5 mg mL−1. In anaesthetized guinea-pigs, an intravenous 50 mg kg−1 dose of Ch-170 caused no changes, and 100 mg kg−1 increased the CBF by 15%. Intravenous Ch-170 dose-dependently increased by 93 (50 mg kg−1), 179 (70 mg kg−1) and 253% (100 mg kg−1) the tracheobronchial mucociliary clearance in rabbits. The effect, studied using 99mTc-labelled red blood cells as a marker, was of similar quantity to that brought about by administering 16, 25 and 40 mg kg−1 doses of bromhexine. It is concluded that unlike many older antitussives, Ch-170 in-vitro only slightly decreases the CBF in rats and has no adverse effects on the CBF in human mucosal explants at concentrations up to 5 mg mL−1. In-vivo, Ch-170 does not significantly alter the CBF in guinea-pigs, but dose-dependently increases the mucociliary clearance in rabbits. The increase is most probably a result of changes in the production and the properties of respiratory mucus.
Antisecretory Activities of Orally Administered Loperamide and Loperamide Oxide on Intestinal Secretion in Rats
Authors: Beubler Eckhard , Badhri Pramila , Schirgi-Degen Andrea
Published: April 2011

In-vivo experiments in the rat jejunum have been performed to compare the antisecretory effect of orally administered loperamide with the effect of its pro-drug, loperamide oxide. Both loperamide and loperamide oxide, administered orally, reduced the secretory effect of prostaglandin E2 (32 ng min−1, intra-arterially) in the jejunum and the colon. Differences between the two drugs as to time course and dose response can be seen. Loperamide oxide shows its antisecretory effect in the jejunum, and at a dose of 2 mg kg−1 also shows its effect in the colon 1 h after administration. The effect was maximal after 2 h and decreased after 4 h. A dose-response relationship was demonstrated at 2 h in the jejunum and the colon. In comparison, the effect of loperamide started later, and a good dose-response relationship was not observed in the jejunum or in the colon, higher doses always appearing less effective than lower doses.
Stable Anticonvulsant Action of Benzodiazepines During Development in Rats
Authors: Kubová H , Mareš P , Vorlíček J
Published: April 2011

The anticonvulsant action of midazolam and clonazepam was studied in 168 immature rats in three age groups (12, 18 and 25 days old). Epileptic after-discharges of the spike-and-wave type accompanied by clonic seizures of facial and forelimb muscles induced by stimulation of sensorimotor cortex were used as a model. The solvent used for clonazepam exhibited a tendency to anticonvulsant action in 12-day-old rats. On the contrary, a proconvulsant action was seen in 25-day-old animals. The action of both benzodiazepines was identical and did not change substantially during development. The highest dose used (1 mg kg−1, i.p.) shortened the duration of epileptic after-discharges, the two lower doses (0·1 and 0·02 mg kg−1, i.p.) suppressed the progressive prolongation with repeated stimulations seen under control conditions. Motor correlates of stimulation remained practically uninfluenced by the two benzodiazepines, myoclonic seizures accompanying epileptic after-discharges were attenuated by the highest dose of both drugs.
Treatment of Antigen-Induced Arthritis in Rabbits by the Intra-articular Injection of Methylprednisolone, 90Y or Chlorambucil
Authors: Green K L , Foong W C
Published: April 2011

Rabbits with a bilateral antigen-induced arthritis were injected intra-articularly (i.a.) in one joint with methylprednisolone (1 mg), 90Y (18·5 MBq) or chlorambucil (1 mg) as a single dose. The severity of arthritis was determined by measuring joint swelling and skin surface temperature, macroscopic and histological changes in the joint being assessed 8 weeks after induction of arthritis when the rabbits were killed. Methylprednisolone injected at the time of antigen challenge or 3 weeks later caused a reduction in joint swelling and temperature (P < 0·05) for 1 to 6 weeks after injection. 90Y had an initial proinflammatory effect lasting several days, but later caused a modest reduction in joint swelling for up to 4 weeks (P < 0·05). Eight weeks after induction of arthritis, neither methylprednisolone nor 90Y-treated joints showed any significant reduction in erosion or histopathology compared with control arthritic joints. Chlorambucil injected 1 week after antigen challenge caused a rapid reduction in joint swelling which was maintained for the duration of the study. Joint surface temperature was reduced to a lesser extent. Eight weeks after induction of arthritis, chlorambucil-treated joints showed a decrease (P < 0·05) in all of the parameters of disease pathology assessed. Treatment with chlorambucil intra-articularly was clearly more effective than with methylprednisolone or 90Y at the doses employed and deserves further study as a potential treatment for chronic synovitis.
Effects of turpentine oil pretreatment on β-blocker pharmacokinetic parameters in rats
Authors: Murai-Kushiya Mami , Okada Satoshi , Kimura Toshio , Hasegawa Ryuichi
Published: April 2011

Turpentine oil treatment (0·2 mL kg−1, s.c.) was used to increase the plasma concentration of α1-acid glycoprotein (0·13 mg mL−1 in control rats) to 1·72 mg mL−1 after 2 days, and allow assessment of its effects on the pharmacokinetics and stereoselective binding of three β-blockers. Racemates (5 mg kg−1) were administered intravenously to control and turpentine oil-pretreated rats and the plasma concentrations were determined up to 90 min. Stereoselective analysis showed the apparent distribution volume and the area under plasma concentration-time curves (AUC) of R-(+)-propranolol to be, respectively, one-quarter and twice those of the S-(–)-enantiomer and differences in pharmacokinetic parameters between the two were magnified by turpentine oil pretreatment. Pharmacokinetic parameters of oxprenolol enantiomers were essentially similar for the controls but after turpentine oil pretreatment, a higher affinity of the R-(+)-enantiomer for plasma was observed. Acebutolol enantiomers behaved non-stereospecifically throughout. These results were consistent with predictions from the in-vitro stereospecific binding properties of these agents to purified rat α1-acid glycoprotein.
Liquid chromatographic determination of magnolol in urine collected from volunteers after a single dose of Saiboku-To, an oriental herbal medicine for bronchial asthma
Authors: Homma Masato , Oka Kitaro , Kobayashi Hitoshi , Nhtsuma Tomoyuki , Yamamoto Shinobu , Itoh Hisao , Takahashi Noriyuki
Published: April 2011

Saiboku-To is an anti-asthmatic herbal remedy which consists of ten herbal extracts. To investigate the clinical relationship between the effects and chemical components of Saiboku-To, a simple and sensitive high-performance liquid chromatographic method (HPLC) for determination of magnolol, one of the major urinary products, was developed. Organic solvent extraction of urinary magnolol was conducted by diatomaceous earth column rapid-flow fractionation using ethanol/dichloromethane (8/92, v/v). Recovery rates of magnolol were more than 99% with coefficient of variations less than 6% in the concentration range 9·7–970 ng mL−1. Subsequent HPLC determination of magnolol was achieved using a conventional silica-gel column, a mobile phase mixture of acetic acid/diethyl ether/n-hexane (0·2/17·0/82·8, v/v), and a UV-absorption detector set at 290 nm. Calibration was on the basis of peak height ratio between magnolol and flavone as an internal standard. The method was used to demonstrate excretion profiles of magnolol in healthy and asthmatic subjects following single administration of Saiboku-To.
A Sulphonylthiourea (BM 20) Related to Torasemide: a new Loop Diuretic with Relative Potassium-sparing Properties
Authors: Masereel B , Schynts M , Krzesinski J M , Pirotte B , Rorive G , Delarge J
Published: April 2011

A series of sulphonylthioureas related to torasemide, a high ceiling loop diuretic, were synthesized and found to inhibit the Na+ 2Cl− K+ co-transporter of the thick ascending limb of the loop of Henlé. Their diuretic properties were studied (30 mg kg−1) after oral administration to rats. Lipophilic derivatives, very active in-vitro, were found inactive orally and intraperitoneally in rats. The four most active compounds were examined for their dose-dependent diuresis. Three of them showed a potency, water and electrolyte excretion similar to torasemide. The fourth molecule, a sulphonylthiourea (BM 20), exhibited relative potassium-sparing properties and a minimal diuretic dose of 0·001 mg kg−1, 200 times lower than torasemide.
Biological Evaluation of Compounds with -NCS- Group or Derived from Thiazole and Imidazole. Activity on Prostaglandin Synthetase Complex
Authors: Moulard ThéRése , Lagorce Jean F , Thomes Jean C , Raby Claude
Published: April 2011

The effects of compounds with activity against thyroid peroxidase were tested on the activity of hydroperoxidase and cyclo-oxygenase of the prostaglandin synthetase complex in-vitro. Active compounds were found to inhibit the peroxidase, and the cyclo-oxygenase function. These compounds were also found to have anti-inflammatory activity as demonstrated by the reduction of carrageenan-induced oedema of the hind paw of the rat. Indomethacin and non-steroidal anti-inflammatory drugs tested under the same conditions were shown to have activity towards the cyclo-oxygenase rather than the peroxidase function of the prostaglandin synthetase complex. A common feature of the active compounds was the presence of an -NCS- linkage or free -SH group.
Effect of okadaic acid on histamine release from rat peritoneal mast cells activated by anti-IgE
Authors: Takei Masao , Mitsui Hideki , Endo Koichi
Published: April 2011

The effect of okadaic acid, a potent inhibitor of protein phosphatase 1 and 2A, on histamine release from mast cells has been investigated. Okadaic acid strongly and dose-dependently inhibited histamine release from mast cells induced by anti-IgE. The IC50 value of okadaic acid on histamine release induced by anti-IgE was 3·2 Nm. However, okadaic acid failed to inhibit histamine release induced by A23187 and compound 48/80. Moreover, okadaic acid showed no effect on the initial rise in intracellular Ca2+, Ca2+-mobilization from intracellular Ca2+-stores and the generation of inositol trisphosphate. These results suggest a possible involvement of protein phosphatase 2A in the histamine release from mast cells induced by anti-IgE.
Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation
Authors: Futaki N , Arai I , Hamasaka Y , Takahashi S , Higuchi S , Otomo S
Published: April 2011

NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl) methane sulphonamide), a newly synthesized potent non-steroidal antiinflammatory drug (NSAID) has a much lesser degree of toxicity, as compared with presently available NSAIDs. We have investigated the inhibition of prostanoid production in inflammatory exudate, gastric mucosa and renal papillary tissue, following oral administration to carrageenan-air-pouch rats. The ID50 values of NS-398 in the inflammatory exudate, gastric mucosa and renal papillary tissue were 0·18, 62·2 and 261·7 mg kg−1, respectively. In contrast, indomethacin decreased the PGE2 concentration in the inflammatory exudate, gastric mucosa and renal papillary tissue, with the same dose range, the ID50 values being 0·23, 0·14 and 0·15 mg kg−1, respectively. The same tendency was seen for 6-keto-prostaglandin F1 and thromboxane B2. Moreover, NS-398 inhibited excess PGE2 production in inflamed tissue but did not affect physiological production of PGE2 in non-inflamed tissue. Indomethacin, in both inflamed and non-inflamed tissues, inhibited PGE2 production to the same degree. These results indicated that NS-398 has some specificity for inflamed tissue, by inhibiting prostanoid synthesis, and this effect may explain the decreased side-effects of this drug.
SR 48968, A Novel Non-peptide Tachykinin NK-2-Receptor Antagonist, Selectively Inhibits the Non-Cholinergically Mediated Neurogenic Contraction of Guinea-pig Isolated Bronchial Muscle
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: April 2011

We have examined the actions of SR 48968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), a novel non-peptide tachykinin NK-2-receptor antagonist, on the response evoked by electrical field stimulation or by acetylcholine and neurokinin A on guinea-pig isolated airway smooth muscle. Electrical field stimulation (1–32 Hz, 0·3 ms, 30 V for 20 s) evoked a biphasic response in a frequency-dependent manner, consisting of a cholinergically-mediated fast contraction followed by a non-adrenergically-mediated relaxation in tracheal muscle and by a noncholinergically-mediated slow contraction in bronchial muscle. SR 48968 (0·01–1 μm) caused a concentration-dependent inhibition of non-cholinergically mediated contraction of bronchial muscle, without significant influence on cholinergically and non-adrenergically-mediated responses. Submaximal contractions of tracheal and bronchial muscles evoked by exogenous neurokinin A (10–300 Nm) were markedly inhibited by SR 48968 (0·1–1 μm), but those by exogenous acetylcholine (1–3 μm) were slightly inhibited by the antagonist. The results indicate that in guinea-pig isolated bronchial muscle, SR 48968 selectively inhibited non-cholinergically mediated neurogenic contraction via antagonism of NK-2 receptors.
Dopamine Antagonists Can Inhibit Methamphetamine Sensitization, But Not Cocaine Sensitization, When Assessed by Ambulatory Activity in Mice
Authors: Kuribara Hisashi , Uchihashi Yoshitaka
Published: April 2011

The repeated subcutaneous administration of methamphetamine (2 mg kg−1) and cocaine (10 mg kg−1) at 3–4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0·003–0·03 mg kg−1) and YM-09151–2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide; 0·003–0·03 mg kg−1), the selective dopamine D1 and D2 antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151–2 in the repeated administration schedule. Although SCH 23390 (0·01–0·1 mg kg−1) and YM-09151–2 (0·01–0·1 mg kg−1) also reduced the ambulation-increasing effect of cocaine (10 mg kg−1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0·03 mg kg−1) or YM-09151–2 (0·03 and 0·1 mg kg−1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D1 and D2 antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.
Human Serum Albumin Conformational Changes as Induced by Tenoxicam and Modified by Simultaneous Diazepam Binding
Authors: Brée F , Urien S , Nguyen P , Tillement J P , Steiner A , Vallat-Molliet C , Testa B , Visy J , Simonyi M
Published: April 2011

The binding of tenoxicam to human serum albumin has been shown by affinity chromatography proton titration and equilibrium dialysis to be dependent on the neutral to basic conformational change of the protein. The influence of diazepam on the interaction was also investigated using the same techniques, suggesting that diazepam increases the association of tenoxicam to albumin. Affinity chromatography revealed that the reciprocal effect also occurs. Displacement studies indicated that diazepam causes a significant increase in the affinity of tenoxicam to its main binding site, albumin site I, which is different from the diazepam site (site II). Tenoxicam seemed to cause an allosteric change in the conformation of the protein during its own binding, as did warfarin. The mechanism of this effect was a pH-dependent conformational change of albumin induced by electrostatic forces within the protein. Diazepam induced a distant accommodation of the protein, an effect accompanied by an enhanced inhibition of the release of protons from albumin.
Inhibition of Intestinal Motility and Secretion by Flavonoids in Mice and Rats: Structure-activity Relationships
Authors: Di Carlo G , Autore G , Izzo A A , Maiolino P , Mascolo N , Viola P , Diurno M V , Capasso F
Published: April 2011

Intraperitoneal administration of some flavonoids (apigenin, flavone, kaempferol, morin, myricetin, naringin and rutin; 12·5–50 mg kg−1) significantly (P < 0·05–0·01) reduced small (28–69%) and large (83–134%) intestinal transit in mice. Other flavonoids (naringenin, silibinin, silymarin and taxifolin, 100–200 mg kg−1) reduced (23–41%; P < 0·5–0·01) intestinal transit at doses of 100–200 mg kg−1 while hesperitin, catechin and phloridzin (up to 200 mg kg−1) had no effect. This effect was antagonized by yohimbine (87–96%) and phentolamine (87–91%) but not by prazosin, propranolol, atropine, hexamethonium, mepyramine, cyproheptadine and naloxone. Yohimbine (92–96%) also antagonized the inhibitory effect of flavonols (12·5–50 mg kg−1) (P < 0·05–0·01) on intraluminal accumulation of fluid and diarrhoea induced by castor oil. By contrast, verapamil potentiated the flavonol effect. It is suggested that these effects, influenced by the structure of the molecules, are mediated by α2-adrenergic receptors and calcium.
Effects of Alkylxanthines on Contractility of Diaphragm Fibres Isolated from Normal and Sensitized Guinea-pigs
Authors: Orón J D , Cortijo J , Perpiñá M , Morcillo E J
Published: April 2011

This study investigates the effects of alkylxanthines on twitch tension generated by electrical stimulation (supramaximal pulses, 0·2 ms duration, 1 Hz) of diaphragm muscle fibres isolated from normal and actively-sensitized guinea-pigs. Caffeine, theophylline and theobromine increased, in a concentration-dependent manner (50–500 μm), twitch tension in normal and sensitized diaphragm. Caffeine (500 μm) enhanced contractility to a greater extent than theophylline or theobromine. Twitch potentiation by caffeine (500 μm) was significantly greater in sensitized diaphragm. Verapamil (0·1–100 μm) did not alter twitch contractions in the absence or presence of alkylxanthines in normal or sensitized strips. Dantrolene (0·01–100 μm) depressed, in a concentration-dependent fashion, twitch contractions of normal and sensitized diaphragm. The inhibitory concentration 50% (expressed as —log IC50) was 6·78 ± 0·13 in normal tissues and 6·15 ± 0·11 in sensitized tissues (n = 6 in each group; P < 0·05). Exposure to Ca2+-free, EGTA (0·1 Mm)-containing medium, depressed twitch contraction of normal diaphragm to a lesser extent than that of sensitized diaphragm. Methylxanthines reversed depression of twitch contractions produced by exposure to dantrolene (5 μm) or a Ca2+ -free medium. Adenosine (1–1000 μm) was without effect whereas enprofylline (50–500 μm) enhanced diaphragm contractility in normal tissues. This indicates that blockade of adenosine receptors is not involved in the inotropic effect of alkylxanthines in guinea-pig diaphragm. Results from this study suggest that alkylxanthines enhance diaphragm contractility in the guinea-pig by releasing intracellular Ca2+ and promoting extracellular Ca2+ entry through verapamil-insensitive pathways. An alteration of Ca2+ movements and stores may be present in the sensitized diaphragm.
Inhibition of Rat Acute Inflammatory Paw Oedema by Dihemiphthalate of Glycyrrhetinic Acid Derivatives: Comparison with Glycyrrhetinic Acid
Authors: Inoue Hideo , Inoue Kazuko , Takeuchi Tadao , Nagata Nobuyuki , Shibata Shoji
Published: April 2011

The anti-inflammatory profile of dihemiphthalate compounds of glycyrrhetinic acid derivatives in acute rat paw oedema induced by various vasoactive agents was compared with the parent compound. Three dihemiphthalate compounds (the di-sodium salt of 18 β-olean-12-ene-3β,30-diol di-O-hemiphthalate, 18β-olean-9(11),12-dione-3β,30-diol di-O-hemiphthalate and olean-11,13(18)-diene-3β,30-diol di-O-hemiphthalate), significantly inhibited development of carrageenan-induced rat paw oedema during the first 3 h (ED50 70, 90, and 108 mg kg−1 respectively, p.o.), while glycyrrhetinic acid (ED50, 200 mg kg−1) showed a significant inhibition of paw oedema 3 h after carrageenan treatment. The dihemiphthalate compounds also suppressed mouse paw oedema induced by histamine, bradykinin, and PAF acether at doses of less than 100 mg kg−1. However, these compounds failed to inhibit 5-HT-induced mouse paw oedema. Glycyrrhetinic acid had little effect on mouse paw inflammation induced by the above irritants. The three compounds at 10−7-10−4  m, inhibited histamine-induced contraction of guinea-pig isolated ileum. However, concentration-response curves to 5-HT and bradykinin were not affected by the same compounds. These results suggest that the dihemiphthalate compounds modulate vascular permeability caused by endogenous vasoactive agents as one of the anti-inflammatory mechanisms. This action is quite different from that of glycyrrhetinic acid.
Regulation of Adrenergic Receptors in the Rat Kidney
Authors: Lübbecke F , Schneider D , Schütterle G
Published: April 2011

Chronic daily application of (±)-isoprenaline induced a selective-down regulation of β-adrenoceptors in the kidney: the concentration of [3H]dihydroalprenolol binding sites was significantly lowered by isoprenaline treatment while [3H]prazosin and [3H]rauwolscine binding, representing α1-and α2-adrenoceptors, respectively, was not markedly altered. Since the proportion of high- and low-affinity sites for the non-selective α- but relatively β1-selective agonist (–)-noradrenaline remained constant and since in [3H]dihydroalprenolol competition experiments the high- and low-affinity site ratio fitted well to the β1/β2 relation, determined independently by employing ICI 118551 as a β2-selective ligand, a parallel decrease of both β1- and β2-adrenoceptor density can be concluded.
Comparison of site-dependent degradation of peptide drugs within the gut of rats and rabbits
Authors: Bai Jane P F , Chang Li-Ling
Published: April 2011

Intestinal luminal degradation of neurotensin and acetyl-neurotensin-(8–13) within the gut of rats and rabbits was compared using brush-border membranes. Patterns of differential proteolysis of these two peptides within the intestine were similar within the same species and between the species. In both rats and rabbits, jejunal brush-border membranes had the highest proteolytic activities degrading neurotensin and acetylneurotensin-(8–13), and caecal or ileocaecal brush-border membranes had the lowest activities. In both species, patterns of site-dependent degradation of neurotensin and acetylneurotensin-(8–13) agreed with the distribution profiles of endopeptidase-24.11 and angiotensin-converting enzyme within the gut. The distal intestine of rats and rabbits has the lowest activities degrading these two compounds. The results demonstrate that distribution of peptidases within the gut will affect site-dependent degradation and absorption of peptide drugs.
Dark effect of 8-methoxypsoralen on human erythrocytes
Authors: Gawron Antoni , Pawlikowska BoŻena
Published: April 2011

Furanocoumarin 8-methoxypsoralen (8-MOP) (1–100 μg mL−1) in the dark showed a protective affect against hypotonic haemolysis of the erythrocyte membrane. However, the effect against heat-induced haemolysis was dependent on the concentration of 8-MOP; lower concentrations of 8-MOP showed an inhibiting effect, whereas higher concentrations caused acceleration of haemolysis. 8-MOP was not able to induce haemolysis in isotonic solution at 20 or 37 C. Reaction of erythrocytes with 8-MOP in the dark resulted in a shrinkage of the cells and alterations of their shapes. We conclude that modification of erythrocyte membrane by 8-MOP proceeds via reaction with membrane lipids and proteins. This indicates that the effect on the cell membrane plays an important role in the mechanism of the action of 8-MOP on the cells.
Deep Tissue Penetration of Bases and Steroids after Dermal Application in Rat
Authors: Singh Parminder , Roberts Michael S
Published: April 2011

The local deep tissue penetration of bases such as diazepam, antipyrine, iodoantipyrine, haloperidol and steroids such as hydrocortisone, fluocinolone acetonide, testosterone and progesterone after dermal application as aqueous solutions was studied in a rat model. The extent of local, as distinct from systemic delivery, for each solute was assessed by comparing the tissue concentrations obtained below a treated site with those in contralateral tissues. Local direct penetration was evident for all solutes below the applied site, although depth of penetration varied between individual solutes. A physiological pharmacokinetic model was employed to estimate local tissue concentrations of various compounds after dermal application.
The Metabolism of a Series of Ester Pro-drugs by NCTC 2544 Cells, Skin Homogenate and LDE Testskin
Authors: Lamb K A , Denyer S P , Sanderson F D , Shaw P N
Published: April 2011

The metabolism of a series of substituted pyrazolopyridine ester pro-drugs was investigated using NCTC 2544 cells, human skin homogenate and LDE Testskin as model systems. The compounds were incubated in each system and the disappearance of drug and the production of the major hydrolysis product was observed with time and quantitated using HPLC. The toxicity of the ester pro-drugs and the metabolites was examined in NCTC 2544 cells using a cell viability assay procedure. Hydrolytic activity was slightly higher in the cell culture model than in skin homogenate solution but the rank order of activity for each pro-drug was similar. The metabolic activity of LDE Testskin was much reduced compared with the other systems, but again the overall pattern of metabolism was not dissimilar. These findings indicate that NCTC 2544 cells provide a reasonable model for human skin ester hydrolysis both in terms of rate and in terms of substrate specificity.
Liposomes as In-vivo Carriers for Citicoline: Effects on Rat Cerebral Post-ischaemic Reperfusion
Authors: Fresta Massimo , Puglisi Giovanni , Di Giacomo Claudia , Russo Alessandra
Published: April 2011

Citicoline is a therapeutic agent widely used in the treatment of brain injury, for example in cerebrovascular disease or traumatic accidents. Unfortunately, the strong polar nature of this drug prevents it crossing the blood-brain barrier. In this paper, the possibility of efficiently trapping citicoline in liposomes to improve its therapeutic effects is reported. The citicoline-encapsulation efficiency, drug leakage and size analysis of various liposome systems were studied. The real therapeutic effectiveness of these citicoline liposome formulations was evaluated by biological assay. The effects of free and liposome encapsulated citicoline on survival rate of ischaemic reperfused male Wistar rats (80–100 g) were investigated. Of the phospholipid mixtures used in citicoline liposome formulation the best in terms of delivery and therapeutic effects was 1,2-dipalmitoyl-sn-glycero-phosphocholine:dipalmitoyl-dl-α-phosphatidyl-l-serine: cholesterol (7:4:7 molar ratio). This phospholipid mixture was also assayed for brain conjugated diene levels in rats, since this parameter is an index of lipid peroxidation in rat cerebral cortex during post-ischaemic reperfusion. A citicoline-loaded phospholipid mixture has produced an increase in rat survival rate of about 24% and a reduction in diene levels of 60%, compared to the free drug.
Kojic Acid, a Cosmetic Skin Whitening Agent, is a Slow-binding Inhibitor of Catecholase Activity of Tyrosinase
Authors: Cabanes Juana , Chazarra Soledad , Garcia-Carmona Francisco
Published: April 2011

It was found that kojic acid, which is used in cosmetics for its excellent whitening effect, inhibits catecholase activity of tyrosinase in a non-classical manner. A decrease in the initial velocity to a steady-state inhibited velocity can be observed over a few minutes. This time-dependence, which is unaltered by prior incubation of the enzyme with the inhibitor, is consistent with a first-order transition. The kinetic data obtained correspond to those for a postulated mechanism that involves the rapid formation of an enzyme inhibitor complex that subsequently undergoes a relatively slow reversible reaction. Kinetic parameters characterizing this type of inhibition were evaluated by means of nonlinear regression of product accumulation curves.
Physicochemical Characterization and Acute Toxicity Evaluation of a Positively-charged Submicron Emulsion Vehicle
Authors: Klang Shmuel H , Frucht-Pery Joseph , Hoffman Amnon , Benita Shimon
Published: April 2011

Fine, homogeneous, positively-charged emulsions with a mean droplet size of 138 ± 71 nm and a zeta potential value of 41.06 mV were prepared using a combination of emulsifiers comprising phospholipids, poloxamer 188, and stearylamine. The pH of these emulsions decreased with time. However, the extent of decrease was dependent on the storage temperature. The mean droplet size of the emulsions that had been prepared with 1% poloxamer began to increase slightly after six months’ storage, particularly when stored at 23 and 37°C. However, emulsions prepared with 2% poloxamer remained stable for at least 10 months at 4°C, suggesting that the poloxamer 188 concentration is critical for prolonged emulsion stability. The results of the ocular tolerance study in rabbit eye indicate that hourly administration of a positively-charged emulsion vehicle was well tolerated without any toxic or inflammatory response to the ocular surface during the five days of the study. Scanning electron microscopy revealed a normal corneal surface, which was not different from that of the animals treated with physiological saline. No marked acute toxicity was observed when 0.6 mL of positively-charged emulsion was injected intravenously to BALB/c mice. Furthermore, no difference was noted between this group of animals and the group injected with the marketed Intralipid emulsion. These results were further confirmed in a rat study where there were no deaths following intravenous injection of 3.3 mL per rat of the positively-charged emulsion or Intralipid. Neither emulsion elicited any hepatotoxic or nephrotoxic effects. The overall results suggest that the novel positively-charged emulsion is suitable for parenteral use, and for ocular application.
Lipophilicity of Teicoplanin Antibiotics as Assessed by Reversed Phase High-performance Liquid Chromatography: Quantitative Structure-property and Structure-activity Relationships
Authors: Altomare Cosimo , Carotti Angelo , Cellamare Saverio , Carrieri Antonio , Ciabatti Romeo , Malabarba Adriano
Published: April 2011

Structure-lipophilicity relationships of a large series of 63-COX teicoplanin antibiotic derivatives were examined, by correlating their capacity factors (log kw), measured through reversed-phase high-performance liquid chromatography on Deltabond C8 stationary phase, with some computed molecular properties such as fragmental log P constants (***x), molecular volumes (Vx) and factors imparting hydrophilicity (e.g. amino groups in the X chain, nN). A number of equations were derived which demonstrate that variations of log kw are mainly related to changes in bulk (modelled by Vx) and polarity (primarily modelled by nN) of X chains of teicoplanin derivatives. QSAR analysis revealed that in-vitro activity against E. coli increases as lipophilicity decreases and isoelectric point increases.
Iron-binding Affinity of Bacterial Vaccine Polysaccharides which Contain Phosphodiester Linkages as Part of the Polymer Chain and of Other Polyphosphates, Including DNA
Authors: Bingham B R , Quinlan G J , Tarelli E
Published: April 2011

The interaction of iron (II) with bacterial polysaccharides, possessing phosphodiester bonds as part of their polymer chain, has been studied by equilibrium binding dialysis using atomic absorption spectrophotometry. Ferrous ions were found to bind with a stoichiometry of one per two phosphates and with a binding constant of about 2.5 times 103 M−1. Similar results, but with larger (ca 1 times 104 M−1) binding constants were observed with DNA. This interaction helps explain the depolymerization of polyphosphates which has been observed in the presence of iron salts, and highlights the need to avoid iron contamination of vaccines (and other substances) which contain phosphodiester bonds. The interaction may also be a means of iron sequestration in bacteria which possess these cell-surface polyphosphates.
Continuous Administration of Low Dose Rates of Physostigmine and Hyoscine to Guinea-pigs Prevents the Toxicity and Reduces the Incapacitation Produced by Soman Poisoning
Authors: Wetherell Janet R
Published: April 2011

A regime was developed, using mini-osmotic pumps, for the continuous subcutaneous administration of low doses of physostigmine (12.1, 9.7, 4.85 and 2.43 μgh−1), in combination with hyoscine (1.94 or 0.39 μg h−1), to guinea-pigs for up to 13 days. Physostigmine, in combination with hyoscine, inhibited plasma Cholinesterase, and red blood cell and brain acetylcholinesterase, in a concentration-dependent manner, did not affect the normal growth rate of guinea-pigs, and produced no obvious signs of poisoning. A dose rate of 4.85 μg h−1 physostigmine and 1.94 μg h−1 hyoscine was required to inhibit red cell acetylcholinesterase by 30% and brain acetylcholinesterase by 5–15%, with an accompanying plasma hyoscine concentration of 700–850 pg mL−1. There was an apparent decline in red cell acetylcholinesterase activity during the 13 days. Hyoscine levels were higher in the cholinergic-rich areas of the brain than in the plasma. Continuous pretreatment (1 or 6 days) with physostigmine (4.84 μg h−1) and hyoscine (1.94 μg h−1) provided complete protection against the lethal effects, and minimized the incapacitation and weight loss produced by soman at a dose equivalent to the LD99 value. Following soman challenge, guinea-pigs exhibited early signs of soman poisoning, but generally these signs of poisoning were minimal by 1–2 h. Extending the pretreatment time to 13 days protected 75% of the guinea-pigs against the lethal effects of soman poisoning. Red cell acetylcholinesterase activity, 24 h after soman poisoning, was higher following continuous pretreatment with physostigmine and hyoscine than after acute treatment with atropine.
Use of Powdered Cellulose for the Production of Pellets by Extrusion/Spheronization
Authors: Lindner H , Kleinebudde P
Published: April 2011

The use of powdered cellulose instead of microcrystalline cellulose in the extrusion/spheronization process was investigated. The aim of the study was to assess differences between two types of powdered cellulose using a 24–1 fractional factorial design. Water content and amount of binder were found to be most important while type of cellulose and screw speed had only negligible influence on the extrusion process and the resulting pellets. Pellets obtained with powdered celluloses showed higher porosities and faster dissolution rates compared with those made with microcrystalline cellulose. Image analysis was found to be an appropriate method for the simultaneous characterization of pellet size and shape.