bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamic Comparison of Regional Drug Delivery for Non-steroidal Anti-inflammatory Drugs, Using the Rat Air-pouch Model of Inflammation
Authors: Martin S W , Stevens A J , Brennan B S , Rowland M , Houston J B
Published: April 2011

The inhibition of prostaglandin E2 (PGE2) synthesis by S-(+)-ibuprofen and piroxicam have been assessed following intravenous and regional (intrapouch) drug delivery using the rat air-pouch model of inflammation. Anti-inflammatory response was defined as the decrease in the area under the exudate PGE2 concentration-time curve between 3 and 10 h, following regional administration of the irritant carrageenan.

Dose-response studies indicated that bolus regional administration of S-(+)-ibuprofen increased potency 30-fold compared with systemic administration and could be further improved 10-fold by regional infusion, whereas regional administration of piroxicam showed no therapeutic advantage. Examination of the concentration-response using AUC revealed that for a given response, average pouch concentrations for S-(+)-ibuprofen during the PGE2 inflammatory response (3 to 10 h) was similar, irrespective of route or mode of administration. In contrast, an advantage following systemic rather than regional administration was revealed for piroxicam, based on plasma concentration-response data, indicating a major systemic anti-inflammatory component for piroxicam but not for S-(+)-ibuprofen.

These observations stress the need to take account of both pharmacodynamics and pharmacokinetics when considering the potential advantages of regional administration.
Small Intestinal Absorption of Bropirimine in Rats and Effect of Bile Salt on the Absorption
Authors: Emori Hisatoshi , Yokohama Shigeharu , Nishihata Toshiaki
Published: April 2011

The intestinal absorption characteristics of a poorly water-soluble drug, bropirimine, were investigated by the in-situ small intestinal loop method using male Sprague-Dawley rats.

Bropirimine in solution was well absorbed in the overall small intestine, following first-order kinetics. The rate determining step for the disappearance of bropirimine from the small intestinal loop after dosing in the suspension was the dissolution process from suspension. Bropirimine was solubilized by sodium glycocholate.

The disappearance of bropirimine from the small intestinal loop was suppressed by sodium glycocholate contained in the solution, because of the loss of thermodynamic activity of bropirimine after its involvement in the micellar complex, not by the direct effect of bile salt on the permeability of intestinal mucosa. The disappearance of bropirimine was also suppressed by sodium glycocholate contained in the suspension.

The suppression by sodium glycocholate seemed to be caused by the greater influence of sodium glycocholate on the thermodynamic activity of bropirimine than on the dissolution from suspension.
Toxicodynamic Analysis of Inflammatory Reactions by an Angiotensin Converting Enzyme Inhibitor (Lisinopril) in Guinea-pig Skin
Authors: Ito Kaori , Ito Kiyomi , Sawada Yasufumi , Iga Tatsuji
Published: April 2011

There have been reports of rash and angioedema in the treatment of hypertension with angiotensin converting enzyme (ACE) inhibitors. To evaluate the inflammatory reaction, we continuously infused lisinopril for three days into the peritoneal cavity of ovalbumin-sensitized guinea-pigs and tested intradermal inflammation with ovalbumin. Inflammatory responses were measured in two perpendicular directions serially, and the areas of rash were used as an index of inflammatory reaction induced by lisinopril.

Inflammatory responses were dose-dependently enhanced by treatment with lisinopril. Plasma concentration of lisinopril required to produce 50% of the maximum potentiation of the inflammatory reaction in guinea-pig skin was 40 times plasma unbound concentration after the clinical treatment of lisinopril in patients.
Vascular β-Adrenoceptor-mediated Relaxation and the Tone of the Tissue in Canine Arteries
Authors: Begonha R , Moura D , Guimarães S
Published: April 2011

The aim of the present investigation was to study the influence of the tone in the response to β-adrenoceptor activation of four different canine arteries: coronary, pulmonary, mesenteric and splenic.

Five different levels of tone were produced (of about 35, 50, 65, 80 and 95% of the maximum) by adding phenylephrine (0·6, 1·0, 2·0, 4·0, and 10 μm, respectively) to the bath.

In the coronary artery at spontaneous tone, low concentrations of noradrenaline or adrenaline (1–3 nm) caused either relaxation or contraction, while after induced tone, both noradrenaline and adrenaline caused concentration-dependent relaxations, noradrenaline being more potent (EC50 of 0·16 (0·13–0·20) and 0·38 (0·28–0·67) μm, respectively; n = 6; P < 0·05). Only in the coronary artery did isoprenaline relax the tissue irrespective of the previous level of tone. In all the other arteries, isoprenaline was able to cause concentration-dependent relaxations only if the previous tone was submaximal. At 80% of the maximum, isoprenaline caused relaxation in the mesenteric and pulmonary arteries, but in the splenic artery it caused relaxation only when the tone was of about 65% of the maximum or less.

While in the coronary artery atenolol and ICI-118,551 (erythro-dl 1(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) were equipotent in antagonizing isoprenaline, noradrenaline and adrenaline, in the other vessels ICI-118,551 was from 58 (splenic artery) to 525 (mesenteric artery) times more potent than atenolol against the isoprenaline relaxant effect.

We conclude that: the tone of the vessel represents a critical factor deciding the sense of the response (coronary artery; low concentrations of noradrenaline or adrenaline), the level at which the relaxant effect is triggered (mesenteric = 80% vs splenic = 65%), and the magnitude of the relaxant effect (always). β-Adrenoceptors predominate in the mesenteric, pulmonary and splenic arteries, while β1-adrenoceptors predominate in the coronary artery. It is unlikely that adrenaline is able to cause vasodilation in any of the vascular beds studied.
Evidence against the Participation of μ- and κ-Opioid Receptors in the Analgesic Activity of Ketorolac in Rats
Authors: Granados-Soto Vinicio , Flores-Murrieta Francisco J , Castaáeda-Hernández Gilberto , Hong Enrique , López-Muñoz Francisco J
Published: April 2011

The possibility that activation of opioid receptors is involved in the analgesic activity of ketorolac was explored. The analgesic effects of ketorolac, of ketocyclazocine, the prototype κ-agonist, and of morphine, the prototype μ-agonist, were assayed in the pain-induced functional impairment model in the rat.

All three drugs induced a significant analgesic effect in this model. Naloxone was able to antagonize the effects of ketocyclazocine and morphine. However, the effect of ketorolac was not blocked by naloxone, although a high dose, 3·2 mg kg−1, capable of blocking κ-receptors was used.

It is concluded that activation of μ- or κ-opioid receptors, by either a direct or an indirect mechanism, does not play a role in the analgesic activity of ketorolac.
Precorneal Clearance of Mucoadhesive Microspheres from the Rabbit Eye
Authors: Durrani A M , Farr S J , Kellaway I W
Published: April 2011

The ocular disposition of hydrated 111In-labelled microspheres was investigated in the rabbit by gamma scintigraphy. Microspheres of cross-linked poly(acrylic acid) (Carbopol 907) were prepared by a w/o emulsification process.

An in-vitro mucoadhesion test of prehydrated microspheres showed that greater adhesion was achieved to a mucus gel at pH 5·0 compared with pH 7·4.

Clearance was a biphasic process with a rapid initial phase preceding a slower basal phase. When hydrated in pH 5·0 phosphate buffered saline, clearance during the basal phase was slower compared with a pH 7·4 buffered preparation. Both prehydrated preparations were retained on the preocular area during the basal phase for longer periods than non-hydrated microspheres.

The retention on the ocular surface of approximately 25% of the instilled dose would suggest this technology will have application for controlled ophthalmic drug delivery.
Synthesis and Inhibition of Human Leucocyte Elastase by Functionalized N-Aryl Azetidin-2-ones: Effect of Different Substituents on the Aromatic Ring
Authors: Joyeau R , Felk A , Guilaume S , Wakselman M , Vergely I , Doucet C , Boggetto N , Reboud-Ravaux M
Published: April 2011

N-aryl-3,3-difluoroazetidin-2-ones featured by a latent electrophilic methylene quinoniminium function have been synthesized and evaluated as inhibitors of human leucocyte elastase.

To promote hydrophobic interactions with the enzyme, to increase the rates of β-lactam ring opening and of benzylic group departure, or to induce hydrosolubility, these compounds incorporate on their aromatic ring either an alkyl moiety, a methoxy substituent or a carboxylic group.

Some of these β-lactams proved to be good inactivators of human leucocyte elastase.
Pharmacokinetic-toxicodynamic Relationships of Adriamycin in Rat: Prediction of Butylated Hydroxyanisole-mediated Reduction in Anthracycline Cardiotoxicity
Authors: Vora Jayesh , Boroujerdi Mehdi
Published: April 2011

Adriamycin, an anthracycline antibiotic, has broad antitumour activity with cumulative dose-dependent cardiotoxicity as its major side effect. This study was designed to quantify and correlate the cardiotoxicity and pharmacokinetics of adriamycin in-vivo in rat. The influence of antioxidant (butylated hydroxyanisole, BHA) co-therapy on the cardiotoxicity and disposition of adriamycin was also studied.

Cardiotoxicity was estimated by serially measuring serum creatine kinase (CK) levels after intravenous administration of adriamycin (4, 10, 20, and 30 mg kg−1) and adriamycin-BHA (10 and 30 mg kg−1 each). Peak serum CK concentrations (CKmax) and area under serum CK-time curves (AUCCK) were used as cardiotoxicity indices. Pharmacokinetic studies were undertaken by sampling plasma and urine from distinct groups of rats treated with [14C]adriamycin (at the above doses) and [14C]adriamycin-BHA (10 mg kg−1 each). Co-administration of BHA resulted in a significant reduction in CKmax and also resulted in a significant reduction in the renal clearance of adriamycin which was fully compensated by an increase in its metabolic clearance. A linear increase in the area under the plasma adriamycin concentration-time curves (AUC) with increasing adriamycin doses suggested dose-independent disposition of the drug. The most significant pharmacokinetic-toxicodynamic relationships included: CKmax = 2.25 × 102 exp(4 × 10-4 AUC), r2 0.941, P < 0.05 and AUCCK = 1.3 × 104 exp(2 × 10-4 AUC0-tmax), r2 = 0.918, P < 0.05 where, AUC0-tmax is the area under the adriamycin concentration-time curve from time 0 to the time of the peak CK level.

The results strongly indicate that the drug-induced cardiotoxicity is initiated shortly after dosing when drug concentrations are high and accumulates with continued exposure. The predicted cardiotoxic indices, obtained from altered adriamycin pharmacokinetic parameters as a result of BHA co-therapy, compared favourably with the observed values.
Pharmacokinetic Study of Zonisamide in Patients Undergoing Brain Surgery
Authors: Ieiri Ichiro , Morioka Takato , Kim Sonyori , Nishio Shunji , Fukui Masashi , Higuchi Shun
Published: April 2011

To test whether the concentration of the anticonvulsant zonisamide in erythrocytes reflects the brain concentration and the clinical response of the drug, its pharmacokinetics were studied in nine patients undergoing surgery for brain tumour. Erythrocyte, total, and free serum concentrations in samples drawn on the day of brain surgery were compared with levels on a day after the operation. In three patients zonisamide and its major metabolite, 2-sulphamoylacetylphenol, were also analysed in urine. The area under the curve of the free and the erythrocyte concentration did not differ between the two study phases whereas the area under the curve of the total serum concentration was significantly lower on the day of the operation, and this was associated with significant increases in total clearance (15.4 compared with 12.7 mL kg−1 h−1, P < 0.05, n = 9) and renal clearance (5.4 compared with 3.3 mL kg−1 h−1, P < 0.05,n=3), and non-significant change in non-renal clearance (7.7 on the day of operation compared with 8.4 mL kg−1 h−1 on the post-operation day, n = 3). Zonisamide distribution was also altered by the operative procedure, as evidenced by a higher volume of distribution (1.48 compared with 0.87 L kg−1, P < 0.05, n = 9). The binding of zonisamide was characterized on both days. Zonisamide binding to erythrocytes seemed to occur by two processes: a saturable process and a non-saturable linear process. The maximum binding capacity to erythrocytes (31.6 vs 29.7 μg mL−1) did not differ on the two days; however, increases in the dissociation binding constant (+28%) and the proportionality constant (+24%) were observed on the day of the operation, suggesting that the zonisamide concentration in erythrocytes was greater on the day of the operation.

Brain surgery appears to be one of the possible factors altering the rate of elimination of zonisamide and the uptake of the drug by erythrocytes.
Effects of 5-Hydroxytryptamine Agonists on Myoelectric Activity of the Forestomach and Antroduodenal Area in Sheep
Authors: Plaza M A , Arruebo M P , Murillo M D
Published: April 2011

To increase knowledge of the role of 5-hydroxytryptamine (5-HT) receptors in the regulation of reticuloruminal, omasal and antroduodenal myoelectric activity in sheep, the effects of 5-HT agonists on forestomach and antroduodenal myoelectric activity have been investigated in conscious sheep. 5-Carboxamidotryptamine, methysergide, α-methyl-5-HT, 2-methyl-5-HT, cisapride, zacopride or metoclopramide were infused intravenously for 5 min and myoelectric recordings were obtained from electrodes chronically implanted in the reticulum, rumen (dorsal sac), omasal body, abomasal antrum and duodenal bulb.

The integrated activity of the reticular and ruminal spike bursts was modified only by the highest doses of α-methyl-5-HT, 2-methyl-5-HT, metoclopramide and cisapride. A phase III-like activity pattern was recorded in the antroduodenal area with all 5-HT-ergic agents and a dose-dependent inhibition of myoelectric activity was recorded in both reticulorumen and omasum at the same time as the antroduodenal effects. In the forestomach, methysergide alone induced inhibition of ruminal secondary contractions; 5-HT, α-methyl-5-HT, cisapride and metoclopramide, moreover, evoked an initial dose-dependent increase in antral activity.

These results suggest that 5-HT1; 5-HT2, 5-HT3 and 5-HT4 receptors are involved in the regulation of the migrating myoelectric complex in sheep and in the genesis of forestomach hypomotility that is occasionally recorded concomitantly with the spontaneous duodenal phase III in sheep. 5-HT4 receptors also have a prokinetic action in the antral area.
Effects of Polyacrylic Polymers on the Degradation of Insulin and Peptide Drugs by Chymotrypsin and Trypsin
Authors: Bai Jane P F , Chang L L , Guo J H
Published: April 2011

The purpose of this study was to determine whether carbopol polymers, polyacrylic acid polymers, can inhibit lumenal degradation of insulin, calcitonin and insulin-like growth factor I (IGF-I) by trypsin and chymotrypsin and to understand whether reducing the pH of the incubation medium by these polymers results in inhibition. Further, the effects of carbopol polymers on the in-situ absorption of insulin were studied in rats.

In saline, carbopol polymers at 1% and 4% (w/v%) inhibited close to 100% of trypsin and chymotrypsin activities against insulin. In 50 mM Tris buffer, carbopol polymers, including 934P, 974P and 971P, at 0ṁ1% only weakly inhibited degradation of calcitonin and insulin by both enzymes; however, as the polymer concentration increased to 0ṁ4%, degradation of insulin, calcitonin, and IGF-I by both enzymes was complete or almost complete. When the Tris buffer was increased to 100 mM, no inhibition was observed at 0ṁ1%. Determination of the final pH of the incubation medium in the presence of polymers revealed that the inhibitory effects of carbopol polymers correlated with the final pH. When the incubation medium has no or low buffer capacity to buffer the protons released by carbopol polymers, these polymers are able to reduce the pH much lower than the optimum pH for the enzyme activities, and thus inhibit proteolytic degradation. When the buffer capacity of the incubation medium increases, the inhibitory effects of carbopol polymers weaken. In-situ absorption of insulin revealed that carbopol polymers improved insulin absorption and induced a significantly greater decline in blood glucose levels.

It is concluded that carbopol polymers with strong bioadhesive properties also can inhibit lumenal degradation of peptide hormones, offering multiple advantages for their uses in oral drug delivery.
Prolonged Immune Response Evoked by a Single Subcutaneous Injection of Microcapsules Having a Monophasic Antigen Release
Authors: Sah Hongkee , Chien Yie W
Published: April 2011

A model antigen, bovine serum albumin (BSA), was successfully incorporated into microcapsules fabricated from blends of poly(d,l-lactide-co-glycolide) and poly(d,l-lactide). The microcapsules possessed diameters ranging from 10 to 100 μm and exhibited a continuous monophasic release of the protein in-vitro for 3 weeks.

They were found to enhance its immunogenicity, thereby potentiating the anti-BSA antibody response following a single subcutaneous injection in mice and rabbits. Enzyme-linked immunosorbent assays demonstrated that the microcapsules provoked high-titre and long-lived immunoglobulin G immune responses over a period of 192 days in mice. When rabbits were immunized by a single subcutaneous injection of BSA-loaded microcapsules, a high level of anti-BSA antibody was still present in the sera obtained at 17 weeks post-injection. The immunization protocol using the BSA-loaded microcapsules was superior to that using BSA dissolved in saline or adsorbed to alum.

These microcapsules providing the controlled release of antigens may be valuable in designing better vaccine formulations.
The role of Gastric Mucosal Sulphydryls in the Ulcer-protecting Effects of Cisapride
Authors: López A , Motilva V , De La Lastra C Alarcón , Martín M J , La Casa C
Published: April 2011

The present study was designed to examine the role of endogenous sulphydryls (SHs) in the gastro-protection induced by cisapride (CIS) (10, 25 and 50 mg kg−1 i.p.), a potent benzamide stimulating gastrointestinal motility in mucosal injury induced by 50% v/v ethanol. Results were compared with those of 5−hydroxytryptamine (5−HT) (10 mg kg−1).

Ethanol mucosal damage was significantly reduced by treatment with CIS and 5−HT. On the contrary, administration of n-ethylmaleimide (NEM) (10 mg kg−1) an SH alkylator, markedly worsened lesion formation and counteracted the protective effect of CIS. Rats pretreated with CIS significantly increased the total sulphydryls as reflected in the non-protein and protein fractions however, 5−HT treatment showed a fall in the non-protein level.

The present results suggest that 5−HT-ergic dependent mechanisms have no relation to the gastro-protection afforded by CIS in this experimental model. It is possible that mucosal SHs could be involved.
Oral Cavity Absorption of (R)−8−Hydroxy−2−(di-n-propylamino)tetralin and (S)−8−Acetyl−2−(di-n-propylamino)tetralin in the Rat
Authors: Yu Hong , Liu Ye , Hacksell Uli , Lewander Tommy
Published: April 2011

The present communication reports on the efficacy of (R)−8−OH-DPAT ((R)−8−hydroxy−2−(di-n-propylamino)tetralin) and (S)-LY−41 ((S)−8−acetyl−2−(di-n-propylamino)tetralin) in displaying the 5−HT1A syndrome and decreasing body temperature after administration of the compound subcutaneously into the gastric ventricle or into the oral cavity in the rat.

The dose range eliciting a clear-cut 5−HT1A syndrome and hypothermia after oral cavity administration was 1/10-1/30 that of the gastric ventricle dose range, but 10−30 times higher than the dose range used for subcutaneous administration of both (R)−8−OH-DPAT and (S)-LY−41. Determination of the concentrations of (R)−8−OH-DPAT in plasma and brain tissue confirmed a higher bioavailability after oral cavity than after gastric ventricle administration; plasma and brain tissue concentrations of the drug were found to be approximately 3 times those after 10 μmol kg−1 orally than after 100 μmol kg−1 gastroventrically at 15−60 min after administration of (R)−8−OH-DPAT.

These findings suggest that the oral cavity may be an important site for drug delivery of 8−OH-DPAT, LY−41 and other compounds with a low gastrointestinal bioavailability.
Pharmacokinetics and Brain Distribution of Magnolol in the Rat after Intravenous Bolus Injection
Authors: Tsai T H , Chou C J , Chen C F
Published: April 2011

The pharmacokinetics of magnolol in rats was studied after 2, 5, or 10 mg kg−1 intravenous bolus injection. Plasma concentration-time profiles of magnolol were fitted by a two-compartment open model. There were no significant differences in the elimination half-life, the total body clearance, steady-state volume of distribution, or mean residence time. The area under the plasma-time curve and area under the moment-time curve of magnolol appears to increase proportionally from a dose of 2 to 10 mg kg−1. These results suggest that magnolol possesses linear pharmacokinetics. Notwithstanding, brain concentration of magnolol showed no significant difference among various regions (cerebral cortex, olfactory bulb, hippocampus, striatum, cerebellum, brain stem and rest of brain) after 10 min of magnolol (5 mg kg−1 i.v.) administration, the mean brain drug concentration was approximately fourfold that of magnolol in plasma.
Involvement of σ-Receptors in the Increase in Contraction of Mouse Vas Deferens Induced by Exogenous ATP
Authors: Matsuno Kiyoshi , Kobayashi Tetsuya , Mita Shiro
Published: April 2011

The effects of σ-receptor ligands on the twitch contraction elicited by the exogenous application of adenosine 5′-triphosphate (ATP) in the unstimulated mouse vas deferens were studied.

(-)-Pentazocine, 1,3−di(2−tolyl)guanidine (DTG) and two pairs of optical isomers of 3−(3−hydroxyphenyl)-N-(1−propyl)piperidine (3−PPP) and N-allylnormetazocine (SKF−10,047) potentiated the exogenous application of ATP-induced twitch-type contraction in a concentration-dependent manner, while (+)-pentazocine did not affect it. The order of potentiating ability was: (+)−3−PPP>(-)-pentazocine>(-)-SKF−10,047> DTG>(-)−3−PPP>(+)-SKF−10,047. On the other hand, haloperidol and rimcazole, putative σ-receptor antagonists, suppressed this twitch contraction. In addition, these antagonists significantly blocked the (+)-3−PPP- and (-)-pentazocine-induced potentiation at concentrations which did not affect contractions per se.

These findings indicate that the exogenous application of ATP-induced twitch contraction in the mouse vas deferens is regulated by σ-receptors. In addition, the present ranking order suggests that the σ-receptor potentiating the ATP-induced twitch contraction at post-junctional sites may differ from the σ1- and/or σ2-receptor subtypes.
Correlation of Pharmacological Properties of a Group of Hypolipaemic Drugs by Molecular Topology
Authors: Cercós-Del-Pozo R A , Pérez-Giménez F , Gálvez-Alvarez J , Salabert-Salvador M T , Garcia-March F J , Antón-Fos G M
Published: April 2011

This investigation was undertaken to test the ability of the molecular connectivity model to predict the percentage of plasma protein binding, the percentage of total cholesterol reduction and oral LD50 in rats of a group of hypolipaemic drugs using multi-variable regression equations with multiple correlation coefficients, standard error of estimate, degrees of freedom, F-Snedecor function values, Mallow's CP and Student's t-test as criteria of fit.

Regression analyses showed that the molecular connectivity model predicts these properties. Corresponding stability (cross validation) studies were made on the selected prediction models which confirmed their goodness of fit.

The results also demonstrated that the presence of substituents and molecular volume, determine the value of these properties in hypolipaemic drugs.
Intestinal Absorption Studies on Peptide Mimetic α-Methyldopa Prodrugs
Authors: Wang Hui-Po , Lu Hsiao-Hwa , Lee Jia-Shuai , Cheng Chih-Yuan , Mah Jin-Ran , Ku Ching-Yi , Hsu Wenlie , Yen Chen-Fang , Lin Chun-Jung , Kuo Harng S
Published: April 2011

Two dipeptide mimetic prodrugs, 1 and 2, and two tripeptide mimetic prodrugs, 3 and 4, of l-α-methyldopa were evaluated for intestinal absorption by in-situ single-pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demonstrated a 3.5-fold increase in permeability (Pm* = 2.27) as compared with that of α-methyldopa (Pm* = 0.65), indicating that this prodrug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In the presence of an inward proton gradient, compound 1 showed Michaelis-Menton saturable kinetics of BBMV uptake with a low value of Km (0.06 ± 0.13 mm) and a high value of Vmax/Km (36.38 nmol (mg protein)−1/30 s mm−1) at a low concentration range and a linear uptake at high concentrations with Kd = 0.14 ± 0.02 mm. Compounds 2 and 3 were mainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while the rate of uptake was much lower than that of compound 1. The uptake of compounds 1 and 4 was significantly inhibited by dipeptides l-Gly-l-Pro and l-Gly-l-Phe, and cephradine, a β-lactam known to be transported via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H+-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of α-methyldopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moiety, d-phenylglycine, is a feasible delivery tool in carrying the parent drug through the intestine.
Effect of Policosanol on Foam-cell Formation in Carrageenan-induced Granulomas in Rats
Authors: Noa M , De La Rosa M C , Más R
Published: April 2011

Policosanol is a new cholesterol-lowering drug isolated and purified from sugar-cane wax. which prevents the development of lipofundin-induced lesions and foam-cell formation in New Zealand rabbits and Wistar rats. This study was conducted to examine the effects of policosanol on foam-cell formation in carrageenan-induced granulomas in rats.

Eighteen Wistar rats were randomly distributed in three experimental groups which received orally for 20 days Tween 20 H2O as vehicle (control group) or policosanol at 2.5 or 25 mg kg−1. At the 11th day. lipofundin was injected intrapcritoneally for 8 days to induce formation of foam cells in the granuloma. At day 13, carrageenan was injected subcutaneously for granuloma induction and seven days later animals were killed. A significant reduction of the foam-cell formation in granulomas of policosanol-treated rats was observed.

It is concluded that policosanol prevents the development of foam cells in carrageenan-induced granulomas (extravascular medium) in rats.
The Effect of Acetylation and Deacetylation on the Disposition of Dapsone and Monoacetyl Dapsone Hydroxylamines in Human Erythrocytes In-vitro
Authors: Coleman Michael D , Pahal Kuldip Kaur , Gardiner John M
Published: April 2011

The fates of both dapsone and monoacetyl hydroxylamine have been studied in terms of acetylation and deacetylation within the human erythrocyte in-vitro.

A comparison between the two metabolites showed equipotency in methaemoglobin generation at 15 min, although the monoacetyl derivative was the more rapid haemoglobin oxidizer. Within the erythrocytes, both dapsone and monoacetyl hydroxylamines were found to undergo acetylation, deacetylation and diacetylation. Of the inhibitors of acetylation studied, folate caused an increase in methaemoglobin formation associated with both metabolites, which led to a rise in both acetylated and non-acetylated amine formation. Amethopterin was associated with a rise in hydroxylamine mediated methaemoglobin formation which coincided with a fall in acetylated products.

It is possible that the hydroxylamines undergo erythrocytic processes of acetylation and deacetylation before methaemoglobin-mediated reduction to their respective amines.
Preparation of Poly(D,L-lactide) and Copoly(lactide-glycolide) Microspheres of Uniform Size
Authors: Shiga K , Muramatsu N , Kondo T
Published: April 2011

In an attempt to prepare monodisperse poly(D,L-lactide) and copoly(lactide-glycolide) microspheres, a novel emulsification technique (membrane emulsification) was employed and the preparation conditions which might affect the monodispersity were evaluated.

With this technique nearly monodisperse poly(D,L-lactide) and copoly(lactide-glycolide) microspheres were successfully prepared and their sizes were controllable only by making use of microporous glass membranes of different pore sizes. However, in the present system of emulsion (methylene chloride/water) the surfactant used was limited to ionic ones and the amount of polymers available for the formation of microspheres was inevitably too small in concentration to entrap sufficient amounts of drug. As for the drug release, the effect of particle size was not appreciable but the method of solvent removal gave a great influence; the solvent extraction method showed a more drug-sustaining effect than did the solvent evaporation method.

The present results suggest the possibility of making drug-loaded and biodegradable monodisperse micro-spheres.
Effect of Nifedipine on the Elimination of Theophylline in the Rabbit Subjected to Hypoxia or to an Inflammatory Reaction
Authors: Barakat M , du Souich P
Published: April 2011

This study was performed to assess whether nifedipine could prevent the decrease in hepatic cytochrome P450 induced by acute moderate hypoxia or an inflammatory reaction. Rabbits were subjected Jo acute moderate hypoxia (PaO2 »37 mmHg), with or without pretreatment with nifedipine (0.5 mg kg−1 subcutaneously every 8 h, for 48 h). Another group received 5 mL of turpentine subcutaneously with or without pretreatment with nifedipine (0.5 mg kg s.c. every 8 h, for 72 h). The kinetics of 2.5 mg kg−1 of theophylline were studied in all rabbits up to 8 h, at which time total cytochrome P450 and malondialdehyde were assessed in the liver.

Compared with control rabbits, hypoxia and an inflammatory reaction increased theophylline plasma concentrations, as a result of a decrease in theophylline systemic clearance. Both experimental conditions reduced hepatic cytochrome P450 by 40 to 50% and increased hepatic malondialdehyde by approximately 50% (P < 0.05). In control animals, pretreatment with nifedipine did not influence theophylline kinetics, the liver content in cytochrome P450 or malondialdehyde. Pretreatment with nifedipine partially prevented the hypoxia- and the inflammation-induced decrease in liver cytochrome P450; however, nifedipine did not prevent the decrease in theophylline clearance or the increase in liver malondialdehyde.

It is concluded that nifedipine affords a partial protection against hypoxia- or inflammation-induced hepatic cellular injury.
Toxicodynamic Analysis of Cardiac Effects Induced by Four Cholinesterase Inhibitors in Rats
Authors: Yamamoto Koujirou , Shimizu Miho , Ohtani Hisakazu , Hayashi Masahiro , Sawada Yasufumi , Iga Tatsuji
Published: April 2011

The cardiac effect of edrophonium (2–20 μmol kg−1), pyridostigmine (0.5-5 μmol kg−1), neostigmine (0.05-0.5 μmol kg−1) and ambenonium (0.02-0.3 μmol kg−1) was investigated after intravenous administration to rats.

For pyridostigmine and neostigmine, the heart rate decreased in a dose-dependent manner, and then gradually recovered to the basal level at about 10 min. Rapid decrease of heart rate was observed after edrophonium and ambenonium administration, and rapid recovery to the basal level within 1 min. For ambenonium, a dose-dependent tachycardiac response was observed. The time-course of heart rate change was analysed by the effect-compartment model. Significant correlation was observed between bradycardiac EC50 values obtained by effect-compartment model analysis and inhibitory constant (Ki) to acetylcholinesterase in-vitro, suggesting that the bradycardiac response was induced by inhibition of this enzyme and following elevation of acetylcholine concentration in the synaptic cleft. On the other hand, the tachycardiac EC50 values of edrophonium and ambenonium based on the effect-compartment model analysis were similar to dissociation constants (Kd) of these drugs to muscarinic receptors in-vitro, suggesting that the tachycardiac activity of these drugs may be associated with antagonistic activity to postsynaptic muscarinic receptors.

We conclude that, clinically, edrophonium and ambenonium are safer drugs than pyridostigmine and neostigmine, at least as regards muscarinic side-effects, including bradycardia.
Effect of Silymarin on Different Acute Inflammation Models and on Leukocyte Migration
Authors: De La Puerta R , Martinez E , Bravo L , Ahumada M C
Published: April 2011

In-vivo anti-inflammatory activity of silymarin was tested in different acute inflammation experimental models.

In carrageenan-induced paw oedema in rats, silymarin given orally reduced in a dose-dependent manner the food-pad abscesses (ED50 = 62.42 mg kg−1). In xylene-induced ear mouse inflammation, silymarin applied topically was more effective than administered intraperitoneally, with effects comparable with those of indomethacin. Silymarin also produced a dose-dependent inhibition of leukocyte accumulation in inflammatory exudates following intraperitoneal injection of carrageenan in mice; silymarin significantly reduced the number of neutrophils. Silymarin was unable to inhibit phospholipase A2 in an in-vitro assay.

Besides its known anti-oxidative properties and its ability to act as a radical scavenger, these results suggest that silymarin exerts an important anti-inflammatory action in-vivo by reducing oedema with the effect markedly influenced by the inhibition of neutrophil migration into the inflamed site.
Mechanism for Synergism between Sulphonamides and Trimethoprim Clarified
Authors: Richards R M E , Taylor R B , Zhu Z Y
Published: April 2011

Pseudomonas aeruginosa, Escherichia coli, Pseudomonas cepacia and Moraxella catarrhalis were selected for their markedly different resistance patterns to sulphonamides and trimethoprim. In addition, strains of E. coli and P. cepacia were selected having different resistance profiles to the inhibition of dihydropteroate synthetase and dihydrofolate reductase.

All inhibitors of dihydropteroate synthetase combined in any combination with inhibitors of dihydrofolate reductase resulted in mutual enhancement of bacterial uptakes of the inhibitors and corresponding increased antibacterial activity of the combinations. High concentrations of sulphonamides or p-aminobenzoic acid plus trimethoprim caused a decrease in overall activity of the combination and indicated that both sulphonamides and p-aminobenzoic acid at high concentrations can interact with dihydrofolate reductase. The antibacterial activity of p-aminobenzoic acid at high concentrations is considered to be a blocking effect on dihydrofolate reductase even though p-aminobenzoic acid at low concentrations is an essential part of the synthesis of dihydrofolic acid.

These findings support an alternative hypothesis for the mechanism of antibacterial action of individual antifolates and their mechanism of synergism in combination.
Magnetizable Solid-phase Supports for Purification of Nucleic Acids
Authors: Bruce I J , Davies M J , Howard K , Smethurst D E , Todd M
Published: April 2011

A simple, small scale non-hazardous procedure for the production of magnetizable solid-phase support (MSPS) beads has been developed based on the extrusion of agarose/iron oxide mixtures.

The MSPS beads were derivatized using various amine ligands. Derivatized MSPS beads were used to adsorb nucleic acids from aqueous solution and to separate RNA/DNA mixtures.
Synthesis and Biological Evaluation of 3-(Prop-2-enyl)- and 3-(Prop-2-ynyl)pyrrolidine-2,5-dione Derivatives as Potential Aromatase Inhibitors
Authors: Barrell K J , Woo W L , Ahmadi M , Smith H J , Nicholls P J
Published: April 2011

3-(4′-Aminophenyl)pyrrolidine-2,5-dione (WSP3), a known reversible inhibitor of P450 aromatase, was modified using molecular graphics and our model of reversible inhibitor and substrate binding to resemble 10β-prop-2-ynylestr-4-ene-3,17-dione (PED), a mechanism-based inactivator of the enzyme.

The analogues prepared were 3-substituted 3-(prop-2-enyl) or 3-(prop-2-ynyl) pyrrolidine-2,5-diones and their N-alkyl derivatives.

The reported compounds demonstrated no irreversible (time-dependent) inhibition of the human placental P450 aromatase enzyme. However, some reversible activity was seen in several of the 3-(prop-2-ynyl) compounds.
Efficient Syntheses of Polyamine and Polyamine Amide Voltage-Sensitive Calcium Channel Blockers: FTX-3.3 and sFTX-3.3
Authors: Moya Eduardo , Blagbrough Ian S
Published: April 2011

Efficient syntheses of FTX-3.3 and sFTX-3.3, voltage-sensitive calcium channel blockers are described. These modified polyamines were prepared from selectively protected polyamines and purified on a practical scale.
Studies with Type I Aldolase to Understand Fructose Intolerance and Combat Parasitic Disease
Authors: Dalby Andrew , Littlechild Jennifer A
Published: April 2011

A structural study of the type I aldolases has been carried out to examine the isozyme specificity of these enzymes and the potential for designing specific inhibitors. Natural mutations in these aldolase enzymes are associated with haemolytic anaemia and fructose intolerance. It has also been proposed that inhibition of the parasitic version of the enzyme may provide a new lead in the design of drugs against malaria and sleeping sickness. X-ray crystallographic data is used with molecular modelling techniques to investigate the structural properties of these enzymes.
A Hydrogel Based on a Polyaspartamide: Characterization and Evaluation of In-vivo Biocompatibility and Drug Release in the Rat
Authors: Giammona G , Pitarresi G , Tomarchio V , Cacciaguerra S , Govoni P
Published: April 2011

This paper deals with the characterization of a new microparticulate hydrogel obtained by gamma irradiation of α,β-poly[N-(2-hydroxyethyl)-dl-aspartamide] (PHEA).

When enzymatic digestion of PHEA hydrogel was evaluated using various concentrations of pepsin and α-chymotrypsin no degradation occurred within 24 h. In-vivo studies showed that this new material is biocompatible after oral administration to rats. PHEA hydrogel was also studied as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that most of the drug was released at pH 6.8. In-vivo studies indicated that diflunisal-loaded PHEA microparticles significantly improved the gastric tolerance and oral bioavailability of the drug in comparison with free diflunisal.

These results suggest the potential application of PHEA hydrogel as a new delivery system for the oral administration of anti-inflammatory drugs.
Stereoselectivity of Butylidenephthalide on Voltage-dependent Calcium Channels in Guinea-pig Isolated Ileum
Authors: Ko Wun-Chang , Sheu Joen-Rong , Leu Yi-Rong , Tzeng Shu-Huey , Chen Chi-Ming
Published: April 2011

Two geometric isomers, the Z- and the E- forms, can be separated from synthetic mixtures of butylidenephthalide (Bdph).

Z-Bdph (50–100 μm) non-competitively inhibited Ca2+-induced contractions in depolarized (K+, 60 mm) guinea-pig ileum longitudinal smooth muscle, with a pD2' value of 3.88 ± 0.20 (n = 5). However, E-Bdph (20–100 μm) competitively inhibited these contractions with a pA2 value of 4.56 ± 0.18 (n = 5) which was significantly (P < 0.05) greater than the pD2' value of Z-Bdph. In contrast, the two isomers had no stereoselective inhibitory action on Ca2+ influx through pre- or post-junctional membranes of cholinergic nerve endings from which the transmitter acetylcholine is released or on Ca2+ release from intracellular stores.

Therefore, the trans-Z and cis-E forms of Bdph might have geometric stereoselectivity for voltage-dependent calcium channels (VDC) in guinea-pig longitudinal smooth muscle. Both isomers might inhibit more selectively the contractile twitch responses evoked by electrical stimulation than by cumulative acetylcholine-or carbachol-induced transient contractions in guinea-pig ileum longitudinal smooth muscle.
Molecular Factors Influencing Drug Transfer across the Blood-Brain Barrier
Authors: Gratton Julie A , Abraham Michael H , Bradbury Michael W , Chadha Harpreet S
Published: April 2011

A recently reported approach to the prediction of blood-brain drug distribution uses the general linear free energy equation to correlate equilibrium blood-brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; π2H, solute dipolarity or polarizability; α2H and β2H, the hydrogen bond acidity or basicity, and VX, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood-brain barrier in the rat.

The permeability (logPS) of the blood-brain barrier to a chemically diverse series of compounds was measured using a short duration vascular perfusion method. LogPS data were correlated with calculated solute descriptors, and octanol-water partition coefficients (logPoct) for comparison.

It is shown that a general linear free energy equation can be constructed to predict and interpret logPS values. The utility of this model over other physicochemical descriptors for interpreting logPS and logBB values is discussed.
Synthesis and Biological Activity of Two New Calcium-channel Blockers, Mebudipine and Dibudipine
Authors: Mahmoudian M , Mirkhani H , Nehardani Z , Ghiaee S
Published: April 2011

Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine.

The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mm)–treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine.

It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.
Bakkenolide G, a Natural PAF-receptor Antagonist
Authors: Liao Chang-Hui , Ko Feno-Nien , Wu Tian-Shung , Teng Che-Ming
Published: April 2011

Because platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) participates in many physiopathological responses, including inflammatory reaction, endotoxic shock, allergic diseases and platelet aggregation, PAF-receptor antagonists are important in the treatment of these diseases.

A biologically active compound, bakkenolide G, extracted from the plant Petasites formosanus selectively and concentration-dependently inhibited PAF-induced platelet aggregation and ATP release. The IC50 of bakkenolide G for PAF (2 ng mL−1)-induced platelet aggregation was 5.6 ± 0.9 μm. Bakkenolide G also concentration-dependently inhibited PAF-induced intracellular signal transductions, including thromboxane B2 formation, and increased intra-cellular calcium concentration and phosphoinositide breakdown without affecting those caused by thrombin (01 units mL−1), collagen (10 μg mL−1), arachidonic acid (100 μm) and U46619 (1 μm). Bakkenolide G shifted the concentration-response curves of PAF-induced platelet aggregation parallel to the right; the Schild plot slope and the pA2 value were 1.31 ± 0.31 and 6.21 ± 0.75, respectively. Moreover, bakkenolide G concentration-dependently competed with [3H]PAF binding to platelets, with an IC50 value of 2.5 ± 0.4 μm.

These data strongly indicate that bakkenolide G is a specific PAF-receptor antagonist as an antiplatelet aggregatory agent.
Potential Efficacy of a Delta 5-Aminolevulinic Acid Bioadhesive Gel Formulation for the Photodynamic Treatment of Lesions of the Gastrointestinal Tract in Mice
Authors: Vonarx V , Eleouet S , Carre J , Ioss P , Gouyette A , Leray A M , Merle C , Lajat Y , Patrice T
Published: April 2011

A delta 5-aminolevulinic acid (ALA) bioadhesive gel has been developed and evaluated in an in-vivo mouse model for photodynamic treatment of gastric cancer or Barrett's oesophagus. Four gels were tested: noveon AA-1, keltrol T, lutrol and blanose.

An initial in-vitro study of gel adhesion showed that noveon and keltrol had longer polyethylene transit times than lutrol and blanose. In-vivo assays indicated that protoporphyrin IX was synthesized by gastric mucosa when ALA-noveon and ALA-lutrol were used (preferable results for noveon). Keltrol was eliminated from the study after these investigations. Only ALA-noveon gel was retained for studies of the relationship between ALA dose and fluorescence. Fluorescence measurements in-vivo showed that ALA concentration and application time had an influence on protoporphyrin IX synthesis. Maximum intensity (2091 counts s−) was found with 2 mg mL− ALA, and fluorescence intensities differed with application time, reaching 1805 counts s− after 240 min.

ALA-noveon, showing good adhesion and enabling efficient diffusion of ALA at a pH < 6, was considered the best formulation for maintaining ALA stability.